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  • Renkonen, Suvi (Helsingin yliopisto, 2012)
    Background Juvenile Nasopharyngeal Angiofibroma (JNA) is a rare, benign tumour affecting adolescent males. Due to its capability to erode bone, JNA can be accompanied by life-threatening complications when growing into the cranium. The etiology of JNA is unknown, as are the factors determing the variable growth patterns of individual tumours. The treatment of choice for JNA is surgery, but high recurrence rates or persistent growth are charasteristic. Aims The aim of this study was to elucidate factors determing the variable outcomes of JNA. For this purpose the various surgical techniques used to resect JNA during the past 40 years at the Helsinki University Central Hospital (HUCH) were investigated, immunohistochemistry was performed and the gene copy number and mRNA expression data of two phenotypically different JNA tumours were combined to seek for processes putatively determining their growth pattern. Methods Retrospective clinicopathological data of all JNA patients diagnosed and treated, during the years 1970-2011, were reviewed. By immunohistochemistry, we investigated the cellular distribution and expression levels of C-KIT, C-MYC, BMI-1, GLUT-1, tenascin-C, syndecan-1, syndecan-2 and SYK in JNA samples, in order to find their possible correlations with clinicopathological factors. Comparative genomic hybridisation and gene expression analyses were performed for two phenotypically different tumour samples to investigate the possible processes leading to more aggressive growth. A gene ontology enrichment analysis for the in silico translated proteins of genes with altered gene expression status was performed to detect the categories with enrichments. Results The primary recurrence rate was 37% and correlated with the surgical approach used, transpalatal approach linked with higher risk of recurrence, vascularity of the tumour and young age of the patient. Contrary to previous reports, C-KIT was expressed in both stromal and endothelial cells of JNA samples and was more prominent in slit-like vessels. A correlation between its endothelial expression and cellular density of the tumour was found. Frequent stromal tenascin-C expression had a strong correlation with vessel density and higher tumour stage. When present, endothelial GLUT-1 expression correlated with higher tumour stage. SYK expression was found to correlate with lower tumour stage. Between the low and high stage JNA tumours studied, 1245 genes showed at least a two-fold- change in their expression. The corresponding proteins of these transcripts were enriched in different biological processes, e.g., hypoxia in the low stage tumour and signal transduction activity in the high stage tumour. Conclusions The type of surgical approach seemed crucial for the outcome. Other clinical factors affecting the recurrence rate were young age of the patient and vascular density of the tumour. In selective cases of JNA, we could thus carefully recommend the consideration of antiangiogenic treatment. Based on our finding of protein expressions, we suggest that at least C-KIT, tenascin-C, GLUT-1 and SYK might be substantial in the growth of JNA by having an effect on tumour cellularity, vessel density and the stage of the tumour. Based on our result of GLUT-1 positivity correlating with higher tumour stage, we suggest that JNAs are not likely to be vascular malformations. Although we were able to identify gene expression changes that relate to particular biological processes, the assessing of clinically relevant molecular profiles of JNA still requires further characterization. In the future, combinating molecular profiling data from several studies will be useful to better understand the molecular background of this rare tumour.
