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  • Raj, Rahul (Helsingin yliopisto, 2014)
    Background: Prognostic models are important tools for heterogeneity adjustment in traumatic brain injury (TBI). Prognoses after TBI have been particularly challenging to predict, with limited availability of robust prognostic models. TBI patients are by definition trauma patients, and often treated in the intensive care unit (ICU). Several prognostic models for ICU and trauma patients have been developed, although their applicability in patients with TBI is uncertain. Recently, however, some new prognostic models specifically designed for patients with TBI were introduced. Still, the optimal type of prognostic model in TBI remains unknown. Aim: To investigate the applicability of different types of prognostic models in patients with TBI and to develop novel models with enhanced performance to previous models, focusing on long- term outcome prediction. Methods: Four patient databases of patients with TBI treated in the ICU were used to validate three TBI specific models, two computerized tomography (CT) scoring systems, one trauma scoring system, and three intensive care scoring systems. Models were validated by assessing their discrimination using area under the curve (AUC), calibration, and explanatory variation. Logistic regression was used for model customization and development. Models were internally validated using a resample bootstrap technique or a split-sample technique. Primary outcome was six-month mortality and unfavorable neurological outcome by the Glasgow Outcome Scale. 30-day in-hospital mortality was used for the trauma scoring system. Results: Study populations ranged from 342 to 9,915 patients. The TBI models showed the best performance with AUCs between 0.80 and 0.85, followed by the intensive care scoring systems and the CT scores with AUCs between 0.68 to 0.80 and 0.63 to 0.70, respectively. Most models showed poor calibration, although good calibration was achieved following customization. The trauma scoring system exhibited modest to good discrimination (AUC 0.76-0.89) for short-term mortality prediction, but poor calibration. Several new prognostic models, with statistically significant superior performance to previous models were created, among them a combined TBI-ICU model ( IMPACT-APACHE ) and a novel CT scoring system ( The Helsinki CT score ). Using a TBI specific model, based on admission characteristics, up to 40 % of the patient s final long-term outcome could be predicted. Conclusion: The TBI models showed superior predictive performance to the intensive care and trauma scoring systems, showing that TBI patients are a highly specific population in the trauma and ICU setting. Thus, the use of a TBI specific model is advocated in the setting of TBI. The newly proposed models were found to be significant improvements over previous models, but require external validation to show generalizability.
  • Tamminen, Jenni (Helsingin yliopisto, 2014)
    The aim of this thesis was to extend the understanding of molecular mechanisms of asbestos exposure related diseases asbestosis (lung fibrosis), lung cancer and mesothelioma. Epithelial-to-mesenchymal transition (EMT) is implicated in fibrosis and in cancer, both asbestos induced diseases. The first of the three studies investigated whether asbestos fibers induced EMT. In the next two studies, the focus was on mesothelioma. In these two studies, the aim was to recognize novel potential therapeutic target molecules and pathways involved in chemoresistance and invasion. We found that exposure to asbestos led to loss of epithelial characteristics when lung epithelial cells retained the type II airway epithelial cell phenotype. This loss of epithelial characteristics was found not to depend on TGF-β or Smad signaling cascades. The MAPK/ERK pathway was found to mediate epithelial plasticity in response to asbestos exposure. A screen for new gremlin-1 interacting proteins discovered fibrillin-2. This finding was validated in mesothelioma tumor samples in which gremlin-1 and fibrillin-2 co-localized in the tumors. Primary mesothelioma cells were harvested from pleural effusion samples of mesothelioma patients. These cells recapitulated primary tumor characteristics and overexpressed gremlin-1, fibrillin-2 and transcription factor slug. Silencing of gremlin-1 downregulated slug, reverted the EMT-phenotype and sensitized the cells to the cytotoxic effect of chemotherapeutic drugs. The concomitant overexpression of gremlin-1 and fibrillin-2 enables gremlin targeting to fibrillin-2 containing fibers in mesothelioma extracellular matrix, where it supports the chemoresistant EMT phenotype through transcription factor slug. Mesothelioma tumors as well as primary mesothelioma cells and mesothelioma cell lines were found to overexpress activin-A and activin-B. Canonical Smad3 response to activin stimulation was attenuated in mesothelioma cells. Attenuation of the Smad3 response associated with migratory and invasive phenotype. Mesothelioma cells switch from canonical Smad3 signaling to non-canonical MAPK/ERK pathway, and this promotes migration and invasion. Invasion, migration and ERK activation was impaired by sequestering extracellular activins by soluble activin-receptor. Likewise, inhibiting MAPK/ERK upstream kinase impaired migration and invasion The results presented in this thesis support the concept that pathological EMT is a central mechanism in the development and progression of asbestos induced fibrotic and malignant diseases. They also suggest gremlin-1 and activin-A as new potential therapeutic targets in mesothelioma.
  • Kaseva, Nina (Helsingin yliopisto, 2014)
    Advancements in neonatal care are resulting in increasing numbers of adult survivors after preterm birth at very low birth weight (VLBW, ≤ 1500 g). VLBW is associated with risk factors of non-communicable diseases, e.g. cardiovascular disease, osteoporosis and diabetes. We investigated mechanisms underlying the effects of preterm birth on later health in VLBW adults, with a focus on 1) physical activity, 2) nutrition and 3) stress response. The participants come from a follow-up cohort study, the Helsinki Study of Very Low Birth Weight Adults. Different subgroups from the original birth cohort (born in 1978-1985) have as young adults participated in the studies of this thesis. The controls, born at term, were group-matched for birth hospital, age and sex. We evaluated physical activity by self-report and objective measurement. The participants completed a physical activity questionnaire and underwent wrist-worn accelerometer measurement. To assess dietary intake, the participants completed a 3-day food record. For evaluation of stress response, the participants underwent the Trier Social Stress Test (TSST). In conjunction with TSST, we measured heart rate, salivary cortisol, plasma ACTH, cortisol, glucose, insulin, adrenalin and noradrenalin. 1) Based on self-report, healthy VLBW adults undertake approximately 50% less conditioning leisure-time physical activity, with lower yearly frequency, total time, total volume and energy expenditure than controls. We were unable to confirm our finding of lower physical activity with wrist-worn accelerometer measurement. 2) VLBW adults had lower consumption of vegetables, fruits, berries and milk products. This was combined with lower intake of calcium and vitamin D. 3) VLBW adults showed a lower hypothalamic-pituitary-adrenal axis (HPAA) response to stress than controls. This was accompanied by a lower insulin response. No evidence of a higher sympathetic-adrenal-medullary (SAM) system stress response was found. Furthermore, we observed a lower noradrenalin response to stress in VLBW women. This study showed that VLBW adults undertake less conditioning leisure-time physical activities and have unhealthier diets, both factors that negatively affect future health in this high-risk population. They may in part underlie the increased risk for chronic non-communicable diseases in VLBW individuals. Further, a lower HPAA response to stress was found in VLBW adults than in controls. For SAM stress response, the results were similar in VLBW and control groups, with lower noradrenalin response to stress in VLBW women only. These findings reinforce the supposition that stress response is programmed early in life. In sum, this study increased understanding of possible mechanisms linking preterm birth and adult risk of disease.
