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(Helsingin yliopisto, 2018)The aim of this dissertation was to investigate the use of computer vision for tissue characterization and patient outcome prediction in cancer. This work focused on analysis of digitized tissue specimens, which were stained only for basic morphology (i.e. hematoxylin and eosin). The applicability of texture analysis and convolutional neural networks was evaluated for detection of biologically and clinically relevant features. Moreover, novel approaches to guide ground-truth annotation and outcome-supervised learning for prediction of patient survival directly from the tumor tissue images without expert guidance was investigated. We first studied quantification of tumor viability through segmentation of necrotic and viable tissue compartments. We developed a regional texture analysis method, which was trained and tested on whole sections of mouse xenograft models of human lung cancer. Our experiments showed that the proposed segmentation was able to discriminate between viable and non-viable tissue regions with high accuracy when compared to human expert assessment. We next investigated the feasibility of pre-trained convolutional neural networks in analysis of breast cancer tissue, aiming to quantify tumor-infiltrating lymphocytes in the specimens. Interestingly, our results showed that pre-trained convolutional neural networks can be adapted for analysis of histological image data, outperforming texture analysis. The results also indicated that the computerized assessment was on par with pathologist assessments. Moreover, the study presented an image annotation technique guided by specific antibody staining for improved ground-truth labeling. Direct outcome prediction in breast cancer was then studied using a nationwide patient cohort. A computerized pipeline, which incorporated orderless feature aggregation and convolutional image descriptors for outcome-supervised classification, resulted in a risk grouping that was predictive of both disease-specific and overall survival. Surprisingly, further analysis suggested that the computerized risk prediction was also an independent prognostic factor that provided information complementary to the standard clinicopathological factors. This doctoral thesis demonstrated how computer-vision methods can be powerful tools in analysis of cancer tissue samples, highlighting strategies for supervised characterization of tissue entities and an approach for identification of novel prognostic morphological features.
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(Helsingin yliopisto, 2018)The aim of this study was to investigate clinical characteristics of cerebral venous thrombosis (CVT), risk-factors, and factors associated with poor outcome. We established retrospectively a database on all CVT patients treated at the Helsinki University Hospital from 1987 to 2015, and patients were invited for a follow-up visit. We formed collaboration with the Academic Medical Centre in Amsterdam, and Sahlgrenska University Hospital in Gothenburg. Helsinki CVT registry collected data on 243 patients. Patients aged from 15 to 82 years (median 42), and 60% were women. In the study investigating sinus recanalization, 43 of 91 patients had complete, 31 had partial, and 17 had no recanalization of the sinuses at follow-up. Poor recanalization was associated with older age, male gender, and absence of known risk factors or causes. In multivariate analysis recanalization was not associated with functional recovery. Fibrin D-dimer was measured in 71 out of 138 patients before initiation of anticoagulation. D-dimer <0.5mg/l was measured in 12.7%, 0.5-2.9mg/l in 52.1%, and >3mg/l in 35.2%. Levels of were lower in patients with longer symptom duration and higher when more sinuses were thrombosed. Hyperglycemia was investigated in 308 patients (169 from Amsterdam and 139 from Helsinki). Hyperglycemia (plasma glucose >7.8mmol/l) was present in 21% of the patients at admission. In multivariate analysis hyperglycemia was independently associated with recovery and mortality. Role of cancer as CVT risk was investigated in 594 cases (243 from Helsinki, 224 from Amsterdam, and 128 from Gothenburg) and 6278 controls. In the first year after cancer diagnosis the risk was clearly elevated in solid cancer, and very high in hematological cancer. The study investigating long-term outcome after CVT included 161 patients, with a mean follow-up of 39 months. Mortality was 11%, with 4% due to CVT. Good functional recovery (mRS 0-1) was observed in 83%, however residual symptoms were reported by 68% of patients. Vocational status analysis included 121 working-aged patients; 23% were unemployed, and 16% were on permanent disability pension. Major stroke symptoms, and compulsory education only were associated with both functional outcome and vocational status in multivariate analysis. In conclusion, our CVT cases in Helsinki are in demographically similar to other CVT series from high-income countries. Recanalization occurred less often in patients with known factors of poor outcome, but the importance of recanalization to recovery needs further studies. Fibrin D-dimer measurements cannot be reliably used to exclude CVT. We established hyperglycemia as a factor affecting outcome. Hyperglycemia should be treated, but optimum level needs investigation. Newly diagnosed cancer is a major risk factor for CV was confirmed. Functional outcome after CVT is generally good, however residual symptoms are common. Patients are often young, so even mild residual symptoms that affect working ability are of large importance.
