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  • Järvinen, Petrus (Helsingin yliopisto, 2014)
    Abstract Pseudomyxoma peritonei (PMP) is best treated by surgery. It was formerly treated by serial debulking. The current gold standard is complete cytoreductive surgery (CRS) to be followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Improved survival figures for patients treated by CRS and HIPEC combined have been reported recently. The aim of this PhD research was to evaluate (I) the outcome of patients treated by serial debulking in Helsinki University Central Hospital, (II) investigate the clinical manifestation of the disease, (III) assess the feasibility of CRS and HIPEC modality in combination, and (IV) compare results of serial debulking and CRS with HIPEC in patients with PMP. The surgical data and the survival outcome of 33 patients that were treated by serial debulking were analyzed in study I. The symptoms and signs of 82 patients with PMP were investigated in study II. Study III included 90 patients, who were evaluated in our facility and then given HIPEC when practicable. The characteristics that were associated with technically successful administration of HIPEC were analysed. The outcome of 87 patients treated in the HIPEC era was compared with those treated before the HIPEC era in study IV. The 5-year and 10-year overall survival (OS) rates were 67% and 31%. Four patients (12%) presented with no apparent evidence of disease at the completion of follow-up (I). The most common symptom of PMP was abdominal pain in 23% of the cases (II). Of 53 women, 26 (49%) underwent their initial operations because of presumed ovarian tumour. Of 29 men, 13 (45%) underwent their initial operations with a suspicion of PMP. Of the 90 patients assessed, 56 (62%) were feasible for HIPEC (III). Low-grade tumour (P=0.013), age under 65 (P=0.004), and serum CEA under 5.0µg/L (P=0.003) were associated with successful administration of HIPEC. The 5-year OS rates were 69% for the HIPEC era and 67% for the debulking era (IV). The proportion of patients who presented with no evidence of disease was higher for the HIPEC-era group than for the debulking-era group (54% vs. 24%). Patients who were treated by CRS and HIPEC combined managed well, but it is unfeasible to deliver HIPEC to every patient. A comparison of the 5-year OS rates of HIPEC era with those of the debulking era showed them to be approximately equal, when the whole patient population was included for the comparison. The natural progression of PMP is slow and thus the survival difference may only become apparent in follow-up periods in excess of 5-years. The proportion of patients who had undergone curative treatment may be higher in the HIPEC era.
  • Karhunen, Janne (Helsingin yliopisto, 2014)
    Sudden hemodynamic collapse after coronary artery bypass surgery is a major complication associated with high mortality and morbidity. There are many well-established risk stratification systems to assess the risk of mortality and morbidity after cardiac surgery. These risk scores, however, do not predict severe immediate postoperative complications such as sudden hemodynamic collapse. This study is based on analysis of patients who suffered from hemodynamic collapse early after coronary artery bypass surgery between 1988 and 1999 in Helsinki University Hospital. One matched control patient was selected for every study patient. Patients, who died, underwent a medico-legal autopsy and a rubber cast angiography to reveal possible surgical errors in myocardial revascularization. Patients still alive in 2009 were traced with respect to mortality data and a health-related quality of life questionnaire was sent to the patients and to the controls. In addition, a comparison was made between patients who suffered from postoperative hemodynamic collapse and patients who underwent a postoperative angiography due to persistent myocardial ischemia. Angiography was introduced in 2000 and this patient series was collected prospectively between 2000 and 2007. This thesis consists of four studies. The specific goals were to explore predictive factors of sudden hemodynamic collapse, to reveal the possible surgical errors that led to hemodynamic collapse and fatal outcome with the means of an autopsy, to find out the impact that postoperative angiography has on the incidence of hemodynamic collapse, and the rate of mortality, and morbidity of patients, and to investigate the quality of life of patients surviving hemodynamic collapse in comparison with an age- and sex-matched national reference population. The results suggest the following: Sudden hemodynamic collapse after CABG is a major complication with high mortality. Inadequate tissue perfusion, postoperative myocardial ischemia, and increased need for inotropic as well as mechanical support are predictive of hemodynamic collapse. Technical graft complications are a major underlying cause of postoperative hemodynamic collapse. Post-mortem angiography improves the accuracy of diagnostics of graft complications. The cause of death could be established in every case. Use of early postoperative angiography in case of hemodynamic compromise or myocardial ischemia reduces the rate of emergency reoperations and decreases morbidity and mortality. It also allows treatment with intravascular medication. Patients who survive hemodynamic collapse and emergency reoperations have a similar prognosis as matched control patients. Health-related quality of life that is also comparable with age- and sex-matched national reference population as long as 15 years postoperatively.
  • Molander, Pauliina (Helsingin yliopisto, 2014)
    In the era of TNFα-blocking therapy, MH and even DR have been suggested as new therapeutic targets in both CD and UC. Recent studies have indicated that DR may be achieved in roughly half of IBD patients on TNFα-blocking maintenance therapy, resulting in more favorable treatment outcomes. However, considering the potential side-effects and economic issues associated with long-term immunosuppressive therapy with TNFα-blocking agents, the possibility of discontinuing therapy should be evaluated at least once after achieving DR. At present, no widely accepted recommendations for discontinuing TNFα-blocking therapy are available. Based on the results of our study, only for about half of patients in DR were candidates for discontinuation of TNF-blocking medication for various reasons. Nevertheless, up to 67% of IBD patients in DR at the time of cessation of TNFα-blocking therapy remained in clinical remission during the 12-month follow-up, and moreover, the majority of these patients also remained in endoscopic remission. Therefore, withdrawal of therapy could be considered in IBD patients in DR even after one-year treatment. Reassuringly, in case of a relapse, the response to restart of TNFα-blocking therapy seems to be effective and well-tolerated. To evaluate treatment response and possible relapse during maintenance therapy or after discontinuation of TNFα-blocking therapy, FC seems to be a reliable surrogate marker to replace endoscopic assessment. A normal FC after induction with TNFα-blocking agents predicts sustained remission in the majority of patients with active luminal disease receiving scheduled treatment. However, an objective cut-off value for treatment response and relapse risk is to some extent still undefined. To predict IBD relapse and identify patients requiring a close follow-up in clinical practice, FC seems to be a useful surrogate marker, as it increases and remains elevated as early as 6 months before symptomatic relapse. FC measurements should therefore be included in monitoring IBD patient s treatment response in everyday clinical practice.
