Lääketieteellinen tiedekunta

 

Recent Submissions

  • Rissanen, Antti-Pekka (Helsingin yliopisto, 2017)
    Oxygen Delivery and Utilization during Acute Dynamic Exercise: Effects of Polycystic Ovary Syndrome, Type 1 Diabetes, and Exercise Training Cardiovascular risk is increased in polycystic ovary syndrome (PCOS) and type 1 diabetes (T1D). Peak pulmonary O2 uptake (V̇O2peak) is a strong and independent predictor of cardiovascular risk. This thesis aimed at studying O2 delivery and utilization (i.e., integrated components of V̇O2 response to exercise) during acute dynamic exercise in healthy individuals and individuals with PCOS or T1D. The adaptations induced by long-term exercise training were also examined in individuals with and without T1D. Data on 22 healthy adult men (Study I), 15 adult overweight or obese women with and 15 without PCOS (Study II), seven adult men with and 10 without T1D (Study III), and eight adult men with and eight without T1D (Study IV) were analyzed. The groups were matched for age, anthropometry, and leisure-time physical activity (II, III) or baseline V̇O2peak (IV). PCOS women and men with T1D had no clinically overt cardiovascular disease. The subjects performed maximal incremental treadmill (I) or cycling (II-IV) exercise tests, and in Study IV the subjects did so both before and after a 1-year individualized exercise training intervention. Alveolar gas exchange (I-IV), arterial O2 saturation (I-IV), heart rate (I-IV), cardiac pump function (II, III), and active leg muscle deoxygenation (I, III, IV) and blood flow (III) (near-infrared spectroscopy [NIRS]), were monitored during the exercise tests. In Study IV, peak O2 pulse was calculated to reflect cardiac pump function. Blood volume (III), hemoglobin concentration (I-IV), and glycosylated hemoglobin A1c (III, IV) were determined. Reduced V̇O2peak, reduced peak systemic O2 extraction, and a pronounced cardiac response to increasing V̇O2 but otherwise intact systemic O2 delivery were observed in overweight and obese PCOS women. Reduced peak cardiac pump function, being associated with reduced blood volume, and independently deteriorated peak active leg muscle blood flow led to reduced V̇O2peak and were suggested to be associated with glycosylated hemoglobin A1c in men with T1D. The 1-year training intervention improved V̇O2peak and peak O2 pulse similarly in men with and without T1D but did not affect NIRS-derived local active muscle O2 extraction or glycosylated hemoglobin A1c in men with T1D. The associations between training dose and responses were consistent in healthy men but not in men with T1D. This thesis provides novel information on PCOS- and T1D-related early signs of subclinical cardiovascular dysfunction and leads future multi-disciplinary research to identify more detailed mechanisms behind and the clinical significance of the findings.
  • Oiva, Jani (Helsingin yliopisto, 2017)
    Acute pancreatitis (AP) is common disease with a wide range of clinical manifestations. In most cases it is a self-limiting local inflammation. However, about 20-30% of the patients develop a more severe form of the disease (moderately severe or severe AP), which is complicated by systemic inflammation, organ dysfunction (OD) and possibly pancreatic necrosis. To prevent mortality, it would be crucial to identify at admission the patients at risk to develop a more severe form of AP, and to provide them with maximal supportive care. The present studies were designed to delineate the blood leucocyte signaling profiles in patients with AP and OD, and to investigate whether circulating trypsinogen-3 is associated with AP. The study consisted of four parts, in all of which the patients were admitted to hospital because of AP, and treated in the Intensive Care Unit for AP complicated by OD and immunosuppression. Studies I-III consisted of a cohort of 13 patients (with additional three patients in study II) and study IV of 82 patients. Phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases (MAPK) p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducers and activators of transcription (STATs) 1,3,5,6 were studied from appropriately stimulated and non-stimulated blood samples using phospho-specific whole blood flow cytometry. In addition, transmigration of monocytes and polymorphonuclear leucocytes (PMNLs) were investigated using cells of an endothelial cell line. Trypsinogen-3 was measured with a new specific sandwich-type immunoassay to investigate it s clinical utility as a diagnostic and predictive tool in AP. We found that in AP patients monocytes have impaired NFκB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to the maintenance of systemic inflammation. ERK1/2 activation is impaired which may depress monocytes transmigration and may increase the risk for infection. The lymphocytes showed impaired NFκB activation, which may increase the risk for secondary infection. p38 activation was enhanced, which may sustain inflammation. Constitutive STAT3 activation may favour Th17 lineage of CD4+ lymphocyte differentiation. STAT1 activation is impaired and STAT6 activation enhanced, which denotes a shift from Th1 towards Th2 differentiation. The PMNLs showed depressed NFκB activation, normal p38 activation and decreased ERK1/2 activation. STAT3 was constitutively activated in five patients. Transmigration of the PMNLs was increased, which may sustain end organ dysfunction. Trypsinogen-3 distinguished AP patients from controls with high accuracy. However, it did not predict the severity of AP. In conclusion, these studies show that AP patients with OD and immunosuppression have multiple aberrations in blood leucocyte signalling pathways. These results may offer a potential predictive marker for the development of OD or secondary infections. Trypsinogen-3 can detect patients with AP but does not predict the severity of the disease.