  • Tonteri, Elina (Helsingin yliopisto, 2014)
    Tick-borne encephalitis virus (TBEV) circulates mainly in the Ixodes ricinus and Ixodes persulcatus tick species, which serve both as hosts and vectors for the virus. Wild rodents are considered as bridges for non-viremic transmission between the ticks, which is the most important maintenance factor for TBEV. The fragile maintenance cycle of the virus is affected by climates and availability of biotic factors thus, TBEV is found in restricted foci. TBEV is transmitted to humans when bitten by an infected tick or when consuming contaminated milk. Infection may lead to a clinical disease, tick-borne encephalitis (TBE). In studies included in this thesis, we targeted both maintenance factors of TBEV in Finland, a country lying in the boreal region at the northernmost range endemic for the virus and surveyed the geographical distribution of all human TBE cases during years 2007-2013. In addition, we surveyed the determinants for development of TBE incidence. Apodemus flavicollis (yellow-necked mouse) has been considered as the main host species for maintenance of TBEV, at least in Central-Europe. However, in this study, the rodent species found in the studied TBEV foci in Finland were Myodes glareolus (bank vole) and Microtus agrestis (field vole). TBEV-RNA could be shown in wild rodents both in absence and presence of antibodies and was detected in wild voles in winter, several months after tick-feeding season. Furthermore, virus persisted in Myodes glareolus up to 168 days post infection also in an experimental setting. TBEV was highly neurotropic in voles both in wild and in an experimental infection study, thus we suggest, that brain is the best target organ for detecting TBEV in voles. Myodes glareolus provides an excellent and resistant model for studies on TBE - even if acute encephalitis was confirmed by histopathological examination, no significant clinical symptoms could be seen. Between years 2007-2013, 233 TBE cases were reported to the Finnish National Institute of Health and Welfare. New geographical places with confirmed patient cases are emerging in Finland. The incidence is increasing and shifting from Åland, where a national vaccination program is running, to the south-western archipelago and to mainland of Finland. In some areas, however, increase in case numbers may be due to the increased clinical alertness rather than or in addition to the changes in climate, ecological factors or human behavior as number of diagnostic samples sent to clinical laboratories did double during the study period. There are three subtypes of TBEV: European, Siberian and Far-Eastern, of which the two latter are mainly carried by I. persulcatus and the European by I.Ricinus. Both tick species and Siberian and European subtypes of TBEV have been found in Finland. In Simo, in Southern Lapland, TBEV was circulating both in Myodes glareolus and in ticks. This is so far the northernmost established TBEV focus known in the world. Furthermore the hosting tick species was found to be I.persulcatus, but unexpectedly the TBEV subtype was European. We suggest, that in the mixing zone of the two main host tick species and the virus subtypes the tick species in an area does not restrict the formation of a TBEV focus regardless of the presented virus subtype.
  • Hiltunen, Leena (Helsingin yliopisto, 2011)
    Factor V Leiden (FV Leiden) is the most common inherited thrombophilia in Caucasians increasing the risk for venous thrombosis. Its prevalence in Finland is 2-3%. FV Leiden has also been associated with several pregnancy complications. However, the importance of FV Leiden as their risk factor is unclear. The aim of the study was to assess FV Leiden as a risk factor for pregnancy complications in which prothrombotic mechanisms may play a part. Specifically, the study aimed to assess the magnitude of the risk, if any, associated with FV Leiden for pregnancy-associated venous thrombosis, pre-eclampsia, unexplained stillbirth, and preterm birth. The study was conducted as a nested case-control study within a fixed cohort of 100,000 consecutive pregnant women in Finland. The study was approved by the ethics committee of the Finnish Red Cross Blood Service and by the Ministry of Social Affairs and Health. All participants gave written informed consent. Cases and controls were identified by using national registers. The diagnoses of the 100,000 women identified from the National Register of Blood Group and Blood Group Antibodies of Pregnant Women were obtained from the National Hospital Discharge Register. Participants gave blood samples for DNA tests and filled in questionnaires. The medical records of the participants were reviewed in 49 maternity hospitals in Finland. Genotyping was performed in the Finnish Genome Center. When evaluating pregnancy-associated venous thrombosis (34 cases, 641 controls), FV Leiden was associated with 11-fold risk (OR 11.6, 95% CI 3.6-33.6). When only analyzing women with first venous thrombosis, the risk was 6-fold (OR 5.8, 95% CI 1.6-21.8). The risk was increased by common risk factors, the risk being highest in women with FV Leiden and pre-pregnancy BMI over 30 kg/m2 (75-fold), and in women with FV Leiden and age over 35 years (60-fold). When evaluating pre-eclampsia (248 cases, 679 controls), FV Leiden was associated with a trend of increased risk (OR 1.7, 95% CI 0.8-3.9), but the association was not statistically significant. When evaluating unexplained stillbirth (44 cases, 776 controls), FV Leiden was associated with over 3-fold risk (OR 3.8, 95% CI 1.2-11.6). When evaluating preterm birth (324 cases, 752 controls), FV Leiden was associated with over 2-fold risk (OR 2.4, 95% CI 1.3-4.6). FV Leiden was especially associated with late preterm birth (32-36 weeks of gestation), but not with early preterm birth (< 32 weeks of gestation). The results of this large population-based study can be generalized to Finnish women with pregnancies continuing beyond first trimester, and may be applied to Caucasian women in populations with similar prevalence of FV Leiden and high standard prenatal care.
  • Harjutsalo, Valma (Helsingin yliopisto, 2007)
    Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.
