Lääketieteellinen tiedekunta

 

Recent Submissions

  • Louhimo, Riku (Helsingin yliopisto, 2015)
    Cancer is one of the leading causes of death in industrialized nations and its incidence is steadily increasing due to population aging. Cancer constitutes a group of diseases characterized by unwanted cellular growth which results from random genomic alterations and environmental exposure. Diverse genomic and epigenomic alterations separately and jointly regulate gene expression and stimulate and support neoplastic growth. More effective treatment, earlier and more accurate diagnosis, and improved management of cancer are important for public health and well-being. Technological improvements in data measurement, storing and transport capability are transforming cancer research to a data-intensive field. The large increases in the quality and quantity of data for the analysis and interpretation of experiments has made employing computational and statistical tools necessary. Data integration - the combination of different types of measurement data - is a valuable computational tool for cancer research because data integration improves the interpretability of data-driven analytics and can thereby provide novel prognostic markers and drug targets. I have developed two computational data integration tools for large-scale genomic data and a simulator framework for testing a specific type of data integration algorithm. The first computational method, CNAmet, enhances the interpretation of genomic analysis results by integrating three data levels: gene expression, copy-number alteration, and DNA methylation. The second computational method, GOPredict, uses a knowledge discovery approach to prioritize drugs for patient cohorts thereby stratifying patients into potentitally drug-sensitive subgroups. Using the simulator framework, we are able to compare the performance of integration algorithms which integrate gene copy-number data with gene expression data to find putative cancer genes. Our experimental results indicate in simulated, cell line, and primary tumor data that well-performing integration algorithms for gene copy-number and expression data use and process genomic data appropriately. Applying these methods to diffuse large B-cell lymphoma, integrative analysis of copy-number and expression data helps to uncover a gene with putative prognostic utility. Furthermore, analysis of glioblastoma brain cancer data with CNAmet suggests that a number of known cancer genes, including the epidermal growth factor receptor, are highly expressed due to co-occuring alterations in their promoter DNA methylation and copy-number. Finally, integration of publicly available molecular and literature data with GOPredict suggests that treating patients with FGFR inhibitors in breast cancer and CDK inhibitors in ovarian cancer could support standard drug therapies. Collectively, the methods developed here and their application to varied molecular cancer data sets illustrates the benefits of data integration in cancer genomics.
  • Bourbia, Nora (Helsingin yliopisto, 2015)
    The central nucleus of amygdala (CeA) is known to be involved in pain and nociception, but the mechanisms or its role in descending control of pain-related behavior is poorly understood. The aim of this study was to investigate the involvement of the neuropeptide corticotropin-releasing factor (CRF) and the glutamatergic system of the CeA in pain and nociception in healthy control animals and in an animal model of chronic neuropathic pain induced by spared-nerve injury (SNI). Two aspects of pain were studied: emotional-like pain behavior was assessed by using the aversive place-avoidance paradigm and sensory-discriminative was assessed by determining the mechanical limb-withdrawal threshold and the thermal (heat) limb-withdrawal latency. Moreover, the aims were to determine whether medullospinal serotoninergic pathways and the midbrain periaqueductal grey (PAG), respectively, were involved in relaying pain-modulation induced by the CeA in SNI and healthy control animals. Additionally, hemisphere of the CeA and submodality of pain stimulus were among studied parameters. Surgical procedures and electrophysiological recordings were performed under general anesthesia. The studies on the role of the CeA in the emotional-like aspect of pain in SNI rats revealed that activation and blocking of the group I metabotropic glutamate receptors (mGluRs) facilitates and inhibits, respectively, the aversive aspect of pain. Furthermore, increase of endogenous CRF as well as blocking glutamatergic N-methyl-D-aspartate (NMDA) receptors in the CeA reduced the aversive aspect of neuropathic pain. The studies on the sensory-discriminative aspect of pain revealed that an increase of endogenous CRF in the CeA is pronociceptive in both control and SNI rats. CeA injection of a high dose of glutamate had a mechanical antinociceptive effect that was mediated by NMDA receptors in healthy but not SNI rats. A low dose of glutamate had a pronociceptive effect mediated by NMDA receptors in SNI rats. Furthermore, tonic descending pronociception induced by NMDA receptors and the mGluR1 in the CeA contributes to the maintenance of neuropathic hypersensitivity. The investigation on the role of serotonergic neurons of the rostroventromedial medulla (RVM) in modulation of spinal nociception by amygdaloid glutamate in SNI rats indicated that the RVM is a relay for both descending pro- and antinociceptive effects from the CeA. The investigation on the role of the PAG in the descending control of nociception induced by glutamate in the CeA of healthy rats indicated that the PAG is a relay in the descending control of nociception induced by amygdaloid glutamate. Furthermore, the right-hemispheric lateralization of the pronociceptive effect by amygdaloid CRF in controls was lost in SNI rats. However, descending antinociception induced by the glutamatergic system of the CeA showed no hemispheric lateralization in healthy controls; a high dose of glutamate in both the left and right CeA induced equal attenuations of mechanical and thermal nociception, which effects were, respectively, NMDA-dependent and NDMA-independent.