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(Helsingin yliopisto, 2018)Somatic cells can be reprogrammed to pluripotent state by ectopic expression of a defined set of transcription factors. These induced pluripotent stem cells (iPSC) hold great potential for biomedical applications, such as disease modelling, drug discovery and cell therapies. The derivation of iPSCs is a complex multistep process that can commonly result in inefficient or incomplete conversion of the cells. The reprogramming efficiency and the quality of the reprogrammed cells can be affected by various components of the reprogramming method, including reprogramming vectors, starting cell populations and the choice of reprogramming factors. The aim of this thesis was to explore novel approaches for improving the pluripotent reprogramming outcome. The particular aims of this thesis were to investigate the use of recombinant Adeno-associated virus (rAAV) as a gene transfer vector for cellular reprogramming, characterization of the effects of old donor age and long term passaging on the reprogramming of fibroblasts, and development of reprogramming methods based on CRISPR/Cas9-mediated activation of endogenous reprogramming factors. In this study, rAAV-mediated transduction of mouse embryonic fibroblasts with OCT4, SOX2, KLF4 and C-MYC was found to successfully induce reprogramming to pluripotency. Unlike initially expected, the AAV vectors were integrated with high efficiency into the host genome during the reprogramming process, resulting in all analyzed iPSCs containing vector integrations. Both donor age and the culture time of the donor fibroblasts correlated with reduction in pluripotent reprogramming efficiency. This effect was found to be associated with upregulation of cellular P21 expression and reduction in cell proliferation. Downregulation of P21 expression by siRNA treatment was able to promote reprogramming of late passage senescent fibroblasts. By optimizing the reprogramming factor guide composition, CRISPR/Cas9-mediated gene activation (CRISPRa) could be used to derive iPSCs reprogrammed fully by targeted activation of endogenous genes. The efficient reprogramming of somatic cells by CRISPRa was found to be dependent on the inclusion of additional guides targeting an embryonic genome activation enriched Alu-motif. Due to the direct targeting of endogenous loci and the high multiplexing capacity of CRISPRa, the reprogramming approach has a high potential for mediating comprehensive and specific reprogramming. Overall, this thesis provides a number of novel tools and insights into the pluripotent reprogramming process. The results of this work can be used to develop more robust reprogramming methods and to improve the quality of reprogrammed cells.
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(Helsingin yliopisto, 2018)ABSTRACT OSBP-related proteins (ORPs) are lipid binding and transport proteins expressed ubiquitously in eukaryotic cells. ORPs localize at specific organelle interfaces designated membrane contact sites (MCSs). They possess a characteristic ligand-binding domain with specificity for oxysterols, cholesterol and phospholipids. Some ORPs have the capacity to mediate bi-directional transfer and exchange of two different lipids over MCSs. However, a number of findings suggest that a majority of the ORP family members act as lipid sensors with cell signalling properties rather than actual lipid transporters. ORP2 localizes on the surface of cellular lipid droplets. Earlier finding suggests that ORP2 contributes in triglyceride (TAG) and cholesterol homeostasis but the comprehensive knowledge of the cellular function of ORP2 is deficient. In my thesis I investigated the sterol regulation of the subcellular localization ORP–VAP complexes and the role of ORP2 in cellular physiology by generating a stable ORP2 knock out (KO) cell line in HuH7 hepatocytes. I demonstrated that the subcellular distribution of OSBP–, ORP4L– and ORP2–VAP-A complexes at MCSs are regulated by ORP oxysterol liganding and by the cellular cholesterol status. Moreover, ORP2-KO impaired a diversity of cellular functions. The ORP2-KO affected mRNAs of >2000 genes, including TAG and glucose processing metabolic enzymes, components of several cell signalling processes and actin cytoskeleton regulators. Analysis of ORP2 interaction partners revealed novel connections of ORP2 with PI3K/Akt and RhoA signalling, important regulators of cell metabolic processes and the actin cytoskeleton. Consistently, the ORP2-KO impaired the hepatocellular energy metabolism by inhibiting the synthesis of TAGs and glycogen, and by reducing the rates of glucose uptake and glycolysis, suggesting an extensive contribution of ORP2 to cellular bioenergetics. In addition, I present novel clues of ORP2 function beyond the lipid and energy metabolism. In migrating cells, ORP2 was found to localize to lamellipodial cell surface protrusions, and the ORP2-KO, on the other hand, was found to impair the lamellipodia formation. Moreover, ORP2-KO resulted in an inhibition of cell adhesion, migration and proliferation, important cell physiological processes involving function of the actin cytoskeleton. The results point at a novel function of ORP2 as a lipid-sensing regulator of the actin cytoskeleton, which importantly involves the integration of cellular metabolism with growth, migration and cell signalling.