  • Hautamäki, Hanna (Helsingin yliopisto, 2014)
    Hot flushes, the most characteristic symptoms in menopause, are encountered by c.a. 80% of women. Hot flushes and other menopausal complaints can significantly impair a woman s quality of life. Additionally, the majority of women experience premenstrual symptoms in their fertile age. Due to the resemblance between premenstrual and menopausal symptoms, women with severe premenstrual symptoms might fear for an increased risk of developing menopausal complaints, such as vasomotor symptoms. It is, however, unclear why some women experience intolerable hot flushes while others remain completely asymptomatic. Hot flushes are characterised by cardiovascular reactions such as rapid episodes of reddening of skin and palpitations. Thus, women with or without hot flushes may differ in their cardiovascular reactivity and responses to hormone therapy. The present study was designed to investigate the impact of hot flushes and different forms of hormone therapy on health-related quality of life and cardiovascular autonomic function. Therefore, 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied before and during six months of hormone therapy. Hot flushes were evaluated prospectively with a two-week hot flush diary. The relationship between a history of premenstrual symptoms and the postmenopausal quality of life and hot flushes was also assessed. The cardiovascular autonomic function was studied with a standardised test series in controlled laboratory settings. Hot flushes were important determinants for the decreased health-related quality of life in menopause. Previous premenstrual symptoms lacked correlation with the severity of postmenopausal hot flushes but associated with deterioration of health-related quality of life, seen as poor sleep, depressive feelings and impaired memory and concentration. Women with hot flushes reacted with more tachycardia and slightly blunted parasympathetic activity in heart rate responses to cardiovascular autonomic testing compared with asymptomatic women. In a randomized study, all hormone therapy regimens alleviated hot flushes and other menopausal symptoms equally effectively. In women with pre-treatment hot flushes, hormone therapy improved health-related quality of life in terms of sleep, anxiety and fears, memory and concentration, and general health. Hot flushes were accompanied with lowered resting blood pressures but increases in blood pressure responses to physical strain during all hormone therapy regimens. Estradiol treatment lowered resting heart rate and reduced maximal heart rate in response to physical strain in women with pre-treatment hot flushes. This beneficial effect on heart rate was attenuated by adding medroxyprogesterone acetate to estradiol treatment. In conclusion, the hot flush status and hormone therapy contribute to cardiovascular autonomic function. Hot flushes seem to associate with slightly pronounced sympathetic responses in autonomic regulation of heart rate and blood pressure, which can be considered unbeneficial for cardiovascular function. This possibly unfavourable sympathetic activity can be reduced with estradiol treatment especially in women with hot flushes, who are potential candidates for hormone therapy in clinical practice. Hot flushes impair the health-related quality of life in recently postmenopausal women, but can be effectively alleviated with hormone therapy. Premenstrual symptoms do not predict severe hot flushes in menopause, which is comforting for women having troublesome premenstrual symptoms.
  • Filppula, Anne (Helsingin yliopisto, 2014)
    The drug-metabolising enzyme cytochrome P450 (CYP) 2C8 is involved in the elimination of several important drugs. The asthma drug montelukast inhibits CYP2C8 potently in vitro, but does not affect the pharmacokinetics of CYP2C8 substrates in vivo. In turn, the cancer drug imatinib is a CYP2C8 and CYP3A4 substrate in vitro, but CYP3A4 inhibitors have little effect on its concentrations in vivo. This thesis aimed to examine these discrepancies, and to study the role of CYP2C8 in the metabolism of montelukast and imatinib. The work comprised in vitro experiments, physiologically based pharmacokinetic (PBPK) simulations, and two interaction studies with a two-phase, placebo-controlled crossover design in healthy subjects. In vitro, CYP2C8 metabolised montelukast extensively. In the clinical study, the strong CYP2C8 inhibitor gemfibrozil increased the area under the plasma concentration time-curve (AUC) of montelukast by 4.5-fold in healthy subjects, thus suggesting that CYP2C8 contributes to ~80% of its elimination. In vitro, imatinib was mainly metabolised by CYP2C8 and CYP3A4, but imatinib also inhibited CYP3A4 irreversibly. In vivo, gemfibrozil unexpectedly reduced imatinib absorption, while it had no effect on imatinib AUC. However, the AUC of the main metabolite of imatinib decreased by ~50%. PBPK simulations suggested that the findings could be explained by a complex interaction involving simultaneous inhibition of an uptake transporter involved in imatinib absorption and of CYP2C8 by gemfibrozil. Furthermore, the simulations proposed that the elimination of imatinib during steady state relies more on CYP2C8 than on CYP3A4, because of CYP3A4 autoinhibition by imatinib. Inhibition of CYP3A4 by imatinib also suggests that concomitant use of imatinib with CYP3A4 substrates may lead to harmful interactions. The findings of this work explain the previously documented in vitro-in vivo inconsistencies and provide important information for a safe use of these drugs. CYP2C8 inhibitors may increase the effect and adverse reactions of montelukast and imatinib. On the other hand, because montelukast is generally well-tolerated and CYP2C8 seems to play a key role in its elimination, these data suggest that it could serve as a CYP2C8 probe in interaction studies. Collectively, the studies of this work strengthen the role of CYP2C8 as an important drug-metabolising enzyme.