  • Lumme, Sonja (Helsingin yliopisto, 2017)
    In most countries, the health care system aims to achieve equity as one of its primary goals. However, evident and persistent inequities in health care exist despite the improvement in the overall level of morbidity, health care performance and health care technology. This thesis develops statistical methods to evaluate socioeconomic equity in health care using register data. Moreover, this thesis provides information on socioeconomic equity in health care in Finland between 1992 and 2010 from several viewpoints. This thesis utilises two outcomes the use of coronary revascularisations and mortality amenable to health care interventions as empirical examples of the use of individual-level register data. Coronary revascularisation is a common invasive procedure and provides a good indication of health care system performance. Amenable mortality refers to causes of death that should be avoided in the presence of timely and effective health care interventions. It serves as an indirect measure of performance and the quality of health care. Data on revascularisations were obtained from the Care Register for Health Care and data on amenable deaths from the National Causes of Death statistics. These datasets were individually linked to population registers maintained by Statistics Finland to obtain sociodemographic data. This thesis develops a method to compare regional differences in socioeconomic equity in health care. The method takes dependence of observations within regions into account and its advantage is in overcoming the problems associated with random error in small regions. Additionally, it takes into account the effect of variation in the population size by age and socioeconomic position in regions in addition to different needs for health care. The existing methods measuring absolute differences do not provide solutions for evaluating absolute inequity in health care while taking the need for care into account. This thesis proposes a non-numerical approach to evaluating absolute horizontal socioeconomic equity in health care. Moreover, this study presents methods to assess uncertainty in the inequity indices when using register data. Evaluation of the uncertainty of the equity measures ensures that comparisons at different levels (between hospitals, areas, countries, in time) are meaningful. Finally, this thesis introduces an improved approach to studying socioeconomic equity in the effectiveness of health care. The approach uses amenable mortality as an indicator of health care performance and allows for an analysis of time trends in equity. Causes of deaths are assigned to categories according to the time and site of the interventions, which allows the indicative estimation of the effect of different sectors of health care systems on inequity. This study detected marked and persistent relative horizontal inequity in the use of revascularisations favouring the better-off in the period 1995 2010 in Finland. Contrary to earlier research, this study found no decrease in relative inequity. The results suggest that absolute horizontal inequity decreased although this cannot be quantified numerically. However, differences in inequity between regions were minor in 2001 2003, especially among men. The results of this study indicate that socioeconomic inequities in relative terms in deaths amenable to health care were marked and increased between 1992 and 2008 in Finland. Inequity was greater in deaths amenable to specialised health care, but the influence of primary health care on widening inequities was more substantial. In absolute terms, major socioeconomic inequity in amenable mortality remained. These results suggest that socioeconomic disparities in either access to or quality of health care in Finland did not diminish. The results of this thesis should prompt a serious consideration of actions to improve equity in health care in Finland.
  • Nurmi, Harri (Helsingin yliopisto, 2017)
    There are two vascular systems in the body, for blood and lymph, and both are indispensable for embryonic development. The closed circuit of blood vessels is responsible for oxygen and nutrient delivery to all compartments of the body and removal of CO2 and waste products from tissues. The open-ended lymphatic system works as a return route for fluid, immune cells and dietary lipids into the blood circulation. The heart is the central engine for blood flow whereas lymphatic flow is achieved by skeletal and smooth muscle contraction around the lymphatic vessels. Differences between the blood vascular and lymphatic systems are apparent, from the molecular to the functional level. However, the two types of vessels also share a number of signaling molecules and building blocks of vessels. The purpose of the studies presented in this thesis was to expand our knowledge about Vascular Endothelial Growth Factors (VEGFs) and their receptors in development and pathological conditions. In the first study, we found, surprisingly, that VEGFR-3, the receptor for the principal lymphatic vessel growth factor, VEGF-C, is crucial for the normal patterning of the developing blood vessels and that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, leads to excessive blood vessel sprouting and branching. Furthermore, macrophages that express the VEGFR-3 and VEGFR- 2 ligand VEGF-C localized to the vessel branchpoints, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. Our second study focused on the pathological aspect of the atherosclerosis. By using the transgenic mouse that overexpress soluble VEGFR-3 (VEGF-C/D trap) we could link the impaired lymphatic vessels to lipoprotein metabolism, increased plasma cholesterol levels, and enhanced atherogenesis. In the third project we focused on the role of lymphangiogenic growth factors in the steady-state homeostasis of lymphatic vessels in adult mice. Our findings from this study indicated that the lymphangiogenic growth factors provide trophic and dynamic regulation of the intestinal lymphatic vasculature, which could be especially important in the dietary regulation of adiposity and cholesterol metabolism. Finally in the last study we discovered a new role of VEGF-C in the embryonic development. To our surprise, we found a striking VEGF-C dependent phenotype with defective fetal liver erythropoiesis that resulted severe anemia in the Vegfc deteled embryos. These studies have revealed a new viewpoint regarding the VEGF-C/VEGFR-3 pathway in embryonic and pathological conditions. With these results, our understanding of the VEGF family members has expanded beyond the blood and lymphatic vessel. Hopefully, this new knowledge will improve the possibilities to target the VEGF-C/VEGFR-3 pathway for the treatment of human diseases such as atherosclerosis, obesity, and vascular diseases.
