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Recent Submissions

  • Baryshnikov, Ilya (Helsingin yliopisto, 2017)
    Mood disorders and both Borderline (BPD) and Schizotypal (SPD) Personality Disorder often co-occur. BPD shares some similar symptoms with both bipolar disorder (BD) and SPD, resulting in difficulties in distinguishing them. The first aim of the study was to define similarities and differences in self-reported features of BD and BPD. The second aim was to determine the overlapping and non-overlapping clusters of self-reported symptoms of BPD and SPD in patients with mood disorders. Concurrent self-reported psychotic-like experiences (PEs) may also complicate the diagnosis of mood disorders; hence the third aim was to investigate the prevalence of self-reported PEs in patients with mood disorders and to examine the factors that predict them. Features of BPD are common in these patients and have a negative impact on the course of the disorders, hence it is important to focus on treatment. However, the relationships between self-reported features of BPD and neuroticism, attachment styles and traumatic experiences in childhood (TEs) are not fully understood. The fourth aim of the study, therefore, was to examine these relationships in patients with mood disorders. The Helsinki University Psychiatric Consortium (HUPC) Study surveyed 282 patients in psychiatric care on the grounds of ICD-10-DCR unipolar depression and BD. The patients were requested to rate themselves on scales for BPD (the McLean Screening Instrument (MSI)), hypomania or mania (the Mood disorder Questionnaire (MDQ)), SPD (the Schizotypal Personality disorder Questionnaire-Brief (SPQ-B)), PEs (the Community Assessment of Psychic Experiences (CAPE-42)), adulthood attachment style (Experiences in Close Relationships-Revised (ECR-R)), TEs (the Trauma and Distress Scale (TADS)) as well as depression (the Beck Depressive Inventory (BDI)), anxiety (the Overall Anxiety Severity and Impairment Scale (OASIS)) and neuroticism (Short 5 (S5)). The total scores of the MDQ and the MSI correlated moderately (r=0.431, P<0.001), and there were significant correlations between the MSI items "impulsivity" and "mood instability" and all the MDQ items (P<0.01). Moreover, the MSI items "impulsivity" and "mood instability" had significant cross-loadings (0.348 and 0.298, respectively) with the MDQ factor in the exploratory factor analysis. The MDQ items "irritability", "flight of thoughts" and "distractibility" (0.280, 0.210 and 0.386, respectively) cross-loaded on the MSI factor. There was a strong correlation between the MSI and the SPQ-B scores. MSI items reflecting disrupted relatedness and affective dysregulation correlated moderately (rφ varied between 0.2 and 0.4, P < 0.005) with the SPQ items. MSI items reflecting behavioural dysregulation correlated only weakly with the SPQ items. Depressive symptoms, gender and MSI were significant predictors of the SPQ-B score, whereas symptoms of anxiety, age and SPQ-B were significant predictors of the MSI score. The “frequency of positive symptoms” score of the CAPE-42 correlated strongly with the total score of the SPQ-B (rho=0.63; p<0.001), and moderately with the total scores of the BDI, the MDQ, OASIS and the MSI (rho varied from 0.37 to 0.56; p<0.001). Symptoms of anxiety, mania or hypomania, and BPD were significant predictors of the “frequency of positive symptoms” score of CAPE-42. A young age, S5 Neuroticism and TADS predicted the MSI scores (p<0.001). ECR-R Attachment Anxiety mediated 33 per cent (CI = 17-53%) of the relationships between TADS and MSI. Self-reported features of BPD and SPD are prevalent in patients with mood disorders. Self-reported features of BD and BPD such as “affective instability”, “impulsivity”, “irritability”, “flight of thoughts” and “distractibility” appear to overlap in terms of content whereas other features are more specific, which may make it easier to distinguish them. Items reflecting cognitive-perceptual distortions and affective symptoms in BPD overlap with disorganized and cognitive-perceptual symptoms of SPD. Symptoms of depression may aggravate self-reported features of SPD, and symptoms of anxiety features of BPD. BPD symptoms of behavioural dysregulation and the interpersonal deficits of SPD appear to be non-overlapping. Several state- and trait-related factors may underlie self-reported PEs among patients with mood disorders. These include cognitive-perceptual distortions in SPD; distrustfulness, identity disturbance, dissociative and affective symptoms of BPD; and cognitive bias related to depressive or manic symptoms. TEs as well as high neuroticism independently predict the features of BPD in patients with mood disorders, and insecure attachment may partially mediate the relationship between childhood TEs and BPD features.
