Lääketieteellinen tiedekunta


Recent Submissions

  • Parkkinen, Markus (Helsingin yliopisto, 2018)
    Tibia plateau fractures are relatively uncommon, but they are among the most challenging intra-articular fractures to treat. These fractures can lead to early posttraumatic osteoarthritis (OA) and cause disability and constant pain. Currently, the most common treatment is open reduction and stable internal fixation (ORIF), allowing early mobilization of the knee. Tibial plateau fractures can be associated with several concomitant soft tissue injuries of the knee. Historically, the operativetreatment with internal fixation has also been related to an increased risk for serious wound complications. The purpose of this study was to investigate the current management and outcome of proximal tibia fractures. The study population consisted of various groups of patients with proximal tibia fractures treated between 2002 and 2013 at our level I trauma center. The study aimed to determine factors predicting the development of posttraumatic OA following tibial lateral or medial plateau fractures. Another focus was on the incidence of concomitant injuries after the most common lateral plateau fracture type and the need for MRI as a diagnostic tool when treating these fractures. Finally, the predictors for deep surgical site infection after plate fixation of proximal tibia fracture were examined. The results showed that relatively good functional outcome can be predicted after internal fixation of lateral and medial tibial plateau fractures. However, patients with lateral plateau fractures with residual depression of the articular surface >2 mm or valgus deformity >5° had significantly more severe (Kellgren-Lawrence grade 3–4) posttraumatic OA. The most significant predictor of posttraumatic OA after medial plateau fracture was the amount of initial depression of the articular surface measured from the preoperative computer tomography, while the quality of reduction was not found to predict OA. MRI had low sensitivity and specificity in the diagnosis of concomitant injuries in the lateral tibial plateau fracture setting. Also nearly all of the clinically relevant concomitant injuries could be treated through the same lateral arthrotomy at the time of ORIF without the need for additional arthroscopy. There is high morbidity associated with deep SSI in plated proximal tibial fractures. Patient’s age ≥50 years, obesity, history of alcohol abuse, and AO type C fracture are independent risk factors for infection. Performing a fasciotomy also increases the risk of deep infection and should be done with meticulous technique only when deemed necessary.
  • Sipilä, Reetta (Helsingin yliopisto, 2018)
    Breast cancer is the most common cancer among women in the Western world. In Finland, approximately 5000 women are diagnosed with breast cancer each year. Due to advances in treatments, disease prognosis has improved markedly. Pain after breast cancer treatments is a common adverse symptom. The purpose of this prospective study was to identify factors associated with the pain experience in women treated for breast cancer, and to uncover clinically feasible factors associated with acute and persistent pain to develop an easy-to-use screening tool to identify women at the highest risk for persistent pain. The whole cohort included 1000 patients (18-75 years) recruited at the Helsinki University Hospital. Preoperatively, they filled in questionnaires about medical history, overall health, and pain symptoms, depressive symptoms, anxiety, and anger regulation. Experimental pain tests (cold 4°C and heat 48°C) were performed preoperatively. Anesthesia protocol and perioperative pain treatment were recorded. Patients documented pain on the first postoperative week (days 1-7) three times daily in the area of surgery. In the follow-ups (1 month, 6 months, 1, 2, and 3 years) patients completed again the same questionnaires about pain, depressive symptoms, and anxiety. The range of pain sensitivity between women treated for breast cancer was high. Of the women treated for breast cancer 13.5% had developed clinically significant persistent pain at the one-year follow-up. The best predictors of pain of any kind; experimental, acute clinical, or persistent pain, were found to be quite similar. Pain (other chronic pain condition, pain in the area of surgery, or intensity of acute pain), more invasive surgery (axillary clearance), and psychological distress (mainly anxiety) were found to be consistent predictors of heightened pain experience. In addition to these, pain expectation and higher need for oxycodone to achieve satisfactory pain relief after surgery were associated with higher pain intensity during the first postoperative week. Obesity was associated with persistent pain at six months and one year after surgery. The adjuvant treatments added to the risk for persistent pain at one year. Screening tools for preoperative and acute phase use to identify women at risk for persistent pain at six months and at one year after surgery were developed. The one-year prediction tool was validated in two other prospective patient cohorts. The average levels of psychological burden were quite low. However, there was a group of women whose distress remained quite stable during the first year. Anger regulation had only a modest association with pain, and was influenced by age and mood. However, anger inhibition was associated with higher depressive symptoms throughout the three-year follow-up. COMT rs4680 was associated with anger-out.