  • Vassilev, Boris (Helsingin yliopisto, 2017)
    Endocytosis is a form of active cellular transport by which cells internalize molecules from the extracellular environment. This thesis studies proteins involved in endocytosis that influence the progression of cancers in humans. Two of the three articles summarized here employ cell biological experiments to elucidate the role of the proteins N-muc downstream-regulated gene 1 (NDRG1) and StAR-related lipid transfer protein 3 (StARD3) in the regulation of endocytic trafficking. The third article describes a novel data analysis method and its application to a large data set of breast cancer patients. We studied the effects of NDRG1 protein depletion on cellular cholesterol content and distribution, low-density lipoprotein receptor (LDLR) localization and turn-over, and the morphology of endosomal organelles. We found that depletion of the NDRG1 protein leads to reduced abundance of LDLR on the plasma membrane (PM) and as a result, reduced LDL uptake. When NDRG1 is depleted, LDLR accumulates in multi-vesicular bodies (MVBs), and while LDLR ubiquitination is increased, its degradation is decreased. The PM levels of LDLR and LDL uptake are rescued upon co-depletion of the inducible degrader of the LDL-receptor (IDOL). Our findings identify NDRG1 as regulator of MVB formation and trafficking. We also found that elevated levels of StARD3 protein alter the cholesterol balance and adhesiveness of breast cancer cells. We studied the effects of StARD3 overexpression in cells, as well as the association of StARD3 protein levels with cancer progression markers in Finnish breast cancer patients. We found that in MCF-7 cells, stable StARD3 overexpression altered the morphological features and the cholesterol balance of the cells. In the breast cancer tumor samples from patients, high StARD3 protein levels associated with ERBB2 (receptor tyrosine-protein kinase erbB-2) amplification. High protein levels also associated with proto-oncogene tyrosine-protein kinase Src (Src) activation and increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) transcript levels. Our findings suggest that elevated StARD3 levels contribute to breast cancer aggressiveness. Finally, a systematic approach to data analysis was developed and demonstrated by applying it to an existing data set of breast cancer patients. High-throughput molecular level data and clinical data were integrated in the study. This revealed a coamplification of NDRG1 and the gene lysosomal-associated transmembrane protein 4B (LAPTM4B), encoding an endosomal protein that regulates ceramide trafficking, and discovered new genes potentially coregulated with LAPTM4B.
  • Mölkänen, Tomi Juhani (Helsingin yliopisto, 2017)
    Introduction. Staphylococcus aureus is a frequent finding in blood cultures from patients with bacteraemia (presence of bacteria in the blood). S. aureus bacteraemia (SAB) SAB is often complicated by deep infection foci. The invasion mechanisms of S. aureus are incompletely characterised. Several other pathogens use plasmin, proteolytic enzyme, in tissue invasion. Pathogens have the capacity to bind plasminogen (inactive form of plasmin) from the blood circulation to the bacterial cell-surface. Binding of plasminogen to cell-surface facilitates the activation of plasminogen to plasmin by the human plasminogen activators. S. aureus produces plasminogen activator, staphylokinase (SAK) and it can also activate plasminogen to active plasmin. Bacterial cell-surface bound plasmin activity could theoretically be one invasion mechanism of S. aureus. The mortality rate with SAB is around 20%. Prognosis depends on the underlying diseases and treatment, severity of the acute disease and development of deep infection foci. Biomarkers to identify complicated cases to guide treatment decisions are needed. C-reactive protein (CRP) has been used as a marker of inflammation, organ dysfunction and treatment response in systemic bacterial infections. In SAB use of CRP as a prognostic marker is incompletely understood. Single nucleotide variations (SNPs) in the CRP gene determine partly the variation in the basal CRP levels. Impact of CRP gene SNPs to CRP levels in generalised severe infections is mainly unclear. Soluble urokinase plasminogen activator receptor (suPAR) is a novel prognostic biomarker. Elevated suPAR levels in malignant and infectious diseases have been detected to associate with poor prognosis. Study bacteria, population and aims. The study I aimed to clarify the interaction of plasminogen, SAK and S. aureus cells and to characterise potential plasminogen receptor molecules of S. aureus in vitro. The II-IV studies were performed to evaluate CRP, white blood cell (WBC) count and suPAR levels as predictors of prognosis in SAB. The study three aimed to evaluate the impact of CRP gene SNPs to CRP levels and prognosis in SAB. The studies II-IV were based on 430 prospectively followed SAB patients in a multicentre study from 1999-2002. Main results. S. aureus bacterial cells and bacterial cell proteins enhanced the activation of plasminogen to plasmin by SAK. Activation was shown to be protected against the activation inhibitor enzyme. Three tentative bacterial cell-surface bound proteins responsible for plasminogen binding were purified and further characterised. CRP levels were higher in patients with fatal outcome compared to survivors starting from day four. CRP level >103 mg/L on day four and >61 mg/L on day 14 were predictive for a 30-day fatal outcome. WBC count (>8.6 x109/L) was predictive only on day 14. CRP levels on the day one >108 mg/L and on day 14 CRP >22 mg/L predicted the presence of deep infection. Deep infection focus was found in 84% of patients. The highest maximal CRP level was shown to be partly determined by the presence of deep infection focus and by carriage of rare CRP gene SNP. In analysis of CRP gene data, no differences were detected in clinical manifestations of SAB, predisposing factors or underlying diseases. SAB patient fatalities could be distinguished from survivors by suPAR levels starting from day three. This difference persisted for ten days. Presence of deep infection focus was not observed to impact to suPAR levels. The result of study I clarifies complex S. aureus virulence mechanisms and as such is not directly applicable to clinical use. The results of studies II-IV are directly applicable in clinical practice, identifying complicated cases and guiding treatment decisions.