  • Pietiläinen, Olli (Helsingin yliopisto, 2014)
    Severe mental disorders including schizophrenia often segregate within the same families. Twin and family studies suggest that this co-occurrence is largely genetic, which implies that the different mental disorders have a shared genetic background. Some symptomatic features, such as cognitive impairment also manifest to a variable degree in the majority of severe mental disorders. Cognitive impairment occurs already before the onset of the disease and healthy family members of patients perform worse in cognitive tests than do the general population, which suggests that the cognitive impairment is indicative of genetic loading of the disease. Furthermore, the cognitive impairment persists throughout the disease and is associated with poorer outcome. This led us to hypothesize that the genetic architecture of schizophrenia is more similar to developmental disorders than had been considered earlier. Specifically, we hypothesized that rare high impact genetic variants play a role in the genetic risk for schizophrenia. Rare recurrent large-scale structural variation has long known to cause developmental syndromes, such as Prader-Willi syndrome or Velocardiofacial syndrome. In this study we investigated the role of large-scale chromosomal copy number variants in the genetic background of schizophrenia and other traits hypothesized to reflect abnormal neuronal development. In this study four chromosomal deletions on 1q21, 15q11.2, 15q13.3 and 22q11.2 were identified to be associated with schizophrenia. Three of the deletions occurred recurrently, whereas the deletion on 22q11.22 was a founder mutation enriched especially in the North-East region of Finland. On a population level, carriers of large deletions were found to have more intellectual disability or sub-normality (IQ<85) than non-carriers. Also milder learning difficulties as measured by repeated grades in school were more common among carriers of large deletions. The four deletions specifically identified as associating with schizophrenia are linked to variable phenotypes with the strongest effect manifesting in intellectual disabilities. The regional enrichment of the deletion on 22q11.22 also enabled the assessment of recessive effects related to the deletion. Four individuals, all presenting with a neurodevelopmental phenotype and/or schizophrenia, were identified as homozygous for the deletion. This deletion overlaps one gene encoding for topoisomerase 3 beta (TOP3β) that forms a protein complex with FMRP, the fragile X mental retardation protein, via tudor domain containing 3 (TDRD3) protein. The results of this study imply that rare high risk variants are present in a sub set of schizophrenia patients and that these variants are shared with developmental disorders. The study also demonstrates that special populations such as population isolates can provide useful study designs in identifying rare genetic risk variants, especially with recessive effects for complex traits.
  • Saarela, Riitta (Helsingin yliopisto, 2014)
    ABSTRACT This study formed part of a developmental project in the Helsinki Metropolitan Area of Finland during 2003 2011 that aimed to develop nutritional care in long-term care facilities. The aim of this study was to assess tooth brushing/denture cleaning habits, dentition, chewing problems, and swallowing difficulties and their associations with nutritional status and eating habits. Furthermore, the aim was to explore the prognostic value of dentition, chewing problems and swallowing difficulties in relation to mortality. In addition, the adequacy of the dietary intake of energy, protein, and other nutrients was examined. Of all the residents in assisted living facilities (N = 2188) in the cities of Helsinki and Espoo, 67% (1475) participated in this study in 2007. Trained registered nurses familiar with the residents assessed each participant and collected demographic data, the medical history, information on the functional and cognitive status, tooth brushing/dentition cleaning habits, dentition, oral symptoms, eating habits and diets. The nutritional status was assessed with the Mini Nutritional Assessment (MNA). In addition, 343 volunteer residents provided one-day food diaries. Their energy, protein, and nutrient intakes were calculated from these detailed food diaries and compared with the recommendations of the Finnish National Nutrition Council as a measure of dietary adequacy. Information on three-year mortality was retrieved from central registers on 6 July 2010. The mean age of the residents was 83 years and 79% of them were women. The educational level was low; 56% of the residents had a primary school level of education or less. In activities of daily living, most residents (84%) required at least prompting or assistance in dressing, hygiene and the keeping of personal effects, or required considerable help with personal care, often involving incontinence. Over half of the residents (55%) had cognitive impairment. Edentulousness was common; more than half of the residents (52%) had lost all their teeth, while 7% (n = 94) were totally edentulous without prosthesis. Of the residents, 17% did not clean or had not cleaned their teeth/dentures daily. According to the MNA, 13% were malnourished, 65% were at risk of malnutrition and 22% were well nourished. Edentulousness without prostheses and infrequent tooth brushing were associated with malnutrition, oral symptoms and infrequent use of oral health care services. Residents with chewing problems (n = 287) were older, had more comorbidities and were more likely to be malnourished according to the MNA, to be dependent in activities of daily living (ADL) and to have poorer subjective health than those without chewing problems. In logistic regression analysis including age, sex, MNA class and the Charlson´s Comorbidity Index as covariates, chewing problems still independently predicted mortality (OR = 1.46, 95% CI = 1.10 1.93). Of the residents, 12% (n = 173) had swallowing difficulties and they were more likely to be malnourished that those residents without swallowing difficulties. Swallowing difficulties also had an independent predictive value for mortality (OR = 1.49, 95% Cl = 1.04-2.12). Large proportions of volunteer participants in the subsample that provided one-day food diaries received less than the recommended amounts of energy, protein or micronutrients. The dietary intake of protein was significantly lower among edentulous subjects without dentures than those with natural teeth. In the adjusted (age, gender and Charlson s comorbidity index) logistic regression model, being in Group 1 (edentulous participants without dentures) and Group 2 (edentulous participants with some removable dentures in one or both jaws) predicted a poorer protein intake (less than 60 g/day; OR 2.4, 95% CI 1.0 5.7, p = 0.042 and OR 1.6, 95% CI 1.0 2.6, p = 0.045, respectively) compared with the reference Group 3 (dentulous participants all or some natural teeth and with or without removable dentures in one or both jaws; OR = 1). Oral problems were common among frail older residents in assisted living facilities and they were associated with nutritional problems. These findings suggest the need for co-operation between nursing staff and oral care personnel.