  • Sokka, Laura (Helsingin yliopisto, 2017)
    Long-term exposure to a stressful working environment where demands of the job exceed the resources of the worker may develop into job burnout. It is a major concern in working life, and in Finland, approximately one fourth of working aged people experience symptoms of burnout. Burnout is a psychological syndrome typically characterized by exhaustion, cynicism, and reduced professional efficacy. Individuals who experience symptoms of burnout often report decreased sense of efficacy in performing their daily work, as well as difficulties in concentration and memory. To date, however, little is known about the relationship between burnout and cognitive processes in the brain. The present thesis explores how pre-attentive auditory processing, and attentional and cognitive control processes are associated with burnout. As a method, we used scalp recordings of event-related potentials (ERPs) extracted from continuous electroencephalogram (EEG). The participants were 41 volunteers reporting a wide range of burnout symptoms, and 26 control participants. The results showed that burnout is associated with alterations in ERP responses reflecting involuntary attention shift and voluntary task-related processes. More specifically, momentary involuntary capture of attention to emotionally valenced speech sounds is faster for negative, and slower for positive utterances in burnout than in the control group as reflected by divergent P3a latencies even when the burnout symptoms are relatively mild. Burnout is also associated with dysfunctions in cognitive control needed to monitor and update information in working-memory as reflected by a decrease in task-related P3b responses over posterior scalp and increase over frontal areas. Perhaps, in burnout, sustaining a similar performance level as that of the control group might require additional recruitment of anterior regions to compensate the decrement in posterior activity. In addition, orienting of attention towards potentially significant unexpected sounds is ineffective in burnout during working-memory processing as indicated by reduced P3a responses elicited by the distractor sounds. Finally, severe burnout is associated with less accurate performance and inadequate processing when rapid shifting of attention between tasks is required as reflected by smaller P3 responses compared to the mild burnout and control groups. The findings of the present thesis provide new information about dysfunctions in electrophysiological processes related to cognitive control in burnout.
  • Pakbaznejad Esmaeili, Elmira (Helsingin yliopisto, 2017)
    Orthodontic treatment is common especially among children and adolescents. A dental panoramic tomograph (DPT) and a lateral cephalometric radiograph (LCR) are the main radiographic tools for orthodontic treatment planning. Children own higher radiosensitivity than adults, because of their developmental and physiological status. Therefore, during dental extra-oral radiography of children, implementation of the two first principles of radiation protection, the principles of justification and optimization, should be highlighted. Notably, however, qualitative assessments of orthodontic radiography had not been published before the present study. The study subjects were a random sample of 7- to 12-year-olds of whom a DPT and/or an LCR had been taken in the Oral Healthcare Department of the City of Helsinki in 2010. For DPTs, the sampling was repeated in 2013-2014 after an intervention. Retrospective analysis of the sample from 2010 revealed that 1) the vast majority of DPTs and all LCRs were ordered for orthodontic diagnostics, 2) the referrals were inadequate for nearly one-third of the images, 3) an adult program was used for taking most of the DPTs, 4) segmented DPT was never used, 5) most of the DPTs and LCRs displayed too extended field-size, 6) the number of repeated radiographs was almost at the permitted level, 7) almost one-third of the images lacked radiographic interpretation and cephalometric analysis, and 8) general and developmental pathologic findings were observed in the area of the dentition only. These results gave reason for an educational intervention program that particularly aimed at more appropriate DPT program selection in children. Its power was analysed by prospective evaluation of DPTs in 2013-2014, and a notable increase became evident in application of both segmented and child panoramic programs. This work disclosed deficiencies throughout the process of dental extra-oral radiography of children. It emerged that further need for continuing education in radiation protection exists for the whole dental team, especially the orthodontists and practitioners involved in orthodontics. Education was proven to positively affect the optimization process. In addition, the results endorse development of DPT- and LCR-device towards enhanced field limitation options for patients of different age and size and indications for dental extra-oral radiography.
