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(Helsingin yliopisto, 2018)Parkinson’s disease (PD) is the most common movement disorder, affecting approximately 1% of the population aged over 60 years. According to current knowledge, there are both genetic and environmental risk factors for this disease. High plasma uric acid level has been shown to reduce the risk of PD and also to decelerate the progression of motor symptoms in patients with PD. In this study, 40 PD patients and 28 spouse controls were recruited to examine whether patients have low plasma and daily urine uric acid levels relative to the controls. Also neuropsychological testing was performed on patients both at baseline and after three years of follow-up to determine whether cognition is associated with the uric acid levels and whether low levels of uric acid at baseline predict future cognitive decline. An electroencephalogram with evoked response potentials (EEG-ERP) was given to a subsample of patients and controls to examine neurophysiological differences between the groups and to investigate whether cognitive alterations are reflected in patients’ EEG-ERP measurements. PD patients had lower levels of plasma uric acid than controls. Low plasma and urine uric acid levels were associated with poor achievement in neuropsychological tests measuring visuospatial and visuoconstructive abilities, sustaining attention and executive control. After three years of follow-up, only minor cognitive decline was noted in patients. Cognition did not seem to be associated with past or present uric acid levels. On the other hand, the stability of the patient sample made it difficult to assess the effect of uric acid on the prognosis of cognitive decline in PD. The EEG-ERP study revealed that PD patients had longer latency and poorer habituation of the evoked response potential N100 than healthy controls. In the patient group, the neurophysiological changes were associated with poor achievement in a neuropsychological test measuring visual working memory, but not with uric acid levels.
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(Helsingin yliopisto, 2018)Status epilepticus (SE), i.e. prolonged epileptic seizure, is a life-threatening medical emergency, which is associated with high mortality and morbidity. International guidelines suggest early and efficient treatment. Thus, long duration of SE is one of the main predictors of poor prognosis and the only prognostic factor that can be affected by shortening the delays in the treatment. However, studies on delays, implementation of treatment guidelines and the effect of delays on outcome are scarce. The aim of this thesis was to systematically investigate delays in the treatment of SE and factors related to the delays along the whole treatment chain. We also aimed at clarifying the effect of delays on the outcome and at identifying the significant delays related to outcome in order to propose evidence-based targets for streamlining the SE treatment protocol. The material of this retrospective study consists of 82 consecutive SE patients treated in a tertiary hospital emergency department over two years. Delays, patient characteristics and parameters related to treatment chain were identified and their relations, correlations and effects were investigated. The results of this thesis reveal that the delays in the treatment of SE are unacceptably long and exceed markedly the suggested time frames in the guidelines. Fulfilment of the suggested SE treatment algorithm is frequently hampered by failing recognition of SE at onset, also by professionals, which may increase the delays in consecutive parts of the treatment chain. Delays seem to be more significant determinants of SE duration than previously established outcome predictors. Additionally, various long delays in the treatment (second- and third-stage medication, diagnostic and tertiary hospital delays) increase the risk of mortality and poor functional outcome at hospital discharge and since the predictive cut-off point of these delays lies under 2,5 hours, the focus of protocol streamlining should be in the pre-hospital phase of the treatment. However, none of the delays are independent risk factors for poor outcome, which reflects the dynamism of SE, but also demonstrates that every step of the treatment chain needs to be optimized. In conclusion, we propose that generation of simplified criteria for suspicion of an imminent SE and streamlining pre-hospital treatment chain are advocated. We suggest amendments to the protocol, such as triaging suspected SE patients with highest priority, recruiting physician-based EMS units upon primary alarm, administration of second-stage medication out-of-hospital and transportation of SE patients exclusively to hospitals with neurological expertise. Also improvement of diagnostic possibilities on emergency site should be considered.