  • Nopola-Hemmi, Jaanamarja (Helsingin yliopisto, 2002)
  • Fagerudd, Johan (Helsingin yliopisto, 2000)
  • Kallinen, Outi (Helsingin yliopisto, 2013)
    To study fatal burns in the Helsinki Burn Center, sixteen years of data on burn deaths were collected and analyzed. These data included information obtained during pre-hospital care, clinical notes and autopsy reports. The study classified clinically missed diagnosis revealed in autopsy and paid special interest in the prevalence of adrenal hemorrhage (AH). The study was carried out in two phases. First phase included all deceased burn victims of Helsinki Burn Center from 1995 to 2005. The clinical charts and medicolegal autopsy reports with organ specific changes were retrieved and compared. The data were evaluated by a team of two plastic surgeons specialized in burn care, an intensivist, and a pathologist. Causes of death, incidence of multiple organ failure (MOF) and AH and occurrence of diagnostic discrepancies were documented and analyzed. The second phase includedburn patients with life-threatening burns in Helsinki Burn Center during 2006-2010.Pre-hospital patient records and clinical data collected during treatment were analyzed with reference to survival. The data were analyzed in groups based on the presence or absence of a physician in the pre-hospital phase. The majority of the burn victims die of untreatable burn injury (40%) or MOF (40%). Kidneys (100%) and liver (82%) were the organs most commonly affected in MOF. Lethal sepsis was never a sole cause of death, but always associated with MOF. Three MOF patients had bilateral adrenal hemorrhage. Medicolegal autopsies revealed major diagnostic discrepancies in less than 6% of patients. These diagnostic discrepancies would have altered the clinical outcome or therapy had they been known in time. The most commonly missed diagnosis was pneumonia. Patients treated by paramedics compared with patients treated by pre-hospital physicians were comparable with regard to age, gender and etiology of the injury. However, patients treated by pre-hospital physicians were more severely injured than patients treated by paramedics in terms of percentage of total body surface area (%TBSA) burned, injury severity score (ISS) and inhalation injuries. Patient s age, %TBSA and ISS are significantly associated with short- and long-term survival in burn patients. The study reveals all the causes of death of the burn patients in the study period in the Helsinki Burn Center.The usefulness of autopsies in providing valuable clinical data for the treatment of burn patients is emphasized. The study also highlights a few missed diagnoses that may occur in burn patients. The prevalence of AH was shown to be higher than previously estimated in non-surviving patients with burns. This study also reveals that the emergency medical system is able to recognize the situations and patients more likely to benefit from physician attendance.
  • Ruohola, Juha-Petri (Helsingin yliopisto, 2007)
    Fatigue fracture is an overuse injury commonly encountered in military and sports medicine, and known to relate to intensive or recently intensified physical activity. Bone responds to increased stress by enhanced remodeling. If physical stress exceeds bone s capability to remodel, accumulation of microfractures can lead to bone fatigue and stress fracture. Clinical diagnosis of stress fractures is complex and based on patient s anamnesis and radiological imaging. Bone stress fractures are mostly low-risk injuries, healing well after non-operative management, yet, occurring in high-risk areas, stress fractures can progress to displacement, often necessitating surgical treatment and resulting in prolonged morbidity. In the current study, the role of vitamin D as a predisposing factor for fatigue fractures was assessed using serum 25OHD level as the index. The average serum 25OHD concentration was significantly lower in conscripts with fatigue fracture than in controls. Evaluating TRACP-5b bone resorption marker as indicator of fatigue fractures, patients with elevated serum TRACP-5b levels had eight times higher probability of sustaining a stress fracture than controls. Among the 154 patients with exercise induced anterior lower leg pain and no previous findings on plain radiography, MRI revealed a total of 143 bone stress injuries in 86 patients. In 99% of the cases, injuries were in the tibia, 57% in the distal third of the tibial shaft. In patients with injury, forty-nine (57%) patients exhibited bilateral stress injuries. In a 20-year follow-up, the incidence of femoral neck fatigue fractures prior to the Finnish Defence Forces new regimen in 1986 addressing prevention of these fractures was 20.8/100,000, but rose to 53.2/100,000 afterwards, a significant 2.6-fold increase. In nineteen subjects with displaced femoral neck fatigue fractures, ten early local complications (in first postoperative year) were evident, and after the first postoperative year, osteonecrosis of the femoral head in six and osteoarthritis of the hip in thirteen patients were found. It seems likely that low vitamin D levels are related to fatigue fractures, and that an increasing trend exists between TRACP-5b bone resorption marker elevation and fatigue fracture incidence. Though seldom detected by plain radiography, fatigue fractures often underlie unclear lower leg stress-related pain occurring in the distal parts of the tibia. Femoral neck fatigue fractures, when displaced, lead to long-term morbidity in a high percentage of patients, whereas, when non-displaced, they do not predispose patients to subsequent adverse complications. Importantly, an educational intervention can diminish the incidence of fracture displacement by enhancing awareness and providing instructions for earlier diagnosis of fatigue fractures.