  • Yadav, Bhagwan (Helsingin yliopisto, 2017)
    Despite recent progress in the field of molecular medicine, the treatment and cure of complex diseases such as cancer remains a challenge. Development of resistance to first-line chemotherapy is a common cause of current anticancer treatment failure. To deal with this problem, the personalized medicine (PM) approach has been adapted toward more targeted cancer research and management. The PM approach is based on each patient s genetic, epigenetic and drug response profiling, which is used to design the best treatment option for the given patient. As the PM approach is increasingly being adopted in clinical practice, there is an urgent need for computational models and data mining methods that allow fast processing and analysis of the massive relevant profiling datasets. High-throughput drug screening enables systematic profiling of cellular responses to a wide collection of oncology compounds and their combinations, hence providing an unbiased strategy for personalized drug treatment selection. However, screening experiments with patient-derived cell samples often results in high-dimensional data matrices, with inherent sources of noise. This complicates many downstream analyses, such as the detection of differential drug activity or understanding the mechanisms behind drug sensitivity and resistance in a given patient. To meet these challenges, a computational pipeline for drug response profiling was developed in this thesis. The pipeline was based on a novel metric to quantify drug response, called the drug sensitivity score (DSS). Further, by combining the normalized drug response profile of each cancer sample with a global drug-target interaction network, a target addiction score (TAS) was developed to de-convolute the selective protein targets and obtain knowledge on their functional importance. Finally, delta scoring was developed to quantify drug combination effects and to address the problem of the clonal evolution of cancer, which often leads to resistance to mono therapies. This novel computational pipeline improves understanding of cancer development and translates compound activities into informed treatment choices for clinicians. As exemplified in two case studies of adult acute myeloid leukemia (AML) and adult granulosa cell tumor (AGCT), the models developed here have the potential to significantly contribute to the effective analysis of data from individual cancer patients and from pan-cancer cell line panels. Hence, these models will play a substantial role in future personalized cancer treatment strategies and the selection of effective treatment options for individual cancer patients.
  • Kruit, Heidi (Helsingin yliopisto, 2017)
    The rates of induction of labor (IOL) are rising worldwide; currently every fourth labor is induced. Prostaglandins and balloon catheters, including Foley catheter (FC), are available for IOL. The vaginal delivery rates are comparable, but FC is associated with lower risk of uterine hyperstimulation and adverse events. The mechanism of FC use consists of direct mechanical dilation of the cervix, and local secretion of endogenous prostaglandins. The aim of this study was to evaluate FC for labor induction in prolonged and post-term pregnancies, in women with premature rupture of membranes (PROM) at term, and in outpatient use. The secondary aim was to investigate cervical biomarkers insulin-like growth factor binding protein-1 (IGFBP-1), matrix metalloproteinases (MMP) -2, -8, and -9, and their tissue inhibitors (TIMP)-1 and -2 in IOL by FC. The study was conducted in the Department of Obstetrics and Gynecology of Helsinki University Hospital between 2011 and 2015. The main outcome measures were the rates of cesarean section (CS) and maternal and neonatal infections. The total study population consisted of 1693 women. The lowest rate of CS (24 %) occurred in women undergoing IOL after term PROM, and the highest rate (44 %) was observed in nulliparous post-term women. In post-term pregnancy, a sixfold risk (OR 6.2, 95 % CI 3.2−12.1) of CS occurred in nulliparous women undergoing IOL compared to spontaneous onset of labor. The CS rates were significantly different neither between FC and misoprostol groups (24% vs. 18 %; p=0.36), nor between outpatients and inpatients (32 % vs. 32 %; p=0.82).The median (range) rate of maternal intrapartum infections following IOL by FC was 5 (2−6) %, and the rate of postpartum infections was 3 (1−4) %. The rate of neonatal clinical sepsis following FC induction was 2 (1−3) %, and the rate of and suspected neonatal infections was 4 (1−5) %. The maternal and neonatal infection rates were similar between the use of FC and misoprostol, and between outpatients and inpatients. There were no significant differences in the concentrations of cervical IGFBP-1 or MMPs -2,-8,or -9 in successful and failed IOL. In conclusion, FC appears safe and feasible for IOL in prolonged and post-term pregnancies, in women with PROM, and in outpatient use. The cervical biomarkers IGFBP-1 and MMPs appear unsuitable for predicting the success of IOL.