  • Parnov Reichhardt, Martin (Helsingin yliopisto, 2015)
    To live a healthy life, humans need to co-exist with foreign organisms. These consist of the thousands of different types of microbes that colonize the human body. But also, in the case of a pregnant woman, the fetus can be viewed as a foreign organism. To avoid disease, the barriers of the human body, e.g. the mucosal surfaces, must be maintained. Here the innate immune defense system plays an important role. The salivary scavenger and agglutinin (SALSA), also known as gp340, DMBT1 and SAG, is a molecule found at most mucosal surfaces. SALSA is associated with the epithelium or secreted into the lining fluids, such as tears, saliva and mucus in the respiratory tract. SALSA is known to bind and agglutinate a broad spectrum of bacteria, as well as viruses, and thus play a role in the innate immune defense against invading microbes. The effect of SALSA is mediated in concert with several other defense molecules such as IgA, surfactant proteins A and D, and the complement component C1q. These have all been shown to be ligands of SALSA. Alongside the role of SALSA in innate immunity, evidence for a function in epithelial and stem cell differentiation has emerged. This thesis work has addressed the function of SALSA in innate immunity, especially in early life. SALSA was found in the amniotic fluid and in meconium and feces of newborns. In fact, SALSA was among the most abundant proteins in the intestines of newborn children. By comparing the SALSA protein in the different samples we found size polymorphisms, varying from one individual to another, but also from compartment to compartment within the same individual. These differences were found to alter the ability of SALSA to bind known endogenous and bacterial ligands. SALSA was also found to be expressed in the human placental and decidual tissues. In the 1st trimester of pregnancy, SALSA was detected sporadically in maternal decidual capillaries. Closer to term SALSA was found to be expressed by the syncytiotrophoblast layer of the placental villous trees. In certain sites, e.g. at disrupted and damaged areas of the syncytium, SALSA was found deposited into fibrinoid formations. It partially co-localized with the fibrinoid component fibronectin. Complement activation has been observed at the feto-maternal interface of both healthy and complicated pregnancies. SALSA had previously been found to bind C1q. Thus, it was of interest to investigate the ability of SALSA to interact directly with the complement system. We found that SALSA bound to both mannan-binding lectin and to some extent to all three ficolins (H, L and M). SALSA activated complement, when it was bound to a surface. In contrast, fluid-phase SALSA was able to inhibit the deposition of complement on SALSA non-binding microbial surfaces. It thus acted in dual fashion to target complement attack. In the human placenta we observed C1q-targeting of the SALSA-positive fibrinoid formations. C1q and complement are known to function in the clearance of apoptotic cells and debris. Thereby SALSA and complement probably have a cooperative function in the containment and clearance of the injured structures, thus linking its innate immune activity with the maintenance of tissue homeostasis.
  • Sandboge, Samuel (Helsingin yliopisto, 2015)
    Background. A small birth size, an indicator of a suboptimal intrauterine environment, is a risk factor for several non-communicable diseases (NCDs), a risk that in many cases is modified by childhood growth patterns. Regional variation in NCD prevalence could partly have its origin in early development. Lifestyle factors further influence NCD prevalence. Aims. We aimed to explore the associations between early growth and adult resting metabolic rate (RMR), body composition, non-alcoholic fatty liver disease (NAFLD), and hypertension. We also studied the associations between fructose intake and NAFLD, and differences in birth size between Helsinki and the Åland Islands. Subjects and methods. The Helsinki Birth Cohort Study consists of 13345 individuals born in Helsinki in 1934‒44. Detailed records are available for all participants including information on maternal and birth characteristics and measurements of childhood body size. 2003 individuals participated in a clinical study in 2001‒04 and 1083 of these additionally participated in a follow-up study in 2006‒08. The Åland records include 1697 births for the years 1937‒44. Results. The association between birth weight and RMR was inverse among women and quadratic among men. A higher attained adult weight than expected, based on weight and height measurements before age 11 years and adult height, was associated with higher adult body fat content. The odds ratio (OR) for NAFLD was 18.5 (95% CI 10.1; 33.6) among those who belonged to the lowest BMI tertile at age 2 years and subsequently were obese as adults, compared to those who were still lean or normal weight as adults. NAFLD was most common among individuals with the lowest dietary fructose intake. Systolic blood pressure (SBP) and the presence of hypertension were inversely associated with linear (height) growth between ages 2 and 11 years. Relative weight gain after age 11 years was positively associated with SBP. Ålandic babies born 1937‒44 were 87 grams (95% CI 61; 111) heavier and 0.4 cm (95% CI 0.3; 0.5) longer than their Helsinki peers. Conclusions. A more pronounced increase in relative weight after age 11 years than would be expected from previous body size, was positively associated with body fat content, NAFLD, and hypertension. Conversely, several growth measurements before age 11 years were negatively associated with the outcomes studied. None of the studied individuals were obese in childhood. Instead, a larger relative childhood body size in this group most likely represents a more beneficial childhood environment. Contrary to previous findings, we found that individuals with the highest fructose intake were least likely to suffer from NAFLD. We found a small but significant difference in birth size between the Åland Islands and Helsinki for the years 1937‒44.