  • Rahkonen, Petri (Helsingin yliopisto, 2014)
    Despite advancements in neonatal intensive care and increased survival of infants born extremely preterm, many of them still develop with motor, sensory, cognitive, and behavioral impairments. Predicting adverse neurodevelopmental outcome as early as possible is a challenge in neonatology. Structural neuroimaging methods partly fail to detect milder brain abnormalities that may interfere with later developmental outcome, and neurological assessment is more unreliable in the neonatal period than in childhood. Thus, additional methods are needed for earlier and more accurate recognition of extremely preterm infants with adverse neurodevelopmental outcome. The first purpose of this study was to assess the value of measuring higher cortical function by neurophysiological methods in predicting outcome of infants born extremely preterm. Second, we aimed to examine possible difficulties in behavioral somatosensory processing and in mother-child interaction and their associations with developmental outcome. The lack of somatosensory evoked magnetic fields from the secondary somatosensory cortex in magnetoencephalography at term equivalent age, reflecting abnormal higher cortical functioning during somatosensory processing, was associated with worse neuromotor outcome of extremely preterm infants at two years of corrected age, not foreseen with structural neuroimaging methods. Further, we showed that responses from the secondary somatosensory cortex can also be detected by measuring somatosensory evoked potentials during electroencephalography. The quality of mother-infant interaction in mother- extremely preterm child dyads did not differ from that in mother-term child dyads. However, among children born extremely preterm worse child adjustment and lower quality of maternal and dyadic behavior were associated with lower neurocognitive outcomes. Half of the children born extremely preterm presented atypical behavioral sensory processing at two years of corrected age. Sensation seeking was common in extremely preterm children with neonatal neuroanatomical lesions. In conclusion, the functional neurophysiological methods magnetoencephalography and measurement of somatosensory evoked potentials during electroencephalography hold promise as valuable additional tools in predicting outcome of children born extremely preterm. The quality of mother-infant interaction may play a significant role in optimizing cognitive outcome after extremely preterm birth. Atypical behavioral sensory processing in children born extremely preterm is common, but the pathogenesis and developmental significance of this phenomenon call for more research in the future.
  • Savolainen, Laura (Helsingin yliopisto, 2014)
    Tuberculosis (TB) still ranks among the most lethal infectious diseases in the world. The traditional distinction between active tuberculosis and latent tuberculosis infection (LTBI) is changing; at the moment, tuberculosis infection is described as a continuum with different stages of infection. The development of TB prevention, treatment and diagnostics is hampered by the diverse pathogenesis of the disease and the ability of the bacteria to fight host defence mechanisms. Traditional culture methods are slow and staining methods not sufficiently sensitive. Nucleic acid amplification techniques (NAAT) tend to be costly and in some cases lack sensitivity. New methods are needed for rapid and inexpensive detection of active disease and to distinguish between stages of infection in cases where the patient presents with symptoms compatible with active TB and with a positive Interferon Gamma Release Assay (IGRA) result, but bacteriological confirmation is not yet available. In addition, methods are needed that enable us to predict the activation of infection or monitor the effects of treatment. The aim of this thesis was to investigate: a) the possible diagnostic use of heparin-binding haemagglutinin (HBHA), a surface protein of M. tuberculosis, in distinguishing between stages of infection in a vaccinated population; b) the effect of sample concentration on the properties of Clearview® TB ELISA, a urine antigen test measuring lipoarabinomannan (LAM), a M. tuberculosis glycolipid, in the diagnosis of active TB; c) the suitability of granzyme B (GrB), perforin (Prf), and interferon-gamma (IFN-γ)-producing and CD107a-degranulation factor-expressing cytotoxic T lymphocytes (CTLs) for differentiating between stages of infection; d) the suitability of IFN-γ, interleukin (IL) -17, IL-4, IL-4δ2 and Forkhead box P3 (FoxP3) mRNA expression levels for differentiation between stages of infection. The results showed that HBHA-specific cells producing IFN-γ were also found in the circulation of healthy subjects who had been given the Bacillus Calmette-Guérin vaccine. In view of this, use of the HBHA antigen for diagnostic purposes does not look promising in countries where a widespread vaccination programme has taken place. No differences were found in the numbers or phenotypic properties of CTLs between persons with active TB and those with LTBI, which is why they are not suited for the differential diagnosis of infection stages. Functional antigen-specific CTLs were found in the circulation of persons who had been treated for TB. This most significant finding of this thesis demonstrates that the T cell memory generated by active TB maintains functionally active CTL populations decades after infection and despite adequate treatment with rifampicin. Although no statistically significant differences were found between patients with active TB and LTBI in the quantitative detection of IFN-γ, IL-17, or IL-4 mRNA from cells stimulated with purified protein derivative (PPD), this approach revealed a trend towards discrimination. The usefulness of combined quantitative IFN-γ, IL-17, and IL-4 mRNA expression for the differential diagnosis of active TB and LTBI should be retested with a larger sample size enrolling more homogenous patients in the LTBI group. The findings indicating that LAM may be detected with moderate sensitivity (57%) in the urine samples of TB patients show the greatest promise from a diagnostic point of view. The 100-fold concentration of urine used in this study improved the sensitivity of the Clearview® TB ELISA test from 7% to 57%, although specificity was decreased somewhat from 98% to 89%. Based on the results, demonstrating the presence of LAM in urine samples may be considered a potential diagnostic tool for detecting active TB. The method does require further development, however.