  • Heikkinen, Sanna (Helsingin yliopisto, 2017)
    Breast cancer is the most common cancer in women in Finland. It is often considered as a disease of affluent, Western societies with many known risk factors such as late age at first birth, small number of children, and sedentary lifestyle, among others. In addition, there are more novel exposures that are popular in modern Western societies and carry suspected carcinogenic potential, including use of hormonal contraceptives and use of cosmetics, such as hair dyes. The aim of the thesis was to evaluate the roles of such lifestyle factors and to assess how they contribute to the spectrum of breast cancer risk factors. The thesis is composed of four sub studies; Study I estimating the association between use of hormonal contraceptives and breast cancer risk and Study II aiming at determining whether use of hair dyes independently increases risk of breast cancer. Study III estimated the proportion of women who had an opportunistic mammography before the age 50 years and assessed the roles of breast cancer family history and educational level in it. Study IV investigated the impact of major life events in breast cancer-specific mortality. Self-reported survey data was used as source of exposure information in all sub studies. Information on the outcomes of interest, namely breast cancer diagnosis and breast cancer-specific deaths were retrieved from the Finnish Cancer Registry. In Studies I and II, analyses by conditional logistic regression were conducted to estimate odds ratios (OR) and 95% confidence intervals (CI). In Study III, percentages of women reporting opportunistic mammography were calculated either directly of by Kaplan-Meier method. In Study IV, different Cox models were used to estimate breast cancer-specific mortality hazard ratios and 95 % CIs. Use of hormonal intrauterine device (HR IUD) increased the risk of breast cancer in post-menopausal women by 52% (OR 1.52, 95% CI: 1.14-2.02). Use of other hormonal contraception was by contrast associated with risk of breast cancer in younger women (OR 1.32, 95% CI: 1.08-1.61). An OR of 1.23 (95% CI: 1.11-1.36) was observed for women using hair dyes, relative to those who had never dyed their hair. Opportunistic mammography was also found to be very common, with more than 60% of responders reporting having had a mammography before screening age. Mammographies were also more common in women who had breast cancer family history and/or higher education. A large number of experienced negative life events was associated with 4% higher risk of breast cancer-specific mortality, some positive events accordingly lowering it. The prevalence of classical breast cancer risk factors, such as obesity and alcohol use have increased markedly over the past decades in Finland. Parity and total fertility are continuing to decline. These factors are more and more commonly complemented by risk effects produced by use of exogenous hormones and cosmetics such as hair dye. Considering increasing usage, further research on the effects of HR IUD use is needed with other populations and a prospective study design. More research is also needed on the long-term effects of hair dye use. With respect to opportunistic mammography, it would be important to start registering the examinations to be able to take them into account in evaluation of the practices and effectiveness of organized screening. Women should also be more extensively informed of the harms of opportunistic mammography, such as accumulating radiation burden and the potential consequences of false positive or negative findings. The observed negative effects of negative life events and positive effects of some positive life events in breast cancer mortality gives grounds for more holistic planning of treatment and patient follow-up.
  • Teirilä, Laura (Helsingin yliopisto, 2017)
    Fungi are associated with a wide range of diseases from superficial skin syndromes to invasive life-threating conditions. Furthermore, exposure to non-infectious fungal components in the context of agricultural work or in water-damaged houses has been associated to illnesses in the respiratory tract. The inadequate knowledge of the immune mechanisms behind these illnesses has triggered an intense research effort attempting to understand how fungi can activate the defense mechanisms of immune system. This thesis focused on the inflammation triggered by the fungal components. The inflammatory response and related mechanisms were studied in vitro in the key defense cell of innate immunity, the macrophage, which were treated with a central cell wall component of fungi, (1,3)- β-glucan. One major outcome of this thesis was the finding that β-glucan evokes a strong pro-inflammatory response via the IL-1 family cytokines in human macrophages. These cytokines are crucial mediators of inflammation, thus their secretion is highly regulated. Our study showed that β-glucan, on its own, could cause the efficient secretion of functional IL-1β and other mediators of inflammation via unconventional secretion pathways by activating both dectin-1 signaling pathway and NLRP3 inflammasome. This β-glucan-induced protein secretion via unconventional pathways was suppressed by inhibition of inflammasome activity or by preventing the process of autophagy. Furthermore, the well-known myeloid cell growth factor, granulocyte-macrophage colony-stimulating factor seems to be one of the factors boosting the β-glucan-triggered inflammatory response of macrophages. In an attempt to obtain direct information about conditions caused by the exposure to fungal and other microbial particles, we characterized the proteomic changes present in the bronchoalveolar lavage obtained from patients suffering illnesses associated with exposure to inhaled microbial particles. The proteomic profiles of hypersensitivity pneumonitis (HP) were different from the profile of damp building-related illness (DBRI), indicating that these conditions are not closely associated. However, the increase in the levels of two well-known markers of inflammation was observed in both HP and DBRI, evidence for the activation of inflammatory mechanisms in both of these conditions. This thesis provides novel knowledge concerning the inflammatory response and related mechanisms triggered by fungal components. These results may help to clarify the mechanisms behind the inflammatory symptoms experienced by individuals with fungal infections or exposure to fungal particles and will provide future tools for the treatment of fungal-related disorders.