  • Pekkonen, Pirita (Helsingin yliopisto, 2015)
    Human tumorigenesis is a process in which a normal cell needs to acquire multiple characteristics to become malignant and metastatic. In short, these so called cancer hallmarks include increased proliferation and cell survival, as well as the ability to invade into the surroundings, induce angiogenesis, and finally metastasize to distant sites. These traits are regulated in a variety of different ways. However, some embryonic signaling pathways, including the Notch pathway, are able to regulate many of these processes. Furthermore, it has been shown that these signaling pathways can be deregulated in cancer, and that their untimely activation can lead to malignancies. In this study, Kaposi's sarcoma herpesvirus (KSHV) associated malignancies, namely Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), as well as melanoma have been used as model cancers. In all these malignancies, the tumor cells show alterations in cell identity and lineage marker expression, i.e. signs of cellular de- or transdifferentiation. In addition, the Notch pathway has been shown to be overly active in all of them. Thus, this thesis has focused on how the pro-tumorigenic traits are affected by cell plasticity and reprogramming in these cancers, and how the signaling pathways leading to these phenotypes, most notably Notch, are in turn regulated. Firstly, the results show that in vivo expression of a KSHV oncogene, viral (v-)cyclin, leads to activation of Notch signaling through Notch3 upregulation as well as fine-tuning of the NF-κB pathway through Cdk6 mediated phosphorylation. These changes in turn lead to defects in T-lymphocyte differentiation and immune functions, as well as to the development of T-cell lymphomas. Secondly, this work demonstrates that KSHV infection in primary lymphatic endothelial cells (LECs) in three dimensional (3D) cell culture model leads to activation of a morphogenic process, endothelial to mesenchymal transition (EndMT), and increased invasiveness through activation of the Notch pathway and matrix metalloproteinase MT1-MMP. Lastly, the data show that the changes in cell plasticity contributing to tumorigenic traits are not confined to virally induced cancers. Melanoma cell interaction with LECs leads to activation of the Notch pathway and increased adhesive, invasive, and metastatic properties of the tumor cells. In conclusion, the results show that regulation of cell plasticity through the Notch pathway takes place in different types of cancers, and it can affect several steps of tumorigenesis. A thorough and comprehensive understanding of the processes discovered herein may help develop better and more efficient treatments for these largely fatal malignancies.
  • Kanduri, Chakravarthi (Helsingin yliopisto, 2015)
    Music perception and performance form a useful tool for studying the normal functioning of the human brain. The abundance of neuroscientific literature has demonstrated that music perception and performance alter the human brain structure and function and induce physiological changes through neurochemical modulation. Emerging evidence from molecular genetic studies have suggested a substantial genetic component in musical aptitude and related traits like creativity in music. This thesis puts a step forward in understanding the molecular genetic background of music perception and performance, using a combination of genomics and bioinformatics approaches. Specifically, the role of copy number variations (CNVs; a form of genetic variation) in musical aptitude and creativity in music was investigated both in the largest families of the MUSGEN-project and also in sporadic cases. The effects of listening to music and performing music by playing an instrument on human transcriptional responses were also investigated. The genome-wide CNV analysis principally identified genes like GALM, PCDHA1-9 as the possible candidate genes that could affect musical aptitude and creativity in music. PCDHA1-9 and GALM genes are known to regulate the serotonergic system, which is responsible for neurocognitive and motor functions, the essential biological processes of music related traits. Overall, the detected genes affect neurodevelopment, learning, memory and serotonergic functions. The findings also demonstrated that large and rare CNV burden does not affect normal traits like musical aptitude. Both listening to music and performing music enhanced the activity of genes that are known to be involved in dopaminergic neurotransmission, neuroplasticity, learning, and memory. Most importantly, one of the most up-regulated genes in both studies - synuclein alpha (SNCA) and its upstream transcription regulator GATA2, are located on chromosomal regions 4q22.1 and 3q21 respectively linking the strongest linkage and associated regions of musical aptitude together. In addition, several of the up-regulated genes in both the studies (like SNCA, FOS, and DUSP1) have been known to be regulated during song learning and singing in songbirds, suggesting a possible evolutionary conservation of genes related to sound perception and production. These novel findings give preliminary information about the genes associated with musical aptitude and the effect of music on the human body. It is obvious that replication studies are required to confirm the results. These pioneering findings could guide further research on the molecular genetics of music perception and performance in humans. These findings will also enhance our understanding of the genetic bases of cognitive traits, the evolution of music and music therapy.