  • Syrjälä, Simo (Helsingin yliopisto, 2014)
    Heart transplant is disconnected from the circulation and preserved in hypothermia before transplantation. Paradoxically, revascularization of the heart transplant results in ischemia-reperfusion injury described as myocardial injury, microvascular dysfunction, and innate and adaptive immune activation. The innate response consists mainly of neutrophils and macrophages and innate lymphoid cells and may lead to sustained adaptive immune response leading to chronic rejection and late graft failure. The heart is especially susceptible for lack of oxygen; therefore, the ischemic time in clinical practice is critical. Prolonged ischemic time due to long distance between hospitals or technically difficult operation is an independent risk factor for primary graft dysfunction and chronic rejection. This study utilized experimental animal model to describe the effect of cardiac allograft ischemia-reperfusion injury on innate immune activation and adaptive immune responses, such as the development of acute and chronic rejection. This study further investigated the effects of either activating or inhibiting the angiopoietin (Ang)/Tie2-signaling pathway in this disease process. The results show that prolonged hypothermic preservation enhanced ischemia-reperfusion injury-related innate immune activation and adaptive immune and worsened the prognosis of the cardiac allografts. Analysis of samples from clinical heart transplant recipients revealed increase in peripheral blood Ang2 levels during the first day after the operation. Similar findings were evident in the recipients of rat cardiac allografts. Primary and late graft dysfunction, either due to ischemia-reperfusion injury, or acute and chronic rejection, limit the survival of patients with solid organ transplant. According to this study, targeting Ang/Tie2-signaling prevents early allograft endothelial activation and inflammatory cell accumulation. Of studied treatment protocols, early systemic recipient treatment with anti-Ang2 antibody had the most robust effect in preventing allograft dysfunction. Ang2-targeted antibody treatment would have clinical implications in induction therapy of transplant patients, as the dosage of other immunosuppressive drugs may be lowered and the adverse side effects of these drugs avoided. These results encourage further studies to determine the clinical significance of Ang/Tie2-pathway modification.
  • Kallio, Elisa (Helsingin yliopisto, 2014)
    Periodontitis is characterized by an inflammatory response to bacterial infection in the supporting tissues of the teeth. The disease manifests with gingival swelling and bleeding, increased periodontal pocket depth, and alveolar bone loss. Intact bacteria or bacterial products, including lipopolysaccharide (LPS), may enter the bloodstream through inflamed periodontal tissue or via saliva. Bacterial dissemination, further potentiated by gastrointestinal microbiota, may result in endotoxemia and low-grade inflammation. The general aim of this thesis research was to investigate whether LPS links periodontitis with cardiometabolic disorders. The following topics were studied: genetic factors associated with the susceptibility to periodontitis, the systemic effects of endotoxemia induced by periodontitis and cardiometabolic disorders, as well as the influence of periodontal treatment on plasma LPS activity and lipoprotein composition. A study of genetic polymorphisms of the human major histocompatibility complex region demonstrated that a haplotype comprising six SNPs of the BAT1, NFKBIL1, and LTA genes was associated with the risk of having periodontitis. The risk haplotype showed an association with bleeding on probing, probing pocket depth ≥6 mm, and severe periodontitis, and the result was replicated in two different study populations with concordance. In addition, the serum lymphotoxin-α (LTA) concentration was associated with LTA SNPs of the risk haplotype in homozygous patients, and LTA was expressed in the inflamed periodontal tissue. The systemic effects of the periodontitis-derived endotoxemia were investigated before and after periodontal treatment. In the serum of periodontitis patients, LPS was associated with the proatherogenic very low-density lipoprotein intermediate-density lipoprotein (VLDL-IDL) fraction. Although local healing of the periodontium was successful, the systemic inflammation status of the patients failed to improve after periodontal treatment, reflecting the complexity and persistence of the disease. There were no significant changes in plasma LPS activity or its distribution among lipoprotein classes after periodontal treatment. However, the VLDL of patients with severe periodontitis induced higher expression of proinflammatory cytokines in macrophages when compared with VLDL derived from patients with moderate periodontitis. In addition, VLDL isolated from patients with severe periodontitis with suppuration contained more LPS and induced higher cholesterol uptake in macrophages. The effect of nutrient intake on the association of serum LPS activity with cardiometabolic disorders was examined in a population-based cohort. Endotoxemia was strongly associated with prevalent obesity, metabolic syndrome (MetS), diabetes, and coronary heart disease (CHD). In addition, high serum LPS activity was associated with an increased risk of future CHD events. Even though energy intake was correlated with LPS activity in lean, healthy subjects, the general associations were independent of energy or macronutrient intake. The results indicate that genetic variation in the MHC class III region may be important in periodontitis susceptibility. Endotoxemia and low-grade inflammation originating from periodontitis may induce the proatherogenic properties of VLDL particles via macrophage activation and foam cell formation, thereby promoting atherogenesis. The association of obesity, MetS, diabetes, and CHD with endotoxemia supports the significance of bacterial infections and the immune response in the etiology of cardiometabolic disorders. In conclusion, the findings highlight the close relationship between genetics, the immune response, and lipid metabolism, promoting the role of LPS as a link between periodontitis and cardiometabolic disorders.