  • Tuuminen, Raimo (Helsingin yliopisto, 2014)
    Transplant ischemia/reperfusion injury (Tx-IRI) remains among the major clinical challenges in organ transplantation. Tx-IRI may result in deleterious short-term consequences such as primary graft dysfunction and increased immunogenicity of the allograft, both of which enhance the propability for late vascular remodeling and fibroproliferative processes, ultimately leading to untreatable chronic allograft dysfunction and compromised long-term survival. The underlying mechanisms in primary graft dysfunction involve microvascular dysfunction culminating in increased vascular permeability, perfusion defects, and leukocyte infiltration into the allograft, which may lead to pro-inflammatory and pro-fibroproliferative prosesses. The pleiotropic, cholesterol-independent vasculoprotective effects of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been well described. Statins improve microvascular integrity and perfusion through endothelial cell (EC) and pericyte function. Statins attenuate the expression and secretion of angiogenic growth factors and microvascular reactivity at the site of vascular injury. Statins seem to have also anti-inflammatory, -oxidative, and -thrombotic effects. They are widely used for primary and secondary prevention of cardiovascular disease. In the transplant recipients, statin treatment decreases allograft inflammation and vasculopathy and cardiovascular morbidity. However, the therapeutic potential of donor statin treatment against Tx-IRI and microvascular dysfunction remains undelineated. The majority of potential cardiac allograft donors from brain-dead donors do not have previous medical track record of cardiovascular diseases nor statin medication. The heart is especially susceptible to donor brain death that elicits cardiotoxic pro-inflammatory cytokine release, cardiovascular disintegration and poor organ perfusion, which often lead to disqualification of a transplant. On the other hand, shortage of donors and different donor-related factors limit the availability of transplants, and thus lead to the use of organ donors with extended criteria such as older age. Aggressive donor management could not only improve the quality of donated organs, but also expand the donor pool by increasing suitability of donors with extended criteria and thus reduce costs of transplantation affecting e.g. need for inotropic support and stay at intensive care unit. Based on these clinically relevant issues, we chose pharmacological approaches to treat donors to improve allograft resistance to Tx-IRI and primary and and chronic allograft dysfunction. Donor rats without brain death were treated with a single peroral dose of lipophilic simvastatin two hours before heart and kidney removal, which is the clinical time-window to treat a brain-dead organ donor. The cardiac allografts were subjected to 4-h and kidney allografts to 16-h cold-ischemic preservation to mimic clinical situation and transplanted to fully major histocompatibility complex (MHC)-mismatched WF rat recipients. As our current clinical practice includes donor treatment with high dose of methylprednisolone, that modulates inflammatory state after brain death, we also investigated whether combined donor simvastatin and methylprednisolone treatment could be superior to either treatment alone on Tx-IRI and allograft survival. Here, we report that the expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a target molecule of statins, was abundant in endothelial cells (ECs) and pericytes of normal hearts as well as in glomerular and peritubular microvascular structures of normal kidneys. Rat cardiac and kidney allograft Tx-IRI resulted in profound microvascular dysfunction; leakage, perfusion defects and increased adhesivity. Donor, but not recipient treatment with peroral single-dose simvastatin two hours before graft procurement inhibited microvascular EC and pericyte RhoA/Rho-associated protein kinase activation and inter-EC gap formation, vascular leakage, the no-reflow phenomenon, danger-associated ligand hyaluronan induction, leukocyte infiltration and myocardial and tubulointersitital injury. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, TGF-β1 signaling and myocardial fibrosis, vasculopathy and improved long-term allograft survival. Furthermore, donor treatment with a combination of simvastatin and methylprednisolone was superior in the prevention of Tx-IRI and significantly prolonged acute survival of non-immunosuppressed major MHC-mismatched cardiac allograft. In conclusion, donor treatment may target microvascular dysfunction, immunomodulation and the initiation of pro-inflammatory and pro-fibroproliferative pathways in cardiac and kidney allografts subjected to prolonged ischemia time using a protocol relevant for clinical cadaveric transplantation. Minimizing microvascular injury and the activation of innate immunity by combined donor simvastatin and methylprednisolone treatment may offer a novel therapeutic strategy to expand the donor pool and furthermore improve the function of donor organs with extended criteria. We have therefore initiated a randomized clinical trial to investigate the effect of combined donor simvastatin and methylprednisolone treatment as an adjunct therapy on short- and long-term results of cardiac and kidney allografts.
  • Roos, Eira (Helsingin yliopisto, 2014)
    Obesity and overweight are common among working aged population. Obesity is associated with a number of long-term illnesses as well as increased mortality. Previous studies have found that obesity is also associated with some forms of work disability. However, longitudinal studies with register-based large data sets are scarce. The aim of this study was to examine the association between working conditions and subsequent weight gain as well as the associations between body weight, weight change and subsequent work disability in a cohort setting among middle-aged employees. This study is part of Helsinki Health Study (HHS), a cohort study on employees of the City of Helsinki. The data consists of a baseline mail questionnaire survey sent in 2000-2002 to 40-, 45-, 50-, 55- and 60-year old employees (respondents n=8960) and a follow-up questionnaire survey sent to the respondents of the baseline survey in 2007 (respondents n=7332). Questionnaire surveys yielded data on a wide range of factors such as socio-economic determinants, health and working conditions. The data from the surveys were combined with data from health check-ups that were carried out among the employees of the City of Helsinki during 2000-2002. The data were additionally linked with register data on employees sickness absence spells and disability retirements from the Finnish Centre for Pensions. Logistic regression analyses, the Cox proportional hazards model and Poisson regression analyses were used as statistical methods. A number of confounding factors were controlled for the analysis, including working conditions, health behaviours, previous health, and physical and mental functioning. Weight gain was common as one in four employees experienced major weight gain during the 5-7 year follow-up. For most of the studied working conditions, no association with weight gain was observed. Night shift work, work that was characterized as having hazardous exposures, passive work, and work where facing physical violence or threats was common were weakly associated with major weight gain. Both obesity and weight change (even among normal-weight employees) were associated with subsequent sickness absence. Obesity increased the risk of long spells of sickness absence in particular, but also elevated the risk of short spells. Weight loss, weight gain and stable obesity increased the risk of sickness absence spells of all lengths. Obesity was strongly associated with disability retirement due to musculoskeletal diseases, and to a lesser degree to mental disorders and other causes. Following adjustment for earlier health, working conditions and functioning, the association between obesity and long sickness absence spells and disability retirement was somewhat attenuated. The results of this study show that weight gain is common among middle-aged employees and that the studied working conditions are weakly or not at all associated with weight gain. The findings also indicate that weight gain and obesity are clearly and consistently associated with both temporary and permanent work disability. Obesity is thus not only a public health issue but also affects occupational health and work ability. Prevention of obesity and weight gain is increasingly important in primary health care as well as in occupational health care.
  • Scifo, Enzo (Helsingin yliopisto, 2014)
    Neuronal ceroid lipofuscinoses (NCL) are common inherited childhood brain disorders. Since 1995, 13 known NCL causative genes (CLN1-8, CLN10-14) have been identified. Despite progress in the NCL field, the primary function and physiological roles of most NCL proteins remain unresolved. In this thesis, we utilized various techniques, such as: functional proteomics, bioinformatics, and mouse disease models, in an effort to clarify disease pathways associated with congenital (CLN10), infantile, late-Infantile (CLN1, CLN5) and juvenile NCL (CLN3) in the human brain. Firstly, we examined the synaptic proteome in a cathepsin D (Ctsd / Cln10) knockout mouse model of congenital NCL, where the synaptic pathology resembles that of patients. Quantitative mass spectrometry analysis of mouse brain synaptosomes, showed that 43 proteins were differentially expressed in the Ctsd knockout mice brains. We used protein-protein interaction databases to generate a network of differentially expressed proteins and checked individual proteins for involvement in processes, pathways or disease phenotypes. This work highlighted defects in migratory functions of cathepsin D deficient cells that were attributed to downregulation of cytoskeletal proteins. We also aimed to map the CLN3-CLN5 protein interactome in the brain by identifying their associated proteins. Protein complexes from CLN3 or CLN5 expressing SH-SY5Y stable cells were analysed by mass spectrometry and processed by bioinformatics, to unravel molecular mechanisms underlying CLN3 and CLN5 diseases. Novel CLN3 and CLN5 interacting partners (42 and 31, respectively) were identified in this study. The extent of crosstalk amongst CLN3 and CLN5, suggests that the mechanisms leading to the functional deficits are shared between them. CLN3 was implicated in new roles of G-protein signalling and protein folding / sorting in the ER. Finally, we analysed protein complexes from human PPT1 (CLN1) expressing SH-SY5Y stable cells as described above. The goal of this study was to identify in vivo PPT1 substrates that could provide insight on the onset and progression of CLN1 disease. Our findings suggest putative new roles of PPT1 in neuronal migration and dopamine receptor mediated signalling pathway.