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(Helsingin yliopisto, 2018)The health of individuals and populations is in many ways affected by migration. Migration impacts not only individual persons and families moving from one country to another, but also communities and populations in origin, destination and transit countries, and even successive generations. Empirical evidence on the health of migrants is abundant, but mixed. Large differences are found both between and within migrant populations. One challenge in migration and health research is using categorizations that produce relevant knowledge rather than false generalizations. This study uses data from the Migrant Health and Wellbeing Study (Maamu, 2010–2012) to examine three significant population groups in Finland. Categorized based on birthplace and mother tongue, the studied populations were considered to consist of three different population groups: persons of Russian, Somali and Kurdish origin. The studied groups comprise more than one fourth of the foreign-born population in Finland, and include persons with various reasons for migration. A comparison group from the general population was selected from the Health 2011 Survey. The aim of this study is to improve knowledge on populations of Russian, Somali and Kurdish origin in Finland. This study specifically examines mobility limitations, mental health symptoms and perceived discrimination. This is the first dissertation to examine the health of foreign-born populations in Finland using survey data. The focuses of this study were chosen based on the preliminary findings of the Maamu Study. The findings of this study suggest certain concerns in the health of Russian, Somali and Kurdish origin populations in Finland. First, this study demonstrates that mobility limitations are more prevalent among Somali and Kurdish origin populations compared to the general population in Finland. Second, the prevalence of mental health symptoms was found to be significantly higher among Russian origin women and Kurdish origin men and women than in the general population. Adjusting for sociodemographic factors showed some reductions in the sizes of the increased odds for mobility limitation and mental health symptoms. An association between mental health symptoms and mobility limitation was also demonstrated. Last, perceived subtle discrimination was found to be more common than experiences of overt discrimination. Perceived discrimination increased the odds for poor self-reported health, limiting long-term illness or disability and mental health symptoms, also for those reporting subtle discrimination only. The high prevalence of mobility limitation and mental health symptoms among the studied populations demonstrates a need for health promotion. Actions should be comprehensive and promote physical activity, healthy diet and social participation, but also address needs related to employment, social security and health services. Efforts against racism and discrimination are also highly needed, as perceived discrimination was shown to be associated with poor health outcomes. Supporting the wellbeing of diverse populations in Finland should include firmer advocacy of shared belonging. This study encourages future research to recognize the constructed and changing nature of groups and explore population health beyond the dichotomist frame of “us” and “them”.
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(Helsingin yliopisto, 2018)Heart failure is a complex clinical syndrome, most often caused by ischemic, hypertensive, and valvular heart disease. In this thesis, we studied how genetic variation contributes to hypertension and acute coronary syndrome, the most frequent causes of heart failure. We also studied the role of genetic variation in Takotsubo cardiomyopathy, a disease which still remains poorly understood and often presents with transient heart failure. To identify trait-associated genetic variants, we analyzed several population-based samples of Finns using genetic association tests. Three of the four publications constituting this thesis are genome-wide association studies (GWAS). In the first study, we identified variants near the PRDM6 gene, which associated with both higher systolic blood pressure and a higher risk of intracranial aneurysms. This result was one of the first to show a shared genetic background for blood pressure and intracranial aneurysms. Based on data on the function of PRDM6 and other trait associations in the locus, we hypothesize that the genetic variants at this locus increase systolic blood pressure and aneurysm risk via an effect on the proliferation of smooth muscle cells in the arterial wall. In the second study, we performed a GWAS separately on the two subtypes of myocardial infarction in acute coronary syndrome, the ST- segment elevation and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI). Genetic variation near DRAM2, encoding a protein participating in the regulation of autophagy, increased the risk of NSTEMI with little to no effect on the risk of STEMI. This finding is rather surprising, given that both infarction types are mostly the result of the same disease process, namely coronary heart disease. The third study addressed atrial and B-type natriuretic peptides (ANP and BNP), which are secreted by cardiomyocytes, both during normal homeostasis and especially during acute heart failure. We identified a new locus near the calcineurin subunit gamma gene PPP3CC, which was 7associated with the ratio of the circulating concentrations of active BNP and the N-terminal fragment of the proBNP prohormone. Based on the genetic results, we also showed that the data specifically supports the blood- pressure-lowering effect of ANP in the general population, and not that of BNP. In the fourth study, we studied the possible genetic background of Takotsubo cardiomyopathy. The cause of this condition is currently unknown but a contribution of genetic variation has been suggested in previous literature. We could not replicate previous genetic findings in the disease to show that if genetic predisposition exists, it is similar to that of complex diseases, such as acute coronary syndromes, with small absolute risks conferred by each of multiple genetic risk variants. The results of this thesis provide new information on the molecular basis of the two most common causes of heart failure: hypertension and acute coronary syndromes. They also limit plausible genetic models that are compatible with observational data for Takotsubo cardiomyopathy.