  • Suojalehto, Hille (Helsingin yliopisto, 2014)
    Asthma and allergic rhinitis can be seen as manifestations of one disease with a common underlying inflammatory process. The aim of this thesis was to investigate airway inflammation biomarkers in asthma and rhinitis in this context in two adult populations. In the nasal biopsies we detected only modest differences between the inflammatory cells and cytokine levels of the patients with allergic rhinitis and asthma and the controls. Three microRNAs were up-regulated in the nasal mucosa of participants with current allergic rhinitis, and one microRNA was down-regulated in the asthmatic patients without current rhinitis symptoms when compared to healthy controls. In the men with long-term asthma, altered expressions of 10 microRNAs were detected, four of which were also differentially expressed in the asthmatic patients without allergic rhinitis. Among the asthmatics, differences in the microRNAs were also detected when no significant changes in the inflammatory cells and cytokines were found. In the future, microRNAs arrays might be useful as a sensitive method for assessing airway inflammation. The level of nasal nitric oxide was slightly elevated in the participants with allergic rhinitis compared to that of the controls. A positive correlation between the nasal and exhaled nitric oxide levels and an inverse correlation between the nasal nitric oxide level and CT score of sinus ostia obstruction were detected. When we evaluated the allergic rhinitis patients without marked sinus ostial obstruction, the nasal nitric oxide level correlated positively with the nasal eosinophil count. The nasal nitric oxide level reflects eosinophilic inflammation in nasal mucosa in allergic rhinitis. However, the level is dependent on sinus ostia obstruction, reducing its feasibility for monitoring allergic inflammation. In the sputum proteome analysis, we identified 31 different proteins, which were also found in the nasal lavage fluid. An increased abundance of fatty acid binding protein 5 (FABP5) was found in the sputum and nasal lavage fluid of the asthmatics. The level of FABP5 in the nasal lavage fluid positively correlated with vascular endothelial growth factor as well as cysteinyl leukotriene levels, suggesting that FABP5 may contribute to airway inflammation and remodeling. Samples from upper airways are easy to obtain, and our findings suggest that they might be useful in investigating biomarkers of lower airway inflammation in asthma.
  • Hetemaa, Tiina (Terveyden ja hyvinvoinnin laitos, 2014)
    The importance of CHD to public health is due not only to the high prevalence of, and mortality due to, the disease, but also to the result of costly invasive treatments such as coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). Although CHD mortality has markedly declined in Finland over the past few decades, it is still the main cause of death. The general aims of this study were to evaluate and describe socioeconomic differences in the use of coronary procedures and the outcomes of CHD patients and to elucidate the factors that have an effect on differences, such as the change in supply for invasive treatments of CHD, the duration of follow-up, co-morbidity, disease severity and regional variations in procedure rates. The study also examines whether similar socioeconomic disparities in invasive treatments and outcomes of CHD exist in patients with chronic angina pectoris (AP), and with potentially more effective access to secondary prevention, such as in patients with acute myocardial infarction (MI) as the first sign of CHD. Data from 1988 to 1998 was gathered from administrative registers of the Social Insurance Institution, Statistics Finland, and STAKES. For each original study the necessary register linkages were performed in Statistics Finland and personal identification numbers were encrypted before the data was transferred to the researchers. The study protocols of the original studies were approved by the Finnish Data Protection Ombudsman and the Ethics Research Committee of STAKES. Age-adjusted rates were calculated for coronary operations, hospitalisations due to CHD, CHD and all cause mortality, and incidences of MI and its case fatality, for men and women separately by social category, as measured by education, occupational driven socioeconomic status, and income. The results of this study indicate that similar patterns emerged in the use of cardiac procedures according to all socioeconomic indicators: patients with higher socioeconomic status underwent more procedures than patients from lower groups. This applied to both patient groups, AP and MI patients, and both genders. Those of higher socioeconomic status also benefitted first from cardiac procedures. More attention should therefore be paid to the equitable distribution of scarce health care resources. Socioeconomic differences in CHD outcomes also exist among angina patients. These results suggest that targeted measures of secondary prevention are needed among CHD patients with lower socioeconomic status to reduce socioeconomic disparities in fatal and non-fatal coronary events. To improve equity, it is vital that all patients should have access to health care and receive treatments according to their need, not according to the social category to which they belong to or to their gender.
  • Tiippana-Kinnunen, Tarja (Helsingin yliopisto, 2014)
    This 15-year follow-up focused on radiographic outcome, functional capacity, work disability and comorbidity in 86 patients (age 18-65 years), with early (≤ 12 months of disease duration) rheumatoid arthritis (RA) collected in 1986-1989 in Helsinki area and treated with early initiated DMARD therapy. The outcome was determined in relation to DMARD continuity, early disease activity, early radiographic remission (ERR) and baseline comorbidity. Of the 70 patients evaluated at 15-year examination, 50 (71%) needed continuous DMARD therapy (group A). In 20 patients (29%) DMARDs were discontinued due to clinical remission. Of these disease flared up and DMARDs were reintroduced in 9 patients (45%, group B) and 11 (55%) remained in remission (group C). The 15-year outcome was most favourable in group C: 64% of patients being in remission, according to American Collage of Rheumatology criteria, compared with 0% in B and 6% in A. Final functional capacity [mean Health Assessment Questionnaire (HAQ)] was 0.24 in C, 0.38 in B and 0.60 in A and radiographic outcome assessed with mean Larsen score (LS) 12, 25 and 54, respectively. As conclusion, patients whose DMARDs are discontinued due to remission, should be followed up closely for a flare-up of the disease. For those whose disease flares up, DMARDs should be reintroduced immediately. The 15-year LS of 69 patients determined in relation to ERR [an increase of LS ≤ 1 Larsen unit (LU) between two sequential sets of small joint radiographs during the first 2 years]. Mean 15-year LS of the small joints (14) and LS of the large joints (0.8) were lower in patients with sustained ERR (both year 1 and year 2), compared with 33 and 1.9 in patients with temporary ERR (either year 1 or year 2) or with 67 and 6.3 in patients with radiographic progression ≥ 2 LU during both first years. Considering these findings, radiographic remission should be a treatment goal in RA and early progression in small joints should be taken as a warning sign for later damage of large joints. Of 80 patients with adequate data, 20% had at least one comorbid condition at baseline and 60 % had comorbidities at the 15-year visit or at time od death, most commonly hypertension (30%), cardiovascular diseases (14%), malignancies (11%) or osteoporosis (11%). Elderly patients with baseline comorbidity showed higher disease activity both during first year of RA and at endpoint than younger patients without comorbidities. Of the 86 patients, 42 (49%) retired due to work disability (WD) during 15 years or before death, most of these due to RA. The Kaplan-Meier estimated cumulative RA-related WD was less frequent in patients with low disease activity during first 12 months (3% at year 5, 10% at year 10 and 22% at year 15) than in those with moderate or high disease activity (28%, 55% and 64%, respectively). The results of this study showed that most patients with RA need continuous DMARD treatment and emphasize the importance of targeting to clinical remission and to radiographic remission in early phase of the disease for the long-term outcome in RA.