  • Korhonen, Essi (Helsingin yliopisto, 2017)
    Dengue virus (DENV) serotypes 1-4 are mosquito-borne flaviviruses that are increasingly being diagnosed from travellers returning from subtropical and tropical regions. At present, 50-100 cases of dengue are diagnosed annually in Finland. A mosquito-borne flavivirus, Zika virus (ZIKV), was considered to be a relatively harmless virus found in Africa and Asia with low case numbers and mild disease associations. Since 2013, however, ZIKV has emerged and swept across Polynesia, the Americas and the Caribbean, causing massive outbreaks with new severe complications becoming apparent. Amongst these new complications, neurological symptoms have been observed in adults and, alarmingly, congenital infections resulting in severe developmental disorders, including microcephaly. Due to environmental changes and globalisation, the distribution areas of vectors of DENV and ZIKV have spread towards north, which emphasises the risk of introduction of new MBVs to new areas. This thesis aimed to explore the best possible practices in dengue and Zika diagnostics by studying the available methods of choice, their combinations and different sample materials collected from Finnish traveller patients at different phases of the illness. Additionally, this thesis includes studies exploring the molecular epidemiology of DENV and ZIKV and detailed characterization of a congenital ZIKV infection patient case. The detection kinetics of DENV NS1 antigen and RNA was explored from serum, urine and saliva samples. It was observed that NS1 antigen was detectable from the sera of travellers for notably longer periods than reported for populations living in endemic areas. Urine and saliva were demonstrated to be potential sample materials for DENV diagnostics. Urine, in particular, provides new opportunities for molecular diagnostics of DENV as the time window for detection of viral RNA is notably later during the infection when compared to serum samples. It was observed that also ZIKV RNA detection was successful from urine whereas the serum sample taken at the same time point remained negative. Nowadays, urine is considered to be a suitable sample material in diagnostics. By studying traveller patients, the DENV strain responsible for the Madeiran outbreak in 2012 was identified as DENV-1, most likely of South American origin. The characterization of a virus from a Finnish traveller revealed the circulation of ZIKV in the Maldives for the first time. This case was followed by a few additional traveller cases identified elsewhere. Subsequently, the local authorities conducted surveillance studies and confirmed local transmission of ZIKV by detecting the virus from local mosquitoes. Study in this thesis was among the first reports to provide concrete evidence for the causality between ZIKV infection in a pregnant woman and malformations of central nervous system in the foetus. In this study the virus was isolated from the brain tissue of the foetus. The mother’s viremia was noticed to be prolonged, an observation that later studies have confirmed to be a common phenomenon. Mother’s viremia was detectable weeks before the abnormalities in brain development were visible. The evidence provided by the studies herein, along with other recently published data, have shown that there is a need to update the diagnostic guidelines.
  • Gautam, Prson (Helsingin yliopisto, 2017)
    Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer that accounts for 15-20% of breast cancer cases. Targeted therapy remains to be established for TNBC that lacks estrogen receptors, progesterone receptors and human epidermal growth factor receptor HER2. This limits the therapy to traditional chemotherapy, radiation and surgery, which is only beneficial to a fraction of TNBC patients. Transcriptomics-based subtyping of TNBC into six classes, but it is unclear how the transcriptomics-based subtypes link to effective therapeutic strategies, resulting in a poor clinical prognosis in comparison to other breast cancer subtypes. Hence, there is an imminent need for identifying molecular markers and druggable targets against TNBC. This study is focused on the establishment of functional profiling of TNBC cell lines based on their drug vulnerabilities, and to identify novel druggable signaling nodes. We studied a panel of 16 TNBC cell lines using a functional profiling approach in which we measured the responses of TNBC cells to 304 oncology compounds and 355 GSK published kinase inhibitors. The clustering analysis based on overall drug-responses did not match the transcriptomics-based subtypes, suggesting the presence of extensive heterogeneity in TNBC and that the genomic or transcriptomic profiles do not always reflect the functional behavior of these cells. First, to go beyond standard anti-proliferative drug effects, we established a multiplexed readout for both cell viability and cytotoxicity. We identified many drug classes (such as anti-mitotics, anti-metabolites), which generally are assumed to have cytotoxic effects, mostly exhibited strong effects on cell viability but failed to kill the cells. However, in a subset of the cell lines, they induced a selective cell death. In those cases, we identified differential levels of protein markers linked to the cytotoxic responses (e.g. high level PAI-1 linked to anti-mitotics), suggesting their potential use in clinics for therapeutic decision. These results highlighted that simple multiplexed cell viability and cytotoxicity measurements provide more insight in cellular responses towards the treatment and thereby may help in providing better translationally predictive readouts. Second, we devised a novel drug response metric, called normalized drug response (NDR), which accounts for many kinds of screening artifacts such as signal growth rate differences in positive and negative control, as well as in drug-treated conditions. We found that the NDR metric is a time-independent method and it significantly improved the drug response curve fitting. Our NDR will be of great value in cell-based high throughput drug screening approaches as it cuts down the cost and time for the replicate experiments and further validation with cytotoxicity assay. Lastly, we used computational approach to decipher the kinase signal addiction of breast cancer cell lines by integrating vulnerabilities to kinase inhibitors and their polypharmacology data. We developed the kinase inhibition sensitivity score (KISS) to predict single and combinatorial signal addictions. For this study, we used 40 kinase inhibitors with well-defined target selectivities. With this approach, we predicted and validated novel synergistic inhibitor combinations against TNBC cells, such as dasatinib with axitinib, bosutinib with foretinib combinations for HCC1937 cells. This study suggests that drug sensitivity profiling is a powerful strategy for de-convolving cancer cell specific target addictions.