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(Helsingin yliopisto, 2018)The potassium-chloride cotransporter KCC2 is a key regulator of chloride homeostasis in neurons of the central nervous system (CNS) and it is critical for the development of fast hyperpolarizing synaptic inhibition. Two full-length isoforms of KCC2, KCC2a and KCC2b, differing by their amino termini have been described. Both isoforms have similar expression levels in neonatal mice, but KCC2b is strongly upregulated in cortical areas during postnatal development, resulting in a developmental shift of GABAergic responses. In contrast to the well-studied KCC2b isoform, the importance of the KCC2a isoform has not yet been demonstrated. My thesis work focuses on characterizing the transcriptional regulation, expression and function of the KCC2 isoforms and a central aim is to elucidate the isoform-specific differences. The molecular mechanisms underlying the regulation of KCC2 gene expression are not yet well understood. Both isoforms show a largely neuron-specific expression pattern and their expression is tightly regulated in development. The KCC2b isoform is also known to be regulated by both normal and pathological neuronal activity. One aim of the present thesis work was to explore the functionality of a conserved E-box site in the KCC2b promoter. Results suggest that the E-box site functions as a binding site for the upstream stimulating factors 1 and 2 (USF1, USF2), two basic helix-loop-helix transcription factors with potentially important roles in brain. Binding of USF proteins to the E-box motif contributes to the upregulation of KCC2b gene expression in immature cortical neurons. Another aim of this study was to compare the postnatal expression patterns of KCC2a and KCC2b proteins in various regions of mouse CNS using immunohistochemistry and isoform-specific antibodies. The cellular expression patterns of KCC2a and KCC2b were largely similar in developing and neonatal mouse. In mature brain, KCC2a is detected in the basal forebrain, hypothalamus, and many areas of the brainstem and spinal cord, but its expression is very low in cortical regions. At the subcellular level, immunoreactivities of the isoforms are only partially colocalized, and KCC2a immunoreactivity, in contrast to KCC2b, is not clearly detected at the neuronal soma surface in most brain areas. Biotinylation experiments suggest that the N-terminal KCC2a epitope might be masked. Results of this thesis work also indicate that the KCC2a isoform, similar to KCC2b, can function as a chloride transporter and decrease the intracellular chloride concentration in cultured neurons. The unique N-terminus of KCC2a includes a SPAK kinase binding site, and the importance of this site and the WNK-SPAK signaling pathway is also explored. Our results indicate that the SPAK kinase is able to bind the KCC2a isoform and to regulate the transport activity of KCC2a more than that of KCC2b.
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(Helsingin yliopisto, 2018)Air ions are constantly generated throughout the atmosphere by natural ionising radiation and they participate in the formation and dynamic processes of atmospheric aerosol particles. Their flow in the atmosphere is the cause for the air conductivity. However, there is a gap in understanding how variations in ionising radiation levels are reflected in air ion properties. Besides, observations related to air ions have been conducted at many sites around the globe, but the knowledge on features in air ions in vapour-limited environments is missing. The work in this thesis is dedicated to fill in these voids in knowledge related to air ions using the observational approach. Factors influencing natural radioactivity in the atmosphere in a boreal forest were identified at the Hyytiälä SMEAR II Station in Finland. We found that the diurnal and seasonal patterns in the natural ionising radiation level were mainly introduced by boundary layer dynamics as well as snow cover and soil conditions. Current instrumentations for measuring the number size distribution of air ions have a lower size limit of 0.8 nm in the Millikan mobility diameter. Based on our analysis, the concentrations of 0.8-1 nm ions were generally seen varying similarly to the natural ionising radiation level. We found a clear enhancement of ionising radiation on 0.8-1.7 nm ion production on atmospheric NPF event days but not on non-event days, which suggests that 0.8-1.7 nm ions undergo less dynamic modifications and are possibly formed over shorter time scale on NPF event days than on non-event days. To study features in air ions under conditions of limited vapours, the Concordia Station at Dome C, Antarctica, was chosen as the measurement site. Air ion processes were found to be active at the Concordia Station, including atmospheric new particle formation (NPF), ion production and loss in relation to cloud formation and wind-induced ion formation. Overall, these results advance our understanding on the ion processes in the atmosphere, which can assist obtaining further insights into atmospheric aerosol formation mechanisms and ultimately finding solutions to air pollution issues and understanding climate variability.
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(Helsingin yliopisto, 2018)Facial fractures are a common problem worldwide. They are often caused by falls, falls from heights, motor vehicle accidents, and violence. In Studies I-IV, we retrieved all 2413 emergency room physicians’ multidetector computed tomography (MDCT) requests for facial injury during a 62-month time period. These were categorized by etiology: 155 cases of fall-from-height accidents, 500 cases of falling accidents, 727 cases due to violence, and 374 cases following a motor vehicle accident. The fractures were divided into groups: nasal bone, orbital, naso-orbito-ethmoid, zygomatic complex, zygomatic arch, Le Fort I, II, and III, frontal bone, maxillary, mandibular, and skull base fractures. These were further classified into different subtypes. Paranasal sinus effusions were noted as well. Further, the age, gender, and a more precise injury mechanism were registered. When taking into account the patients with a fracture, males predominated in all our studies (I-IV). In falls, the difference between genders was the smallest and most distinctive in falls from heights. In falls from heights, nasal bone and zygomatic arch fractures were seldom solitary fractures, but were indicators of a more severe fracture. There was a slight increase in the number and severity of fractures with increasing height. However, there was considerable overlap in heights, and thus, falling height cannot be the only predictor of injury probability. In falls, the most common fracture was the zygomatic complex fracture, whereas in violence-related fractures nasal and orbital fractures predominated. In motor vehicle accidents, Le Fort, frontal bone, and zygomatic arch fractures were always accompanied by other fractures. We also found that a clear sinus sign is a valuable aid in detecting facial fractures, but it might be less reliable than previously thought. Le Fort fractures were often asymmetric or unilateral. Postoperative maxillofacial imaging has earlier been somewhat challenging due to the artifacts caused by metal. In Study V, we compared different devices and protocols by scanning a phantom with a 64-slice computed tomography, cone-beam computed tomography, and a high-definition multislice computed tomography with dual-energy scan and iterative reconstruction methods. For postoperative maxillofacial imaging, cone-beam computed tomography was not optimal. Multidetector computed tomography with adaptive statistical iterative reconstruction offers fast image volume reconstruction with good image quality.