  • Spillerova, Kristyna (Helsingin yliopisto, 2017)
    Background: Critical limb ischemia (CLI) presented as a foot ulcer with or without gangrene requires the quick re-establishment of arterial blood supply. The recently introduced angiosome concept has offered a new perspective on the treatment of CLI. The idea of angiosome-targeted (direct) revascularization⎯the restoration of blood flow directly to the angiosome affected by an ischemic wound appeared among vascular surgeons. The concept has rised interest among vascular specialists as several studies supported the hypothesis of a better clinical outcome after direct revascularization. Despite the promising results, the feasibility of the concept in endovascular treatment has not been addressed, nor has a comparison of revascularization methods, endovascular versus open surgical, been investigated. Furthermore, the methodology is not consistent, and the definition of direct revascularization is unclear, especially if the wound spreads over several angiosomes. Therefore, clinical value of the hypothesis is yet to determined. Aim of the study: The aim of this study was to investigate the importance of the angiosome concept in the treatment of CLI with tissue loss (Rutherford 5,6). The main goals were to evaluate the feasibility of the concept in endovascular procedures; to compare the clinical outcomes of direct and indirect revascularization; and to obtain a consensus concerning the angiosome-targeted approach. Patients and methods: The study comprises patients referred for infrapopliteal revascularization, endovascular or open surgical, between 2008 and 2013. We analyzed patient s records retrospectively, focusing on wound location, the feasibility of infrapopliteal direct revascularization, and differences in clinical outcome, with the main interest in wound healing and leg salvage. We also compared the clinical outcome of two existing definitions of angiosome-targeted revascularizations as they differ in revascularization approach of leasions located in forefoot and the heel. Definition A accepts into the direct group if any of the affected angiosomes is revascularized, while Definition B accepts only revascularization of posterior tibal artery. Main Results: For the feasibility of the angiosome concept in endovascular infrapopliteal revascularization, the wound was isolated to a single angiosome in only 24% of the cases, and 33% of the patients had only one infrapopliteal artery suitable for revascularization. The success rate of direct revascularization, however, was 75.9%. When comparing direct and indirect revascularization, the propensity score analysis yielded significantly better leg salvage (p=0.019) and a trend towards improved wound healing (p=0.058) for the direct approach, and when adjusted for revascularization method, direct bypass was associated with a significantly higher wound-healing rate than endovascular revascularization (HR 1.295, 95%CI 1.005 1.668). Among diabetic patients, the findings showed that direct bypass yielded significantly better wound healing than indirect PTA (p=0.001, HR 2.83, 95%CI 1.35 3.04), and, furthermore, indirect PTA was associated with the poorest leg salvage rate. The analysis of the two different angiosome-targeted approaches revealed a significantly better feasibility of the conventional method (definition A) compared to definition B (p less than 0.05). Furthermore, the prognostic ability for better clinical outcome using definition A was confirmed by both the Cox proportional hazard analysis (p= 0.044 for wound healing, p= 0.047 for leg salvage) and the propensity score analysis (p= 0.037 for wound healing, p= 0.044 for leg salvage). Conclusion: The tissue lesion affects several angiosomes in the majority of the cases, and a consensus on the accurate definition of angiosome-targeted revascularization needs to be achieved to standardize the methodology of arterial selection. Despite the inconsistent methodology in the literature, our findings seem to suggest that observing the angiosome concept in the decision-making yields better clinical outcomes, especially in endovascular therapy. In bypass surgery, however, the concept seems to be of less value, and the artery with the best runoff should be selected as the outflow artery.