  • Tikka, Anna (Helsingin yliopisto, 2018)
    Johdanto: Väitöstyön tarkoituksena oli tutkia ANGPTL3 puutoksen aiheuttamia muutoksia ihmisessä rasva-aineenvaihdunnan osalta kliinisesti, populaatiotasolla sekä solutasolla. ANGPTL3 proteiinin on osoitettu säätelevän lipoproteiinilipaasin (LPL) toimintaa ja siten osallistuvan maksasta sekä ohutsuolesta syntetisoitujen kolmiarvoisten (triglyseridi, TG) rasvojen poistoon verenkierrosta. ANGPTL3 toiminnan estymiseen vaikuttavat mutaatiot (LOF; loss of function) aiheuttavat familiaaliseen hypolipidemian fenotyypin (FHBL2), jonka pääpiirteenä on matalat veren VLDL, LDL ja HDL lipoproteiinien tasot. Päämenetelmät: Solumalleilla tutkittiin ANGPTL3:n kudosspesifistä toimintamekanismia hiljentämällä ANGPTL3 shRNA-lentivirus vektorilla hepatosyyteissä sekä enterosyyteissä. Tutkittavien lipidien ja proteiinien tasoja mitattiin sekä soluista että solumediasta entsymaattisilla menetelmillä sekä ELISA menetelmillä. Leimattujen substraattien avulla selvitettiin solujen metabolian muutoksia. Geenien ilmentymistä soluissa tutkittiin kvantitatiivisella PCR (qPCR)-analyysillä. Koe-henkilöt, joihin kuului ANGPTL3 LOF kantajia sekä kontrollihenkilöitä nauttivat rasvapitoisen aterian, jonka jälkeen kerätyistä plasmanäytteistä mitattiin lipoproteiinien, rasva-aineenvaihdunnan markkereiden sekä TG:ien, kolesterolin ja fosfolipidien pitoisuuksia. Populaatiotutkimuksessa suomalaisten ANGPTL3 varianttien kantajien lipiditasot määritettiin tarkoituksena selvittää ANGPTL3 varianttien osuutta dyslipidemioissa. Verenkierrossa olevan ANGPTL3-proteiinin konsentraatio mitattiin henkilöiltä, joiden lipidiarvot vastasivat hyper- tai hypolipidemiaa, jonka jälkeen tasoja verrattiin lipidiarvoihin sekä muihin lipidimetabolian biomarkkereihin mahdollisten korrelaatioiden löytämiseksi. Johtopäätökset: Tulosten perusteella ANGPTL3:n ilmentymistä soluissa säätelevät insuliini, PPARy-agonisti rosiglitazone sekä LXR-agonistit. ANGPTL3-hiljennys aiheuttaa VLDL-partikkelien lipidaation laskua hepatosyyteissä insuliini stimuloinnin aikana sekä CD36- ja PLTP-geenien ilmentymistason laskua soluissa. ANGPLT3-LOF kantajien kliinisessä tutkimuksessa havaittiin, että ANGPTL3-puutoksen omaavilla homotsygooteilla LOF kantajilla ei esiintynyt postprandiaalista hyperlipidemiaa, toisin kuin heterotsygooteilla kantajilla ja kontrollihenkilöillä, ja tämän fenotyypin voidaan katsoa olevan ateroskleroosia ehkäisevä tekijä. ANGPTL3 puutos aiheuttaa myös veren rasvahappojen määrän vähenemistä verenkierrossa ja siten mahdollisesti vähentää maksaan päätyvien rasvahappojen määrää ja niiden oksidaatiota. Populaatiotutkimuksessa ANGPTL3-varianttien kantajien osuus oli vähäinen, ja dyslipidemiaa oli havaittavissa yhdellä haitallisen variantin kantajalla. Varianttia ei vähäisen kantajien määrän takia pystytä luotettavasti kausaalisesti yhdistämään fenotyyppien aiheuttajaksi. ANGPTL3:n plasma tasot eivät eronneet hypo- tai hyperlipideemisten henkilöiden välillä, ja täten voidaan todeta, että ANGPTL3:n plasmapitoisuudet eivät toimi hyvänä biomarkkerina ennustettaessa veren lipiditasoja.