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(Helsingin yliopisto, 2018)Early life stress, sleep disturbances and alterations in neuronal plasticity have been associated with depression, yet the relation between these factors and depression remain poorly understood. This project explored the interconnection between depression and sleep disturbances, starting from early stage of development. Possible molecular mechanisms (such as brain derived neurotrophic factor (BDNF) and adenosine) underlying this interaction were assessed using animal models. The investigation of sleep disturbances in early-onset depression in humans was performed in depressed adolescents. The association between BDNF gene polymorphism (Val66Met) and the development of sleep was studied using a birth cohort. First, we investigated the epigenetic mechanisms of BDNF gene regulation during spontaneous sleep and after sleep deprivation using methylated DNA immunoprecipitation in rats. We showed that the dynamics of BDNF transcription during spontaneous sleep-wake cycle in brain areas crucial for sleep regulation (basal forebrain (BF) and frontal cortex) is partially regulated by brain area specific DNA methylation, and that the degree of sleep deprivation-induced BDNF up-regulation is transcript- and brain area-dependent. To assess the effect of early life stress on sleep and possible mechanisms of this effect, we used cross-fostering in rats (pups were changed between mothers). Cross-fostered rats demonstrated negligible changes in behaviour. However, they showed profound changes in sleep architecture: duration and number of rapid eye movement (REM) sleep episodes was significantly increased compared to controls. Moreover, cross-fostering led to persistent molecular changes in the brain, which was evidenced by decreased adenosine level during spontaneous sleep-wake cycle and by a tendency towards lower BDNF gene expression in the BF. Further, to investigate sleep disturbances in early-onset depression we studied sleep in depressed adolescent boys using polysomnography. The sleep of depressed boys was characterized by lower SWA and its slower rise during the course of first NREM sleep episode compared to healthy boys. The SWA dissipation through the night in depressed patients had flatter shape compared to healthy subjects. Moreover, a negative correlation between SWA dissipation and depression severity was detected. All the changes were more pronounced in the frontal derivation compared to central derivation that support the idea that sleep regulation and depression might share common neurobiological mechanisms. To examine whether the BDNF Val66Met polymorphism can predispose individuals to depression and sleep disturbances Finnish CHILD-SLEEP birth cohort was used. The association between this polymorphism and early life developmental parameters (e.g. sleep, psychomotor development, temperament) in infants of 3 and 8 months of age was assessed. We found no robust association between BDNF Val66Met polymorphism and studied parameters during early postnatal life of infants. In summary, early life stress leaves persistent molecular trace in the brain, and sleep appears to be one of the most prominent indicators of early stressful events. Early life onset depression is characterized by changes in sleep macro-and microarchitecture that are associated with depressive symptoms severity. Although BDNF is playing an important role in sleep and mood regulation, its Val66Met polymorphism is not associated with development of these parameters during early stages of life.