  • Kauppi, Juha (Helsingin yliopisto, 2015)
    Adenocarcinoma (AC) of the esophagus and esophagogastric junction (EGJ) is a disease with poor prognosis and increasing incidence in western countries. Its pathogenesis is associated with oxidative stress (OS) in the esophageal epithelium. Long-term survival is associated with successful radical surgery, early stage of the disease, and successful downstaging with neoadjuvant therapy. As surgery is accompanied with a large number of possible complications, it is essential to identify patients who might not benefit from surgery and on the other hand, could be treated with less invasive options. The aims of this study were 1) to assess the role of OS below EGJ in the pathogenesis of Barrett s esophagus (BE) and AC, 2) to assess the prognoses and causes of death in early esophageal AC, 3) to determine the value of 18F-fluorodeoxy-D-glucose positron emission tomography with computed tomography (FDG-PET-CT) in quantifying the response to neoadjuvant therapy and 4) to compare the novel mini-invasive technique (MIE) to traditional open esophagectomy (OE) in radical surgery. To quantify OS, we measured 8-isoprostane (8-IP), glutathione content (GSH), and 8-OH- deoxyglucose (8-OHdG) values from mucosa below EGJ, BE-mucosa, and AC-tumors from 43 patients with BE and/or AC and compared them to samples from corresponding sites of 15 healthy control patients. To determine the long-term prognosis of patients with early esophageal AC, we studied patient records and causes of deaths for 85 patients, treated with radical esophagectomy over a 27-year time span. To evaluate pre-treatment response to neoadjuvant therapy in locally advanced AC, we recorded FDG-PET-CT results before and after induction therapy in sixty-six consecutive patients who were to be operated on for locally advanced AC. Decrement in radioactive glucose uptake values was associated with survival and histological treatment response. We compared MIE to OE, to see, if minimal invasiveness reduces the rate of complications and if they are comparable in terms of oncologic radicality and survival. Proximal gastric GSH content was lower and 8-IP and 8-OHdG levels higher with statistical significance in the study patients (BE and AC) as compared to healthy controls. In patients with early esophageal AC, overall and long-term (>5 year) survival rates were mostly affected by diseases related to aging. During the first five years after the operations, disease recurrence was the most common cause of death. However, recurrence-free survival was 80% at five years and no new recurrences were detected after that. Microscopic eradication of locally advanced AC was optimally predicted by a 67% decrease in uptake values before and after induction chemotherapy, with a sensitivity of 79% and specificity of 75%. However, this association was not linear and complete eradication of radioactive glucose uptake, was not always associated with a complete histologic response. However, a decrease in glucose uptake was associated with improved overall and recurrence free survival. MIE and OE were equivalent in terms of 90-day mortality, pneumonia-, leak-, and overall complication rates. Also a minimally invasive technique was associated with significantly shorter overall hospital stay and significantly less blood loss during the operations. OS levels are also elevated below the EGJ, as lipid peroxidation can be detected (8-IP) and antioxidant defense (GSH) is reduced. Also the levels of 8-OHdG adducts were higher showing that DNA is being damaged by free radicals. This suggests that inflammation of the proximal gastric mucosa induced by gastroduodenal content, has a role in the pathogenesis of BE and esophageal AC. As the prognoses for patients with early esophageal AC were good, recurrence was still the most important cause of death. The risk was highest for patients with lymph node metastases and deep submucosal infiltration. Therefore radical surgery should be preferred with patients with a low risk of surgical complications and submucosal infiltration. In patients with intramucosal AC, endoscopic ablation should be considered. Evaluation of the patients responses to induction chemotherapy with FDG-PET-CT was not accurate enough to give indications better than the exclusion of metastatic disease. However, a significant decrease in radioactive glucose uptake was associated with improved survival, independently of histopathologic response. This information can be useful when balancing the risks of surgery against expected benefits. The perioperative and oncological results for MIE were comparable to those of the open approach and MIE seems to shorten hospital stay. However, the MIE technique is demanding and its mastery requires a sufficient number of cases and skilled practitioners.