  • Bryk, Saara (Helsingin yliopisto, 2017)
    Adult-type granulosa cell tumors (AGCTs) belong to the sex cord-stromal group of ovarian tumors and account for 3-5% of ovarian neoplasms. Etiological factors of AGCTs remain mostly unknown, although studies have found a somatic missense mutation in the transcription factor FOXL2. AGCTs are usually diagnosed at an early stage and have a favorable prognosis compared with the more common epithelial ovarian cancer. However, tumor recurrence develops in up to 35% of patients, even in early-stage disease - often unpredictably and several years or even decades after the primary diagnosis. The aims of this study were to determine the incidence and epidemiological background of AGCTs in a large, multinational Nordic cohort and to estimate the incidence of other, especially endocrine-related primary malignancies among patients with AGCT. Furthermore, the objective was to describe the clinical characteristics and prognostic factors linked to AGCT–related recurrence and survival, and to introduce an optimal follow-up strategy for these patients. Our epidemiological registry study on AGCT incidence utilized the Finnish, Icelandic, Norwegian, and Swedish Cancer Registry data on AGCTs over several decades. We showed that the age-adjusted incidence rates were quite constant in 1953-2012: about 0.6-0.8 per 100,000 for most of the study period. The age-specific incidence was highest at 50-64 years of age, and there were no occupations with significantly increased risk of AGCT. The conclusions drawn from these results point to AGCT as a primarily sporadic, not exposure-related cancer, typically occurring in peri- or postmenopause. We estimated the incidence of other primary malignancies among AGCT patients using data from the Finnish Cancer Registry in 1968-2013. After AGCT, we found increased risks for cancers of the soft tissue and thyroid as well as leukemia, which likely indicate shared risk factors and therapy-induced side effects. The incidence of AGCT was significantly increased among women with previous breast cancer, suggesting shared hormonal etiology or treatment-induced effects. To evaluate the clinical and prognostic factors, all AGCT patients diagnosed at Helsinki University Hospital during nearly six decades were included in the clinical study cohort (n=240). After a histological review, we analyzed the clinical data for association with both AGCT-related and overall survival and tumor relapse. Of the original study cohort, the diagnosis was histologically confirmed in 78% of patients and molecularly confirmed for the FOXL2 mutation in 68% of patients. In multivariate analysis, stage was the only independent prognostic factor related to AGCT-specific survival. Spontaneous or iatrogenic tumor rupture was independently associated with tumor recurrence. By utilizing the extensive cancer registry data together with the internationally unique, large and carefully validated single-institute patient cohort, these studies reveal the diagnostic challenges of AGCTs, and provide novel epidemiological data and evidence-based tools to develop follow-up strategies for this rare cancer.
  • Tolvanen, Tuomas (Helsingin yliopisto, 2017)
    Background: Type 2 diabetes, characterised by insulin resistance, is an everincreasing problem in the world. Diabetic nephropathy is a renal microvascular complication of diabetes that is a common cause of end-stage renal disease worldwide. Low levels of albumin can be detected in the urine at an early stage of diabetic nephropathy, and more severe albuminuria develops as the disease progresses. Insulin resistance is associated with albuminuria in patients with type 1 or type 2 diabetes. Also, the loss of podocytes plays a major role in the pathogenesis of diabetic nephropathy. The mechanisms underlying the development of insulin resistance and apoptosis in podocytes are still not fully understood. This study aimed to investigate the pathophysiological mechanisms leading to insulin resistance and podocyte apoptosis at the molecular level, and concentrated to the roles of CD2-associated protein (CD2AP) and SH2-domain containing 5’ inositol phosphatase 2 (SHIP2) in these processes. Results: We found that the lack of CD2AP in podocytes led to attenuated glucose uptake, without affecting PI3K-AKT-mediated insulin signalling. This led us to investigate the role of CD2AP in glucose transporter trafficking. Indeed, live-cell imaging revealed that internalized Glucose transporter 4 (GLUT4) was trapped in the perinuclear region of podocytes lacking CD2AP. CD2AP co-fractionated with known components of GLUT4 vesicles and interacted with clathrin and clathrin adaptor GGA2. These results suggest that CD2AP plays a role in GLUT4 vesicle trafficking. We further observed that the level and activity of SHIP2, an interaction partner of CD2AP, was increased in the absence of CD2AP in podocytes. Also, production of reactive oxygen species (ROS) and the rate of apoptosis were increased when CD2AP was lacking from podocytes. We hypothesized that inhibition of SHIP2 would decrease the production of ROS and apoptosis, but even though we detected reduced ROS production, inhibition of SHIP2 increased podocyte apoptosis in the absence of CD2AP. In the search for novel SHIP2 inhibitors we found an old anti-diabetic drug, metformin, to bind to and inhibit the activity of SHIP2 in silico, in vitro and in vivo. By inhibiting the activity of SHIP2, metformin increased glucose uptake and protected podocytes from apoptosis initiated by SHIP2 overexpression. SHIP2 exhibited higher activity in the kidney pieces received from nephrectomy patients with type 2 diabetes receiving non-metformin medication compared to nephrectomy patients without diabetes; in comparison, the activity of SHIP2 did not differ between metformin receiving patients with type 2 diabetes and people without diabetes. Patients with type 2 diabetes with metformin medication also showed reduced podocyte loss. Conclusions: In the light of our results we suggest a novel role for CD2AP in the regulation of sorting of internalized GLUT4 and regeneration of insulin responsive GLUT4 vesicle compartment. We also suggest that SHIP2 inhibitors, including metformin, can be used to reduce the oxidative stress of podocytes and to prevent podocyte loss, except in the case of patients suffering from reduced expression of CD2AP.