  • Matero , Pirjo Helena (Helsingin yliopisto, 2017)
    Rapid detection and identification of the pathogenic agents in biological weapons is critical in limiting their impact when used against civilian or military targets. Fast and accurate detection is also important in clinical microbiology where modern protocols seek to extend the diagnostic technology of automated central laboratories to the patient bedside or doctor s office, i.e., so-called point-of-care (POC) testing. The aim of this study was to develop rapid and accurate detection and identification assays for biothreat agents and other pathogenic bacteria from diverse sample types using molecular amplification methods. Secondly, the aim was to evaluate field-deployable platforms for use in remote or resource-limited locations. This thesis consists of a series of studies of pathogenic bacteria that can cause severe disease in humans. The pathogens studied, Yersinia pestis, Bacillus anthracis, Francisella tularensis, Vibrio cholerae, and Brucella spp., have been listed as biothreat and biological weapons agents. In addition to the above-mentioned biothreat agents, real-time PCR assays were developed for the detection of Bacillus thuringiensis and Yersinia pseudotuberculosis. We also conducted an international multicentre accuracy study of a novel isothermal amplification platform. The main methods used in these studies were real-time PCR and a novel isothermal amplification technique known as strand invasion based amplification (SIBA). Several sample types, such as DNA, powder, spiked, environmental, and clinical samples were utilised in these studies. The developed multiplexed real-time PCR for the simultaneous identification of Y. pestis and Y. pseudotuberculosis was shown to be specific and sensitive, and was validated with spiked clinical samples. For the detection of non-pathogenic and pathogenic V. cholerae from environmental samples, real-time PCR assays for the toxR and ctxA target genes were developed, and specificity was tested with a panel of several serotypes of Vibrio cholerae and other bacteria and with spiked environmental water samples. The V. cholerae and real-time PCR assays for Y. pestis, B. anthracis, F. tularensis, and Brucella spp. Were transferred to a small, field-deployable RAZOR instrument. A field-training assay with a simple sample preparation technique was developed and tested in field conditions for powder samples with insecticidal simulant containing spores of B. thuringiensis. In the final study, the accuracy of a newly-developed portable instrument, based on isothermal amplification, was assessed in an international multicentre study using 1160 faecal patient samples for the specific detection of toxigenic Clostridium difficile. This new test system was found to be comparable to the methods in routine use at three participating hospital laboratories. Molecular amplification, such as real-time PCR and isothermal amplification are sensitive and specific methods that are suitable for rapid testing of bacterial biothreat agents and pathogenic bacteria from several types of samples following suitable sample preparation. With appropriate instruments, molecular nucleic acid amplification methods can be of significant advantage in field use for rapid identification of biothreat agents. These methods are also useful in POC situations where fast and reliable identification of pathogens is important.
  • Wood, Graham (Helsingin yliopisto, 2017)
    The research focus is a specific case study analysis of collective violence in the North of England, in particular West and South Yorkshire. There are three cases: the Bradford Riots June 9-11th, 1995, The Battle of Orgreave, June 18th, 1984 and a violent encounter between Leeds United and Manchester United fans at Elland Road on October 11th, 1975. The cases are set within the dynamic of violence mutation revealed in both their specific genres and in the fusion of violence that draws together the cases and manifestations of violence in the region throughout the period covered. The unique challenges of violence research are addressed and a triangulation methodology was employed drawing upon extensive newspaper sources, official reports, secondary sources and a limited sample of supporting interviews to garner an insight into the events. Fundamental problems of definition were broached, highlighting the difficulties of undertaking a multidisciplinary study of violence. This was compounded by different disciplines seeing the phenomenon through their own restrictive lens, resulting in divergent and contradictory conceptualisations of violence. This necessitated the formulation of a conceptual framework - violent conflictual contention, to obviate some of the weaknesses in violence definition. Inculcated within the framework were thematic strands of grievance and identity formation set within the contentious repertoire of non-institutional actors leading up to and emanating from the cases themselves. Primary attention was devoted to the non-institutional actors, although recognition was made of the role played by the police in all the cases. Yet irrespective of the level of social control employed by the police, and all three cases exhibited differing crowd control strategies, they nonetheless could not prevent the outbreak of violence and may have in fact have inadvertently exacerbated an increased recourse to violence. A grievance framework was proposed in which suddenly imposed grievances were identified in the unfolding events and reference was made to grievances of illegitimate inequality and violated principles that may have been key causal factors or factors that perpetuated the continuation of the violence. Grievance factors were juxtaposed with identity considerations that highlighted the fragility and transitory nature of identity formation. As the research developed it became evident that those confronting the non-institutional actors in the cases were derived not from some external other but were in part sourced from their own fractured communities. Compounding the volatility of grievance and identity formation was a realisation of violence that transformed in both time and space and effectively negated any essentialist approach to the study of violence, thereby compromising the concept of violent conflictual contention. The actors involved could only access a limited and at times vicarious contentious repertoire, so their invocation of violence reflected an instrumentality and a self-belief in the virtuosity of their use of violence at specific points in time. Placed within their historical pathways, the cases moved from the 1970 s, through the 1980 s and 1990 s and finally into the twenty-first century. Demarcated in their own clearly defined temporal context, the cases demonstrated significant levels of non-fatal violence. When transfused into a totality that merged the cases together into a landscape of violence, then the region was witness to significant and perpetual levels of violence during this period. This has resulted in a Yorkshire particularism fraught with contradiction and a resort to violence that has found refuge in the different communities.
