Advanced epithelial ovarian cancer – studies on preoperative [18F] FDG PET/CT and HE4 profile during primary chemotherapy

Epithelial ovarian cancer (EOC) is usually diagnosed in an advanced stage. The prognosis depends highly on the amount of the residual tumor in surgery. In patients with extensive disease, neoadjuvant chemotherapy (NACT) is used to diminish the tumor load before debulking surgery. New non-invasive methods are needed to preoperatively evaluate the disease dissemination and operability. [18F] FDG PET/CT (Positron emission tomography/computed tomography) is a promising method for cancer diagnostics and staging. The biomarker profiles during treatment can predict patient’s outcome. This prospective study included 41 EOC patients, 21 treated with primary surgery and 20 with NACT and interval surgery. The performances of preoperative contrast enhanced PET/CT (PET/ceCT) and diagnostic CT (ceCT) were compared. Perioperative visual estimation of tumor spread was studied in primary and interval surgery. The profile of the serum marker HE4 (Human epididymis 4) during primary chemotherapy was evaluated. In primary surgery, surgical findings were found to form an adequate reference standard for imaging studies. After NACT, the sensitivity for visual estimation of cancer dissemination was significantly worse. Preoperative PET/ceCT was more effective than ceCT alone in detecting extra-abdominal disease spread. The high number of supradiaphragmatic lymph node metastases detected by PET/ceCT at the time of diagnosis brings new insight in EOC spread patterns. The sensitivity of both PET/CT and ceCT remained modest in intra-abdominal areas important to operability. The HE4 profile was in concordance with the CA125 profile during primary chemotherapy. Its role in the evaluation of EOC chemotherapy response will be clarified in further studies.

CT and PET/CT Hybrid Imaging of Coronary Artery Disease

Coronary artery disease (CAD) is a chronic process that evolves over decades and may culminate in myocardial infarction (MI). While invasive coronary angiography (ICA) is still considered the gold standard of imaging CAD, non-invasive assessment of both the vascular anatomy and myocardial perfusion has become an intriguing alternative. In particular, computed tomography (CT) and positron emission tomography (PET) form an attractive combination for such studies. Increased radiation dose is, however, a concern. Our aim in the current thesis was to test novel CT and PET techniques alone and in hybrid setting in the detection and assessment of CAD in clinical patients. Along with diagnostic accuracy, methods for the reduction of the radiation dose was an important target. The study investigating the coronary arteries of patients with atrial fibrillation (AF) showed that CAD may be an important etiology of AF because a high prevalence of CAD was demonstrated within AF patients. In patients with suspected CAD, we demonstrated that a sequential, prospectively ECG-triggered CT technique was applicable to nearly 9/10 clinical patients and the radiation dose was over 60% lower than with spiral CT. To detect the functional significance of obstructive CAD, a novel software for perfusion quantification, CarimasTM, showed high reproducibility with 15O-labelled water in PET, supporting feasibility and good clinical accuracy. In a larger cohort of 107 patients with moderate 30-70% pre-test probability of CAD, hybrid PET/CT was shown to be a powerful diagnostic method in the assessment of CAD with diagnostic accuracy comparable to that of invasive angiography and fractional flow reserve (FFR) measurements. A hybrid study may be performed with a reasonable radiation dose in a vast majority of the cases, improving the performance of stand-alone PET and CT angiography, particularly when the absolute quantification of the perfusion is employed. These results can be applied into clinical practice and will be useful for daily clinical diagnosis of CAD.