  • Ruotsalainen, Hanna (Helsingin yliopisto, 2017)
    Hypoplastic left heart syndrome (HLHS) is the most common so called univentricular congenital heart defect. Despite advances in treatment, HLHS is still associated with significant morbidity and mortality. Myocardial dysfunction is a known risk factor for morbidity and mortality in HLHS patients throughout the treatment protocol. The etiology of myocardial dysfunction in HLHS is still poorly understood. The aims of this study were to evaluate advanced echocardiographic functional methods and to utilize them in the follow-up of patients with HLHS. In methodological studies, advanced echocardiographic methods were compared to magnetic resonance imaging in 51 HLHS infants and children at different phases of treatment protocol. All parameters had a good correlation with MRI. Advanced echocardiographic methods provide reliable measurements of myocardial function and since no anesthesia is required, they are suitable for cardiac follow-up of pediatric patients. However, there was a measurement bias and wide limits of agreement between different automatic methods and therefore, different methods cannot be used interchangeably. In clinical retrospective follow-up studies, velocity-vector imaging (VVI) was used to assess myocardial function during the treatment protocol in a population-based cohort of HLHS neonates, infants and children (n=66) born between 2003 and 2010 in Finland. Before operations, prenatal diagnosis of HLHS was associated with improved postnatal RV function as compared to neonates diagnosed postnatally. The surgical treatment protocol for HLHS comprises of three heart operations. In this study, infants palliated with a Blalock-Taussig shunt (BT shunt) at stage 1 operation had higher RV volumes and more tricuspid valve regurgitation before stage 2 operation than infants palliated with a right ventricle to pulmonary artery conduit (RV−PA conduit). In BT shunt patients, myocardial function improved after stage 2 and was better after stage 3 as compared to those initially palliated with an RV−PA conduit. This finding may have an influence on decision making regarding selection of the shunt type. In the future, the prognostic value of the methods used in this study and the effect of medical and surgical treatment in the long-term follow-up need to be evaluated in this challenging group of patients.
  • Puttonen, Henri (Helsingin yliopisto, 2017)
    Biogenic amine neurotransmitters are important modulators of the central nervous system. Studies on the roles of the histaminergic system have revealed that it regulates many key brain functions. It has also been implicated to be involved in many brain disorders. Modulation of histamine signalling may thus provide an option for the treatment of these conditions. Due to its relatively recent discovery, many unanswered questions about the histaminergic system remain. In this thesis, I studied the neuropharmacology of the histaminergic system using the zebrafish as a model of the vertebrate brain. In the first study, the effect of acute ethanol on the histaminergic and dopaminergic systems was analysed. The mRNAs of enzymes synthesizing dopamine and histamine were upregulated by a short ethanol exposure in a dose-dependent manner. The morphology of the histaminergic and dopaminergic systems was unaltered by ethanol treatment, suggesting that the changes observed were localized to cells that produce these transmitters under normal conditions. No significant changes were seen in histamine levels following ethanol treatment. Ethanol treatment resulted in a rapid, dose-dependent increase in locomotion of larvae. The behavioural and transcriptional changes occurred within a similar time frame, suggesting that histamine and dopamine may play a role in the locomotor effects of ethanol. In the second study, pharmacological inhibition of the vesicular monoamine transporter 2 (VMAT2) was shown to result in an almost total loss of histamine immunoreactivity in neuronal fibres and a decreased number of histamine neurons. Additionally, levels of histamine and other amine neurotransmitters were decreased. Depletion of histamine did not upregulate its synthesis, although enzymes synthesizing the other aminergic transmitters were upregulated. Behaviourally, VMAT2 inhibition resulted in a decreased histamine-dependent dark-induced flash response of zebrafish larvae, a brief spike in locomotor activity during the first second of sudden onset of darkness, which has been described as histamine dependent. In the third study, we characterized the expression of the zebrafish histamine receptor hrh3 and generated a hrh3 knockout strain using the CRISPR-Cas9 method of targeted genome editing. Double fluorescent in situ hybridization revealed that the majority of hrh3 expressing neurons in the telencephalon were glutamatergic, suggesting that hrh3 regulates glutamatergic transmission in the zebrafish. We saw that hrh3 knockout larval zebrafish adapted faster to sudden onset of darkness, indicating that hrh3 can regulate adaptation to sudden changes in the environment. Although basic behavioural parameters of hrh3 knockout larvae were unaltered, adult hrh3 knockout fish showed decreased locomotor activity, suggesting that hrh3 signalling may have different roles at different ages. No changes were seen in the morphology and transcriptional profile of other aminergic networks. However, zebrafish larvae had decreased levels of dopamine and serotonin, supporting a role for hrh3 in the regulation of these systems. In total, these results provide some new answers to open questions in the field of histamine neuropharmacology, specifically concerning the effects of alcohol on the histaminergic system, the mechanisms of vesicular storage of histamine and interactions between histamine and other aminergic systems. This information will be valuable when planning further studies to fully elucidate the pharmacological potential of this system.