  • Rouhe, Hanna (Helsingin yliopisto, 2015)
    Every 10th pregnant women suffers from severe fear of childbirth. It causes anxiety and physical symptoms during pregnancy, and may interfere with mother-infant bonding. Caesarean sections on maternal request are rising worldwide. The major indication is fear of childbirth. There is no clinical guideline regarding how to help these women. This present study was designed to investigate the background factors of fear of childbirth; to assess the methods to screen fear of childbirth; analyse the effect of group psycho-education on delivery mode, delivery experience, costs and postnatal psycho-social well-being; and also to evaluate the psychiatric morbidity of women with fear of childbirth. We tested the fear of childbirth questionnaire in the Finnish population and simultaneously gathered the obstetrical background information of 1,348 pregnant women. We used the Fear of Childbirth VAS for the first time in measuring fear of childbirth. With a cut-off of Fear of Childbirth VAS over 5.0, the sensitivity is 98%, and the specificity is 67% for severe fear of childbirth. Nulliparous women have more fear of childbirth than parous women. Women who were more afraid of childbirth preferred caesarean section as delivery mode. Women who had have previously delivered by caesarean section or had vacuum-assisted delivery, were more fearful. The Fear of Childbirth VAS is a simple method for screening fear of childbirth. In a register-based study, we analysed specialised care with psychiatric diagnoses and psychotropic medication of 2,500 women with fear of childbirth and 5,000 control women. The prevalence of mental health problems was higher (54%) among women with fear of childbirth than among control women (34%). The most common mental disorders were anxiety disorders and depression. Mental health problems should be acknowledged in maternity care. In randomised study, nulliparous women were screened for fear of childbirth, and 371 women with severe fear of childbirth were included in our study. These women were randomised into an intervention group and convetional care. The intervention consisted of six times of group psycho-education with mindfulness relaxation exercises led by a psychologist during pregnancy and one session postnatal. Women in the intervention group had more often normal vaginal delivery (63% vs. 48%) than women in the control group. The childbirth experience was less frightening for women in the intervention group, regardless of the delivery mode. Group psycho-education improved maternal adjustment and reduced the risk of postnatal depressive symptoms. The costs of group psycho-education were saved in delivery costs, and thus this treatment causes no additional expenses to conventional care. By providing nulliparous women with group psycho-education, more resources can be appointed to parous women with fear of childbirth in special maternity care.