  • Tuulasvaara, Anni (Helsingin yliopisto, 2017)
    The immune system should react effectively towards harmful pathogens but tolerate own tissues. The tolerance comprises central and peripheral tolerance. Negative selection, where cells reacting harmfully towards own tissues are eliminated, is part of central tolerance. One part of peripheral tolerance is the regulatory T cell population. Errors in tolerance cause autoimmune diseases, an example of which is APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. The basis of tolerance is the development of T lymphocytes in the thymus. During this process most of the developing thymocytes die. To survive, thymocytes have to recognize peptides presented in the major histocompatibility complex (MHC) with proper affinity with their αβ T cell receptor (TCR). TCRs have a huge variation in sequence in their complementarity determining region 3 (CDR3), due to somatic recombination and additional editing. In this thesis I have studied this development of T cells in the human thymus, and then more specifically the regulatory CD4+ FOXP3+ T cell population. The effect of positive and negative selection on the TCR repertoire of developing thymocytes was analyzed. Very few shared sequences were found between different populations, showing the huge diversity of the TCR repertoire. In physicochemical analysis the basic TCR structure remained the same from already the most immature population before selections. A reduction in the average CDR3 length was seen between the CD4+CD8+ double-positive (DP) and CD4+ populations, probably reflecting the effect of thymic selections. To study thymic selection in APECED patients, the observed reduction in the length of CDR3 was used as an indicator of selection. The average CDR3 length of the peripheral CD4+ and CD8+ T cell populations of APECED patients was compared with healthy controls. No significant differences in CDR3 lengths between the patients and healthy controls were found, not even in the CD8+RA+ population that is abnormal in APECED patients. As most studies have been done in mouse models, the precise steps of regulatory T cell development are poorly known in human. DP thymocytes are thought to be the precursors of CD4 FOXP3+ regulatory T cells. After an overnight culture and flow cytometry analysis more apoptotic DP thymocytes than CD4+ thymocyte were found, showing their precursor cell characteristics. Furthermore, the effect of interleukin 7 (IL-7) on developing thymocytes was studied. Mature regulatory T cells express the IL-7 receptor α chain CD127 at low levels. However, stimulation with IL-7 in culture increased the percentage of FOXP3+ DP and CD4 single-positive thymocytes. The mechanism behind this seemed to be an inhibition of apoptosis and possibly also increased FOXP3 expression. These results increase the knowledge on T cell development in human but many details are yet to be revealed.
  • Salo, Heini (Helsingin yliopisto, 2017)
    This study presents the materials, methods, and results of the economic evaluations of 7-valent pneumococcal conjugate vaccination (PCV7) programme, influenza vaccination programme and human papillomavirus (HPV)-associated cost of illness study, all of which were used in the vaccine adoption decision-making process in Finland in 2001 2011. Vaccinations of all children aged 6 36 months with influenza vaccine were accepted into the NVP in 2007, infant pneumococcal vaccinations in 2010 and HPV vaccinations of all girls in 2013. When a new vaccine is considered for inclusion into the NVP in Finland the expected public health benefit, the safety of the vaccine for an individual, the safety of the vaccination programme at the population level, and the cost-effectiveness of the vaccination programme are evaluated. An economic evaluation is needed to support the decision-making process. The decision-makers have not specified an explicit range of cost-effectiveness threshold values below which an intervention would automatically be accepted and lead to funding. In the first economic evaluation of the infant PCV7 vaccination programme (excluding indirect herd effects) the cost per QALY gained was EUR 54 600. In the economic re-evaluation, including the indirect herd effects of the vaccination programme in older age groups reduced the cost per QALY gained to EUR 20 600. The influenza vaccination programme of healthy children was found to yield cost savings from the health care provider perspective even though the indirect herd effects and influenza-associated deaths were excluded. The vaccination programme was estimated to save annually EUR 7.6 per vaccinated child aged 0.5 4 years when the assumed vaccine efficacy was 60%. In Finland, there is a considerable annual disease burden of HPV-related genital disease in the female population. Most of it is detected by the 446 000 annual screening tests, 55% of which are carried out as opportunistic tests. The opportunistic tests account for 71% of the total of EUR 22.4 million screening costs. Further diagnostics, management and treatment of HPV-related genital disease resulted in an additional cost of EUR 22.3 million, of which the costs of less severe HPV-related disease manifestations were EUR 15.5 million. Considering all tests taken both within and outside the organised programme, the 5-year coverage of Pap testing in Finland was 87% among women aged 25 69 years. At present, the successful reduction in the cervical cancer incidence and mortality is due to tests taken both within and outside organised screening. Opportunistic Pap testing both substitutes and overlaps with the tests taken within the organised programme. Overlapping tests stem from the lack of coordination and result in over-management of reversible lesions. In order to be able to coordinate organised and opportunistic Pap testing without losing the high coverage, it is essential to establish a nationwide Pap test register. Furthermore, such a register is necessary for the effective and cost-effective secondary prevention of cervical cancer, which will be needed in both unvaccinated and vaccinated populations.