  • Torppa, Auri Martina (Helsingin yliopisto, 2017)
    Clinical supervision (CS) in medicine has been defined as provision of monitoring, guidance and feedback on matters of personal, professional and educational development in the context of the physician’s care of patients, with the aim of maximizing patient safety. It is aimed at promoting reflection and professional development. The Balint group method is the most commonly used method of CS among physicians. However, properly carried out studies on the prevalence of CS, its associated factors, needs and benefits among GPs have largely been lacking. In this study the aim was to investigate the nature of student Balint groups, the use of and need for CS, emotional exhaustion among GPs and characteristics and work-related issues associated with CS. This study involved three samples. Mixed methods, i.e. both qualitative and quantitative were used. Study I involved analysis of the field notes of 15 student Balint group discussions of nine medical students in their clinical years. Most cases in the group discussions arose from patient encounters, but there was also a need to accept issues arising from other experiences as medical students. Many themes in the discussions dealt directly or indirectly with students’ future identity as physicians. In addition, feelings related to patients were a very common theme. These groups may foster medical students’ professional development. Study II the material of the annual Finnish Medical Association survey of 2008, focusing on specialists in general practice (n=1252) was analysed to assess the use of and need for CS and associations of them. In Study III and IV the survey material concerning health-centre physicians (n=165) was used to explore in Study III the prevalence of emotional exhaustion among them and factors associated with it and in Study IV associations of certain work-related factors with CS. In Study II, 42 % of GPs, and in Study IV, 35 % had either previous or current experience of CS. Furthermore, 25 % and 36 % of GPs reported having a need for CS, respectively. Study II indicated that female GPs had used CS, and acknowledged a need for it more often than their male colleagues, and that younger GPs had recognized a need for CS more often than older GPs. Study II also revealed that CS was associated with active participation in continuing medical education. In Study IV the experience of CS was associated with being older, whereas both the experience of and the need for CS were related to experiencing the job as being emotionally draining. In Study III indicated that the mean degree of satisfaction with work was high among GPs working as health-centre physicians, while at the same time 18 % of the GPs were emotionally exhausted, 30 % felt alone at work and 32 % felt that they had to work too hard. A longer working history, feeling alone at work, and having committed a medical error predicted emotional exhaustion, whereas good tolerance of uncertainty protected GPs from it.
  • Dawson, Caitlin (Helsingin yliopisto, 2017)
    The auditory system can be shaped by exposure to different auditory environments, such as native language and musical training, and these effects have been demonstrated at behavioral, cortical, and subcortical levels. However, it is not yet understood how these effects could be modulated by musical expertise within different linguistic groups. Thus, the main objective for this thesis was to investigate interacting effects of native language patterns and musical experience on early auditory processing of basic sound features. Methods included electrophysiological brainstem recording as well as a set of behavioral auditory discrimination tasks designed to find discrimination thresholds for intensity, frequency, and duration in single-feature conditions, and for intensity and duration in multifeature conditions. A musical sophistication self-report questionnaire was also used in correlational analyses. Native Finnish speakers showed enhanced subcortical duration processing compared to native German speakers. For Finnish speakers, musical expertise was associated with enhanced behavioral frequency discrimination. Greater musical sophisticaton was also associated with a greater decrement in perceptual duration discrimination in a complex multifeature task. Mandarin speaking musicians showed enhanced perceptual discrimination for both frequency and duration compared to Mandarin speaking nonmusicians. However, there was no difference between Mandarin speaking musicians and nonmusicians in subcortical onset responses or either of two measures of subcortical pitch tracking. Perceived intensity, frequency, and duration are related, but intensity and frequency give independent contributions to perceived duration. The results suggest that musical expertise does not enhance all auditory features equally for all language speakers; native language phonological patterns may modulate the enhancing effects of musical expertise on specific features. The perceptual effects of musical expertise were not reflected in brainstem responses, indicating that native language experience may apply a subcortical ceiling effect on the auditory features encoded in the language, and/or that musical expertise and task relevance can give additional perceptual benefits. This supports the idea that musical expertise encourages efficient processing of complex sounds in a natural sound environment, as in music performance or conversational speech, and that the sensitive nature of plasticity of the efferent pathway has a significant effect on basic auditory processing.
  • Lokki, A. Inkeri (Helsingin yliopisto, 2017)
    The human pregnancy is a unique immunological process. The foetus is tolerated and nourished through the complex yet transient organ, placenta, which bears the genetic fingerprint of the developing baby. Human placentation involves several waves of invasion, whereby the placenta is deeply attached to layers of the uterine wall, through the mucosal lining of the uterus, the decidua and into the underlying muscle, the myometrium. In order for adequate but not inappropriate depth of placentation to occur, the maternal immune system must be fine-tuned to tolerate yet control the invasive trophoblast cells, which originate in the placenta. Pre-eclampsia is a common vascular disease of the human pregnancy. Pre-eclampsia, particularly in its severe form, is intrinsically linked to failure of deep-placentation. While pre-eclampsia has long been known to have a familial, i.e. genetic component, the genes contributing to the disease have not been well characterised thus far. This thesis addresses the question of role of the complement system in pre-eclampsia by comparing pre-eclamptic women to non-pre-eclamptic controls using several methods. Using immunofluorescence and immunohistochemistry, placental tissues were stained for one angiogenic receptor and nine components of the complement system to determine the localisation and extent of complement activation, and on the other hand, complement regulation in placentae from pre-eclamptic and healthy pregnancies. In two candidate gene studies, the variants within coding regions and flanking sequences surrounding exons of a key complement regulator, membrane cofactor-protein (CD46) gene (MCP/CD46) and activator, complement component 3 gene (C3) were explored in women with a history of severe pre-eclampsia and non-pre-eclamptic controls. Finally, using a targeted exomic sequencing approach we studied known candidate genes in pre-eclampsia to identify low-frequency variants in the Finnish population that may predispose to or protect from pre-eclampsia. We combined pre-eclamptic patients from the FINNPEC (Finnish genetics of pre-eclampsia consortium) and the national FINRISK studies to characterise health consequences of the most important variants that associate to pre-eclampsia. While we did not find a genetic association to pre-eclampsia in the membrane bound complement regulator, MCP, we found three out of forty-three observed single nucleotide polymorphisms to be associated with pre-eclampsia in the C3. Furthermore, a section of tight linkage disequilibrium was identified within the C3 that depending on the sequence context, may predispose to, or protect from pre-eclampsia. Most recently, the first maternal genetic association of the fms related tyrosine kinase 1 gene (FLT1) coding for an anti-angiogenetic marker soluble fms-like tyrosine kinase 1 elevated in pre-eclampsia was discovered. Two SNPs within the FLT1 protect women from not only pre-eclampsia, but also from heart failure in later life. The work presented in this thesis sheds light to some of the many inherited traits that contribute to the aetiology of pre-eclampsia. The results present a first genetic association to pre-eclampsia in C3 and they may provide a maternal genetic link between angiogenesis process during pregnancy and heart failure in later life. The crucial effect of the complement system for the successful pregnancy is demonstrated by genetic association as well as comparative localisation of complement components on the pre-eclamptic and healthy placenta tissue.