  • Rönkä, Riitta (Helsingin yliopisto, 2004)
  • Räsänen, Kati (Helsingin yliopisto, 2010)
    Paracrine regulation between the components of the tumour microenvironment cancer cells, activated fibroblasts, immune and endothelial cells is under intense investigation. The signals between the different cell types are mediated by soluble factors, such as growth factors, proinflammatory cytokines and proteolytic enzymes. Nemosis is an experimental in vitro model of fibroblast activation, leading to increased production of such mediators. Nemotic activation of fibroblasts occurs as they are forced to cluster thereby forming a multicellular spheroid. The aim of the present studies was to elucidate the mechanisms underlying the nemotic response of cancer-associated fibroblasts (CAF) and the role of nemosis in paracrine regulation between activated fibroblasts and benign and malignant epithelial cells. The results presented in this thesis demonstrate that the nemotic response of CAFs and normal fibroblasts differs, and inter-individual variations exist between fibroblast populations. In co-culture experiments, fibroblasts increased colony formation of squamous cell carcinoma (SCC) cells, and CAFs further augmented this, highlighting the tumour-evolving properties of CAFs. Furthermore, fibroblast monolayers in those co-cultures started to cluster spontaneously. This kind of spontaneous nemosis response might take place also in vivo, although more direct evidence of this still needs to be obtained. The HaCaT skin carcinoma progression model was used to study the effects of benign and malignant keratinocytes on fibroblast nemosis. Benign HaCaT cells inhibited fibroblast nemosis, observed as inhibition of cyclooxygenase 2 (COX-2) induction in nemotic spheroids. In contrast, malignant HaCaTs further augmented the nemotic response by increasing expression of COX-2 and the growth factors hepatocyte growth factor / scatter factor (HGF/SF) and vascular endothelial growth factor (VEGF), as well as causing a myofibroblastic differentiation of nemotic fibroblasts into fibroblasts resembling CAFs. On the other side of this reciprocal signalling, factors secreted into conditioned medium by the nemotic fibroblasts promoted proliferation and motility of the HaCaT cell lines. Notably, the nemotic fibroblast medium increased the expression of p63, a transcription factor linked to carcinogenesis, also in the highly metastatic HaCaT cells. These results emphasize the paracrine role of factors secreted by activated fibroblasts in driving tumour progression. We also investigated the epithelial-mesenchymal transition (EMT) of the HaCaT clones in response to transforming growth factor β (TGF-β), which is a well-characterized inducer of EMT. TGF-β caused growth arrest and loss of epithelial cell junctions in the HaCaT derivatives, but mesenchymal markers were not induced, suggesting a partial, but not complete EMT response. Inflammation induced by COX-2 has been proposed to be a key mechanism in EMT of benign cells. Corroborating this notion, COX-2 was induced only in benign, not in malignant HaCaT derivatives. Furthermore, in cells in which TGF-β caused COX-2 induction, migration was clearly augmented. The concept of treating cancer is changing from targeting solely the cancer cells to targeting the whole microenvironment. The results of this work emphasise the role of activated fibroblasts in cancer progression and that CAFs should also be taken into consideration in the treatment of cancer. The results from these studies suggests that nemosis could be used as a diagnostic tool to distinguish in vitro activated fibroblasts from tumour stroma and also in studying the paracrine signalling that is mediated to other cell types via soluble factors.
  • Markkula, Ritva (Helsingin yliopisto, 2014)
    Fibromyalgia: Background factors and impact on mortality and ability to work The aim was to update the prevalence of fibromyalgia (FM) symptoms, their predictors, and their impact on mortality and ability to work, in an epidemiologically representative cohort. For this we used the older Finnish Twin Cohort, which enabled evaluation of genetic backgrounds, as well. This cohort (originally 17 357 twins born before 1958) participated in three surveys with extensive health questionnaires in 1975, 1981, and 1990; response rates were 89%, 84%, and 77%. Applying their responses and clinical FM patients´ responses to an FM question-set from 1990, we could classify this cohort into three latent symptom classes: LC1 with no or few FM-associated symptoms, LC2 with some symptoms, and LC3 with a high number of symptoms, resembling FM patients and thus serving as a proxy for FM. Of all responders, almost equally from each gender 13% were classified into LC3. The statistical analyses estimated heritability behind this symptom classification as 51% (95% CI 45-56%). Of the suggested risk factors (assessed by the surveys in 1975 and 1981), what emerged as independent predictors of FM-associated symptoms (LC3) were headache and back and neck pain. Obesity or high body mass index and sleep problems also predicted FM symptoms, but confounding by familial factors seemed probable. For analysis of disability retirement, 8 448 individuals at risk remained after exclusions, and for analysis of mortality, 9 759. During the 14-year follow-up, the cumulative incidence for disability retirement in general was 6.8% in LC1, 10.6% in LC2, and 25.7% in LC3. The multi-adjusted hazard ratio for general disability retirement in LC3 was three-fold and for musculoskeletal disability five-fold that in LC1. As for mortality, the follow-up lasted 19 years and revealed the age- and gender-adjusted hazard ratio of death to be 1.4 (95% CI 1.2-1.8) in LC3 and 1.2 (95% CI 1.0-1.4) in LC2. This excess risk disappeared with further adjustment for lifestyle factors: smoking, alcohol intake, and body mass index. FM symptoms and associated lifestyle factors and co-morbidities require active management in health-care systems, not only to alleviate individual suffering, but also to prevent disability and increased mortality. Further research is essential to clarify whether early active management of confirmed risk factors would prevent FM-symptom development.