  • Haapaniemi, Emma (Helsingin yliopisto, 2015)
    Primary immunodeficiency diseases (PIDD) compromise a heterogeneous group of clinical entities, ranging from isolated susceptibility for certain pathogen to widespread, early-onset infections or overwhelming autoimmunity. Although rare, PIDDs cause significant morbidity and mortality. Over 300 genes are associated with PIDD development, and multiple gene defects can cause a similar phenotype. On the other hand, phenotypes caused by the same mutation can vary considerably even between family members. Therefore, genetic diagnostics in PIDD is challenging with standard candidate gene approach. In this study, three novel primary immunodeficiency conditions are characterized: early-onset multiorgan autoimmune disease caused by STAT3 hyperactivity, combined immunodeficiency as due to DOCK2 deficiency, and generalized infection susceptibility caused by recessive HYOU1 mutations. The mutations were discovered using exome sequencing. In the first and second part of this study, the authors studied a cohort of six patients with missense STAT3 mutations that were shown to be activating by luciferase reporter assay. The patients presented with multi-organ autoimmunity that commonly started in infancy. Additionally, some had lymphoproliferation and developed hypogammaglobulinemia in their teens, and one patient had delayed-onset mycobacterial disease. Three patients were immunologically characterized. They showed peripheral eosinopenia and deficiency of regulatory T cells, T helper 17 cells, NK cells, and dendritic cells. Notably, one patient developed large granular lymphocyte (LGL) leukemia at age 14 and another had LGL cells in her bone marrow without clinical disease. In third part of the study, compound heterozygous DOCK2 mutations were identified in a patient that showed mild hematological autoimmunity and susceptibility to bacterial and viral infections. Four additional patients with a similar phenotype and homozygous DOCK2 mutations were subsequently independently identified in four additional research groups in US, Austria, and France. All patients showed profound lymphopenia with defective B, T and NK cell responses, and invasive viral and bacterial infections that were fatal without stem cell transplantation. Finally, a patient with anemia and combined deficiency of granulocytes, B cells and dendritic cells was studied. She presented with severe early-onset bacterial and herpetic infections and stressinduced hypoglycemic episodes. She was found to harbor compound heterozygous mutations in HYOU1, an endoplasmic reticulum chaperone, and the mutations altered HYOU1 substrate binding specificity. The defective HYOU1 function compromised the redox balance in patient neutrophils and skin fibroblasts, and led to altered endoplasmic reticulum stress response. This study shows that next generation sequencing tools such as exome sequencing are powerful in PIDD diagnostics. With these techniques it is possible to identify causal variants even in situations where only a single individual is affected. The results show that monogenic immunological conditions have considerable phenotypic variation even between patients with similar gene defects. The study also identifies novel genes with previously undescribed roles in human immunity, and broadens the general understanding of human immunobiology.
  • Laaksonen, Esti (Helsingin yliopisto, 2015)
    The estimated number of heavy consumers of alcohol is about 20 percent of population, of which 10 percent suffer from alcohol dependency. Many heavy consumers of alcohol also smoke. The effectiveness of treatments can be significantly improved with medical treatment. The problems are: how medical treatment can be utilized in practical treatment, and how to ensure treatment adherence. The aim of this study was to investigate the effectiveness of pharmacotherapies combined with a brief manual-based cognitive-behavioural intervention (CBT) in treating alcohol-dependent patients. In the large-scale clinical treatment study, which ran for 2.5 years, the effectiveness and patient response to the three drugs (naltrexone, acamprosate and disulfiram) were compared. The study used a survey drawn up guidebook for patients, Winning at last defeating the drinking problem. In addition, we researched how the reduced alcohol consumption affects the quality of life, mood and smoking. In the study of sweet preference we analyzed possible associations between sweet preference and efficacy of naltrexone treatment. In addition, we researched patients treatment adherence and medication adherence to targeted naltrexone, as well as reduction of problem drinking and craving. This combined treatment (medication and CBT) significantly reduced alcohol consumption resulting in improved quality of life. Noticeable is that compared to the other study medicines, especially during the continuous medication period, supervised disulfiram appeared superior. During the targeted medication period, there were no other significant differences between the groups except for that the abstinence days were significantly more frequent in the disulfiram group. The treatment was also associated with success in quitting smoking among patients using disulfiram. The study of sweet preference, it was significantly related to treatment measures in the naltrexone group when the outcome was relapses to heavy drinking. Our study offers a possible new explanation of the clinical observation that naltrexone is not effective for every patient. Adherence to the targeted use of naltrexone added treatment compliance and efficacy of the medicine. Patients who had less symptoms of alcohol dependence, suffered from high craving for alcohol, were unemployment, young or could not keep the drinking diary were less committed to treatment. Problem drinking can be changed to abstinence or moderate drinking with the combination of medical therapy, CBT and good treatment commitment. The benefits of treatments are probably long-term, because part of the positive results lasted over two years. The treatment methods used in this study were usable and they can be implemented in all levels of Finnish health care.