  • Surakka, Ida (Helsingin yliopisto, 2014)
    Circulating blood lipids are well-established risk factors for cardiovascular diseases. Levels of high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglycerides are affected by environmental and genetic factors. As the genetic factors explain around half of the population lipid variation based on twin studies, knowledge of the genetic determinants is crucial in prevention and early treatment of harmful lipid levels. In this thesis, genetic markers associated with lipid levels were screened using genome-wide marker datasets to better understand the biological and heritable mechanisms behind lipid levels. To identify different types of associated loci, genome-wide single nucleotide polymorphism (SNP) data from multiple European cohorts was combined. In addition, this thesis presents the effect of using Finnish imputation panel as reference on the quality of genotype imputation, which enables the usage of denser SNP marker sets in association analysis. In total, 95 genetic loci with genome-wide significant association (P-value less than 5×10-8, accounting for one million independent tests) on lipid levels were identified. In one of these loci, the SNP genotype modified the association between total cholesterol and waist-to-hip ratio. Common genetic markers found in the first publication together with the previously associated loci in publications of other research groups explained up to 4.8% of the lipid level variation. When combining all the genetic information available from different sources at the end of this thesis project, up to 16.6% of the trait variation could be explained, which corresponds to 33% of the trait heritability. In the work described in this thesis almost a hundred genetic loci associated to circulating blood lipids were successfully identified using large-scale genome-wide approaches. This thesis demonstrates new biology behind lipid levels, in addition to how large scale studies with dense SNP panels enabled by genotype imputation, can be a key in revealing biological determinants behind complex diseases and traits. Keywords: Circulating blood lipids, genome-wide association, gene-environment interaction, genotype data imputation
  • Sahi, Helka (Helsingin yliopisto, 2014)
    Background and purpose: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, with a high tendency to both relapse and metastasize. 70-80% of MCCs carry the recently detected Merkel cell polyomavirus (MCV). MCV integrates clonally into the tumour genome and harbors specific mutations, which suggest a causal role in the tumorigenesis. Predispositional factors for MCC include advanced age, Caucasian race and immunocompromising states. The purpose of this study was to examine the etiological factors of MCC, particularly in the subgroups of immunodeficient and unusually young MCC patients. We also aimed to elucidate the biology and molecular mechanisms underlying the pathogenesis of the subgroup of tumours that do not present with MCV. Methods: In the clinicopathological studies (I, IV and V), we combined clinical data derived from the Finnish Cancer Registry and patient records with biological features of MCC. All MCC diagnoses were confirmed histologically from the primary tumour paraffin blocks used as samples in the molecular analyses. MCV was analysed by quantitative PCR of the tumour samples. Expression of bcl-2 and RB proteins were examined by immunohistochemistry of tissue array blocks constructed from the primary tumour samples. Chromosomal aberrations were determined with array genomic hybridization, and the methylation of the RB1 promoter with methylation-specific multiplex ligation-dependent probe amplification technique. Standard statistical methods were employed to compare the findings between MCV-negative and positive tumour subgroups, and between patients younger and older than 50 years of age. In the epidemiological studies (II and III) we utilized record linkage of the Finnish Cancer Registry and the National Prescription Register of the Social Security Institution. A case-control study with all MCC patients diagnosed in Finland was conducted to determine the role of autoimmune diseases as predictors of MCC. The effects of statin use on the incidence of MCC were studied in a cohort consisting of all statin users in Finland. Results: The young MCC patients were frequently immunocompromised and MCV-positive. Bcl-2 expression did not vary according to MCV status and was associated with good survival in both groups. MCV-negative tumours were found to be chromosomally more unstable than MCV-positive tumours, and to harbor more frequent deletions of the chromosome 11p and the RB1 locus (7.7% vs 38 %). The RB1 promoter was methylated in a distinctive pattern in MCC tumours, but did not vary according to MCV status. Autoimmune diseases in general (OR 1.63, 95%CI 1.19-2.22), and specifically rheumatoid and diabetic conditions, led to a predisposition for MCC. The incidence of MCC was significantly increased among young Finnish statin users (SIR 1.94, 95%CI 1.23-2.90). Paradoxically, the risk decreased significantly moving towards older age-groups of statin users. Conclusions: Based on our results, autoimmune diseases and statin use play a part in the pathogenesis of MCC. The unusually young patients included in our material were also often immunocompromised. MCC should be kept in mind when dealing with skin manifestations of these subgroups. RB1 deletions and chromosomal instability are of importance in the pathogenesis the MCV-negative MCC tumours, whereas no differences were observed in bcl-2 expression between the subgroups. These findings provide further evidence that MCV infection defines subgroups of MCC.