Metabolic syndrome – early cardio-metabolic, vascular and hepatic changes

Background: Metabolic syndrome (MetS) is a combination of several cardio-metabolic risk factors including obesity, hyperglycemia, hypertension and dyslipidemia. MetS has been associated with increased levels of apolipoprotein B (apoB) and low-density lipoprotein oxidation (OxLDL) and with an increased risk of cardiovascular disease and non-alcoholic fatty liver disease. Aims: To establish the relation of apoB and OxLDL with the MetS development and to determine the status of MetS as a risk factor for adverse liver changes and for subclinical atherosclerosis. Subjects and Methods: The present thesis is part of the two large scale population-based, prospective, observational studies. Cardiovascular Risk in Young Finns study was launched in 1980 including 3,596 subjects aged 3-18 years. Thereafter follow-up studies have been conducted regularly. In the latest follow-ups that were performed in 2001 (N=2,283) and 2007 (N=2,204), non-invasive ultrasound studies were introduced to the study protocol to measure subclinical atherosclerosis i.e. carotid intima-media thickness (IMT), carotid artery distensibility (Cdist) and brachial flow-mediated dilatation (FMD). Alanine-aminotransferase (ALT) and gammaglutamyltransferase (GGT) were measured in 2007 to assess liver function. The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors launched in 1972 in a biracial community of Bogalusa, Louisiana, USA. Total of 374 youths (aged 9-18 years at baseline in 1984-88) who underwent non-invasive ultrasound studies of the carotid artery as adults, were included in the analyses of the present thesis. Results: The odds ratios (95% confidence intervals) for MetS incidence during a 6-year follow-up by quartiles of apoB were 2.0(1.0-3.8) for the second quartile, 3.1(1.7-5.7) for the third quartile and 4.2(2.3-7.6) for the fourth quartile. OxLDL was not independently associated with incident MetS. Youth (aged 9-18 years) with MetS or with high body mass index were at 2-3 times the risk of having MetS, high IMT, and type 2 diabetes 24-years later as adults. IMT increased 79±7μm (mean±SEM) in subjects with MetS and 42±2μm in subjects without the MetS (P<0.0001) during 6- years. Subjects who lost the MetS diagnosis during 6-year follow-up had reduced IMT progression compared to persistent MetS group (0.036±0.005vs.0.079±0.010 mm, P=0.001) and reduced Cdist change compared to incident MetS group (-0.12±0.05vs.-0.38±0.10 %/mmHg, P=0.03) over 6-year follow-up. MetS predicted elevated ALT (β±SEM=0.380±0.052, P<0.0001 in men and 0.160±0.052, P=0.002 in women) and GGT (β±SEM=0.240±0.058, P<0.0001 in men and 0.262±0.053, P<0.0001 in women) levels after 6-years. Conclusions: These findings suggest that apoB may give additional information on early metabolic disturbances predisposing MetS. MetS may be used to identify individuals at increased risk of developing atherosclerosis and non-alcoholic liver disease. However, recovery from the MetS may have positive effects on liver and vascular properties.

Imaging of Tumour Microenvironment for the Planning of Oncological Therapies Using Positron Emission Tomography

Tumour cells differ from normal tissue cells in several important ways. These differences, like for example changed energy metabolism, result in altered microenvironment of malignant tumours. Non-invasive imaging of tumour microenvironment has been at the centre of intense research recently due to the important role that this changed environement plays in the development of malignant tumours and due to the role it plays in the treatment of these tumours. In this respect, perhaps the most important characteristics of the tumour microenvironment from this point of view are the lack of oxygen or hypoxia and changes in blood flow (BF). The purpose of this thesis was to investigate the processes of energy metabolism, BF and oxygenation in head and neck cancer and pancreatic tumours and to explore the possibilities of improving the methods for their quantification using positron emission tomography (PET). To this end [18F]EF5, a new PET tracer for detection of tumour hypoxia was investigated. Favourable uptake properties of the tracer were observed. In addition, it was established that the uptake of this tracer does not correlate with the uptake of existing tracers for the imaging of energy metabolism and BF, so the information about the presence of tissue hypoxia cannot therefore be obtained using tracers such as [18F]FDG or [15O]H2O. These results were complemented by the results of the follow-up study in which it was shown that the uptake of [18F]EF5 in head and neck tumours prior to treatment is also associated with the overall survival of the patients, indicating that tumour hypoxia is a negative prognostic factor and might be associated with therapeutic resistance. The influences of energy metabolism and BF on the survival of patients with pancreatic cancer were investigated in the second study. The results indicate that the best predictor of survival of patients with pancreatic cancer is the relationship between energy metabolism and BF. These results suggest that the cells with high metabolic activity in a hypoperfused tissue have the most aggressive phenotype.