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(Helsingin yliopisto, 2018)Acute pancreatitis (AP) is a common gastrointestinal disease of varying severity. While mild AP is a local inflammation of the pancreas that resolves within days, in severe AP (SAP) systemic inflammatory response, complicated by persistent organ dysfunction (OD), is comparable to that seen in bacterial sepsis and associated with substantial morbidity and mortality. In half of the SAP patients the clinical signs of OD are not yet present on admission to hospital, potentially delaying the diagnosis of SAP and the initiation of maximal supportive care, thus worsening the prognosis. The aims of this study were (i) to identify early predictive markers of SAP among patients with no OD on admission to hospital and (ii) to elucidate the aberrations in blood leukocyte signaling pathways in the early phase of AP and sepsis, which could reveal novel predictive markers of OD. This clinical study consists of four prospective studies. All AP patients investigated were admitted to Helsinki University Hospital within 72 or 96 hours of onset of symptoms during the years 2003-2008 (Studies I and III), 2011-2014 (Study II), and 2010-2012 (Study IV). The levels of circulating 48 cytokines in 163 patients (Study I), interleukin (IL)-8 and hepatocyte growth factor (HGF) in 176 patients (Study II), and nucleosomes in 74 patients (Study III) were determined on hospital admission to identify predictors of SAP, especially in AP patients presenting without OD. In the fourth study, the phosphorylation of nuclear factor kappa B (NF-ĸB), signal transducers and activators of transcription (STATs) 1 and 3, and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinases (MAPK) were examined in appropriately stimulated or non-stimulated circulating leukocytes in 18 patients with AP, 14 patients with sepsis, and 28 healthy controls. Our results show that IL-8, HGF, granulocyte colony-stimulating factor (G-CSF), and nucleosomes are associated with the severity of AP and predict development of SAP among AP patients without OD on admission. The result concerning IL-8 and HGF was confirmed in a second study, which also shows that among patients with OD on admission IL-8 may predict persistent OD, i.e. SAP. The discovered signaling aberrations in NF-ĸB, STAT1, STAT3, and ERK1/2 MAPK pathways are largely similar in sepsis and SAP. However, only the results concerning STAT1 and STAT3 are associated with the severity of AP. Additionally, STAT3 distinguishes patients with persistent OD (i.e. sepsis and SAP) from those without OD (i.e. mild and moderately severe AP). In conclusion, circulating levels of IL-8 and HGF may serve as useful predictors of SAP in AP patients without OD on admission. Additionally, G-CSF and nucleosomes may predict development of SAP. Among patients with OD on admission, IL-8 may predict persistent OD. Signaling aberrations of circulating leukocytes in sepsis resemble those discovered in SAP. Aberrations in STAT1 and STAT3 pathways associate with the severity of AP and those in STAT3 with the presence of OD. Possibility that aberrations in STAT1 and STAT3 pathways provide novel markers for predicting development of OD warrants further studies. Early and accurate identification of patients at risk for SAP or OD may improve their prognosis. Additionally, such early markers may help to identify individual patients that will potentially benefit from immunomodulatory treatment modalities in the future.
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(Helsingin yliopisto, 2018)Smoking is a major preventable risk factor for global morbidity and mortality and is influenced by both genetic and environmental factors. With the central goal of understanding the links between the complex trait of smoking behavior and genetic as well as epigenetic variation in the genome, this thesis focuses on identifying novel associations and validating the involvement of candidate genes in smoking behavior. An unbiased, hypothesis-free genome-wide scanning approach for association with genetic variants (single nucleotide polymorphisms; SNPs) in study I and epigenetic variants (DNA methylation) in study II were applied utilizing biomarkers of nicotine metabolism and exposure respectively. Taking a hypothesis-driven targeted approach, in study III, the involvement of neuregulin signaling pathway genes in smoking behavior was examined and validated in a phenotypically rich family sample. With the increasing and due emphasis on interpretation of associations identified in non-protein coding parts of the genome, we investigated the regulatory potential of the highlighted variants as well as assessing mediation via epigenetic mechanisms, utilizing in-house data and publicly available multi-omics resources. In study I, utilizing a biomarker for nicotine clearance rate (nicotine metabolite ratio, NMR) in a genome-wide association study (GWAS) meta-analysis, we identified novel association on chromosome 19, represented by three independent loci mapping to or near the main nicotine metabolizing enzyme CYP2A6. We examined the regulatory potential of the SNPs and identified a subset of genome-wide significant SNPs (173 of 719) as methylation quantitative trait loci (meQTLs). Using causal inference test, we observed methylation at one CpG in DLL3 mediates the effect of genotype on NMR. We also constructed a genetic risk score (GRS) with the independent SNPs identified in the GWAS meta-analysis, which explain ~30% variance observed in NMR. As evidenced by clinical trial studies, NMR influences the efficacy of cessation pharmacotherapeutics highlighting the potential value of our findings. In study II, we utilized cotinine, an established biomarker of nicotine exposure, and performed epigenome-wide association study (EWAS) in regular smokers. We identified several novel loci in smoking-related genes, underlining the value of using biological phenotypes. Cotinine levels are influenced by nicotine intake as well as nicotine clearance, we utilized the GRS constructed in study I to account for such confounding, identifying additional novel loci. We further assessed the role of genetic variants in the highlighted genes and identified several cis and trans meQTLs. A handful of these meQTLs were also directly associated with cotinine levels. At these loci, we examined whether DNA methylation is a mediator between the observed association of genotype and cotinine levels and detected mediation at seven CpG sites, implying DNA methylation may be a cause, not a consequence of nicotine exposure, as commonly assumed. Our results point at an interplay between the genome and epigenome while identifying novel nicotine exposure pertinent loci. In study III, we applied a targeted approach to examine the role of the neuregulin signaling pathway (NSP) genes in smoking behavior utilizing a phenotypically rich family sample. Extensive association and joint linkage and linkage disequilibrium analysis of common, low frequency and rare variants in the ten key NSP genes with a wide spectrum of smoking behavior phenotypes revealed significant association with seven of the ten genes. No significant associations were observed with alcohol use phenotypes hinting at NSP’s involvement specifically in smoking instead of addictions in general. Utilizing integrative methods and multi-omics data from an independent population sample and publicly available resources, we show the majority (56 of 66) of highlighted SNPs have regulatory potential. Our results provide evidence for the involvement of the NSP in smoking behavior, a candidate pathway for smoking and comorbid disorders. Key points from this thesis: 1. Biomarkers can be powerful in identifying meaningful associations even with moderate sample sizes in complex behavioral traits. 2. Genetic and epigenetic differences between individuals influence smoking behavior via genes involved in nicotine metabolism, nicotine dependence, and neuronal pathways. 3. DNA methylation is a molecular mechanism mediating the effects of genotype on smoking behavior phenotypes at some loci. 4. Multi-omics data including, but not limited to, genetics, epigenetics, and transcriptomics can immensely aid in assessing the functional consequences of otherwise seemingly non-functional associations identified via genome-wide association studies providing potentially druggable targets for personalized medication.