  • Schreier, Nadja K. (Helsingin yliopisto, 2014)
    Background. The environment has a major impact on human beings. Extreme environmental conditions such as hot temperatures can have huge health impacts, as shown during the heat wave in Europe that occurred during the summer 2003. The main causes of death were non-communicable diseases (NCDs) such as respiratory and cardiovascular diseases. Natural and man-made disasters can cause the collapse of health infrastructure through a combination of marked increase in demand due to injuries, diseases and increased stress levels and the physical disruption/destruction of hospital buildings, roads and transport that follows such disasters. Extreme weather events and disasters are predicted to increase in the course of the ongoing climate change. Therefore, impacts on NCDs are very likely to increase, which raises the importance of the hitherto paucity of knowledge about this research area. Aims. This study investigates the associations of weather conditions, temporal variations, in addition to the impact of a disaster, namely the bombings of Helsinki during the Second World War (WWII) on NCDs, specifically for coronary heart disease (CHD), cerebrovascular disease, type 1 diabetes mellitus (T1DM), hypertension, and obesity. Materials. Three main data sets were used for this study: 1) All fatal and non-fatal coronary events in seven cities in Finland recorded in the years 1983, 1988, and 1993 (n=9243), 2) Data that originate from the Helsinki Birth Cohort Study (HBCS) include information about birth characteristics and about life-long disease outcomes in addition to deaths of subjects born in Helsinki between 1934-1944 (n=13 039), 3) Data that originate from the DiaMond project including standardized data from 112 centers in 56 countries of all children aged between 0-14 years with diagnosis of T1DM during 1990-1999 (n=31 091) Methods. The following methods were used to achieve the specific aims: 1) Comparison of regression models with weather and temporal variation variables for the prediction of coronary events was implemented for the assessment of the influence on the case-fatality of the events, 2) Log-linear regression with Fourier terms were used to assess seasonal patterns for the incidence of childhood T1DM in different geographical locations, 3) Survival analysis and regression models were used to assess life-long health outcome due to exposure to bombings in utero, and to outdoor ambient temperature at the time of conception. Results. Influences of temperature at the time of conception for hypertension and obesity were observed. Women who were conceived during the months with the warmest mean temperatures of the time-series were found to have a significantly higher probability of developing hypertension in adult life. Furthermore, women conceived during those months with very low mean temperatures had lower BMI, lower risk of obesity and also lower fat percentage in adult life. The seasonality of the incidence of the T1DM in children was demonstrated to be a global phenomenon. In addition it was shown that the further from the equator a location is in terms of latitude the higher is the probability of that location to exhibit a seasonality pattern for T1DM. A slight positive influence for the life-long development of CHD and cerebrovascular disease was found for women who were in utero during the bombings of Helsinki in WWII. Furthermore, the case fatality of coronary events during the 1983-1993 period turned out to be negatively influenced by temporal variation. Case-fatality of CHD was higher in the December holidays and on Sundays. An attempt to predict coronary events on the basis of the weather forecast for the same study period appeared not to have any useful value. Conclusions. This study contributes to the research of the fundamentals about the influence of weather, temporal variation, and disasters on NCDs. The results showed that hypertension, obesity, T1DM, CHD, and cerebrovascular disease were particularly affected by those factors. The ongoing climate change will potentially increase the impacts on NCDs. Preparedness for these increases - including the prevention of disease and the prevention of the further exacerbation of a disease – is an important task for the near future. Further, the collection of data in developing countries where data are sparse needs close collaboration between interdisciplinary scientific teams in order to address the complexity of this type of research and to contribute to the preparedness of health authorities in such challenging regions.
  • Ahola, Sofia (2014)
    Mitochondrial diseases are comprised of a large variety of disease phenotypes that can range from an infantile-onset, lethal multisystem disorder to late-onset myopathy and ophthalmoplegia. There is currently no established therapy for mitochondrial diseases and the exact disease mechanisms are largely unknown. The aim of this PhD thesis project has been to develop new therapy options, to test these with animal models and eventually translate these results into clinical use. Another aim of this project has been to identify novel gene defects underlying mitochondrial diseases. Progressive external opthalmoplegia (PEO) is an adult-onset disease featuring ophthalmoparesis, ptosis and exercise intolerance. Additional symptoms are variable, and may include cataracts, sensory axonal neuropathy, ataxia, severe retarded depression and hypogonadism. In this project we have utilized a mouse model for late-onset mitochondrial myopathy, Deletor mouse in order to develop new therapy options for mitochondrial diseases, which could be further tested in human patients. I have focused on testing the potential therapeutic effect of high-fat, low-carbohydrate ketogenic diet in mice and in human patients. In the ketogenic study with Deletor mice, we were able to improve the disease pathogenesis in myopathic muscle and improve the general metabolic status of the mice. The ketogenic diet increased mitochondrial biogenesis and rescued the ultrastructural changes in affected muscle fibers. Deletor mouse muscle appears to be in a starvation-like state, as it signals to recruit macronutrients from other deposits in the body such as liver and adipose tissue. The high-fat feeding was able to diminish this process and enhance mitochondrial function. Based on these positive findings in mice, we tested the effect of ketogenic, modified Atkins diet on human patients with PEO. The diet had a rather dramatic effect on PEO patients causing muscle pain and degradation. The muscle cell death seemed to be targeted to individual mitochondrial deficient muscle fibers. Metabolomic and transcriptomic analyses as well as spiroergometric studies revealed that PEO patients are highly dependent on glucose metabolism, and the consequently reduction in dietary carbohydrates further enhances this metabolic shifting. The results from mice and human studies extends our knowledge of disease pathology in mitochondrial myopathies and can direct future studies as we progress towards a better understanding of the signalling pathways that impact mitochondrial functions. These results also emphasize the importance of appropriate nutrition for these types of bioenergetic diseases. Nutritional guidance should be given to patients with mitochondrial diseases as nutrition clearly plays a crucial role in the patients well-being. The other aspect of this thesis work has been finding the molecular diagnosis for patients with suspected of having a mitochondrial disorder. In this work, we utilized exome-sequencing technology and identified three novel heterozygous mutations in TSFM gene (Ts translation elongation factor, mitochondrial) in two sisters with mitochondrial cardiomyopathy and encephalopathy and in one patient with optical neuropathy. All three patients shared one heterozygous mutation that was compound with a second heterozygous mutation. The shared mutation is enriched in Finnish population and has a high carrier frequency (1/90) but no homozygous individuals were found among 35 000 Finnish controls. We demonstrated experimentally the pathogenicity of these mutations by showing that they cause protein instability and early degradation with defects in mitochondrial translation. These findings expanded the spectrum of disease phenotypes in mitochondrial translation defects. Importantly, phenotypes characterized by later onset and less severity can be caused by errors in mitochondrial translation machinery and mutations in these genes should also be considered as candidates for adult mitochondrial patients.