  • Hirvonen, Karoliina (Helsingin yliopisto, 2017)
    Patients suffering from adenoid cystic salivary gland carcinoma have variable prognosis and longterm follow up is recommended In 35 years follow up it was noted that of those patients suffering from adenoid cystic carsinoma (ACC) of salivary glands, 54% of major salivary glands and 42% of minor salivary glands carcinoma patients were alive 10 years after treatment. One factor that significantly worsened the survival was distant metastases appearing during the follow up. They appeared in 50% of major- and 34% of minor salivary glands cancer patients, most commonly in lungs. Almost all distant metastases appeared within 10 years after treatment. It is thus recommended to actively follow up ACC-patients at least 10 years after treatment. Some ACC-patients however live long and therefore the risk of ACC and other salivary gland cancer patients developing second primary cancer during their lifetime was investigated in this study. The risk was 43% higher compared to the cancer risk of general population. The risk was most elevated for thyroid cancer, but the risk for melanoma of the skin, other skin cancers, cancers of breasts, respitarory organs and male genital organs was also significantly higher. The risk was higher during the the first 5 years and then again 20 years after salivary gland cancer diagnosis. Prolonged follow-up time in primary health care center is warranted as early detection of second primary cancer may prolong the survival. The role of Toll-like receptors (TLRs) 5 and 7 in ACC was also investigated in this study as TLR expression is known to correlate with survival in many cancers. In this immunohistochemical study TLR 5 and 7 were shown to also express in ACC but there was no direct correlation to survival. The materials for this study were patient records and tumor samples of patients with major salivary gland ACC treated between 1974-2014 and minor salivary gland ACC treated between 1974-2014 in Helsinki University Hospital district area. During this time period there were 54 major- and 68 minor salivary gland ACC patients. The data from Finnish Cancer Registry between 1953-2014 were used in the study investigating the second primary cancers. During this time period there were 1727 salivary gland carcinoma patients of which 222 developed second primary cancer. Aim of this study was to asses the factors that determine the long term outcome of ACC patients as well as to investigate the risk of salivary gland carcinoma patients to develop second primary cancer. In Finland approximately 60 new salivary gland cancer patients appear annually, approximately one third of these are ACCs. Main treatment modality is surgery followed by post operative radiotherapy in some cases. Treatment or survival have not markedly changed during the years. Distant metastases are more common than neck metastases or local recurrences. Molecular biology of ACC is under active research in order to find new prognostic markers and treatment protocols.