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(Helsingin yliopisto, 2018)This study investigated i) the relationship of temperament and character with paranoid ideation over age in adulthood ii) the association of explosive temperament profile with the development of character dimensions self-directedness and cooperativeness, and whether this association is modified by social support and attachment security iii) the co-occurrence of depressive symptoms with paranoid ideation from late adolescence to middle age in the general population. The participants (n = 2028, 2137, and 2109 in Studies I‒III) were selected from the prospective Cardiovascular Risk in Young Finns Study, which started in 1980. Paranoid ideation and depressive symptoms were assessed at several time points over a 20-year follow-up in 1992‒2012. Temperament and character, social support, and attachment security were measured multiple times between 1997‒2012. We used multilevel models for repeated measurements, which were controlled for participants’ age, gender, and socioeconomic status both in childhood and adulthood. The results revealed that single temperament dimensions of high novelty seeking, high harm avoidance and low reward dependence and also explosive temperament profile (consisting of high novelty seeking, high harm avoidance, and low reward dependence) were related to a higher level of paranoid ideation in adulthood. These associations appeared to be mediated by character dimensions. Specifically, high self-directedness, high cooperativeness, and low self-transcendence could protect individuals with temperament-related susceptibilities from paranoid ideation. Explosive temperament was associated with lower self-directedness and cooperativeness as compared to other temperaments, but high social support and secure attachment had a positive influence on character development in individuals with explosive temperaments. Additionally, we found that depressive symptoms were linked with the course of higher paranoid ideation, especially in late adolescence and early adulthood. Regarding various depressive subsymptoms, high negative attitude and high performance difficulties were associated with the course of more severe paranoid ideation over age in adulthood, whereas the influence of somatic symptoms became significant only after early adulthood. Finally, depressive symptoms appeared to be more strongly related to the development of trait- than state-level paranoid ideation. Specific variants of single temperament dimensions and profiles represented susceptibilities for paranoid ideation. The presence of supportive and confidential relationships was linked with more mature character (i.e. higher self-directedness and higher cooperativeness), which appeared to have a protective role against paranoid ideation in individuals with risky temperaments. The co-occurrence between depressive symptoms and paranoid ideation was especially evident in late adolescence and early adulthood. Individuals, who have temperament-related susceptibilities for paranoid ideation, might benefit from interventions, which promote the abilities to form confidential and supportive social relationships. This might help them to internalize more mature concepts about the self and interpersonal relationships, which, in turn, could enhance the self-regulation of temperament-related susceptibilities and lower the risk for paranoid ideation. Individuals with co-occurring depressive symptoms and paranoid ideation might benefit from neurocognitive rehabilitation, social skills training, and community-based treatments in order to enhance interpersonal activities and metacognitive abilities.
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(Helsingin yliopisto, 2018)Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 %. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA% value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13% (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48% and 26%, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.