  • Salmenperä, Pertteli (Helsingin yliopisto, 2012)
    Cancer is a complex disease. It is a multistep process where genetic changes lead to cellular transformation and uncontrolled proliferation. However, cancer is not only a disease of these transformed cells, since tumor stroma and microenvironment synchronously evolve and become activated together with these genetic changes. The interactions between different cell types in tumor microenvironment are mediated by soluble factors, such as cytokines, chemokines, growth factors and proteases. They modulate cell proliferation, activation and differentiation, as well as the composition of the extracellular matrix in tumor and its microenvironment. Nemosis is an in vitro model of fibroblast activation, which is initiated by forcing fibroblast to cluster together instead of providing solid support for attachment. This results in a multicellular spheroid that upregulates soluble paracrine molecules known to be important mediators of tumor microenvironment. Furthermore, nemotic fibroblasts affect cancer cell proliferation, invasion and differentiation through these soluble factors. In addition to direct effects on cancer cells they stimulate angiogenesis and the chemotaxis of leukocytes. This thesis study shows that fibroblast spheroid formation depends on the interaction between fibronectin (FN) with its integrin receptors, more accurately α5 and β1 integrin subunits, whereas fibroblasts activation in spheroids was mediated by the interaction of FN with α5, αV and β1 integrin subunits. The activation was mediated by the binding of integrins to the RGD -motif in FN molecules and the synergy site that is known to stimulate RGD-motif binding to integrins enhanced it. Unexpectedly, FN-matrix assembly was not essential for the activation of fibroblasts in spheroids although it had an effect on spheroid formation. FN deposit to matrix is an acknowledged consequence of integrin binding to fibronectin. Nemosis was accompanied by a dramatic change in gene expression. The change could be roughly categorized in three classes; the upregulation of secreted molecules and downregulation of cell cycle and cytoskeleton. Nemosis was associated with a quiescent withdrawal from the cell cycle, as the cells downregulated cyclin D and upregulated p27, the driver and the inhibitor of the cell cycle, respectively. Furthermore, nemotic fibroblasts resumed to the cell cycle when taken out from the spheroid, indicating reversible cell cycle arrest, a known characteristic of quiescence. Fibroblast activation by spheroid formation was accompanied by stress-related changes in the cellular ultrastructure, such as dilated endoplasmic reticulum, increased lipofuscin and degenerated organelles. Hence, nemosis is a cellular stress response. This observation was in agreement with the induction of autophagy in fibroblasts spheroids. Autophagy is a well-known stress response that helps cell survival under stress conditions. Furthermore, nemosis resembled another cellular stress condition, the cellular senescence. They both had a similar secretory phenotype, expressed senescence-associated β-galactosidase and lipofuscin, and there was a cell cycle arrest in both. However, there were also features to distinguish nemosis from senescence, such as nemosis being a reversible phenotype, and cell cycle inhibitors that regulate senescence being downregulated in nemosis. Nemosis attenuated tumor growth in vivo in a mouse xenograft model. The attenuation was associated with the expression of senescence-associated β-galactosidase and the expression of the p14ARF cell-cycle inhibitor in human RT3 malignant keratinocytes. This suggests that nemosis causes cellular senescence in the RT3 keratinocytes in vivo. In addition to the senescence response, nemosis was found to increase the cytokeratin-7 (CK7) mediated differentiation of RT3 cells in xenografts. It is becoming obvious that cancer is not just a disease of uncontrolled proliferation of cancer cells, but a disease where normal stromal fibroblasts actively participate in its progression. The current work reveals new mechanistic insights of fibroblast activation and concludes that nemosis can be a useful model to study the activation of fibroblasts and interactions between fibroblasts and cancer cells.