Motoneuronitautiin liittyvä hengitysvajaus: hengitystoiminnan ja energia-aineenvaihdunnan mittaaminen

Tavoitteet: Tämän tutkimussarjan tavoitteena oli tutkia hengitystoiminnan sekä energia-aineen¬vaihdunnan muutoksia motoneuronitautia (amyotrofinen lateraaliskleroosi, ALS) sairastavilla potilailla. Erityisenä mielenkiinnon kohteena olivat kotihoitoon soveltuvan hengityslaitteen vai¬kutus elinajan ennusteeseen sekä hengitysvajauksen etenemistä kuvaavien keuhkotoimintakokei¬den arviointi ALS-potilailla, epäsuoran kalorimetrian mittaustarkkuus ja perusaineenvaihdunnan (PAV) suuruus kajoavaa hengityslaitetta käyttävillä ALS-potilailla. Aineisto ja menetelmät: Kajoamattoman hengityslaitteen käytön ja iän vaikutusta elinajan en¬nusteeseen arvioitiin 84:llä ja hengitystoiminnan muutoksia 42 ALS-potilaalla. Epäsuoran kalo¬rimetrian mittaustarkkuutta kajoamatonta hengityslaitetta käytettäessä arvioitiin hereillä olevilla 12 vapaaehtoisella mieshenkilöllä. PAV:n suuruutta arvioitiin viidellä kajoavaa hengityslaitetta käyttävällä ALS-potilaalla. Osatöistä kaksi ensimmäistä olivat luonteeltaan havainnoivia (retros¬pektiivisiä) ja kaksi viimeistä seurantatutkimuksia (prospektiivisia). Tulokset: Alle 65-vuotiailla ALS-potilailla ei havaittu eroa elinajan ennusteessa kajoamaton¬ta hengityslaitetta käyttävien ja käyttämättömien potilaiden välillä. Sen sijaan yli 65-vuotiail¬la ALS-potilailla elinajan ennuste piteni merkittävästi kajoamatonta hengityslaitetta käyttävillä potilailla (elinaika diagnoosin jälkeen 22 vs. 8 kk, Hazard Ratio = 0.25, 95 % luottamusväli 0.11 – 0.55, p <0.001). ALS-potilailla, joilla kajoamaton hengityslaite katsottiin tarpeelliseksi kuuden kuukauden kuluessa diagnoosihetkestä, hengitystiheys osoittautui diagnoosihetkellä mer-kittävästi kiihtyneeksi (21/min) ja rintakehän liike merkittävästi alentuneeksi (2.9 cm) verrattuna ALS-potilaisiin, joille kajoamaton hengityslaite katsottiin tarpeelliseksi myöhemmin (16/min ja 4.0 cm). Kajoamattoman hengityslaitehoidon aikana keskimääräinen mitattu PAV vapaaehtoisilla miehillä oli 1858 kcal/vrk kun PAV ilman hengityslaitetta oli 1852 kcal/vrk, p = 0.8. Kajoavaa hengityslaitehoitoa käyttävien viiden ALS-potilaan keskimääräinen PAV vastaavalla mittausase¬telmalla mitattaessa oli 1130 kcal/vrk, kun vastaava PAV laskettuna viidellä eri laskentakaavalla oli 1700 kcal/vrk, p < 0.001. Johtopäätökset: Yli 65-vuotiailla ALS-potilailla, jotka eivät sopeutuneet kajoamattomaan hen¬gityslaitehoitoon, oli nelinkertainen riski menehtyä aiemmin kuin kajoamattomaan hengityslai¬tehoitoon sopeutuneilla ALS-potilailla. Hengitystiheys osoittautui merkittävästi kiihtyneeksi ja rintakehän liike alentuneeksi ALS-potilailla, joille kajoamaton hengityslaitehoito katsottiin ai¬heelliseksi kuuden kuukauden kuluessa diagnoosihetkestä. Kajoamattoman hengityslaitehoidon aikana mitattu PAV ei poikennut mitatusta PAV:sta itsenäisen hengityksen aikana. Näin ollen epäsuoraa kalorimetriamenetelmää voidaan käyttää luotettavasti PAV:n määrittämiseen käytet¬täessä samanaikaisesti kotihoitoon soveltuvaa hengityslaitehoitoa. Elämää ylläpitävää kajoavaa hengityslaitehoitoa käyttävien ALS-potilaiden PAV oli merkittävästi hidastunut laskennallisella menetelmällä arvioituun PAV verrattuna.