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(Helsingin yliopisto, 2018)Background: Preterm birth (before 37 weeks of gestation) is a major cause of infant mortality and morbidity worldwide, and preventing its burden is a health care priority. Even in adulthood, individuals who were born preterm perform, on average, worse on tests of cognitive functioning than term-born peers do, and may have more mental health problems. Early growth failure is common among preterm individuals, and some studies have suggested that those preterm individuals who grow poorly in infancy have more neurodevelopmental problems later on in childhood. It is unclear whether these associations persist into adulthood and whether they extend beyond the smallest and most immature of preterm infants, to the majority of preterm infants who are born late preterm (at 34-36 completed weeks of gestation). It also remains unknown whether early postnatal growth patterns predict mental health outcomes - some partly conflicting evidence suggests that intrauterine growth restriction at least associates with mental health problems. The mechanisms explaining the associations between growth and neurodevelopment are also unclear. Early growth reflects a number of intertwined early-life environmental factors and individual characteristics, and while altering neonatal nutrition can affect growth, it is not known whether changes in nutrition can improve long-term neurodevelopmental outcomes. It has even been suggested that faster growth and higher nutritional intakes during the early postnatal period can present a trade-off between improved neurodevelopment and increased cardiovascular risk. Methods: The 157 participants of the Helsinki Study of Very Low Birth Weight Adults (HeSVA, birth weight <1500g) and the 108 participants of the Arvo Ylppö Longitudinal Study (AYLS, gestational age 34-36 completed weeks) examined in this thesis were born in Finland between 1978 and 1986. They were invited to adult follow-up visits between 2004 and 2012. Among these young adults, I examined whether growth in weight, length, and head circumference between different early growth periods (between preterm birth, term age, and 12 months of corrected age in HeSVA, and between late preterm birth, 5 and 20 months of corrected age, and 56 months of age in AYLS) was associated with performance in neuropsychological tests, with self-rated symptoms of depression, attention deficit hyperactivity disorder, and other mental health problems, or with diagnosis of mental disorder based on a psychiatric interview in adulthood. In the AYLS cohort, the participants also reported final grade point average and special education in comprehensive school. I further examined whether daily intakes of energy in total, of energy from human milk, and of carbohydrates, protein, and fats during the initial hospitalization, which were relatively low compared to modern recommendations, predicted adult cognitive functioning (HeSVA). As growth variables, I used standardised residual change scores from linear regression models where weight, length, and head circumference z scores were regressed on corresponding measures at previous time points, creating uncorrelated residuals that reflect growth conditional on previous history. These growth variables were then used as independent variables in linear and logistic regression models to predict the outcomes, while taking into account several potential confounders including child and parental background characteristics and neonatal morbidity. Results: Faster growth during the first months of life was associated with better adult cognitive functioning in both cohorts. The size and direction of the effects were similar: for each SD faster growth in weight, head circumference, and length between birth and term age, the HeSVA participants had 0.23-0.41 SD higher general intelligence quotient, executive functioning component, and visual memory scores. For each SD faster weight gain and head growth from birth to 5 months, and head growth from 5 to 20 months, the AYLS participants had 0.19-0.41 SD higher general intelligence quotient and executive functioning component scores and grade point average. Those who grew faster also had lower odds of having received special education at school. Growth after these time periods did not predict cognitive functioning or school outcomes. In contrast, there were no consistent associations between early growth and adult mental health in either cohort. Even when taking into account several important neonatal complications and illnesses, the associations between early growth and adult cognitive functioning could not be wholly explained. Neonatal morbidity however seemed to largely account for the associations between higher energy intake between the first six weeks of life and better cognitive functioning among the HeSVA participants. Conclusions: Faster growth during the first weeks and months of life after preterm birth is associated with better cognitive functioning, and these associations persist into adulthood. The mechanisms explaining these associations are largely unclear, but seem outcome-specific. Early intakes of nutrition may reflect or possibly even mediate the effects of neonatal morbidity on neurodevelopment, however the neonatal morbidities commonly associated with preterm birth do not wholly account for the associations between early growth and long-term neurodevelopment. Keywords: premature birth; infant, very low birth weight; gestational age; birth weight; cognition; intelligence; executive functioning; memory; mental health; depression; attention deficit disorder with hyperactivity; substance-related disorders; anxiety disorders; education; growth; weight gain; body height; cephalometry; energy intake; milk, human; infant; adult; risk factors; follow-up studies; longitudinal studies; developmental origins of health and disease