  • Kaskinen, Anu (Helsingin yliopisto, 2017)
    Congenital heart defects (CHD) are classified as acyanotic and cyanotic. In cyanotic CHD, a mixing of deoxygenated in oxygenated blood reduces arterial oxygenation and the child may be cyanotic, i.e., bluish. Many children with CHD need cardiac surgery. Congenital cardiac surgery often aims to restore normal circulation and correct the defect as seen in vast majority of pulmonary atresia with ventricular septal defect (PA+VSD), but palliative surgery may also be needed or may be the only possible treatment strategy. After congenital cardiac surgery excessive extravascular lung water (EVLW) may appear and impair optimal gas exchange. Effective clearance of EVLW and lung edema rests on active airway epithelial Na+ transport. Postoperative lung edema after congenital cardiac surgery has principally been assessed by chest radiography (CXR), which may be inaccurate and causes irradiation. Excessive EVLW promotes appearance of artifacts called B-lines in lung ultrasound (US), whereas lung compliance associates negatively with increased EVLW. In this thesis the effect of chronic hypoxemia on lung liquid transport was studied in children with CHD. Second, feasibility of lung US and lung compliance in assessment of EVLW and in predicting short-term clinical outcome was tested after congenital cardiac surgery. Third, the long-term survival of a cyanotic CHD was retrospectively evaluated in patients with PA+VSD. According to our findings, the airway epithelial Na+ transport was impaired in profoundly hypoxemic children with cyanotic CHD. After congenital cardiac surgery, lung US B-line score and static lung compliance correlated with CXR lung edema assessment. However, ventilator-derived dynamic lung compliance may not reflect the state of lung parenchyma similar to static compliance. Furthermore, both early postoperative lung US B-line and CXR lung edema scorings predicted short-term outcome interpreted as length of postoperative mechanical ventilation and intensive care. Among factors affecting the long-term survival of PA+VSD the primary anatomy of pulmonary circulation and achievement of repair were most important. In summary, our results emphasize the effect of postoperative pulmonary complications on short-term outcome after congenital cardiac surgery. Our data suggests that hypoxemia may attenuate the constitutional mechanism of the lung to prevent excessive lung liquid accumulation. To detect this, lung US can be used to complement CXR when assessing EVLW in children undergoing cardiac surgery. This may be particularly useful in profoundly hypoxemic children with cyanotic CHD and may promote early recognition of postoperative pulmonary complications. Although primary anatomical factors affect long-term outcome of PA+VSD, an important form of cyanotic heart disease, the treatment should aim for corrective surgery in all PA+VSD patients.
  • Smeds, Eero (Helsingin yliopisto, 2017)
    Accurate control of motor performance requires close co-operation between the motor and sensory functions of the human nervous system. Proprioceptive information about the positions and movements of one s own body parts needs to be carefully monitored to allow fine-tuning of motor output. At the same time, the brain needs to block the influence of distracting external stimuli, such as movements of other persons and various sounds, on the ongoing movements. My thesis focuses on the cortical processes related to these phenomena. In the first studies of this thesis, we explored motor stability by recording brain and muscle activity with magnetoencephalography (MEG) and electromyography, respectively, from healthy adults who were maintaining a steady finger pinch. We analyzed the effects of simple auditory and visual distractors as well as observed movements of another person on the functional state of the primary motor (MI) cortex. All studied stimuli caused transient enhancement of the coupling between cortical and muscular activity at ~20 Hz, reflecting the maintenance of stable motor output. As expected based on earlier studies, movement observation also caused mirror activation in the MI cortex of the viewer, demonstrated by MEG-power suppression at ~7 and ~15 Hz. Importantly, these two simultaneous but opposite processes occurred at distinct frequency bands, suggesting that they were mediated by different populations of MI neurons. The results might explain how the human brain blocks the effects of external distractors on motor behavior and prevents unintentional imitation of observed movements. The latter part of my thesis focuses on cortical activity evoked by proprioceptive afference in adults and newborns. In adults, we recorded MEG responses to proprioceptive input elicited by passive finger extensions and flexions. The amplitudes of the ~70-ms (extension) and ~90-ms (flexion) responses in the primary somatosensory cortex increased by a factor of ~3 and ~6, respectively, when the interstimulus interval was prolonged from 0.5 to 8 s. These findings suggest an optimum interstimulus interval of 1.5 3.0 s for future applications in research and in the clinic. Finally, we showed using electroencephalography that proprioceptive stimulation with continuous passive hand movements elicits a prominent cortical response already at the neonatal phase. Such a passive-movement-based stimulation method could help assess the integrity of somatosensory pathways in neurologically impaired newborns. This thesis improves understanding of the cortical mechanisms essential for proper motor control. The gained knowledge can ultimately benefit diagnostics, treatment, and follow-up of motor-system impairments ranging from movement disorders to neonatal cerebrovascular problems.