Quantitative Magnetic Resonance Imaging of the Liver and Heart In Iron Overload

Systemic iron overload (IO) is considered a principal determinant in the clinical outcome of different forms of IO and in allogeneic hematopoietic stem cell transplantation (alloSCT). However, indirect markers for iron do not provide exact quantification of iron burden, and the evidence of iron-induced adverse effects in hematological diseases has not been established. Hepatic iron concentration (HIC) has been found to represent systemic IO, which can be quantified safely with magnetic resonance imaging (MRI), based on enhanced transverse relaxation. The iron measurement methods by MRI are evolving. The aims of this study were to implement and optimise the methodology of non-invasive iron measurement with MRI to assess the degree and the role of IO in the patients. An MRI-based HIC method (M-HIC) and a transverse relaxation rate (R2*) from M-HIC images were validated. Thereafter, a transverse relaxation rate (R2) from spin-echo imaging was calibrated for IO assessment. Two analysis methods, visual grading and rSI, for a rapid IO grading from in-phase and out-of-phase images were introduced. Additionally, clinical iron indicators were evaluated. The degree of hepatic and cardiac iron in our study patients and IO as a prognostic factor in patients undergoing alloSCT were explored. In vivo and in vitro validations indicated that M-HIC and R2* are both accurate in the quantification of liver iron. R2 was a reliable method for HIC quantification and covered a wider HIC range than M-HIC and R2*. The grading of IO was able to be performed rapidly with the visual grading and rSI methods. Transfusion load was more accurate than plasma ferritin in predicting transfusional IO. In patients with hematological disorders, the prevalence of hepatic IO was frequent, opposite to cardiac IO. Patients with myelodysplastic syndrome were found to be the most susceptible to IO. Pre-transplant IO predicted severe infections during the early post-transplant period, in contrast to the reduced risk of graft-versus-host disease. Iron-induced, poor transplantation results are most likely to be mediated by severe infections.