  • Erra, Elina (Helsingin yliopisto, 2013)
    The mosquito-borne flavivirus infections Japanese encephalitis (JE) and dengue pose a considerable disease burden in the tropical and subtropical regions of the world. Sometimes these infections also affect international travelers visiting areas endemic for the diseases. This thesis addresses the prevention of Japanese encephalitis and diagnostics of dengue, with a focus on traveler s health. The main aim was to find solutions to some practical clinical questions, and thus provide clinically important new data on travel-associated flavivirus infections. The first three studies assessed the immunogenicity of two inactivated JE vaccines, the new Vero cell derived (JE-VC) and the traditional mouse brain derived (JE-MB) preparation, in 120 Finnish and Swedish adult travelers, by determining the pre- and post-vaccination titers of JE virus neutralizing antibodies with plaque-reduction neutralization test (PRNT). A PRNT50 titer ≥10 was considered protective. Study I addressed the boosting capacity of the SA14-14-2 based JE-VC vaccine in subjects previously primed with the Nakayama strain based JE-MB preparation. The response rates were 91% after a homologous (JE-MB) and 95%-98% after a heterologous booster dose (JE-VC). Among those with no seroprotection at baseline, a higher proportion of JE-MB primed (100%) than non-primed (40%) subjects seroconverted after a single JE-VC dose. The data suggest that a single JE-VC dose suffices for boosting JE-MB immunity, and call for re-evaluation of guidelines recommending two JE-VC doses for JE-MB primed subjects. Study II demonstrated that both JE-VC and JE-MB elicit neutralizing antibodies, not only against the vaccine genotype, but also against heterologous JE virus genotypes. The seroprotection rates against the heterologous strains were 93%-97% after JE-VC, and 83%-92% after JE-MB primary series. The data imply that the two vaccines are expected to confer seroprotection against all major JE virus genotypes circulating. Study III evaluated long-term seroprotection after JE-VC primary and booster vaccinations. Two years after primary immunization, 93% of vaccinees were seroprotected against the vaccine strain but only 73% against the emerging genotype GI. JE-MB primed vaccinees were seroprotected against both vaccine (100%) and non-vaccine (89%-95%) genotype strains two years after the heterologous JE-VC booster dose, further supporting the use of a single JE-VC dose for boosting JE-MB immunity. Study IV explored the diagnostic markers of dengue in 93 Finnish traveler patients. The duration of viremia (9 days, 95% CI: 8-10) and NS1 antigenemia (15 days, 95% CI: 12-20) were longer than reported in endemic settings, presumably due to a high proportion of primary infections among travelers. The data support use of test combinations, e.g. antibody and NS1 detection, for efficient diagnostics. The relative levels of viremia and NS1 antigenemia were associated with some central clinical parameters, suggesting these virologic markers as predictors of the clinical manifestations in travelers dengue.
  • Heikkilä, Annukka (Helsingin yliopisto, 2013)
    Follicular thyroid carcinoma (FTC) is the second most common malignancy of the thyroid gland, with predisposing genetic alterations such as rat sarcoma (RAS) mutation and paired box gene 8-peroxisome proliferator-activated receptor γ (PAX-PPARγ) alteration, as well as suggested risk factors such as iodine insufficiency and female gender. Distinguishing FTC from the most common neoplasm of the thyroid, follicular thyroid adenoma (FTA), or even from a non-neoplastic goitrous nodule, is often impossible preoperatively, leading to unnecessary surgery and exposing patients to surgical complications. In this study, 127 follicular thyroid neoplasia patients (83 FTAs and 44 FTCs) treated at Helsinki University Central Hospital (HUCH) in Finland between 1990 and 2009 were examined to find methods for differential diagnosis between follicular thyroid lesions. Tissue markers were investigated by immunohistochemistry in follicular neoplasms and non-neoplastic control tissues, and were correlated with clinical parameters, such as with metastatic disease and survival. Additionally, cancer registry data were gathered, concerning the diminishing incidence of FTC accompanied by an increase in the incidence of papillary thyroid carcinoma. Carcinomas were reanalysed according to the new World Health Organization classification of endocrine tumours, in which a new tumour entity, poorly differentiated carcinoma of the thyroid, was introduced. Markers with possible clinical utility were found; e.g. in an attempt to differentiate between non-neoplastic and neoplastic follicular lesions of the thyroid (HES5) as well as between FTA and FTC (MIB-1, Cyclin D1, TLR-2, ERβ), a marker with prognostic value in carcinomas (ERβ), as well as a marker correlating with the presence of metastatic disease (TLR-4). These results aid in the challenging field of diagnostics in follicular thyroid lesions. Measuring the expression of HES5 may help in differentiating between neoplastic and non-neoplastic follicular thyroid lesions. Markers, such as MIB-1 and ERβ, are partly able to differentiate between benign and malignant follicular thyroid neoplasias, whereas ERβ and TLR-4 have prognostic value in FTC.