  • Sillanpää, Heidi (Helsingin yliopisto, 2014)
    Lyme borreliosis (LB) is a bacterial infection spread by the bite of Ixodes sp. ticks. Borrelia burgdorferi sensu lato group of spirochaetes is causing the infection. Less than 10 species are known to be pathogenic to humans. Distribution of B. burgdorferi sensu lato species varies geographically and LB is endemic in Europe, Asia and North America. The typical initial manifestation of LB is a ring-like rash, erythema migrans (EM). EM appears around the tick bite site after a couple of days or weeks. Diagnosis of LB is based on EM and the infection is treated with antibiotics. In some cases, the tick bite or EM may go unnoticed. Manifestations of late-stage LB are Lyme arthritis, cardiac symptoms, neuroborreliosis (LNB) manifesting as meningoradiculitis or meningitis, or chronic atrophic skin changes (acrodermatitis chronica atrophicans). These late-stage manifestations may appear within weeks, months, or in rare occasions after years. Frequently, laboratory tests are needed to confirm the clinical diagnosis. Laboratory testing is mainly based on the detection of Borrelia specific antibodies, usually with ELISA method or immunoblotting. There are no markers of active LB and antibody responses may persist for years after the treatment of the infection. The aim of this study was to identify new immunological markers for the laboratory diagnostics of LB. A large amount of serum and cerebrospinal fluid (CSF) samples were collected from patients with different manifestations of LB from Europe and the United States. Five peptide variants of IR6 (= invariable region 6 of the VlsE protein) as antigens were compared to commercial C6 Immunoassay in the serodiagnosis of early and disseminated stages of LNB. Recombinant decorin binding proteins A (DbpA) and B (DbpB) (three variants of each) as antigens were evaluated in the serodiagnosis of LNB. CXCL13 Immunoassay was used to measure chemokine CXCL13 levels in children with early LNB. As a conclusion, the use of a combination of different IR6 peptide variants in one assay may improve the laboratory diagnostics of LB by increasing the sensitivity of the test. DbpA and DbpB may serve as supplementary antigens in diagnostic assays. Appearance of CXCL13 in the CSF seems to be an early immunological marker of inflammation in CNS. Measurement of CXCL13 concentrations in the CSF may improve the diagnostics of LNB.
  • Nieminen, Mikko (Helsingin yliopisto, 2014)
    Cancers of the upper digestive tract (oral, pharyngeal, laryngeal, oesophageal and stomach) are among the ten most common cancers worldwide and are associated with high mortality and morbidity. Despite improved treatment strategies, the prognosis of these cancers remains poor. The main aetiological factors for the upper digestive tract cancers are alcohol consumption and smoking. Dietary and genetic factors can also contribute to an increased risk. Alcohol consumption, smoking and poor oral hygiene all lead to exposure of the upper digestive tract mucosa to salivary acetaldehyde. Ethanol is not carcinogenic, but acetaldehyde, its first metabolite, is. The International Agency for Research on Cancer has classified acetaldehyde associated with alcoholic consumption as a group I carcinogen. Cigarette smoke contains acetaldehyde, as does saliva after alcohol intake. Microbially fermented food products can also contain high levels of acetaldehyde. Therefore, salivary acetaldehyde levels are a result of its direct intake as well as systemic, local and microbial ethanol metabolism. The ability of the mucosa and microbes to remove acetaldehyde has been shown to be limited. Chronic Candida mucositis is associated with oro-oesophageal carcinogenesis. Candida yeasts are common colonisers of the upper digestive tract, with an extraordinary ability to form biofilms. Candida albicans is the dominant species in health and disease. The biofilm structure protects fungal cells against hostile actions, and infections are mainly biofilm-related. This is highlighted by high resistance to antifungals by yeast biofilms. Fungal cells can become dispersed from a biofilm, making it a constant source of infection. In immunocompromised patients, this process can lead to fatal systemic infections. The similarity of fungal and human cells makes the development of antifungals difficult, and treatment is often compromised. The primary aim of the research presented in this thesis was to investigate the ability of clinically important Candida yeasts to produce carcinogenic acetaldehyde in planktonic and biofilm modes of growth in vitro. Fermented milk mursik constitutes a major part of the diet in western Kenya, an area with a high local incidence of oesophageal cancer and a low prevalence of common risk factors. The second aim was to identify the microbiota of the starter cultures used for the production of mursik. The ability of these mixed cultures of bacteria and yeast to produce acetaldehyde and ethanol was assessed in a fermentation experiment. Finally, the potential anti-biofilm and anti-inflammatory effect of a Lactobacillus metabolite, 2-hydroxyisocaproic acid (HICA), was explored in vitro and in vivo. HICA has previously shown efficacy against various planktonically grown microbes. The results of the research presented in this thesis demonstrate that C. albicans biofilms can produce mutagenic levels of acetaldehyde when incubated with ethanol and glucose at clinically relevant concentrations. In addition, planktonic C. albicans and non-albicans Candida (NAC) species produce significant levels of acetaldehyde in the presence of ethanol. C. glabrata shows a unique ability among NAC species to produce mutagenic acetaldehyde in the presence of sugars. Interestingly, the production of acetaldehyde by Candida species can be significantly reduced by the sugar alcohol xylitol. Highly mutagenic levels of acetaldehyde and ethanol can be measured during the production of mursik. Candida yeasts are associated with high acetaldehyde and ethanol production during fermentation. C. albicans biofilm formation is significantly reduced in response to HICA treatment in vitro. Interestingly, certain genes belonging to the fermentative pathway and acetaldehyde metabolism are highly up-regulated under stress and during biofilm formation. An attenuated inflammatory response was observed when a C. albicans biofilm was treated with HICA in vivo. Overall, these results underline the significant potential of clinically relevant Candida yeasts to produce carcinogenic acetaldehyde. Colonisation of the upper digestive tract with Candida spp. could expose the mucosa to mutagenic levels of acetaldehyde in the presence of alcohol and dietary sugars. This could play a role in the carcinogenesis associated with Candida infection. In addition, the consumption of fermented food products such as mursik, with a high acetaldehyde and ethanol content, could elevate the risk of cancer. HICA could provide a safe and efficient approach to treat biofilm-related Candida infections and reduce the inflammation and mutagenicity associated with C. albicans biofilms.