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(Helsingin yliopisto, 2018)Despite advances in acute treatment of stroke, over third of the patients suffer from a disability, most often upper-limb paresis, still five years after stroke. To improve rehabil- itation, further understanding of stroke-induced plasticity is required. During the plastic period, cortical excitability increases, likely promoting cortical reorganization. Afferent input modulates the rolandic 20-Hz rhythm. The modulation, reflecting motor- cortex excitability, is observable as the activation-associated suppression and inhibition- associated rebound of the 20-Hz rhythm. In this Thesis, motor-cortex excitability was monitored by applying two different afferent inputs while recording the 20-Hz rhythm with magnetoencephalography (MEG), first in healthy controls and then in stroke patients in a one-year longitudinal study. Study I, comprising 22 healthy controls, focused on the modulation of the 20-Hz rhythm to tactile stimulation and passive movement as proprioceptive stimulation. The suppres- sion of the rhythm was similar to both stimuli whereas the rebound was stronger to pas- sive movement. Thus, passive movement could better serve in studying motor-cortex excitability changes. In Studies II and III, modulation of the 20-Hz rhythm to afferent input was measured in 23 patients having their first-ever stroke in the territory of the middle cerebral artery and related upper-limb paresis. Passive movement of the index finger (Study II) and tactile stimulation (Study III) were applied during MEG recordings in the acute (T 0 ; 1–7 days), subacute (T 1 ; one month) and chronic (T 2 ; 12 months) phases after stroke onset in conjunction with clinical testing of hand motor performance. The results showed that in the acute phase, the rebound was strongly diminished to both stimuli compared to the controls and increased significantly during the first month. During the follow-up period, the rebound strengths to both stimuli correlated with motor performance of the impaired hand. The bilateral weakness of the rebounds in the acute phase indicate hyperexcitability of both hemispheres after stroke. The subsequent increase in the rebound strength during the first month, reflecting an increase in motor-cortex inhibition, is in line with earlier studies in animals and humans suggesting a sensitive and motor-recovery-related plastic period immediately after stroke. The rebound strength to impaired-hand stimulation correlatedwith hand motor performance across the follow-up indicating that adequate integration of afferent input with motor functions is important for motor recovery. During the follow- up, the 20-Hz rebound to both tactile and passive-movement stimuli increased similarly. However, the rebounds to tactile stimuli recovered to the level of the controls whereas those to proprioceptive stimuli did not. This might indicate that proprioception did not recover fully in our patients. It would be most important to be able to predict and evaluate the progress of an individual patient during recovery from stroke to intensify and tailor rehabilitation for individual needs. Though, the efficacy of rehabilitation may be evaluated with different neuroimag- ing methods and clinical tests in a group level, so far there are no objective biomarkers to evaluate rehabilitation in an individual level. The results of this Thesis indicate that the 20-Hz rebound magnitude strongly reflects motor-cortex excitability and thus could serve as a robust noninvasive marker of stroke-induced neurophysiological processes that are relevant for motor recovery. Such a biomarker may enable to assess the efficacy of new therapeutical methods in stroke rehabilitation in both group and individual levels.
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(Helsingin yliopisto, 2018)Tämä tutkimus käsittelee kallon saumojen ennenaikaisen sulkeutumisen (kraniosynostoosi) leikkaushoitoa. Perinteiseen leikkausmetodiin avoimeen kallon uudelleen kokoamiseen (kranioplastia) liittyy useita haasteita: leikkauksessa syntyvät luupuutokset jäävät joskus luutumatta,kestävän luiden välisen liitoksen saavuttaminen on haastavaa, toimenpide on hyvin invasiivinen henkeä uhkaavine komplikaatioineen. Uuteen vähemmän invasiiviseen hoitomuotoon kallon venytykseen liittyy myös tällä hetkellä usein ongelmia kuten luun venyttimien hajoamista tai irtoamista. Tutkimuksessa etsittiin ratkaisuja näihin ongelmiin.18:sta kraniosynostoosipotilaalle avoimen kranioplastian aikana luupuutosten peitoksi oli laitettu demineralisoitu luulevy (DML). Nämä luupuutokset osoittivat parempaa luutumista (74%) kuin vastaavat tyhjät luupuutokset (54%) saman potilaan kallossa. Vertailu tehtiin viikko ja vuosi leikkauksen jälkeen otetuista tietokonetomografia kuvista. DML osoittautui turvalliseksi ja hyödylliseksi materiaaliksi luuputosten peitoksi. Aalto-yliopiston kanssa yhteistössä kehitettiin metodi, jotta kallon venytyshoidossa syntyvät voimatpystytään määrittämään. Mittauksissa todettiin venytystä vastustavan voiman kasvavan jyrkästi venytyksen aikana ja laskevan tämän jälkeen merkittävästi (keskimäärin 69.9%). Keskimääräinen venytyksen aloitusvoima oli 20.4 N ja lopetusvoima 57.6 N. Tutkimuksesta voidaan päätellä, että kallon venytyshoidon komplikaatioita voidaan vähentää jakamalla venytys useampiin lyhyempiin venytys kertoihin. Aalto-yliopiston kanssa yhteistyössä tehdyssä laboratoriokokeissa todettiin, ettei kahdella erilaisellabiohajoavalla luun kiinnitysmekanismilla, perinteisellä ruuvilla ja ultraäänellä aktivoitavalla pinnillä, ole kliinisti merkittävää kestävyys eroa. Toisessa samantyyppisessä laboratoriokokeessa testattiin kolmen erilaisen biohajoavan kiinnitysmekanismin soveltuvuutta kallon luun venyttimen kiinnittämiseen. Tutkimuksessa todettiin, että luun venytin voidaan kiinnittää kalloon 8 biohajovallaruuvilla tai 12:sta biohajoavalla lämmöllä aktivoitavalla pinnillä. Biohajoavalla kiinnityksellä voidaan mahdolisesti vähentää hoitoon liittyviä komplikaatioita ja vähentää luun venyttimen poistoleikkauksen laajuutta.