  • Pihlajoki, Marjut (Helsingin yliopisto, 2014)
    The main steroidogenic organs, adrenal cortex and ovary, arise from a common pool of progenitors in the developing embryo. Similar signaling pathways regulate the differentiation, growth, and survival of cells in these tissues. Proper development of the adrenal cortex and ovary requires precise spatiotemporal control of gene expression and apoptosis; disruption of these processes may lead to congenital disorders or malignant transformation. Earlier in vitro studies demonstrated that transcription factor GATA6 regulates the expression of multiple steroidogenic genes in the adrenal cortex. To show that GATA6 is a crucial regulator of adrenocortical development and function in vivo, we generated a mouse model in which Gata6 is conditionally deleted in steroidogenic cells. These mice exhibited a complex adrenal phenotype that includes cortical thinning, blunted aldosterone production, lack of an X-zone, impaired apoptosis, and subcapsular cell hyperplasia. These results offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells. Ovarian granulosa cell tumors (GCTs), the most common sex-cord stromal tumors in women, are thought to be caused by aberrant granulosa cell apoptosis during folliculogenesis. A somatic missense mutation in transcription factor FOXL2 (402C→G) is present in vast majority of human GCTs. FOXL2 plays a key role in the development and function of normal granulosa cells. Wild type (wt) FOXL2 induces GCT cell apoptosis, while mutated FOXL2 is less effective. To clarify the molecular pathogenesis of GCTs, we investigated the impact of FOXL2 and two other factors implicated in granulosa cell function, GATA4 and SMAD3, on gene expression and cell viability in GCTs. We found that these factors physically interact and that GATA4 and SMAD3 synergistically induce CCND2 promoter transactivation, which is reduced by both wt and mutated FOXL2. Finally, we demonstrated that GATA4 and SMAD3 protect GCT cells from wt FOXL2 induced apoptosis without affecting the apoptosis induced by mutated FOXL2. These findings suggest that mutated FOXL2 disrupts the balance between growth and apoptosis in granulosa cells, leading to malignant transformation. The treatment of recurrent or metastatic GCTs is challenging, and biologically targeted treatment modalities are needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) activates the extrinsic apoptotic pathway. Interestingly, TRAIL is able to induce apoptosis in malignant cells without affecting normal cells. Vascular endothelial growth factor (VEGF) is the key regulator of both physiological and pathological angiogenesis. Cancer cells often express VEGF receptor, and an autocrine VEGF/VEGFR signaling loop exists in several types of cancer cells. We found that GCT cells express functional TRAIL and VEGF receptors, and that treatment with TRAIL and the VEGF-binding antibody (bevacizumab) induce GCT cell apoptosis. These findings establish a preclinical basis for targeting these two pathways in the GCT treatment.
  • Boldt, Robert (Helsingin yliopisto, 2014)
    Hearing is a versatile sense allowing us, among other things, to avoid danger and engage in pleasurable discussions. The ease with which we follow a conversation in a noisy environment is astonishing. Study I in this thesis used functional magnetic resonance imaging to explore the large-scale organization of speech and non-speech sound processing during a naturalistic stimulus comprised of an audio drama. Two large-scale functional networks processed the audio drama; one processed only speech, the other processed both speech and non-speech sounds. Hearing is essential for blind subjects. Anatomical and functional changes in the brains of blind people allow them to experience a detailed auditory world, compensating for the lack of vision. Therefore, comparing early-blind subjects brains to those of sighted people during naturalistic stimuli reveals fundamental differences in brain organization. In Study II, naturalistic stimuli were employed to explore whether one of the most distinguishing traits of the auditory system the left-lateralized responses to speech changes following blindness. As expected, in sighted subjects, speech processing was left-hemisphere dominant. Curiously, the left-hemisphere dominance for speech was absent or even reversed in blind subjects. In early-blind people, the senses beyond vision are strained as they try to compensate for the loss of sight; on the other hand, the occipital cortices are devoid of normal visual information flow. Interestingly, in blind people, senses other than vision recruit the occipital cortex. Additional to changes in the occipital cortex, the sensory cortices devoted to touch and hearing change. Data presented here suggested more inter-subject variability in auditory and parietal areas in blind subjects compared with sighted subjects. The study suggested that the greater the inter-subject variability of the network, the greater the experience-dependent plasticity of that network. As the prefrontal areas display large inter-subject spatial variability, the activation of the prefrontal cortex varies greatly. The variable activation might partly explain why the top-down influences of the prefrontal cortex on tactile discrimination are not well understood. In the fourth study, anatomical variability was assessed on an individual level, and transcranial magnetic stimulation was targeted at individually-chosen prefrontal locations indicated in tactile processing. Stimulation of one out of two prefrontal cortex locations impaired the subjects ability to distinguish a single tactile pulse from paired pulses. Thus, the study suggested that tactile information is regulated by functionally specialized prefrontal subareas.
  • Eriksson, Johanna (Helsingin yliopisto, 2014)
    Cutaneous melanoma is one of the most aggressive malignancies, typified by a high metastatic tendency and refractoriness to treatments. Identification of the molecular mechanisms behind the development and progression of melanomas could provide new insights into treating this challenging disease. The aim of this study was to identify and characterize genes and proteins associated with melanoma development and progression by comparing genome-wide gene expression profiles from different stages of melanoma, and to evaluate their potential as diagnostic and prognostic markers and therapeutic targets. A further aim was to develop sensitive RT-PCR and immunohistochemical assays for the detection of melanoma micrometastases. We found the outgrowth of melanoma metastases to be associated with the activation of stromal fibroblasts, increased TGFβ/Smad2 signaling, and an up-regulation of TGFβ-target genes encoding extracellular matrix proteins fibronectin, collagen-I, periostin, and versican. These proteins were found to form around tumor cells fibrillar networks, which, suggested by our functional studies, promote the growth and migration of tumor cells as well as stromal fibroblasts and endothelial cells. In addition, periostin and cellular fibronectin were found to be specifically up-regulated in newly-formed tumor blood vessels. We further found a common up-regulation of collagen triple helix repeat containing 1 (CTHRC1) and cysteine cathepsin B and L1 proteases during melanoma progression. Our analyses suggest that CTHRC1 is, together with fibronectin and integrin β3, part of the pro-invasive and pro-angiogenic transcriptional program induced by the NFATC2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2) transcription factor. Cathepsins B and L1 (and TGFβ signaling), in turn, were found to play essential roles in the co-invasive process of melanoma cells and activated fibroblasts. Further, our results suggest that high expression of CTHRC1, fibronectin, and cathepsin B in primary melanomas may serve as prognostic factors predicting poor survival. Combined, these results suggest that TGFβ receptors, fibronectin, periostin, and CTHRC1, as well as cathepsins B and L1 are attractive therapeutic targets against advanced melanomas. In addition, we identified the best gene expression markers for the detection of melanoma lymph node metastases. Of the identified genes, melan-A (MLANA), tyrosinase (TYR), melanoma inhibitory activity (MIA), preferentially expressed antigen in melanoma (PRAME), and osteopontin (SPP1) were tested as potential melanoma micrometastasis markers by RT-PCR and immunohistochemistry (IHC). Graded MLANA- and TYR-RT-PCR analyses were found to detected clinically significant metastases better than IHC, suggesting that quantifiable RT-PCR analyses should be used to confirm and complement histological and immunohistochemical examinations. Further, the melanoma-specific genes, PRAME and SPP1, may be used to differentiate melanoma cells from benign nevus cells occasionally residing in lymph nodes.