  • Myntti, Tarja (Helsingin yliopisto, 2017)
    Chorioamnionitis, the main single cause of preterm delivery, can be subdivided into clinical and subclinical forms. The latter is more common and includes intra-amniotic infection (IAI), inflammation, and histologic chorioamnionitis (HCA). Amniotic fluid (AF) biomarkers can help in diagnosing subclinical chorioamnionitis, which is necessary for optimal timing of delivery. The aim of the study was to evaluate AF biomarkers in the diagnosis of intra-amniotic infection. The study population comprised 155 cases with a suspicion of IAI or preterm prelabor rupture of the membranes (PPROM) and 46 controls. Amniocentesis was performed in 105 cases between 22+0 and 36+5 weeks of gestation and in 46 controls. AF was obtained vaginally from 53 cases. In such AF samples, AF-lactate dehydrogenase (AF-LD) and AF-Glucose concentrations were determined. Determination in amniocentesis samples was of AF-LD, AF-Glucose, AF-matrix metalloproteinase (MMP)-8, AF-cathelicidin, AF-MMP-9, AF-myeloperoxidase, AF-interleukin-6, AF-neutrophil elastase (HNE), AF-elafin, AF-MMP-2, AF- tissue inhibitor of matrix metalloproteinases -1 (TIMP-1), AF-MMP-8/TIMP-1 molar ratio, and AF-C-reactive protein (CRP) levels. AF-MMP-8 measurement was by an immunoenzymometric assay, AF-LD and AF-Glucose by immunochemiluminometric assays, and others by commercial ELISA. Microbiological analyses were based on molecular microbiology and culture techniques. Placental histopathologic examination was performed. The most optimal cut-off value based on the ROC-curve for AF-LD in vaginally obtained AF against HCA was 1029 IU/L with a sensitivity of 65% and specificity of 69%. In such samples, glucose concentrations did not differ between women with or without HCA. In amniocentesis samples, AF-LD and AF-Glucose correlated with HCA and MIAC, and the most optimal cut-off values for both end-points were a respective 429 IU/L and 0.7 mmol/L. When AF-LD and AF-Gluc concentrations were adjusted by gestational age at amniocentesis, the association disappeared. AF-MMP-8, AF-cathelicidin, AF-MMP-9, AF-MPO, AF-IL-6, AF-Elafin, AF-HNE, and AF-TIMP-1 were associated with MIAC, but AF-MMP-2 and AF-CRP were not. The results were similar also when adjusted by gestational age at amniocentesis. Neutrophil-produced biomarkers were associated with IAI. In conclusion, the accuracies of AF-LD and AF-Glucose were quite poor, and better biomarkers for IAI diagnostics are essential. None of the other biomarkers studied out-performed others. IAI seemed, however, to be associated with neutrophil activation. The usefulness of each biomarker for clinical purposes depends more on local circumstances and laboratory method availability than on exact differences in accuracy.
  • Moisala, Mona (Helsingin yliopisto, 2017)
    Executive functions are pivotal in our everyday lives, as they form the basis for complex and goal-directed behavior. For example, the ability to maintain information in memory while making a decision requires executive processes. Whether or not executive functions can exhibit experience-dependent changes is still a topic of debate, but generally accepted principles of brain plasticity suggest that environmental factors can have an impact on cognitive processes and the activity and structure of their respective brain networks. One such environmental factor is the increasingly ubiquitous daily interaction with technology, which has been suggested to affect mental faculties such as the ability to maintain focus on a single task or to actively maintain information in short-term memory. The aim of the present thesis was to study activity in cortical networks of attention and working memory. In addition, we investigated whether any associations could be found between the recruitment of these networks or performance speed and accuracy in working memory and attention tasks, and the extent of daily technology-mediated activities reported by adolescent and young adult participants. In all studies, functional magnetic resonance imaging (fMRI) was used to record brain activity during task performance. By using novel experimental paradigms, the present results shed more light on the specific cortical networks recruited by different executive functions by showing that both common and specific brain regions are recruited by auditory and visual selective attention, divided attention and working memory processes. Furthermore, they demonstrate that during division of attention between two concurrent tasks (listening to speech and reading text), competition for neural resources in regions shared by the component tasks is a major contributor to performance limitations observed during multitasking. Importantly, the results of the present thesis also demonstrate that detectable associations exist between different types of daily technology use and cognitive functioning already in adolescence. More specifically, the results demonstrate that a tendency to use several media simultaneously (i.e., media multitasking) is related to increased distractibility. The extent of computer gaming in daily life, in turn, is associated with enhanced working memory functioning. These findings are of great importance, since it is vital to understand how the increasing amount of on-screen time might affect or interact with the cognitive and brain functioning of the current youth.