  • Haapaniemi, Aaro (Helsingin yliopisto, 2017)
    Laryngeal cancer is one of the most common head and neck cancers. The treatment of laryngeal squamous cell carcinoma (LSCC) has evolved towards non-surgical treatment, namely radiotherapy and chemoradiotherapy. However, the treatment outcome of LSCC has not improved. LSCC recurs in up to 30% of patients. The current knowledge on prognostic factors for recurrence is too limited to aid in treatment decisions. In this study, the treatment outcome and recurrences of 342 patients treated with curative intent for LSCC at the Finnish university hospitals during 2001-2005 were evaluated. The outcome of T1a glottic carcinomas was excellent; none of the patients died of LSCC. The results for T2 carcinomas was worse than expected; the 5-year disease-specific survival for glottic and supraglottic carcinomas in this group was 78% and 54%, respectively. The results for T3-4 carcinomas were comparable with those reported in the literature. Recurrence was observed in 22% of patients and 91% of the recurrences occured within 36 months of treatment. None of the patients with glottic T1a tumors had recurrence after 36 months, which questions the feasibility of routine 5-year follow-up for this patient group. WHO performance status >0, presence of neck metastases, and non-surgical primary treatment were significant independent predictors of recurrence. Local recurrence of glottic LSCC could be successfully salvaged. Regional or distant recurrence and any recurrence of supraglottic LSCC carried a poor prognosis. These results underline the importance of sufficiently aggressive primary treatment, particularly for supraglottic LSCC. Some LSCCs persist or recur after non-surgical treatment. Currently, there are no validated tools to identify these tumors. In this study, the expression of survivin, an inhibitor of apoptosis, Wrap53β, a protein associated with DNA double-strand break repair and telomere elongation, and p16INK4a, a surrogate marker for human papillomavirus infection, and their relation to treatment response and prognosis was investigated in LSCC tissue samples of 149 Finnish and Swedish T2-3N0M0 glottic LSCC patients treated with radiotherapy or chemoradiotherapy. Survivin showed no predictive or prognostic value. Cytoplasmic expression of Wrap53β was associated with reduced disease-free survival and overall survival. P16INK4a expression was rare in LSCC patients (7%) and more common among patients under the age of 60. In this younger patient group, none of the patients with p16INK4a expression experienced tumor recurrence. Surgery is the only standard salvage option for patients with LSCC recurrence after non-surgical therapy. Other salvage options are being investigated, one of which is boron neutron capture therapy (BNCT). In BNCT, non-radioactive boron, B10, commonly in a compound of boronophenylalanine-fructose (BPA-F), is infused intravenously. This substance has a tendency to accumulate preferably in tumor cells. After infusion, the tumor is irradiated with epithermal neutrons. This leads to boron neutron capture reaction, which releases lethal doses of radiation within the cells containing BPA-F. BNCT has the ability to deliver high doses of radiation to the tumor with low toxicity to surrounding tissues. In the current study, BNCT toxicity and outcome were evaluated in a group of nine patients with persistent or recurrent LSCC after primary non-surgical treatment. Of the eight evaluable tumors, six (75%) responded to BNCT. No serious (Grade 4-5) toxicity was encountered. Despite good responses, only one patient was permanently cured without surgery. With treatment intensification, BNCT could show potential as a larynx-sparing treatment.
  • Rechardt, Martti (Helsingin yliopisto, 2017)
    Upper extremity soft tissue disorders (UESTDs) are common painful conditions relating to tendons and their adjacent structures. The etiology of UESTDs, particularly the role of metabolic and inflammatory factors, is unknown. Some studies have found associations between obesity and diabetes with UESTDs. To date, few studies have assessed the role of cytokines in UESTDs and virtually nothing is known about the role of adipokines in these disorders. Animal experiments as well as studies conducted with human tissue samples have found evidence of inflammation in tendons, suggesting that pro-inflammatory cytokines play a role in UESTDs. The expressions of pro-inflammatory cytokines and adipokines in serum are altered in obesity, however it is unclear whether these compounds contribute to the symptoms experienced by UESTD patients. The overall aim of this study was to explore the role of metabolic and inflammatory factors in shoulder pain and UESTDs. This study utilized the Health 2000 Survey, a health examination of a representative sample of the Finnish general population conducted by the National Institute of Health and Welfare (N = 6354). In addition, a sample of actively working patients with incipient UESTDs (N = 163) and a healthy control group (N = 42) were examined in the Finnish Institute of Occupational Health. In a representative sample of the general population, the prevalence of shoulder joint pain in the past month was 16% and that of possible or probable chronic rotator cuff tendinitis was 3%. Every third patient with incipient UESTDs, reported full or substantial recovery within three months. Body mass index, waist circumference and type 2 diabetes were associated with shoulder joint pain, whereas waist circumference was associated with chronic rotator cuff tendinitis. Moreover, waist circumference, low levels of HDL cholesterol, high levels of triglycerides and high levels of an adipokine, visfatin, were associated with the intensity of upper extremity pain in patients with incipient UESTDs. Serum levels of soluble interleukin 1 receptor 2 and soluble ST2 receptor were higher and those of interleukin 18 lower in patients with incipient UESTDs compared with the healthy controls. Furthermore, high levels of two adipokines, resistin and visfatin, predicted a higher recovery rate from UESTDs. The study findings suggest that obesity and diabetes are associated with upper extremity pain and chronic rotator cuff tendinitis. The underlying mechanisms are largely unknown, however the increased expression of pro-inflammatory cytokines in obesity may modify pain sensitivity and promote inflammation in tendon and its adjacent structures. In diabetes, the precipitation of advanced glycation end products in tendons is thought to increase the tissue s susceptibility to tendon disorders. Furthermore, the findings point towards an independent role of interleukin 1 family biomarkers in UESTDs. Therefore, incipient UESTDs may promote inflammatory activity, potentially altering serum biomarker levels. Finally, adipokines are recognized to exert a role in inflammation; the findings of this study suggest that they may play a role as modifiers of upper extremity pain intensity and also in the recovery from UESTDs.