  • Marbacher, Serge (Helsingin yliopisto, 2014)
    Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed. Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry. Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus. Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model.
  • Lilius, Tuomas (Helsingin yliopisto, 2014)
    Opioid analgesics are effective in relieving acute and chronic pain. However, adverse effects and the development of opioid dependence and tolerance may restrict the use of opioids and result in inadequate pain relief. The effects of four structurally and functionally different drugs already on the market, ibudilast, atipamezole, spironolactone, and ketamine, were studied in coadministration with morphine, the prototypical mu-opioid receptor agonist. Experiments were conducted using thermal and mechanical tests of nociception in male Sprague-Dawley rats. Morphine tolerance was produced during four days by subcutaneous or intrathecal delivery of morphine. Drug and metabolite concentrations were measured using high-pressure liquid chromatography-tandem mass spectrometry. The objective of the thesis study was to search for potential drugs to augment morphine antinociception and prevent opioid tolerance. Ibudilast, a phosphodiesterase and macrophage inhibitory factor inhibitor, had transient sedative effects, but it restored the antinociceptive effect of morphine in morphine-tolerant rats after single and repeated administration. It did not prevent the development of opioid tolerance. Atipamezole, an alpha-2-adrenoceptor antagonist used for the reversal of sedation in animals during anesthesia, was effective in augmenting intrathecal morphine antinociception in both opioid-naïve and opioid-tolerant animals. These effects were observed at doses lower than those required for the antagonism of alpha-2-adrenoceptors. In subcutaneous administration, low doses of atipamezole did not influence morphine antinociception. The mineralocorticoid receptor antagonist spironolactone dose-dependently enhanced morphine antinociception. This effect was mediated via the increased access of morphine to the central nervous system by the inhibition of the efflux protein P-glycoprotein. Spironolactone did not inhibit the metabolism of morphine to the pronociceptive metabolite morphine-3-glucuronide, and it did not prevent the development of opioid tolerance. The effects of ketamine in augmenting opioid analgesia in tolerance are thought to result from a beneficial pharmacodynamic interaction. When acute ketamine was administered to rats under chronic morphine treatment, the brain concentrations of morphine, ketamine and norketamine were increased compared with the situation where either morphine treatment or acute ketamine were administered alone. The results indicate a potentially beneficial pharmacokinetic interaction between the two drugs. The results of the thesis study demonstrate that ibudilast and atipamezole modulate nociception at systemic and spinal levels in preclinical models of pain, and they may prove advantageous as an adjuvant to opioid therapy. Spironolactone had a pharmacokinetic interaction with morphine, leading to increased morphine concentrations in the central nervous system. Ketamine, a drug used for the treatment of opioid tolerance in cancer patients, may undergo previously unrecognized beneficial pharmacokinetic interactions with morphine.
  • Kolehmainen, Pekka (Helsingin yliopisto, 2014)
    Human parechovirus (HPeV) and Ljungan virus (LV) are non-enveloped, single-stranded RNA viruses that form the genus Parechovirus in the family Picornaviridae. The interest in these viruses has notably increased over the past 15 years because of their strengthened associations to human and animal diseases. HPeV types 1 and 3 have been associated with more severe infections in young children, such as infections of the central nervous system (CNS) and sepsis-like disease. Rodent-infecting LV has been suggested to possess zoonotic potential and induce various human diseases. However, the proof for this remains lacking. This study aimed to describe the epidemiological features of HPeVs in Finland and in the Netherlands, to examine the connection between HPeV-induced infection and human diseases and to study the circulation of LV in Finland. The epidemiological analysis of stool samples, collected from 1996 to 2007, revealed that HPeVs are highly common in healthy Finnish children. HPeV was primarily detectable in children under 2 years of age. Altogether, 39% of the study participants tested positive for HPeV at least once during the study period. HPeVs circulated throughout the year, with a distinct seasonal peak in October-November. The results indicated that not only the previously described HPeV1 but also HPeV genotypes 3 and 6 circulate in Finland. Microneutralisation assays, which were set up to detect HPeV1 to 6, the most common genotypes in Europe, provided a deeper understanding of HPeV seroprevalence in the Finnish and Dutch populations. Seropositivity for HPeV1, 2 and HPeV4 to 6 was high and moderate in adults, in contrast to seropositivity for HPeV3, which was extremely low. The serological data demonstrate that HPeV types 1 to 6 might be even more prevalent than previously assumed. All six HPeV types circulate in Finland. In addition to HPeV detection in background populations, we presented the first cases of severe infection in neonates with HPeV4 and, subsequently, the first isolation of this genotype in Finland. Five hospitalised neonates with a sepsis-like disease in the fall of 2012 were positive for HPeV. Four of these children had HPeV4, indicating a potential small epidemic of this genotype, whereas one HPeV remained untyped. In addition, we detected HPeV3 in a neonate with suspected viral sepsis in October 2011 and another untyped HPeV in a child with symptoms corresponding to acute disseminated encephalomyelitis in May 2012. Following these findings, we promoted the addition of HPeV detection to routine diagnostics of young children. To extend the knowledge regarding other parechoviruses in Finland, we studied LV antibody prevalence in both humans and rodents. The seroprevalence detected for LV was 38% in humans and 18% in bank voles (Myodes glareolus). The observation of LV antibodies in humans is relatively high because LV has never been isolated from humans. These results suggest that an LV or LV-like virus, in addition to HPeVs, circulates frequently among human populations in Finland.