  • Salmiheimo, Aino (Helsingin yliopisto, 2017)
    Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Options for treatment are limited, and the only possibility of cure is radical surgery combined with chemotherapy. Inflammation and tumor stroma are important mediators in PDAC progression. Tumor-associated macrophages (TAMs), among other cells, create an immunosuppressive microenvironment and enhance tumor progression. Because they pivotally participate in tumorigenesis, TAMs are a potential target for therapeutic intervention. The aim of these studies was to explore inflammation and TAMs in PDAC. Three of the studies were conducted in cell cultures, and one was a retrospective clinical study. We polarized macrophages in cell cultures towards inflammatory M1 and anti-inflammatory M2 phenotypes and assessed the changes in the signaling pathways and the effect they had on pancreatic cancer cell migration. We studied the association of preoperative systemic inflammatory response (SIR), based on laboratory data, with the outcome of 265 patients with resectable PDAC. Tumor-associated anti-inflammatory M2 macrophages promoted pancreatic cancer cell migration in co-cultures by activating their MMP9 and ADAM8 expression. Support of the pro-inflammatory M1 phenotype causes these macrophages to inhibit cancer cell migration. Several intracellular STAT pathways and the NFkB pathway were activated by the interactions of cancer cells and macrophages. In preoperative laboratory data, patients elevated C-reactive protein (CRP), an indicator of SIR, predicted worse postoperative survival. Moreover, low levels of albumin, the most abundant protein in human blood circulation, as well as elevated tumor markers CA19-9 and CEA, were associated with worse survival. These studies provide novel insight into the interaction of TAMs and PDAC. The results encourage further research into TAMs and exploration of the possibilities of skewing macrophage polarization toward the inflammatory M1 phenotype. Development of SIR seems detrimental for patients with PDAC and predicts worse outcome. Preoperative CRP, in combination with albumin and tumor markers and clinical data, could prove useful when evaluating patients prognosis.
  • Nyberg, Solja (Helsingin yliopisto, 2017)
    Work is a common source of stress in modern societies. Job strain is the most widely used definition of work stress referring to a condition in which an employee has simultaneously high psychological job demands and a low level of work control. The aim of this study was to examine the extent to which job strain might increase the risk of incident type 2 diabetes and is associated with diabetes risk factors, such as obesity and physical inactivity. Data were obtained from the cohort studies participating in the European IPD Work Consortium. The analyses were based on individual-level data from 19 studies and up to 170 000 participants. Job strain and lifestyle factors were assessed by questionnaires and biological risk factors were measured in a biomedical examination in eight studies. Incident type 2 diabetes was ascertained from electronic health and mortality registers, repeated glucose-tolerance tests during the follow-up, or annual questionnaires. Operationalized definitions of job strain, lifestyle and covariate variables were harmonised before any analysis of the associations or linkage to outcome data. In harmonisation analyses, abbreviated scales, that were comparable to the complete scales, were developed. Job strain was associated with diabetes and its risk factors. After adjustment for age and sex, the odds ratio of having job strain was 1.19 (95% CI 1.13-1.25) times higher for class-I obese participants (BMI 30 to less than 35km/m2), and 1.30 (95% CI 1.16-1.46) times higher for the combined class II and III obesity groups (BMI at least 35 kg/m2), compared to normal-weight participants (BMI 18.5 to less than 25 kg/m2). Job strain was also associated with physical inactivity (odds ratio 1.36, 95% CI 1.25-1.48). The risk of incident diabetes was 1.15 (95% CI 1.06-1.25) times higher among the participants who reported job strain than among those who did not. This association was also observed in the subgroups, including those with and without lifestyle risk factors, and before and after adjustment for lifestyle factors including obesity and physical inactivity. According to cross-sectional analysis adjusted for age, sex and socioeconomic position, the odds for diabetes were 1.33 (95% CI 1.13-1.56) higher among participants with job strain as opposed to those without. In conclusion, these findings show a robust association between job strain, diabetes and its key risk factors. Nonetheless, the effect size was modest, suggesting that interventions to reduce job strain would not be very effective in combating diabetes on the population level.