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(Helsingin yliopisto, 2018)The thesis addresses the impact of androgen deprivation in combination with gene functions in prostate cancer (PCa), as well as the development of ex vivo cancer models. The studies extended to assess of drug efficacies that may employed in future strategies for precision therapies in PCa. The patient-derived-cells (PDCs) from kidney cancer or renal cell carcinoma (RCC) patients further provided opportunities to study clonal evolution pathways, and to evaluate, how the intra-tumor heterogeneity may influence drug resistance at subclonal level. The biology of PCa revolves around androgen receptor (AR) signaling, thus, it remains the key target for therapeutic strategies. However, development of combinatorial therapies is of critical importance, since targeting AR alone is not enough for long-term benefits of patients. The two projects in the thesis address different avenues of finding novel treatment strategies for PCa. In the first project, RNA interference (RNAi) screens with 2068 human genes, was design to understand the combinatorial impact of individual gene functions and environmental challenges posed by androgen depletion in PCa. The screen identified several known genes, as well as novel ones, such as HSPBAP1, that inhibited proliferation exclusively in androgen-deprived PCa cells. HSPBAP1 was found to interact with AR in the cell nuclei, and its inhibition led to reduced AR-mediated transcription. The data suggested that the AR-interacting protein HSPBAP1 could be a potential target for intervention in combination with androgen-deprivation in PCa cells. Our second approach to discover treatment avenues for PCa was to generate novel PCa cell models from patient-derived material for ex vivo evaluation of drug efficacies. The PDCs from PCa patients displayed an AR-negative predominantly basal/transit-amplifying phenotype. The cancer culture retained cancer-specific copy number changes and exhibited a distinct drug response when profiled with 306 oncology compounds. The drugs included taxanes, bexarotene, tretinoin, oxaliplatin, mepacrine and navitoclax function independently of AR signaling, and most of these have already been explored in clinical trials for treating advanced PCa. Next, we took the strategy applied in PCa to RCC. Since RCC is well-recognized to be genetically heterogeneous disease, we explored the impact of intra-tumor heterogeneity and clonal evolution on drug efficacies based on multiple PDCs generated from the patients. The PDCs were sensitive to established drugs already applied in clinical practice for RCC treatment, such as the mTOR-inhibitor temsirolimus and multi-kinase-inhibitor pazopanib. The individual PDC models from the same patient exhibited diverse drug response patterns suggesting that clonal evolution of cancer directly contributes to differences in drug response. Furthermore, cure in advanced RCC will depend on the design of combinatorial treatments that block each such clone. In summary, in our first project on RNAi-based functional screening in PCa, we established that knockdown of the HSPBAP1 gene will synergize with androgen-depletion in inhibiting PCa cell growth. We then generated comprehensive drug sensitivity testing (DST) on ex vivo models of prostate and renal cancer cells with the aim to discover additional treatment options. DST profiles measured from patient-specific cancer models could in the future pave the way for exploring new indications for existing drugs, to prioritize drug leads and to allocate individualized therapies to cancer patients.
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(Helsingin yliopisto, 2018)Rintasyöpä on yksi maailman yleisimmistä syövistä. Diagnostiikan ja hoitokeinojen kehittyminen on merkittävästi parantunut taudin ennustetta. Kuitenkin joka vuosi tuhannet naiset saavat rintasyöpädiagnoosin ja läpikäyvät rintasyöpäleikkauksen toivoen parantumista. Nykyaikainen kirurgia vaatii tehokasta kivunlievitystä, sillä voimakas kipu altistaa elimistön merkittävälle rasitukselle. Elimistön suojaamiseksi leikkauksen aikana ja sen jälkeen potilaalle annostellaan kipulääkkeitä, joista opioidit ovat käytetyin kipulääkeryhmä keskivaikean ja vaikean postoperatiivisen kivun hoidossa. Opioidihoitoon liittyy kuitenkin vakavia haittavaikutuksia, kuten pahoinvointi ja hengityslama, joiden vuoksi kaikki opioidit joudutaan titraamaan analgeettiseen annokseen asteittain. Tämä pitkittää riittävän kivunlievityksen saavuttamiseen kuluvaa aikaa.. Oksikodoni on ollut vuosikausia Suomen käytetyin opioidi postoperatiivisen kivun hoidossa. Tämän väitöskirjan tarkoitus oli tutkia, onko oksikodonille määritettävissä analgeettista pitoisuutta sekä määrittää postoperatiivisen kivun voimakkuuteen ja oksikodonin tarpeeseen vaikuttavia tekijöitä. Näiden tekijöiden tunnistaminen helpottaisi riskipotilaiden tunnistamista sekä voimakkaan postoperatiivisen kivun että suuren oksikodonin tarpeen suhteen. Näin hoitohenkilökunta voisi jo ennalta varautua haastavaan postoperatiivisen kivun lievitykseen. Tutkimuspopulaatio koostui 1000 naisesta, jotka olivat menossa rintaleikkaukseen havaitun rintasyövän vuoksi. Potilaiden tauti affisioi vain toista rintaa, eikä heillä ollut havaittu metastaaseja. Ennen