Imaging Neuroinflammation in Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system CNS), where inflammation and neurodegeneration lead to irreversible neuronal damage. In MS, a dysfunctional immune system causes auto‐reactive lymphocytes to migrate into CNS where they initiate an inflammatory cascade leading to focal demyelination, axonal degeneration and neuronal loss. One of the hallmarks of neuronal injury and neuroinflammation is the activation of microglia. Activated microglia are found not only in the focal inflammatory lesions, but also diffusely in the normal‐appearing white matter (NAWM), especially in progressive MS. The purine base, adenosine is a ubiquitous neuromodulator in the CNS and also participates in the regulation of inflammation. The effect of adenosine mediated via adenosine A2A receptors has been linked to microglial activation, whereas modulating A2A receptors may exert neuroprotective effects. In the majority of patients, MS presents with a relapsing disease course, later advancing to a progressive phase characterised by a worsening, irreversible disability. Disease modifying treatments can reduce the severity and progression in relapsing MS, but no efficient treatment exists for progressive MS. The aim of this research was to investigate the prevalence of adenosine A2A receptors and activated microglia in progressive MS by using in vivo positron emission tomography (PET) imaging and [11C]TMSX and [11C](R)‐PK11195 radioligands. Magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed to evaluate structural brain damage. Non‐invasive input function methods were also developed for the analyses of [11C]TMSX PET data. Finally, histopathological correlates of [11C](R)‐PK11195 radioligand binding related to chronic MS lesions were investigated in post‐mortem samples of progressive MS brain using autoradiography and immunohistochemistry. [11C]TMSX binding to A2A receptors was increased in NAWM of secondary progressive MS (SPMS) patients when compared to healthy controls, and this correlated to more severe atrophy in MRI and white matter disintegration (reduced fractional anisotropy, FA) in DTI. The non‐invasive input function methods appeared as feasible options for brain [11C]TMSX images obviating arterial blood sampling. [11C](R)‐PK11195 uptake was increased in the NAWM of SPMS patients when compared to patients with relapsing MS and healthy controls. Higher [11C](R)‐PK11195 binding in NAWM and total perilesional area of T1 hypointense lesions was associated with more severe clinical disability, increased brain atrophy, higher lesion load and reduced FA in NAWM in the MS patients. In autoradiography, increased perilesional [11C](R)‐PK11195 uptake was associated with increased microglial activation identified using immunohistochemistry. In conclusion, brain [11C]TMSX PET imaging holds promise in the evaluation of diffuse neuroinflammation in progressive MS. Being a marker of microglial activation, [11C](R)‐ PK11195 PET imaging could possibly be used as a surrogate biomarker in the evaluation of the neuroinflammatory burden and clinical disease severity in progressive MS.

Translational models of coronary artery disease, myocardial infarction and heart failure. Development, validation and in vivo imaging studies using positron emission tomography

Coronary artery disease is an atherosclerotic disease, which leads to narrowing of coronary arteries, deteriorated myocardial blood flow and myocardial ischaemia. In acute myocardial infarction, a prolonged period of myocardial ischaemia leads to myocardial necrosis. Necrotic myocardium is replaced with scar tissue. Myocardial infarction results in various changes in cardiac structure and function over time that results in “adverse remodelling”. This remodelling may result in a progressive worsening of cardiac function and development of chronic heart failure. In this thesis, we developed and validated three different large animal models of coronary artery disease, myocardial ischaemia and infarction for translational studies. In the first study the coronary artery disease model had both induced diabetes and hypercholesterolemia. In the second study myocardial ischaemia and infarction were caused by a surgical method and in the third study by catheterisation. For model characterisation, we used non-invasive positron emission tomography (PET) methods for measurement of myocardial perfusion, oxidative metabolism and glucose utilisation. Additionally, cardiac function was measured by echocardiography and computed tomography. To study the metabolic changes that occur during atherosclerosis, a hypercholesterolemic and diabetic model was used with [18F] fluorodeoxyglucose ([18F]FDG) PET-imaging technology. Coronary occlusion models were used to evaluate metabolic and structural changes in the heart and the cardioprotective effects of levosimendan during post-infarction cardiac remodelling. Large animal models were used in testing of novel radiopharmaceuticals for myocardial perfusion imaging. In the coronary artery disease model, we observed atherosclerotic lesions that were associated with focally increased [18F]FDG uptake. In heart failure models, chronic myocardial infarction led to the worsening of systolic function, cardiac remodelling and decreased efficiency of cardiac pumping function. Levosimendan therapy reduced post-infarction myocardial infarct size and improved cardiac function. The novel 68Ga-labeled radiopharmaceuticals tested in this study were not successful for the determination of myocardial blood flow. In conclusion, diabetes and hypercholesterolemia lead to the development of early phase atherosclerotic lesions. Coronary artery occlusion produced considerable myocardial ischaemia and later infarction following myocardial remodelling. The experimental models evaluated in these studies will enable further studies concerning disease mechanisms, new radiopharmaceuticals and interventions in coronary artery disease and heart failure.