  • Satopää, Jarno (Helsingin yliopisto, 2017)
    Intracerebral haemorrhage (ICH) is a deadly subtype of stroke with an average 12-month mortality exceeding 50%. Despite advances at other frontiers of stroke treatment, treatment options for ICH are limited. Neurosurgical treatment for ICH has been discussed in recent multicentre studies, but no definitive answer of its utility has emerged. Age, ICH volume and location, and extent of ventricular haemorrhage among other factors affect the prognosis after ICH. We studied the effect of neurosurgical treatment (1) in patients with intracerebellar haemorrhage; (2) in patients with ICH-related hydrocephalus; and (3) in young adults in an observational, retrospective analysis of consecutive ICH patients admitted to Helsinki University Hospital during a five-year period. In addition, we studied the different prognostic scores for ICH to find the best tool for estimation of the risk of death after ICH. Traumatic and aneurysmal ICHs were excluded from the study. We found 19 prognostic scores, many of which were based on the original ICH score. For estimating the risk of in-hospital death, the National Institutes of Health Stroke Scale performed as well as the best dedicated scores. For 3- and 12-month mortality, the ICH Functional Outcome Scale (ICH-FOS) performed best. However, all prognostic scores share the risk of self-fulfilling prophecies, the estimated poor outcome resulting in limitations of care. Based on a mutual consensus among neurologists and neurosurgeons, cerebellar ICH is usually treated surgically in patients with a declining level of consciousness and a large haematoma. However, in our series, surgical and medical treatment did not differ in short- or long-term mortality, but surgically treated patients were left in a poor clinical condition at hospital discharge. The surgically treated patients were younger, had larger ICHs and their level of consciousness on arrival was lower than the conservatively treated patients. Although surgically treated patients were left in a poor condition, no data exist on long-term functional outcome and recovery after intracerebellar haemorrhage. ICH-related hydrocephalus is usually considered a predictor of poor outcome. In our series, hydrocephalic patients had very high mortality, but surgical treatment – either by external ventricular drainage or evacuation of a hydrocephalus-causing cerebellar ICH – was associated with lower in-hospital and 3-month mortality. Only a small subgroup of all hydrocephalic patients received surgical treatment, but a difference in mortality between surgically and conservatively treated patients was observed in a propensity-matched case-control comparison. The high mortality previously attributed to ICH-related hydrocephalus may be a self-fulfilling prophecy. ICH in the young was caused most often by hypertension and structural vascular anomalies such as arteriovenous malformations or cavernous angiomas. The predictors of poor outcome did not differ from those in older patients, these being Glasgow coma score < 8, infratentorial location, intraventricular blood, hydrocephalus, and haematoma volume > 30 ml. However, surgical treatment was associated with significantly lower mortality than conservative treatment. In conclusion, surgical treatment was associated with a lower short- and long-term mortality in patients with ICH-related hydrocephalus and in young adults. More studies are needed to elucidate the advantages and disadvantages of surgical treatment in patients with intracerebellar haemorrhage and ICH-related hydrocephalus.
  • Hyysalo, Jenni Emilia (Helsingin yliopisto, 2017)
    Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition and at least two different forms exist. ‘Obese/Metabolic NAFLD’ characterizes subjects with metabolic syndrome and insulin resistance, whereas NAFLD associated with the common PNPLA3 I148M variant (‘PNPLA3 NAFLD’) is not accompanied by insulin resistance. This thesis was undertaken to elucidate the pathogenetic mechanisms of NAFLD (Studies I and III) and to estimate the prevalence of non-alcoholic steatohepatitis in Finnish subjects (Study II). The study groups consisted of 417 (I) and 372 (III) subjects, as well as 296 bariatric surgery patients from Finland and 2849 subjects from a population-based D2D-sample (II). In Study II, 380 non-bariatric surgery patients who had undergone a liver biopsy for suspected NAFLD from Italy were used as an external validation cohort. In Study I liver fat content was measured by proton magnetic resonance spectroscopy (1H-MRS), in Study II by either biopsy or 1H-MRS, and in Study III in 75% by 1H-MRS and in 25% by biopsy. Clinical characteristics (I, II, III), plasma apoC3 concentrations (I), and serum cytokeratin 18 fragments (II) were determined. In Study III, lipidomic analyses were performed using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-MS). Individuals were genotyped for rs2854116 and rs2854117 in APOC3 (I) and the known rs738409 in PNPLA3 (I, II, III). In Study II, we developed and validated a ‘NASH score’ in the Finnish and Italian biopsy cohorts, which was then used to predict NASH prevalence in the population-based D2D study. In Study III, the subjects were divided into groups based on PNPLA3 genotype or obesity, and the absolute and relative triacylglyceride concentrations were compared between the subgroups. No difference existed between the APOC3 variant allele (T-455C or C-482T or both) carriers and non-carriers in liver fat or apoC3 concentrations, whereas those with the PNPLA3 GG genotype at rs738409 had a 2.7-fold higher liver fat content than those with the CC genotype (I). The ‘NASH score’ included PNPLA3 genotype, aspartate aminotransferase (AST), and fasting insulin. The area under the ROC for this score was 0.774 (95% CI 0.709-0.839) in Finns and 0.759 (95% CI 0.711-0.807) in Italians (NS) (II). The prevalence of NASH based on this score in the D2D study was 6.0% (95% CI 5.0-6.9%) (II). Sensitivity analysis was performed by a Bayesian model, which gave a NASH population prevalence of 3.6% (95% CI 0.2-7.7%) using the ‘NASH Score’ (II). Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3148MM/148MI as compared with the PNPLA3148II group (III). Genotypes in the obese and ‘non-obese’ groups were similar but the obese subjects were insulin-resistant (III). Liver fat was increased in both obese and PNPLA3148MM/148MI groups (III). Multiple changes in the relative TAG concentrations were observed between obese and ‘non-obese’ groups (III). These closely resembled those between obese subjects with ‘obese NAFLD’ versus the ‘PNPLA3 NAFLD’ (III). Variation in liver fat cannot be explained by genetic variants in APOC3 (I). The population-based prevalence of NASH in Finnish subjects is ~5% (II). The circulating TAG profile depends on the aetiology of NAFLD (III). In ‘PNPLA3 NAFLD’
a relative deficiency of TAGs is observed, supporting the idea that the I148M variant prevents lipolysis rather than stimulates TAG synthesis in the liver (III).