leikkausta potilaat täyttivät kyselyt demografisista tiedoistaan, sairaushistoriastaan, kipuoireistaan sekä masennus- ja ahdistustasostaan. Lisäksi potilaiden kuuma- ja kylmäkivun sieto sekä intensiteetti testattiin. Postoperatiivisesti kaikille potilaille annosteltiin suonensisäistä oksikodonia, kunnes he ilmaisivat olevansa kivuttomia. Postoperatiiviset kipuintensiteetit ja oksikodonin käyttö kirjattiin ensimmäisen 20 postoperatiivisen tunnin ajalta. Oksikodonille ei pystytty määrittämään analgeettista pitoisuutta. Postoperatiiviseen liikekivun voimakkuuteen assosioituvat tekijät olivat nuori ikä, kainaloevakuaatio (vs. vartijaimusolmukebiopsia), korkeampi kylmäkipuintensiteetti ja kylmäkivun sieto. Nämä tekijät selittivät yhteensä 8,5 % postoperatiivisen liikekivun voimakkuudesta. Postoperatiivisen liikekivun intensiteetti taas assosioitui vahvasti postoperatiiviseen oksikodonin kulutukseen, samoin kuin BMI, ikä, kainaloevakuaatio, OPRM1 genotyyppi ja preoperatiivinen kipu rinnassa. Nämä tekijät selittivät jopa 28 % oksikodonin tarpeen kokonaisvariaatiosta. Vain postoperatiivinen liikekivun voimakkuus ja kainaloevakuaatio assosioituivat oksikodonin analgeettiseen plasmakonsentraatioon. Yhdessä ne selittivät 17 % tämän variaatiosta. CYP2D6 genotyyppi ei assosioitunut postoperatiiviseen oksikodonitarpeeseen tai analgeettiseen plasma konsentraatioon, mutta se vaikutti plasman postoperatiivisiin oksimorfoni- ja noroksimorfonikonsentraatioihin. Väitöskirjan tulokset auttavat tunnistamaan rintasyöpäleikkauksen läpikäyneitä potilaita, joilla on korkea riski voimakkaalle postoperatiiviselle kivulle sekä suurelle oksikodonin tarpeelle.
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(Helsingin yliopisto, 2018)Introduction: Managing extensive bone and soft tissue defects in head and neck region remains a reconstructive challenge. The aim of the reconstruction is to manage the three-dimensional tissue defect and preserve functions like swallowing, talking, breathing and aesthetics. The modern microsurgical practice is reported to be highly reliable. Still, when complications occur, they can be devastating. Understanding the advantages and disadvantages of the different reconstruction alternatives ensures the optimal choice of treatment. Aims: This thesis comprises four studies from Helsinki Head and Neck Center Department of Plastic Surgery, analysing the pratice of head and neck reconstruction from 1995 to 2012, comparing the iliac crest (DCIA), the scapular and the fibular flap in maxillomandibular reconstruction, presenting local pedicled submental artery flap (SAF) in oral cancer reconstruction and analysing novel ear-based alternatives in maxillofacial microvascular reconstruction. Patients and methods: The first study included 541 patients receiving 594 head and neck free flaps from 1995 to 2012. The second study compared 163 patients with a scapular, fibular or DCIA flap for mandibular, maxillary or orbital reconstruction. The third study investigated the outcome of reconstruction with SAF in a series of 10 patients with early or locally advanced intraoral cancer. In the fourth study three external ear-based free flaps in facial reconstruction were described in a series of 19 patients with 20 reconstructions with temporal artery posterior auricular skin (TAPAS), helical or hemiauricular flaps. Results: The most commonly used free flap from 1995 to 2012 was the radial forearm flap. The number of different flap types and combinations expanded from 15 during the first study trimester to 24 during the last study trimester. The flap survival remained constant being 97%. The prevalence of surgical complications decreased. The overall survival rate of scapular, fibular and DCIA flaps from 2000 to 2012 was 91%. The most reliable flap was scapular flap with 100% survival, followed by the fibular with 97% survival and the least reliable was the DCIA with 85% survival. The overall complications favoured fibula and scapula. Two patients with SAF reconstruction developed major complications of which one was total flap loss. The SAF was lifted in three cases in combination with sentinel lymph node biopsy to rule out positive neck disease and in two cases there was nodal sampling combined. The follow-up showed no signs of metastatic neck disease, but six patients developed local recurrences. Three of patients were treated primarily with palliative intent. The free flaps lifted from ear region included 12 helical flaps, 7 TAPAS flaps and 1 hemi-auricular flap. Flap survival rate was 95%. Donor-sites healed uneventfully, and aesthetic and functional outcomes were good in all flaps. Conclusions: Head and neck microsurgery was established in our institution during recent decades. The flap selection has been constantly expanding along with the increasing mean age of the patient population, without sacrificing outcome. In composite reconstructions, fibular, scapular, and DCIA flaps are all useful and reliable tools, with DCIA being least favorable in terms of flap survival and complications. Local flap reconstruction with SAF is an alternative tool in selective patients not suitable for conventional microvascular surgery. Development of free flaps from the ear region has added versatile flap alternatives in the armamentarium.