Value at Risk in measuring market risk: Historical simulation

In this study the theoretical part was created to make comparison between different Value at Risk models. Based on that comparison one model was chosen to the empirical part which concentrated to find out whether the model is accurate to measure market risk. The purpose of this study was to test if Volatility-weighted Historical Simulation is accurate in measuring market risk and what improvements does it bring to market risk measurement compared to traditional Historical Simulation. Volatility-weighted method by Hull and White (1998) was chosen In order to improve the traditional methods capability to measure market risk. In this study we found out that result based on Historical Simulation are dependent on chosen time period, confidence level and how samples are weighted. The findings of this study are that we cannot say that the chosen method is fully reliable in measuring market risk because back testing results are changing during the time period of this study.

Pain-evoked alterations on gingival blood flow and gingival crevicular fluid (GCF) neuropeptide SP and collagenase-2 (MMP-8) levels

Previous studies have demonstrated that clinical pulpal pain can induce the expression of pro-inflammatory neuropeptides in the adjacent gingival crevice fluid (GCF). Vasoactive agents such as substance P (SP) are known to contribute to the inflammatory type of pain and are associated with increased blood flow. More recent animal studies have shown that application of capsaicin on alveolar mucosa provokes pain and neurogenic vasodilatation in the adjacent gingiva. Pain-associated inflammatory reactions may initiate expression of several pro- and anti-inflammatory mediators. Collagenase-2 (MMP-8) has been considered to be the major destructive protease, especially in the periodontitis-affected gingival crevice fluid (GCF). MMP-8 originates mostly from neutrophil leukocytes, the first line of defence cells that exist abundantly in GCF, especially in inflammation. With this background, we wished to clarify the spatial extensions and differences between tooth-pain stimulation and capsaicin-induced neurogenic vasodilatation in human gingiva. Experiments were carried out to study whether tooth stimulation and capsaicin stimulation of alveolar mucosa would induce changes in GCF MMP-8 levels and whether tooth stimulation would release neuropeptide SP in GCF. The experiments were carried out on healthy human volunteers. During the experiments, moderate and high intensity painful tooth stimulation was performed by a constant current tooth stimulator. Moderate tooth stimulation activates A-delta fibres, while high stimulation also activates C-fibres. Painful stimulation of the gingiva was achieved by topical application of capsaicin-moistened filter paper on the mucosal surface. Capsaicin is known to activate selectively nociceptive C-fibres of stimulated tissue. Pain-evoked vasoactive changes in gingivomucosal tissues were mapped by laser Doppler imaging (LDI), which is a sophisticated and non-invasive method for studying e.g. spatial and temporal characteristics of pain- and inflammation-evoked blood flow changes in gingivomucosal tissues. Pain-evoked release of MMP-8 in GCF samples was studied by immunofluorometric assay (IFMA) and Western immunoblotting. The SP levels in GCF were analysed by Enzyme immunoassay (EIA). During the experiments, subjective stimulus-evoked pain responses were determined by a visual analogue pain scale. Unilateral stimulation of alveolar mucosa and attached gingiva by capsaicin evoked a distinct neurogenic vasodilatation in the ipsilateral gingiva, which attenuated rapidly at the midline. Capsaicin stimulation of alveolar mucosa provoked clear inflammatory reactions. In contrast to capsaicin stimuli, tooth stimulation produced symmetrical vasodilatations bilaterally in the gingiva. The ipsilateral responses were significantly smaller during tooth stimulation than during capsaicin stimuli. The current finding – that tooth stimulation evokes bilateral vasodilatation while capsaicin stimulation of the gingiva mainly produces unilateral vasodilatation – emphasises the usefulness of LDI in clarifying spatial features of neurogenic vasoactive changes in the intra-oral tissues. Capsaicin stimulation of the alveolar mucosa induced significant elevations in MMP-8 levels and activation in GCF of the adjacent teeth. During the experiments, no marked changes occurred in MMP-8 levels in the GCF of distantly located teeth. Painful stimulation of the upper incisor provoked elevations in GCF MMP-8 and SP levels of the stimulated tooth. The GCF MMP-8 and SP levels of the non-stimulated teeth were not changed. These results suggest that capsaicin-induced inflammatory reactions in gingivomucosal tissues do not cross the midline in the anterior maxilla. The enhanced reaction found during stimulation of alveolar mucosa indicates that alveolar mucosa is more sensitive to chemical irritants than the attached gingiva. Analysis of these data suggests that capsaicin-evoked neurogenic inflammation in the gingiva can trigger the expression and activation of MMP-8 in GCF of the adjacent teeth. In this study, it is concluded that experimental tooth pain at C-fibre intensity can induce local elevations in MMP-8 and SP levels in GCF. Depending on the role of MMP-8 in inflammation, in addition to surrogated tissue destruction, the elevated MMP-8 in GCF may also reflect accelerated local defensive and anti-inflammatory reactions.