  • Al-Samadi, Ahmed (Helsingin yliopisto, 2015)
    Recurrent aphthous ulcer (RAU) is an ulcerative disease of the oral mucosa characterised by the appearance of ulcerations in the oral mucosa accompanied by an erythematous halo area surrounding the ulcer and showing signs of acute inflammation. While RAU affects approximately 20% of the population globally, its pathogenesis remains poorly understood. Furthermore, most studies concentrate on treatment while few address the pathogenesis of the disease. This project aimed to determine the mechanisms of oral epithelial cell death in RAU, the role of these cells in disease pathogenesis in terms of toll-like receptor (TLR) expression, and the ability of the these cells to produce chemokines, pro-inflammatory cytokines, and antimicrobial peptides. Together these may first aggravate and, then, down-regulate the inflammation and initiate the healing process. For this purpose, we collected 13 aphthae and 11 healthy control biopsies for immunohistochemical staining, immunofluorescence staining, and quantitative PCR. For functional studies, we cultured primary oral keratinocytes and oral squamous cell carcinoma cell-line SCC-25 and tested their responses to different stimuli. Our results highlight the importance of oral epithelial cells in RAU; interestingly, oral epithelial cells in RAU tested positive for apoptosis markers caspase-3, especially at the superficial and spinous layer, and TUNEL, but negative in controls. We also found that TLRs are primarily present in the basal and suprabasal layers of control epithelium, but their expression extends to the superficial layer in RAU epithelium. Additionally, we found significally higher expressions of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-17C, and beta defensin 2 (BD-2) in RAU oral epithelium compared with control epithelium. Functional studies on cultured primary oral keratinocytes and SCC-25 supported our results from RAU biopsies since these cells responded to damage-associated molecule patterns (DAMPs), such as self-DNA and pro-inflammatory cytokines including IL-17C, TNF-α, and interferon gamma (IFN-γ), through a significant increase in the expression of selected molecules including TLR2, TNF-α, and BD-2. Based on our findings, RAU may begin with a strong initiating factor activating a self-amplificatory cycle. This cycle is characterised by the induction of epithelial cells apoptosis at the superficial layer down to the basal layer, a change in the pattern of TLR distribution, the up-regulation of several chemokines and pro-inflammatory cytokines, and, finally, the secretion of antimicrobial peptides initating the healing process. As a result of the lack of adaptive immunity in RAU, the cycle recurs when the mucosa is subjected to an initiating factor of the same sequence.
  • 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.
  • Siikamäki, Heli (Helsingin yliopisto, 2015)
    Study I analyzed Finnish travellers health problems abroad during 2010 2012. Information was drawn from a database kept by an assistance organization of insurance companies covering 95% of Finnish cases requiring aid abroad. The study included 50 710 cases. These data were compared to numbers of Finnish travellers from the Official Statistics of Finland to calculate incidences of illness and injury at various destinations. The most common diagnostic categories proved to be infections (60%) and injuries (14%); the most frequent diagnoses were acute gastroenteritis (23%) and respiratory infections (21%). Incidence was high in Africa, southern Europe plus the eastern Mediterranean, and Asia. Pre-travel counselling appears advisable also for visitors to southern Europe. Means for preventing gastrointestinal and respiratory infections are needed. Study II explored the final diagnoses of returning travellers with fever. This retrospective investigation comprised 462 febrile adults returning from malaria-endemic areas admitted to the Helsinki University Central Hospital emergency room during 2005 2009. The most common diagnostic categories were acute diarrhoeal disease (27%), systemic febrile illness (15%), and respiratory illness (15%). One traveller in four had a potentially life-threatening illness; septicemia proved as common as malaria (5% vs. 4%); one in ten had more than one diagnosis. The results suggest that the diagnostic protocol in tertiary hospital should in addition to malaria smears comprise blood cultures, influenza rapid test, and HIV test. Study III analyzed surveillance data on malaria cases reported to the National Infectious Disease Register 1995 2008 totalling 484 cases, and related them to travel statistics and antimalarial drug sales. The number of visits to malaria-endemic areas increased, whereas malaria cases did not, and a decreasing trend appeared in antimalarial drug sales. Infections were mostly acquired in Africa (76%). The most common species was Plasmodium falciparum (61%). Of all cases, 42% proved of foreign origin; in 89%, the infection was contracted in the region of birth, implying that immigrants visiting friends and relatives constitute a risk group with a particular need for pre-travel advice. Study IV analyzed in detail the background information on malaria cases diagnosed in Finland 2003 2011. The data included 265 cases, 54% of whom were born in malaria-endemic countries, and 86% currently lived in non-endemic regions. Of those born in non-endemic regions, 81% had received pre-travel advice, but only 20% of those born in endemic ones. Among travellers infected with P. falciparum, 4% reported regular use of appropriate chemoprophylaxis, yet individual rechecking by interview revealed that none had been fully compliant. These data suggest that, if taken conscientiously, mefloquine, atovaquone/proguanil, and doxycycline are effective as chemoprophylaxis against P. falciparum malaria.