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(Helsingin yliopisto, 2018)Sickness absence indicates ill-health among working populations and gives rise to notable costs due to lost working days. Employees in lower occupational classes have more sickness absence compared to those in higher classes. Extending working careers by reducing sickness absence has been a target at the national level in many Western countries due to ageing workforce and weakening economic dependency ratio. Socioeconomic differences in health, in turn, have remained significant over time. However, less is known about changes in occupational class differences in sickness absence over time in nationwide populations. The aim of this study was to examine occupational class differences in long-term sickness absence and underlying diagnostic causes of the class differences over time in the Finnish employed population. The study was based on data obtained from national registers. A 70% random sample of working-age Finnish residents was linked to data on medically certified sickness absence of over 10 working days based on paid sickness allowances retrieved from the Social Insurance Institution of Finland. Data on occupational class was obtained from Statistics Finland. The study focused on upper non-manual employees, lower non-manual employees and manual workers. The study covered the years from 1996 to 2014, the diagnosis-specific examination spanning from 2005 to 2014. Statistical methods included a direct age-standardisation method, the Slope Index of Inequality (SII), the Relative Index of Inequality (RII) and a negative binomial hurdle model. The results showed that, despite modest annual variations, occupational class differences in all-cause sickness absence were clear and persistent among both genders over time. Lower occupational class was consistently associated with higher all-cause sickness absence, both in absolute and relative terms, with men having larger differences than women. The most prominent class differences were detected in sickness absence due to musculoskeletal diseases throughout, with men having very large relative differences. With regard to specific musculoskeletal diagnoses, the class differences in the occurrence of absence were by far the largest in shoulder disorders and back pain. Chronic musculoskeletal diseases, namely rheumatoid arthritis, disc disorders and, among men, also hip osteoarthritis, caused the largest class differences in the length of absence. During the study period, large occupational class differences were also detected in sickness absence due to home and leisure injuries, particularly among men. In contrast, modest occupational class differences were found in sickness absence due to mental disorders among both genders. Among women, a divergent pattern was found in sickness absence due to breast cancer: the higher the class, the greater the cumulative incidence but the shorter the duration of absence throughout. Health inequalities have remained prominent over time in the Finnish working population. No major progress has taken place, despite several health policy programs aiming at reducing socioeconomic health differences over time. Future actions should have a specific emphasis on employees in lower occupational classes and on manual workers in particular in order to tackle the class differences in sickness absence effectively. The study further highlights that sickness absence due to musculoskeletal diseases, especially prevention of sickness absence due to back pain and shoulder disorders, and home and leisure injuries should be paid attention in the future.
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(Helsingin yliopisto, 2018)Obesity remains a major health problem, partly due to our limited understanding of this complex disease. Obesity carries with it the risk of many other diseases including type 2 diabetes, cardiovascular disease, hyperlipidemia and some types of cancer. The variability in the disease as well as its related comorbidities makes it a complex, multi-factorial condition that is not easily categorised and treated. ‘Omics technologies and bioinformatics tools allow for the investigation of the complex biology behind obesity. These technologies enable production of complex multivariate datasets that can be investigated using bioinformatics tools to identify patterns in the data as well as associations between different features of the data. However, while advances in ‘omics technologies have allowed production of large amounts of data from biological samples, extraction of useful information from the data remains a huge challenge. Choosing the correct methodology and tools to transform heterogeneous data into biological knowledge is especially difficult when different methods on the same data may yield different results, requiring further statistical or biological validation. This thesis uses existing bioinformatics tools and methods to first combine and analyse transcriptomics and biochemical data and then, separately, metabolomics and biochemical data to gain an understanding of obesity. Body mass index (BMI)-discordant as well as BMI-concordant monozygotic (MZ) twin pairs were used to investigate the molecular effects of obesity by looking at gene expression and metabolite profiles in subcutaneous adipose tissue (SAT) and blood plasma, respectively, to gain biological insights into pathways that are associated with obesity and obesity-related clinical manifestations. The SAT was further interrogated using isolated adipocytes, to examine the transcriptomics patterns in obesity of this specific cell type. Using the blood plasma, metabolites associating with different cardiometabolic risk factors were also identified. Variations in the global profiles were also studied to assess if study participants form different subgroups of obesity according to their gene expression or metabolite profiles. Adiposity and blood biochemistry measure differences between these obesity subgroups were also examined.