Flexible Multibody Simulation Approach in the Dynamic Analysis of Bone Strains Activity

The objective of this study is to show that bone strains due to dynamic mechanical loading during physical activity can be analysed using the flexible multibody simulation approach. Strains within the bone tissue play a major role in bone (re)modeling. Based on previous studies, it has been shown that dynamic loading seems to be more important for bone (re)modeling than static loading. The finite element method has been used previously to assess bone strains. However, the finite element method may be limited to static analysis of bone strains due to the expensive computation required for dynamic analysis, especially for a biomechanical system consisting of several bodies. Further, in vivo implementation of strain gauges on the surfaces of bone has been used previously in order to quantify the mechanical loading environment of the skeleton. However, in vivo strain measurement requires invasive methodology, which is challenging and limited to certain regions of superficial bones only, such as the anterior surface of the tibia. In this study, an alternative numerical approach to analyzing in vivo strains, based on the flexible multibody simulation approach, is proposed. In order to investigate the reliability of the proposed approach, three 3-dimensional musculoskeletal models where the right tibia is assumed to be flexible, are used as demonstration examples. The models are employed in a forward dynamics simulation in order to predict the tibial strains during walking on a level exercise. The flexible tibial model is developed using the actual geometry of the subject’s tibia, which is obtained from 3 dimensional reconstruction of Magnetic Resonance Images. Inverse dynamics simulation based on motion capture data obtained from walking at a constant velocity is used to calculate the desired contraction trajectory for each muscle. In the forward dynamics simulation, a proportional derivative servo controller is used to calculate each muscle force required to reproduce the motion, based on the desired muscle contraction trajectory obtained from the inverse dynamics simulation. Experimental measurements are used to verify the models and check the accuracy of the models in replicating the realistic mechanical loading environment measured from the walking test. The predicted strain results by the models show consistency with literature-based in vivo strain measurements. In conclusion, the non-invasive flexible multibody simulation approach may be used as a surrogate for experimental bone strain measurement, and thus be of use in detailed strain estimation of bones in different applications. Consequently, the information obtained from the present approach might be useful in clinical applications, including optimizing implant design and devising exercises to prevent bone fragility, accelerate fracture healing and reduce osteoporotic bone loss.

Tietotyön avainhenkilöiden sitoutuminen - Case Kymenlaakson sairaanhoitopiirin lääkärit

Tutkielmassa tarkasteltiin affektiivista eli tunnepohjaista sitoutumista organisaatioon ja selvitettiin, mitkä ovat sitä lisääviä ei-taloudellisia motivointikeinoja. Tulokset osoittivat, että organisaatioon sitoutumista lisääviä ulottuvuuksia ovat itsensä kehittäminen, työtehtävien vaihto ja työn arvostus. Lisäksi selvitettiin affektiivisen sitoutumisen ja innovatiivisuuden välistä suhdetta ja niiden välillä todettiin merkittävä positiivinen yhteys. Tarkastelun kohteena olivat tietotyön avainhenkilöt, joiden sitoutuminen organisaatioon on merkityksellisintä sen toiminnan ja tuottavuuden kannalta. Ilmiötä tarkasteltiin ensisijaisesti tilastollisin menetelmin. Teoriaa testattiin empiirisesti Kymenlaakson sairaanhoitopiirin lääkäreihin, jotka edustavat erikoisosaamista julkisella sektorilla.