  • Aavikko, Mervi (Helsingin yliopisto, 2014)
    Identification of tumor susceptibility genes has contributed significantly to our understanding on molecular basis of cancer. Over one hundred high risk tumor susceptibility genes have been identified during past few decades, but some remain still to be characterized, including those that do not cause other clinically recognizable syndromic features, and present with incomplete penetrance. The aim of this study was to assess the familial aggregation of cancers in Finland and to identify novel tumor predisposition families and genes in families with Kaposi sarcoma (KS), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and intracranial meningioma. First, to assess the familial aggregation of cancers in Finland, we conducted a computerized clustering of 878 593 patients in FCR, based on family name at birth, municipality of birth, and tumor type. Additional clustering, based on family name at birth and tumor type, was also conducted. We calculated a cluster score to assess the frequency of familial aggregation of different tumor types. The top scoring types included those with well-established genetic background, but also those with unknown genetic etiology such as KS. We performed genealogy analysis from the clustered KS cases, and identified a family with five affected individuals and several smaller KS families. Furthermore, we showed that KS incidence is unevenly distributed in Finland, with more cases in the western and northeastern than other parts of the country. Second, we examined the genetic susceptibility in the KS family with five affected cases. We mapped the shared genomic regions and performed whole genome and exome sequencing. We identified 14 candidate variants, among them a missense variant (c.1337C>T, p.Thr446Ile) in the DNA binding domain of STAT4. We showed that healthy variant carriers had decreased IFN-γ production in the activated T-cells. We studied STAT4 in a large number of familial and sporadic KS cases, but detected no additional mutation carriers. Our results suggest STAT4 as a KS predisposing gene. However, further genetic and functional validation is needed to claim causality. Third, a family of four cousins with a rare subtype of Hodgkin lymphoma, namely NLPHL, was studied for genetic predisposition. Linkage analysis and exome sequencing revealed a frameshift mutation (c.2437-2438_delAG) in NPAT segregating with NLPHL in the family. We sequenced NPAT from a large number of HL patients, and detected an in-frame deletion (c.2171-2173delCTT, p.Ser725del) that was more prevalent in cases than in population matched controls (odds ratio 4.11, P=0.018), supporting the role of NPAT as a candidate predisposition gene. Fourth, we studied a family with five affected siblings with intracranial meningiomas, four of whom had multiple meningiomas. We identified a c.367C>T (p.Arg123Cys) mutation in SUFU that segregated with the meningiomas in the family. The tumors from the affected individuals showed loss of heterozygosity of the wild-type allele at the site of the mutation. We showed that the mutation led to lowered SUFU activity and dysregulated Hedgehog signaling. Our genetic and functional analyses indicate that germline SUFU mutations predispose to meningiomas, particularly multiple meningiomas.
  • Hiltunen, Matti (Helsingin yliopisto, 2014)
    Traditional cardiovascular risk factors in midlife are known to associate with memory illness in later life. In late-life, however, this association is less clear. Recognition of new modifiable cardiovascular risk factors with prognostic capacity on memory illness are needed in the older population. In recent years, the association between natriuretic peptides, biomarkers of direct cardiovascular stress, and cognitive decline has been addressed within a few studies. Severe cognitive decline and depressive symptoms have been linked to increased mortality amongst the elderly. The impact of mild cognitive decline on mortality has been less clear. Increased cardiovascular morbidity, mood disorders and memory illnesses are conditions that may overlap in older people. The aim of this study was to investigate the impact of B-type natriuretic peptide (BNP) a marker of cardiovascular stress on mortality, together with the Mini Mental State Examination Score (MMSE) and depressive symptoms in combination with established cardiovascular risk factors in an older general population. Another aim of this study was to investigate how the prognostic capacity of BNP on memory illness varies with aging, and to examine the relationship between BNP and the severity of memory illness. This study was based on the Kuopio 75+ health study, a prospective age-stratified cohort study with 601 individuals aged 75 years or over. The participants were examined at the entry of the study and during a five-year follow-up visit. Clinical examination including assessment of cognitive function and laboratory count including BNP were performed. Mortality data were obtained from Statistics Finland. BNP was a strong predictor of all-cause and cardiovascular mortality when examined together with MMSE score or depressive symptoms. An MMSE score of 18-23 was a predictor of total rather than cardiovascular mortality. Depressive symptoms had no significant independent predictive value on total or cardiovascular mortality. BNP had prognostic capacity on memory illness in the 75-78 years age-group, but not in older age-groups. BNP was also associated with mild memory illness, but this association was lost in the more severe forms of memory illness. In conclusion, BNP showed good performance as a predictor of all-cause and cardiovascular mortality when tested together with MMSE score or depressive symptoms in combination with established cardiovascular risk factors in the elderly population. The relationship between BNP and memory illness varies by age and progression of disorder, as the previously found link between BNP and memory illness is present only in the population aged under 79 years and in mild stages of disorder. More information is needed especially for recognizing prognostic tools for the identification of older individuals at elevated risk of mortality and developing a memory illness.
  • Hiltunen, Laura (Helsingin yliopisto, 2014)
    Suicides and attempted suicides in relation to weather and daylight in Finland, from 1969 to 2010 Suicide statistics show higher figures during spring and summer compared to autumn and winter. No explanation to this phenomenon has been found, but seasonal changes in weather have been suspected to be involved. The objective of this study was to find out whether correlation between suicide statistics and weather variables exists in Finland. Suicide statistics from 1969 to 2010 in Finland were compared to daily, monthly, and annual weather data, on the national level as well as in the Helsinki, Jyväskylä and Oulu regions. Suicide mortality was at its highest between May 15 and July 25. During that period the day length is at its longest. No weather correlation as to that period was found. However, temperature did correlate with suicide mortality on an annual basis, and more clearly during winter; the lower the temperature was, the lower the suicide rate was. Furthermore, global solar radiation correlated negatively with suicide mortality between September and April. These correlations were more pronounced among men, and in the Helsinki region. For attempted suicides, in the Helsinki region, a correlation with atmospheric pressure was found. For women the correlation was positive, but for men, it was negative. Any biological or social mechanisms that may contribute to these correlations remain currently unknown. However, the biological intrinsic clock which follows the light-dark cycle cannot be ruled out as a biological mechanism. Furthermore, earlier studies have shown correlations between hormonal changes and weather variables. In severe depressive disorder, which is a major risk factor for suicide, disruptions in the biological rhythms, and hormone secretions do occur, but it is not known to which extent these disruptions might be triggered due to weather conditions. Therefore, more research is needed to evaluate the clinical significance and implications of these findings, and to further improve suicide prevention.
  • Krebs, Rainer (Helsingin yliopisto, 2014)
    The aim of this study was to investigate the role of VEGF ligands A and C and their receptors (VEGFR-1, VEGFR-2, VEGFR-3) in the development of experimental OB. To this effect, tracheal allografts were transplanted heterotopically into MHC-mismatched mice and rats. In the heterotopic tracheal allograft model, an early inflammatory phase with its peak at 10 days after transplantation is followed by a fibroproliferative phase that results in complete luminal occlusion of the graft at 30 days after transplantation. We found that the expression of VEGF-A and VEGF-C as well as their receptors changed location and intensity during the development of experimental OB in tracheal allografts. The alloimmune response in tracheal transplants upregulated the expression of VEGF-A and VEGF-C primarily in graft-infiltrating mononuclear inflammatory cells and the microvasculature in the airway wall. The VEGF receptors showed a similar expression pattern. Overexpression of VEGF-A and VEGF-C significantly increased luminal occlusion at 30 days after transplantation. Blocking signaling through receptors VEGFR-1, VEGFR-2, and VEGFR-3, on the other hand, had beneficial effects and prevented the development of experimental OB. Blocking VEGFR-1 and VEGFR-2 alleviated the innate immune responses at three days after transplantation, especially on the natural killer cell level, thereby downscaling the subsequent adaptive immune response by CD4+ T cells at 10 days after transplantation and the development of luminal occlusion at 30 days after transplantation. Blocking VEGF-C/VEGFR-3 signaling inhibited intragraft lymphangiogenesis at both time points, influx of CD4+ T cells at 10 days, and traffic of dendritic cells out of the graft at 30 days after transplantation. These findings suggest a regulatory role for VEGF ligands in the pathogenesis of OB. Intervention at the VEGFR level could reduce early inflammatory reactions (VEGFR-1, VEGFR-2) or downscale antigen export and thus antigen presentation to alloreactive lymphocytes (VEGFR-3), thereby improving the long-term results of lung transplantation.