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(Helsingin yliopisto, 2018)Genetic factors are of key importance in governing bone health and usually determine an individual’s skeletal characteristics in a complex and polygenic manner. Recent research has, however, identified several monogenic forms of bone diseases where the deleterious molecular changes in one gene overrule and lead to a distinct skeletal pathology. In 2013, our research group showed that a heterozygous mutation in WNT1 leads to severe, early-onset dominantly inherited osteoporosis. Although many other families with WNT1-related skeletal fragility have since then been identified worldwide, much of the molecular and clinical features of WNT1 osteoporosis remain unclear. This study aimed to define the main clinical skeletal and extra-skeletal characteristics of WNT1 osteoporosis in children and adults. The cohort comprised affected individuals from two Finnish families with the same heterozygous missense mutation c.652T>G (p.Cys218Gly) in WNT1. As healthy controls, we recruited mutation-negative members from the same families. We evaluated their skeletal and extra-skeletal characteristics with biochemistry, radiography, magnetic resonance imaging (MRI), and dual-energy X-ray absorptiometry. Bone and bone marrow biopsies were further evaluated with histomorphometry, immunohistochemistry, and microscopy for detailed architectural, cellular, and molecular changes. We also evaluated serum concentrations of circulating microRNAs with qPCR. Clinical evaluation of mutation-positive individuals showed that mutated WNT1 leads to significant, early-onset and progressive skeletal pathology. Affected young individuals exhibited abnormal bone shaping, low bone mineral density and multiple peripheral fractures already in childhood. Vertebral compression fractures were apparent and prevalent in the over 50-year-old subjects, causing exaggerated kyphosis and loss in adult height. Bone biopsies showed inactive bone cells, low bone turnover and altered osteocyte protein expression. The mutated WNT1 also led to several extra-skeletal changes, such as deteriorated cartilaginous structures in spine and increased reticulin formation in bone marrow. Lastly, serum qPCR analysis revealed a unique microRNA profile in mutation-positive subjects. Although variable in its phenotypic features, individuals with a pathogenic, heterozygous WNT1 mutation are affected by severe skeletal morbidity. Based on our findings, WNT1 osteoporosis is characterized by multiple peripheral fractures and abnormalities in long bone shape already in childhood. Progressive loss in bone mineral leads to osteoporosis and prevalent thoracic compression fractures by early adulthood. The WNT1 mutation can also lead to various extra-skeletal changes and comorbidities such as in cartilaginous tissues and the bone marrow. The differentially expressed microRNAs could serve as potential new biomarkers in diagnosing and monitoring clinical course and treatment response in WNT1 mutation-positive subjects. Questions concerning effective treatment of WNT1 osteoporosis remain unanswered and warrant future studies.
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(Helsingin yliopisto, 2018)In the modern abundant food environment, the relationship between dietary carbohydrates and health outcomes is complex. The main aims of this thesis were to investigate the role of added sugar intake in the diet, and the relationship between dietary carbohydrates, the dietary glycaemic index (GI) and load (GL) and obesity. Another aim was to examine the dietary assessment methodology from the dietary carbohydrates perspective. This study was based on health examination surveys in the Finnish adult population conducted in 2000-2007: the DILGOM Study, the National FINRISK/FINDIET 2007 Study, the Health 2000 Survey and the Helsinki Birth Cohort Study (overall n=13 800, age 25+). The examinations included measured anthropometrics and questionnaires. The habitual diet was assessed with a food frequency questionnaire (FFQ). Food records served as a reference method in FFQ validation. Food GI values were based on a previous Finnish epidemiological GI database and were documented using international controlled vocabularies used in the Finnish national food composition database (Fineli). Intake of added sugars was estimated based on sucrose and fructose derived from foods other than fruits, berries, vegetables, and 100% fruit juices. On average, 40% of sucrose and fructose were from natural sources and the remaining 60% were added sugars. Subjects in the highest added sugar intake quartile were younger and had lower fibre, fruit, vegetable, rye, and fish intakes than subjects in the lowest added sugar intake quartile. Added sugar intake was associated positively with the intake of butter and butter mixtures. These results support the recommendation for the restriction of added sugars in the diet. In the meta-analysis of three cross-sectional studies (n=12 342), 23% of the subjects were classified as obese (body mass index, BMI ≥ 30 kg/m2). The likelihood of being obese was 35% lower in the highest quartile of total carbohydrate intake than in the lowest quartile. Total sucrose intake and dietary GL were also inversely associated with obesity. Dietary GI and fibre intake were not associated with obesity. Prospective cohort studies are needed to assess possible temporal relations. Instead of sucrose only, added sugars should be investigated. Between-method Spearman rank-correlation coefficients ranged from 0.27 (total sugars, men) to 0.70 (lactose, men). Based on the two methods, 73% of the subjects were correctly classified into the same or adjacent carbohydrate intake distribution quintile. Between-method agreement improved with decreasing age and with higher education, especially in women. The ability of the FFQ in ranking subjects according to most carbohydrate-related exposures is on the same level as in the international literature. However, sex, age and education represent important confounding factors. The origin and derivation methods of the GI values were successfully documented with the controlled vocabularies generally used in Fineli. This provides a foundation for the comparison of GI databases in international contexts.