Lipotoxicity in Obesity and Coronary Artery Disease. Studies by PET, CT and MR

Lipotoxicity is a condition in which fatty acids (FAs) are not efficiently stored in adipose tissue and overflow to non-adipose tissue, causing organ damages. A defect of adipose tissue FA storage capability can be the primary culprit in the insulin resistance condition that characterizes many of the severe metabolic diseases that affect people nowadays. Obesity, in this regard, constitutes the gateway and risk factor of the major killers of modern society, such as cardiovascular disease and cancer. A deep understanding of the pathogenetic mechanisms that underlie obesity and the insulin resistance syndrome is a challenge for modern medicine. In the last twenty years of scientific research, FA metabolism and dysregulations have been the object of numerous studies. Development of more targeted and quantitative methodologies is required on one hand, to investigate and dissect organ metabolism, on the other hand to test the efficacy and mechanisms of action of novel drugs. The combination of functional and anatomical imaging is an answer to this need, since it provides more understanding and more information than we have ever had. The first purpose of this study was to investigate abnormalities of substrate organ metabolism, with special reference to the FA metabolism in obese drug-naïve subjects at an early stage of disease. Secondly, trimetazidine (TMZ), a metabolic drug supposed to inhibit FA oxidation (FAO), has been for the first time evaluated in obese subjects to test a whole body and organ metabolism improvement based on the hypothesis that FAO is increased at an early stage of the disease. A third objective was to investigate the relationship between ectopic fat accumulation surrounding heart and coronaries, and impaired myocardial perfusion in patients with risk of coronary artery disease (CAD). In the current study a new methodology has been developed with PET imaging with 11C-palmitate and compartmental modelling for the non-invasive in vivo study of liver FA metabolism, and a similar approach has been used to study FA metabolism in the skeletal muscle, the adipose tissue and the heart. The results of the different substudies point in the same direction. Obesity, at the an early stage, is associated with an impairment in the esterification of FAs in adipose tissue and skeletal muscle, which is accompanied by the upregulation in skeletal muscle, liver and heart FAO. The inability to store fat may initiate a cascade of events leading to FA oversupply to lean tissue, overload of the oxidative pathway, and accumulation of toxic lipid species and triglycerides, and it was paralleled by a proportional growth in insulin resistance. In subjects with CAD, the accumulation of ectopic fat inside the pericardium is associated with impaired myocardial perfusion, presumably via a paracrine/vasocrine effect. At the beginning of the disease, TMZ is not detrimental to health; on the contrary at the single organ level (heart, skeletal muscle and liver) it seems beneficial, while no relevant effects were found on adipose tissue function. Taken altogether these findings suggest that adipose tissue storage capability should be preserved, if it is not possible to prevent excessive fat intake in the first place.

Modern Metallic Materials for Arctic Environment

This thesis is part of the Arctic Materials Technologies Development –project, which aims to research and develop manufacturing techniques, especially welding, for Arctic areas. The main target of this paper is to clarify what kind of European metallic materials are used, or can be used, in Arctic. These materials include mainly carbon steels but also stainless steels and aluminium and its alloys. Standardized materials, their properties and also some recent developments are being introduced. Based on this thesis it can be said that carbon steels (shipbuilding and pipeline steels) have been developed based on needs of industry and steels exist, which can be used in Arctic areas. Still, these steels cannot be fully benefited, because rules and standards are under development. Also understanding of fracture behavior of new ultra high strength steels is not yet good enough, which means that research methods (destructive and non-destructive methods) need to be developed too. The most of new nickel-free austenitic and austenitic-ferritic stainless steels can be used in cold environment. Ferritic and martensitic stainless steels are being developed for better weldability and these steels are mainly developed in nuclear industry. Aluminium alloys are well suitable for subzero environment and these days high strength aluminium alloys are available also as thick sheets. Nanotechnology makes it possible to manufacture steels, stainless steels and aluminium alloys with even higher strength. Joining techniques needs to be developed and examined properly to achieve economical and safe way to join these modern alloys.