  • Ketola, Sirpa (Helsingin yliopisto, 2014)
    Vertigo and dizziness are among the most frequent complaints in primary care. The symptoms are usually self-limited, and the clinical course is benign, with full recovery. In many cases, however, vertigo and dizzy spells recur, leading to impairment and chronic outcome. A number of studies have documented a high prevalence of psychiatric comorbidity in vertiginous patients. Vertigo and dizzy symptoms themselves can provoke psychological distress, because recurrent unpredictable attacks can induce fear of losing control, concern of serious illness, and worry about severe attacks compromising one s ability to adapt. Recurrent spells can also provoke earlier mental problems. Yet the degree of subjective handicap and emotional distress has shown no close relationship to measures of vertigo symptom severity. Psychiatric disorders do not cause vertigo or dizziness, but can, together with vertigo and dizzy symptoms, lead to persistent complaints. Anxiety and depression are the most common disorders associated with vertigo and dizziness. Vertigo and dizziness in children is not rare. One population-based study found a prevalence of vertigo of 14% (Russell and Abu-Arafeh 1999). The etiology varies, but usually involves organic causes. Psychiatric etiology is investigated only after the exclusion of organic etiology. Psychosomatic symptoms are common in children and adolescents, often reflecting problems in psychosocial background. The first study aimed to evaluate the adapting ability of patients with Ménière s disease based on the sense of coherence scale. Data were collected with two different postal questionnaires involving 547 recipients (Study I). Studies II and III evaluated the prevalence of psychiatric symptoms in vertiginous patients. This study group comprised 100 vertiginous subjects from a randomly selected community sample participating in a vertigo prevalence study in the Helsinki University Hospital district. The investigative program entailed a neuro-otological examination and psychiatric evaluation in questionnaire form. Study IV assessed the prevalence of psychiatric disorders in a group of 119 children and adolescents between the ages of 7 months to 17 years who had visited the ear, nose and throat clinic with a primary complaint of vertigo. An otologist and a psychiatrist reviewed and evaluated each patient s detailed medical history. The results indicate a high sense of coherence (SOC) to represent deeper contentment in life and less psychological distress despite the chronic disease. Although SOC scores did not relate to the severity of illness, subjects with low SOC scores exhibited more symptoms of both vertigo and psychological distress (Study I) than did subjects with high SOC scores. In Studies II and III, the prevalence of depressiveness was 19%, and the prevalence of symptoms of anxiety, 12%. A total of 68% of subjects reported psychiatric symptoms, the most common of which was personality disorder. Comorbidity between depressive, anxiety and personality symptoms were ample and related significantly to reduced functional capacity. In Study IV, the prevalence of psychogenic vertigo was 8%. Major depression was the most common disorder, and 2.5% of patients suffered from somatization disorder. The psychiatric distress commonly reflected psychosocial problems and affected seriously on daily life functioning. In conclusion, this study found that psychiatric symptoms are common in vertiginous patients. Comorbidity may lead to a more debilitating course of vertigo independently of an organic cause or the severity of vertigo symptoms. Feelings of disability correlated with psychological distress. In children and adolescents, vertigo symptoms with compromised daily functioning, together with psychosocial stress factors, should invoke at least the possibility of psychiatric distress. Keywords: vertigo, depression, anxiety, personality disorder, comorbidity, disability, coping, chronic 
  • Kanerva, Noora (Juvenesprint, 2014)
    Obesity causes metabolic dysregulations that increase the risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). Diet is known to play a key role in preventing obesity. In epidemiological studies, because single food and nutrient studies focusing on obesity have produced generally inconsistent results, nutrition researchers have shifted to exploring the health related effects of the whole diet, measured with dietary scores. Recently, a diet constructed of healthy Nordic foods has been suggested as having obesity and metabolic health enhancing features. However, there is a lack of population-based studies on this topic. The aim of the research presented in this thesis was to develop a dietary score reflecting the healthy Nordic diet, and to assess its associations with obesity, metabolic risk factors (e.g., low-grade inflammation, lipid fractions) and T2D in an epidemiological setting. This study was based on data from three health surveys conducted between 2001-2007: the DILGOM study (n = 5024), the Health 2000 survey (n = 6772), and the Helsinki birth cohort study (HBCS) (n = 2003). In clinical examinations, the weight, height, waist circumference and blood pressure of participants were measured, and blood samples were drawn. Information on the past medical history was derived from nationwide health registers. Participants habitual diet was assessed with a validated food frequency questionnaire, which was used to derive the Baltic Sea Diet Score (BSDS) reflecting the healthy Nordic diet. The BSDS included nine components typical of the Nordic diet, which were scored according to the predictable health effect of each component, using sex- and population specific quartile cut-offs. The final summary score ranged between 0-25 points. Participants with high adherence to the healthy Nordic diet (BSDS ≥ 17) had significantly higher intake of carbohydrates, fibre, vitamins, minerals and sodium, and lower intake of saturated fat and alcohol compared to those who did not adhere to the diet (BSDS ≤ 9). Moreover, those who adhered to the diet were 35-52% less likely to be abdominally obese and 27-42% less likely to have elevated C-reactive protein (CRP) concentrations compared to the others. In contrast, women adhering to the healthy Nordic diet were 40% more likely to have a low concentration of high-density lipoprotein (HDL) cholesterol than the others. The BSDS did not associate with T2D incidence during 10 years of follow-up. In conclusion, the BSDS appears to be a valid tool for measuring adherence to a healthy diet. The findings related to abdominal obesity and low-grade inflammation, if proven causal, may lead to decrement in chronic disease risk, and therefore, be relevant from the public health perspective.