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(Helsingin yliopisto, 2018)During recent decades, changes in society and environment have led to changes in lifestyle. As a result, risk factors for type 2 diabetes, such as obesity and physical inactivity, have increased in the population. Further, socioeconomic factors play a role in the development of type 2 diabetes. The aim of the present study was to examine the role of socioeconomic status in determining the risk factors, occurrence, comorbidities, and prevention of type 2 diabetes. The present study is based on three population-based, cross-sectional surveys (FIN-D2D, FINRISK and AVTK), and one clinical, longitudinal, randomized intervention study (DPS). When appropriate, the incident diagnoses of type 2 diabetes and other chronic diseases were identified through linkage with the national registers on reimbursement rights, hospitalizations, and mortality. Hyperglycaemia was more common among those with low education compared with those with medium and high education. The incidence of type 2 diabetes has increased among Finnish men, but not among women, and has occurred predominantly among men with low and middle educational attainment. Obesity explained some but not all of this variation between socioeconomic classes. On the other hand, no evidence was found to suggest that low socioeconomic status increases the development of comorbidities among people with diabetes or decreases the effectiveness of lifestyle intervention aiming to prevent type 2 diabetes among people at risk. Furthermore, the national diabetes prevention programme succeeded in increasing awareness of type 2 diabetes among the population, regardless of socioeconomic status. This study provides knowledge to support future activities to prevent type 2 diabetes and other chronic diseases and suggests that interventions can diminish health disparities.
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(Helsingin yliopisto, 2018)During the last decades neuroscientists have put significant efforts towards a definition of a unique and comprehensive emotion brain circuit. However, internal and external variables influencing emotion behavior are much more prominent than expected. The present doctoral thesis aims to add some crucial knowledge on individual differences of emotions, as well as their biological underpinnings, by merging evidence obtained with psychological, genetic and brain imaging assessments. In particular, I adopted a protocol of affective state induction, by which I investigated the effect of temporary variations of mood on the emotion processing in healthy subjects at both the behavioral and neuronal level. Then, I have also investigated the interaction between affective states and affective traits on the emotional behavior as well as the interaction between affective states and genetic traits. Moreover, this thesis has characterized in healthy subjects the neural correlates of the emotion intelligence ability, an additional important aspect in the emotional panorama. Finally, I studied emotion brain connectivity in a schizophrenia population and in a population of healthy subjects at familial or genetic risk for schizophrenia. Findings of the thesis demonstrated that temporary affective states are capable of modulating emotions even at an early, automatic stage of processing, at both behavioral and neuronal level. Moreover, this modulation is affected by personality and genetic traits of the individual. Furthermore, this thesis revealed that social and emotional abilities also represent a source of variability in the way brain processes the emotional information, positing the neural basis of conceivable interventions in this direction. Finally, the present work discovered that emotional anomalies in schizophrenia subtend a specific breakdown of the brain connectivity. Particularly, this breakdown is also found in healthy individuals at familial risk for schizophrenia or simply carrying a dopamine variant conferring risk for the disorder.