  • Ovaska, Mikko (Helsingin yliopisto, 2014)
    Mikko Ovaska. Complications in Ankle Fracture Surgery. Helsinki Bone and Joint Research Group, Department of Orthopaedic Surgery and Traumatology, Faculty of Medicine, University of Helsinki, Finland. Helsinki 2014. Ankle fractures are among the most frequently encountered surgically treated fractures. The operative treatment of this fracture may be associated with several complications. The most frequently encountered complications are related wound healing, and deep infection may have devastating consequences. As the population continues to age, the number of elderly patients with comorbidities sustaining ankle fractures continues to rise. In the future, an increase in complications related to ankle fracture surgery is expected. The purpose of this study was to investigate complications related to ankle fracture surgery. The study population consisted of 5123 consecutive ankle fracture patients, who were operatively treated at a level I-trauma center during the years 2002─2011. The study aimed to determine the most common technical errors resulting in early reoperation following ankle fracture surgery, and to identify the most important risk factors for deep surgical site infection (SSI) following operative treatment of ankle fractures. Additionally, the study aimed to assess the outcome of patients treated with flap reconstruction following deep infection with exposed hardware, and recognize the main factors predisposing to a treatment failure of an infected ankle fracture. The study showed that problems related to syndesmotic reduction together with fibular shortening were the most important indications for early reoperation following ankle fracture surgery. Several modifiable risk factors for deep infection were identified; most importantly, the multivariable analysis showed that smoking (OR = 3.7, 95% CI 1.6-8.5), and duration of surgery > 90 minutes (OR = 2.5, 1.1-5.7) were independent risk factors for deep infection. Cast application in the operating room was independently associated with a decreased infection rate (OR = 0.4, 95% CI 0.2-0.8). The study also revealed that soft-tissue defects around ankle with infected hardware can be successfully treated with local flaps. However, flap-related complications are common. Despite eventual reconstructive success, patients perceive a poorer health-related quality of life than the general population, and only half of them recover their pre-injury level of function. The study confirmed the hypothesis that hardware removal prior to fracture union leads to a poor clinical outcome following deep ankle fracture infection (OR = 3.3, 95% CI 1.0-10.7). The devastating nature of deep infection following operative treatment of an ankle fracture emphasizes the crucial role of preventive measures. Therefore, recognition of red flags such as diabetes, smoking, alcohol abuse, and compromised soft tissue condition is of paramount importance. Reinforcing the surgical armamentarium with meticulous preoperative planning and implementation of a check-list together with recognition of the most common surgical errors may be valuable adjuncts in reducing the number of complications. Deep infections following ankle fracture surgery are best managed by a multidisciplinary musculoskeletal infection team. Keywords: ankle fracture, reoperation, surgical site infection, complication, flap reconstruction.
  • Kylmälä, Minna (Helsingin yliopisto, 2014)
    Myocardial infarct size is clinically relevant, affecting heart function and patient prognosis. After myocardial infarction (MI), it is important to establish whether myocardial dysfunction is due to permanent infarct damage, or if the myocardium is viable, in which case contraction may be improved by revascularization. Established methods for assessing infarct size and viability, such as cardiac magnetic resonance imaging with delayed contrast enhancement (DE-CMR) and myocardial perfusion imaging are neither readily available nor suitable in acute MI. In contrast, electrocardiography (ECG) and echocardiography are widely available diagnostic methods at the patient’s bedside at any hour. Echocardiographic strain rate imaging, based on measurement of myocardial velocities by tissue Doppler, is a sensitive and objective method for quantification of myocardial contraction. If myocardium contracts, it is viable. Body surface potential mapping (BSPM) records ECG with multiple leads covering the entire thorax, with a variety of ECG variables automatically calculated from its recordings. The aim of the studies for this thesis was to evaluate whether infarct size and myocardial viability can be assessed by strain rate imaging and BSPM. The studies included up to 57 patients with acute coronary syndrome, most with an infarction. BSPM with 123 leads and echocardiography were performed within 48 hours after onset of chest pain, and repeated during recovery of the infarction, at 1 to 4 weeks, and after healing, at 6 to 12 months. Global infarct size and segmental extent of infarct were determined by DE-CMR after healing. Strain rate imaging allowed assessment of viability and global infarct size in both acute and chronic MI. Strain mapping was validated, for the first time, as a semi-quantitative method for the assessment of systolic strain, and showed excellent correlation with quantitative strain values. In chronic MI, segments with systolic strain values less than -6% were most probably viable, having no infarct or a non-transmural infarct. Strain mapping proved as good as quantitative strain in distinguishing transmural from non-transmural infarcts. In acute MI, strain- and strain-rate variables could distinguish viable from non-viable segments, post-systolic strain having the best accuracy at predicting recovery of severe contraction abnormality (AUC 0.78). BSPM could estimate infarct size at all stages of the infarction, with Q- and R-wave variables, as well as the QRS integral having the strongest correlations with infarct size at all time-points. The repolarization variables were clearly inferior; only in chronic MI did the T-wave variables have nearly as strong correlations with infarct size as did QRS variables. In contrast, the repolarization variables proved good at predicting recovery of left ventricular (LV) function in acute MI, irrespective of MI location. The 1st QRS integral was the only depolarization variable good at predicting recovery of LV dysfunction, and the only variable able to estimate infarct size in addition to viability. In conclusion, strain rate imaging as well as computed ECG variables can predict recovery of myocardial function in acute MI and can assess infarct size in both acute and chronic MI. Strain values can be quickly and accurately estimated by the strain-mapping method, validated now for the first time in the assessment of infarct transmurality. These methods, easily performed at bedside, may help the clinician assess patient prognosis and the need for revascularization after MI.