  • Sammalkorpi, Henna (Helsingin yliopisto, 2017)
    Background and aims: Diagnostic scoring is a method for stratifying patients according to the probability of appendicitis, and therefore works as an excellent basis for a diagnostic algorithm. This study aimed at developing a new diagnostic score, the Adult Appendicitis Score (AAS), and validating its routine use as an integral part of a new diagnostic algorithm. Diagnostic accuracy of the imaging studies depends on the pre-test probability of the disease. This study aimed to assess how accurate the imaging was in various AAS-stratified pre-test probability groups. The effect of in-hospital delay on the risk of perforation is controversial. The research in this thesis aimed to further clarify the matter. Patients and methods: The study enrolled 1737 patients with acute right lower quadrant abdominal pain. The first data collection of 829 patients was used to develop the AAS and compare it with two previously published scores as well as with the clinical assessment. The validation study of AAS enrolled 908 patients in two university hospitals. The negative appendectomy rate was compared between the first and second patient cohort. Patients that had diagnostic imaging were stratified into three probability-of-appendicitis groups according to the AAS, and the diagnostic accuracy of ultrasound (US) and computed tomography (CT) were compared between the score groups. To find the best marker to detect pre-hospital perforations, laboratory results and two previously published diagnostic scores were analyzed. The effects of total duration of symptoms, pre-hospital delay, and in-hospital delay on the risk of perforation were analyzed. Results: After the AAS was developed and incorporated into a new diagnostic algorithm the negative appendectomy rate decreased from 18.2% to 8.2%. With a specificity of 93%, the AAS stratified half of all patients with appendicitis into the high-probability group. The probability of appendicitis was only 7% for the low-probability group. The AAS outperformed both the clinical assessment and two previously published scores. The diagnostic accuracy of imaging depended on the pre-test probability of appendicitis. When compared to the two other groups allocated by the AAS, in the low-probability group a positive CT and US findings yielded lower post-test probability for appendicitis. More false than true positive US results were found in the low-probability group. C-reactive protein (CRP) was the best marker for pre-hospital perforation. For patients with CRP values less than 99 mg/l longer in-hospital delay increased the perforation risk whereas the duration of pre-hospital delay showed no difference between patients with uncomplicated and complicated appendicitis. For patients with CRP values 99 mg/l or more, the in-hospital delay did not increase the perforation risk. Conclusions: The AAS provides an accurate method to stratify patients according to their probability of appendicitis. After the score was implemented into clinical routine, it led to a dramatic reduction in the negative appendectomy rates. When the AAS stratifies the patient to have a low probability of appendicitis, the benefits of imaging are questionable. False positive imaging results can even induce negative appendectomies. Most perforations in acute appendicitis occur as pre-hospital events. However, some of the perforations can be avoided by minimizing the in-hospital delay.
  • Puolakka, Tuukka (Helsingin yliopisto, 2017)
    Ischaemic stroke is an important cause of death and disability worldwide. The occluded cerebral artery can be opened using recanalization therapy, but only within the first few hours after symptom onset. Early hospital admission is therefore essential. The aim of this thesis was to describe the current performance of the Finnish emergency medical service (EMS) system in prehospital stroke care and explore new innovations to improve it. The thesis was based on the analysis of emergency phone call tapes, prehospital patient reports and in-hospital data. The emergency medical dispatchers used the stroke code in more than 60% of the calls and dispatched more than 80% of the ambulances with high priority. The paramedics suspected less than 90% of the patients to have stroke symptoms and transported the patients using the high priority designation at nearly the same frequency. The prehospital time intervals of patients who received recanalization treatment were analysed sequentially. Both the door-to-needle time (DTT) and onset-to-treatment time (OTT) were significantly reduced during the study period, which was reciprocated by the increasing number of treated patients, but none of the prehospital time intervals [onset-to-door time (ODT), onset-to-dispatch time, transportation time] changed appreciably. Ambulance transport using high priority and onset-to-call time duration were the most significant predictors of early hospital arrival (ODT <90 minutes) and treatment (OTT <2 hours). The most significant additional delay for late arriving patients (OTT > 2h) was the onset-to-call time (41 minutes), the single most dominant operational variable in the mean additional delays was OST, with >2 minutes of added delay. Using fire engines to support ambulances in prehospital stroke care more than doubled the number of EMS personnel on the scene but no change in on-scene time (OST) or other prehospital time intervals was observed. Only the use of stroke code in ambulance dispatch was associated with a short OST (<22 minutes). An EMS training programme decreased the OST from 25 to 22.5 minutes. Consulting a physician via telephone was associated with a longer OST, whereas advanced life support training of the EMS personnel promoted a shorter OST when compared to basic life support -trained crews. A total of 55% of the patients had a good outcome (modified Rankin Scale 2), which was associated with the patient’s age, stroke severity and DTT. As a conclusion, the most significant delays of the prehospital phase were seen in the decision to call the emergency phone number and OST. Early emergency call, more severe symptoms and high priority ambulance transport were the most important determinants of early hospital arrival and treatment. Implementing a systematic training programme for EMS staff successfully decreased the OST by 10%.