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Weight concerns and abdominal obesity among ever-smokers: A population-based study of Finnish adults (Helsingin yliopisto, 2018)Smoking-specific weight concerns are one factor involved in smoking and the smoking cessation process. Previous literature has reported inconsistent findings regarding the association of weight concerns with self-efficacy and motivation to quit. In addition, inconsistent findings about smoking-specific weight concerns as an obstacle for quitting have been reported. Even though daily smokers tend to weigh less, they tend to have more abdominal obesity than never smokers. This thesis aimed to assess the level of smoking-specific weight concerns according to smoking status, the association of weight concerns with self-efficacy and motivation to quit, and weight concerns as a predictor of subsequent smoking status in the Finnish adult population. An additional aim was to assess the association of smoking with abdominal obesity. This thesis is based on national FINRISK/DILGOM studies conducted in 2007 and 2014. Four different datasets were used in this study. In 2007, a population-based sample of 10,000 Finnish people (67% participation rate) aged 25 to 74 years from six geographical regions was drawn from the Population Register to form FINRISK 2007. FINRISK 2007 data was used in Study IV. DILGOM 2007, a subsample of FINRISK 2007, was formed to study metabolic factors and obesity. Studies I and II utilised a special sub-sample of ever smokers identified within the DILGOM 2007 study. A sub-sample of ever smokers and follow-up DILGOM 2014 was used in Study III. Smoking status was mainly self-reported, with biochemically-verified data among sub-samples. Weight concerns were measured by a modified Weight Concern Scale administered in the 2007 questionnaire, and nicotine dependence by the Fagerström Test for Nicotine Dependence (FTND). Self-efficacy and motivation to quit, as well as the majority of confounders, were also self-reported measures. Weight, height, waist circumference, and expired air carbon monoxide were measured by study nurses. Cotinine, a metabolite of nicotine, was derived from blood samples. Daily smokers were found to have higher levels of weight concerns compared to occasional smokers, recent quitters, and former smokers. Among daily smokers, weight concerns were associated with lower self-efficacy to quit but not with lower motivation to quit. Nicotine dependence attenuated the association between weight concerns and self-efficacy to quit. Baseline weight concerns predicted smoking cessation and reduced tobacco usage by 2014 (from daily smoking to occasional use) among those daily smokers with low nicotine dependence (FTND 0–3), but not among those with high nicotine dependence (FTND ≥4). The association of smoking status with abdominal obesity was significant among women who were overweight/obese heavy daily (≥20 cigarettes per day) or ex-smokers. Daily smokers report more weight concerns compared to other ever smokers. Weight concerns are associated with a lower self-efficacy to quit among daily smokers. Weight concerns predict subsequent smoking status only among smokers who are not highly dependent on nicotine. Hence, in the Finnish population, weight concerns seem to have a role in some factors involved in the smoking cessation process. However, considering successful cessation as the outcome, those concerns seem to interplay with nicotine dependence. Among overweight/obese women, daily heavy smokers and ex-smokers have more abdominal obesity compared to never smokers. Further investigations in clinical settings, including longitudinal designs and repeated measurements during the smoking cessation process, may be useful to provide a deeper understanding of the complex interplay between weight concerns and other determinants of smoking cessation.
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(Helsingin yliopisto, 2018)Previous imaging studies have shown that activation in human auditory cortex (AC) is strongly modulated during active listening tasks. However, the prevalent models of AC mainly focus on the processing of stimulus-specific information and speech and do not predict such task-dependent modulation. In the present thesis, functional magnetic resonance imaging was used to measure regional activation in AC during discrimination and n-back memory tasks in order to investigate the relationship between stimulus-specific and task-dependent processing (Study I) and inter-regional connectivity during rest and active tasks (Study III). In addition, source analysis of scalp-recorded event-related potentials was carried out to study the temporal dynamics of task-dependent activation in AC (Study II). In Study I, distinct stimulus-specific activation patterns to pitch-varying and location-varying sounds were similarly observed during visual (no directed auditory attention) and auditory tasks. This is consistent with the prevalent models which presume parallel and independent “what” (e.g. pitch) and “where” processing streams. As expected, discrimination and n-back memory tasks were associated with distinct task-dependent activation patterns. These activation patterns were independent of whether subjects performed pitch or location versions of these tasks. Thus, AC activation during discrimination and n-back memory tasks cannot be explained by enhanced stimulus-specific processing (of pitch and location). Consistently, Study II showed that the task-dependent effects in AC occur relatively late (200–700 ms from stimulus onset) compared to the latency of stimulus-specific pitch processing (0–200 ms). In Study III, the organization of human AC was investigated based on functional connectivity. Connectivity-based parcellation revealed a network structure that consisted of six modules in supratemporal plane, temporal lobe, and inferior parietal lobule in both hemispheres. Multivariate pattern analysis showed that connectivity within this network structure was significantly modulated during the presentation of sounds (visual task) and auditory task performance. Together the results of this thesis show that (1) activation in human AC strongly depends on the requirements of the listening task and that task-dependent modulation is not due to enhanced stimulus-specific processing, (2) regions in inferior parietal lobule play an important role in the processing of both task-irrelevant and task-relevant auditory information in human AC, and (3) the activation patterns in human AC during the presentation of task-irrelevant and task-relevant sounds cannot be fully explained by a hierarchical model in which information is processed in two parallel processing streams.