  • Veistinen, Lotta (Helsingin yliopisto, 2015)
    The flat bones of the skull, the calvarial bones, develop by intramembranous ossification during which mesenchymal cells first condense and subsequently differentiate into osteoblasts. Sutures separate the calvarial bones and facilitate the synchronized growth of the underlying brain and the calvaria. Hedgehog (Hh) signalling has an indisputable role in craniofacial development as well as during endochondral ossification. Yet, little is known about its function during intramembranous ossification of the calvarial bones. GLI-Kruppel family member 3 (Gli3) is a zinc-finger transcription factor that mediates Hh signalling. In the absence of Hh ligand Gli3 is proteolytically cleaved into a repressor that inhibits transcription of Hh target genes. Mutations in GLI3 cause Greig cephalopolysyndactyly syndrome in humans, in which an infrequent, but significant feature is premature fusion of the metopic suture (interfrontal suture in mice). We have used Gli3 loss-of- function mouse (Gli3Xt-J/Xt-J) as a model to investigate the effects of aberrant Hh signalling during calvarial development. In my thesis I describe how loss of Gli3 causes craniosynostosis of the lambdoid as well as interfrontal sutures in mice. Elevated proliferation and ectopic differentiation of osteoprogenitors underlies this phenomenon. We were able to rescue craniosynostosis in these mice by two mechanisms. Firstly, by elevating fibroblast growth factor (Fgf) signalling in the suture prior to its fusion by imbedding Fgf2 soaked beads in tissue culture. This induced Twist1 expression, which inhibits function of ectopically expressed Runx2. Secondly, craniosynostosis was prevented by genetically reducing Runx2 activity by generating Gli3Xt-J/Xt-J;Runx2+/- mice, which normalized elevated levels of Bmp signalling in the affected sutures. We also put forward a model of how Hh signalling helps to maintain the integrity of bone margins during calvarial development. The repressor isoform of Gli3 inhibits Runx2 activity in the early osteoprogenitor cells. Runx2, on the other hand, activates Ihh expression in the mature osteoblasts, which then induces osteogenesis by inhibiting the function of Gli3 repressor. Our findings indicate that Gli3 and Hh signalling have an important role in mediating the location of osteoblast differentiation and the speed of bone formation in the developing calvaria. Uncovering the cellular and molecular mechanisms that underlie normal calvarial development, as well as pathological processes, is a vital step in developing treatment strategies for patients with craniosynostosis.
  • Mäkinen, Laura K. (Helsingin yliopisto, 2015)
    Predicting the clinical course of an early-stage oral tongue squamous cell carcinoma (OTSCC) is challenging, as even small tumors can behave aggressively. OTSCC often metastasizes to the cervical lymph nodes, and the presence of lymph node metastasis at the time of diagnosis is considered the most important tumor-related prognostic factor in OTSCC. The mechanisms of this disease progression are poorly understood. Despite slight improvement in the prognosis of OTSCC in recent decades, the outcome of these patients is still modest. Therefore, a deeper understanding of the phenomena behind tumor progression would enable medical professionals to evaluate the aggressiveness of the disease and to adjust its treatment more effectively. The extracellular matrix and basement membrane must be broken down before a tumor can invade surrounding tissues and further spread into blood and lymph vessels. This is a process that involves various proteolytic enzymes, the most important of which are matrix metalloproteinases (MMPs). Over 25 structurally related, but genetically distinct, human MMPs have been identified and characterized: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Toll-like receptors (TLRs) are pattern-recognition molecules involved in innate immunity that are also expressed in many types of cancer. TLRs apparently play a pivotal role in malignant disease: they are related to tumor progression and, conversely, to cancer inhibition. Their expression pattern and role in oral cancer, however, remains unclear. In this thesis we studied the expression of MMPs 2, 7, 8, 9, 13, and 25 and TLRs 2, 4, 5, 7, and 9 in early-stage OTSCC. The study comprised 73 consecutive clinically T1N0M0 and T2N0M0 OTSCC patients treated at the Helsinki University Hospital, Helsinki, Finland in 1992-2002. We prepared tissue array blocks from primary tumors and immunostained them. We also used whole section slides from patients with metastasized or recurrent disease. We compared immunoexpression of MMPs and TLRs to tumor and patient characteristics as well as to patient outcomes. We also used Western