  • Wegelius, Asko (Helsingin yliopisto, 2017)
    Pre- and perinatal environmental factors have been associated with increased schizophrenia risk, particularly in combination with genetic liability. Both low and high birth weight have been associated with an increased risk of autism spectrum disorders and schizophrenia. The interaction of specific schizophrenia susceptibility genes and specified pre- and perinatal environmental factors have recently been described in relation to augmented schizophrenia risk. In this thesis, the relationship between birth weight and schizophrenia risk was investigated as part of a large Finnish schizophrenia family study sample based on the Genetic Epidemiology and Molecular Genetics of Schizophrenia in Finland study, in which genetic susceptibility for schizophrenia is known to be elevated relative to the general population (Study I). The study sample consisted of two subsamples having at least one sibling with a diagnosis of schizophrenia. The associations between birth weight and symptom severity of schizophrenia and psychotic disorders (Study II) and cognitive functioning in schizophrenia (Study III) were also characterized. A gene-environment interaction, focusing on birth weight and specific genes from the DISC1 network (Study IV), which had previously been found to be associated with increased schizophrenia risk in the same cohort, was also investigated in relation to schizophrenia risk. A 1.68-fold increase in schizophrenia risk was observed in subjects presenting with a high birth weight (>4000 g) relative to subjects with an intermediate birth weight of 3000-4000 g (Study I). In particular, schizophrenia risk was elevated among high birth weight individuals in combination with specific variants of the NDE1 gene (Study IV). Both low and high birth weight were found to be associated with increased severity of disorganized and negative symptom dimensions, whereas birth weight was not associated with symptoms of reality distortion (Study II). Both low and high birth weight, compared with the intermediate birth weight range, were associated with a slight decrease in cognitive performance among both subjects with schizophrenia and their unaffected first-degree relatives (Study III). The observations in the thesis corroborate existing findings describing an association between high birth weight and increased schizophrenia risk. An association between low birth weight and increased schizophrenia risk, a finding widely documented in the literature, was not seen here. Birth weight was found to influence both symptom severity and cognitive performance in schizophrenia. The findings also suggest that the functions of NDE1 during the early stages of neurodevelopment are vulnerable to the influence of pre- and perinatal environmental factors associated with high birth weight, with the propensity to augment subsequent schizophrenia susceptibility among offspring. The mechanisms underlying the association between high birth weight and schizophrenia risk are speculative, but may involve factors such as pre- or perinatal hypoxia, maternal metabolic and immunological mechanisms during pregnancy.
  • Galambosi, Päivi (Helsingin yliopisto, 2017)
    Venous thromboembolic event (VTE) is one of the leading causes of maternal deaths in the Western world, with highest risk during the postpartum period. Low-molecular-weight heparin (LMWH) is currently the medicine of choice for the management of acute VTE and for VTE prophylaxis during pregnancy. The aims of the study were to evaluate the maternal and neonatal safety and the efficacy of the long-term use of LMWH during pregnancy, and the incidence, risk factors, and mortality of postpartum VTE in Finland through 180 days after delivery. The safety and efficacy of LMWH exposure during pregnancy were evaluated in studies I-III. LMWH exposed women (n=475), were included in Study I (1994-2007). Study II was a sub-study of Study I concerning recurrent VTEs in women with a history of previous VTE (n=271). Whether there is a subsequent decrease in bone mineral density (BMD) after long-term use of LMWH during pregnancy, was observed in study III (2008-2012), by measuring BMD in women with (n=92) and without LMWH exposure (n=60). Study IV (2001-2011) was a population-based study to assess the incidence and risk factors for postpartum VTE 180 days after delivery. The study population consists of all women with deliveries (N=634292) and all fertile-aged non-pregnant women (N=1232841). Women with VTE after delivery were collected. The incidences of thrombocytopenia, bleeding, preterm delivery, stillbirth, pre-eclampsia, or fetal growth restriction were same between LMWH-exposed women and healthy controls and no heparin-induced thrombocytopenia or osteoporotic fractures were observed. Few allergic reactions for LMWH occurred. The incidence of VTE despite ongoing LMWH prophylaxis was high in women with a history of at least two VTEs, prior estrogen - or antiphospholipid antibody syndrome -related VTE. LMWH was not associated with decreased BMD. The risk of postpartum VTE was highest during the first week declining thereafter, but small residual risk remained through 175 postpartum days. The VTE risk remained elevated for 180 days in women with thrombophilia, Cesarean section, twin birth, varicose veins, and cardiac disease. Three VTE-related deaths occurred. We showed that the use of LMWH during pregnancy was safe for both the mother and the fetus. The recurrence rate of VTE was high in high-risk women. Small residual VTE risk remained elevated for six months after delivery. Studies on the optimal dosing and duration of LMWH in high-risk groups are needed.