immunoblot to examine TLR-2 and -4 expression in the highly invasive and aggressive HSC-3 OTSCC cell line. In addition, we studied the effect of TLR-2 and -4 antagonist GIT27 (4,5-dihydro-5-isoxasoleacetic acid) on the invasion of the HSC-3 cell line in myoma organotypic invasion assay. OTSCC tumors expressed both MMPs and TLRs. Nuclear expression of MMP-13, but not cytoplasmic expression of MMP-2, -8, and -9, associated with deeper invasion and advanced tumor size. Furthermore, high nuclear MMP-13 expression predicted poor disease-specific survival. High MMP-7 protein expression associated with the presence of occult cervical metastases, increased invasion depth, and higher tumor grade, and also predicted poor outcome. Immunostaining of MMP-25 failed to correlate with any clinical parameters. High TLR-2, -4, and -9 expression correlated with deeper tumor invasion. Cytoplasmic expression of TLR-2 and -4 also correlated significantly with higher tumor grade, whereas high TLR-5 expression associated with lower tumor grade. High expression of TLR-9 correlated with advanced tumor size. Negative or mild TLR-5 expression predicted poor disease-specific survival. OTSCC primary tumors, neck metastases and recurrent tumors expressed TLR-2, -4, and -9. TLR-2 and -4 antagonist GIT27 did not affect the invasion of the HSC-3 cell line in myoma organotypic invasion assay. Thus, TLRs may operate under a different mechanism of action depending on whether they are activated by damage-associated molecular patterns in cancer or by pathogen-associated molecular patterns in infection. Our results suggest that MMP-7 and MMP-13 in particular may have prognostic value in OTSCC. Their use as prognostic biomarkers, however, calls for further study. TLR-2, -4, and -9 seemed to predict invasive tumor growth. Primary tumors and neck metastases as well as recurrent tumors of OTSCC express these TLRs, suggesting that TLRs seem to play a role in both the development and progression of tongue carcinoma.
  • Soininen, Leena (Helsingin yliopisto, 2015)
    THE HEALTH OF THE FINNISH SAMI IN THE LIGHT OF MORTALITY AND CANCER PATTERN The Sami are regarded as indigenous people of Scandinavia and northwest Russia. Their traditional dwelling zone consists of the most northern parts of those countries. In addition to the Arctic environmental circumstances, some radioactive and chemical pollution has been found in the environment of the Sami. In this study, the mortality and cancer incidence of the Finnish Sami groups (North-, Inari- and Skolt Sami) are studied and also compared to the Sami in Sweden and Norway. The survival of the Finnish Sami cancer patients was compared to that of the Finnish general population. A person representing at least 75 per cent of any ethnic subgroup of Sami was classified as Sami. The follow-up has been from 1979 to 2010. The disease mortality among the Northern and Inari Sami was statistically significantly lower, and that of the Skolt Sami higher than that of the general population of Finland. Standardized mortality ratio (SMR) among Northern Sami was 0.88 (95% Confidence Interval (CI) 0.78-0.99), among the Inari Sami 0.85 (0.73-0.96) and among the Skolt Sami 1.20 (1.00-1.41). The mortality from accidents and suicides was significantly increased among Sami men, SMR 1.88 (1.36-2.52) and 1.78 (1.14-2.65) correspondingly. The cancer incidences of the North- and Inari Sami were low. For the North Sami, the standardized incidence rate (SIR) was 0.68 (95% Confidence Interval 0.55-0.82) and for the Inari Sami 0.57 (0.43-0.74). The SIR of Skolt Sami was 0.96 (0.71-1.27) because of the high SIR of stomach cancer, SIR 3.40 (1.47-6.69). The common cancers among the Finnish main population, prostate-, breast- and skin cancers are especially rare among the Finnish Sami. The incidence and the mortality of cancers among the Finnish Sami are rather similar to those of the Swedish and Norwegian Sami, with the exception of the Swedish Sami women, whose incidence was the same as that of the Swedish general population. The survival of the Finnish Sami cancer patients was the same as that of the corresponding cancer patients in the general population. There were no signs of radioactive or chemical pollution in the mortality or cancer incidence results. The living habits and environment of the Sami have changed, and hence also the mortality and cancer morbidity is nowadays more like that of the majority of Finnish and other western populations. They have gone through an epidemiological transition, different subgroups in different times. The traditional Sami living has been a good example of a healthy way of living, except for the risk-taking of Sami men. When looking at the low figures of some cancers, the genetic features of the Sami as a cause for it cannot be excluded.