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Kaksoisraskaudet lisäävät riskiä sekä peri- että postnataalisiin komplikaatioihin. Suomessa onkin 2000-luvun aikana siirrytty hedelmöityshoidoissa kahden alkion siirrosta yhden alkion siirtoihin kaksoisraskauksien vähentämiseksi, ja vuonna 2018 Suomessa tehdyistä IVF/ICSI-hoidoista yli 95 prosentissa siirrettiin vain yksi alkio. Väestön normaalijakaumasta tehdyt tutkimukset ovat kuitenkin osoittaneet, että useat parit toivovat saavansa useamman kuin yhden lapsen. Tästä syystä koimme tärkeäksi selvittää, mitkä ensimmäiseen IVF/ICSI-hoitokertaan liittyvät ennustavat onnistumista myös myöhemmissä hoidoissa. Tutkimukseen sisällytettiin naiset, jotka vuosina 2000-2017 aloittivat IVF/ICSI-hoidot ja joille siirrettiin yksi alkio ensimmäisellä hoitokerralla. Tutkimuksen ulkopuolelle rajattiin kaksoset tai kolmoset synnyttäneet naiset. Aineisto kerättiin kansallisesta LUMI-tietokannasta ja analysoitiin SPSS-ohjelmalla. Totesimme, että suurin osa aineiston naisista sai vain yhden lapsen, mutta yli puolet (62 %) heistä, jotka hakeutuivat ensimmäisen syntymän jälkeen uudelleen hoitoon, saivat vähintään yhden lapsen lisää. Keskimäärin potilaat tarvitsivat vain yhden uuden munasarjojen stimulaatiohoidon saadakseen toisen lapsen. Ensimmäisen hoitokerran tekijät, jotka ennustivat onnistumista myös myöhemmissä hoidoissa, olivat naisen ikä, syntymä ensimmäisessä hoitosyklissä sekä gonadotropiinin määrä suhteessa munasolujen määrään. Alkioiden laadun arvioon on kehitetty erilaisia menetelmiä, ja tutkimuksessa todettiin, että parhaimman arvosanan saaneiden alkioiden määrä lisäsi todennäköisyyttä onnistua myöhemmissä hoidoissa, mikäli niitä oli useampi kuin yksi. Lapsia oli kuitenkin mahdollista saada useampi, vaikkei laadukkaimpia alkioita ollut yhtäkään.

Introduction: The characteristics of sitting height ratio (SHR) in an undernourished population, and particularly in different ages, are still unclear. The aims of this study were to describe the characteristics of SHR in different ages in a population where undernutrition is prevalent and to investigate associations between SHR and other anthropometric variables. Methods: Anthropometrics of 1838 individuals were measured cross-sectionally in rural Malawi. SHR growth curves and SHR as a function of the study variables were plotted. The study variables were pubertal stage and z-scores of weight-for-height (WHZ), height-for-age (HAZ), and socioeconomic status. Linear regression models of SHR as a function of WHZ and HAZ were made. Results: The growth curves had a similar pattern as elsewhere in the world. Puberty affected sitting height growth and leg length growth differently. SHR was inversely proportional to HAZ and directly proportional to WHZ. Conclusions: Changes in SHR and its components throughout childhood in an undernourished population are described. There is an inverse association between SHR and HAZ, and a direct association between SHR and WHZ. Children in an undernourished population have higher SHRs throughout childhood compared to healthy growing children.

Wilms tumor is the most common kidney cancer in children. The origin of Wilms tumor is thought to arise from disturbed embryonic development. Wilms tumor is characterized by so called nephrogenic rests consisting of undifferentiated metanephric mesenchyme, that are precursor lesions for tumorigenesis. In addition, the tumors themselves contain tissue types normally found only in the developing kidney and they resemble embryonic kidneys transcriptionally. Since the tumors are heterogenous and contain blastemal, stromal, and epithelial components, all three progenitor populations of the developing kidney, nephron, collecting duct and stromal progenitors, are possible origins of tumors. MAPK/ERK pathway plays a significant role in kidney development for example by affecting nephron progenitor self-renewal and regulating collecting duct progenitor maintenance. Previous studies suggest that MAPK/ERK activity plays a role in Wilms tumor by mediating the intracellular effects of IGF2 overexpression. The aim of this master’s thesis is to compare transcriptional profiles of Wilms tumor to the transcriptional profiles in mouse MAPK/ERK deficient nephron progenitors and ureteric bud epithelium. This is done by utilizing internet-based tool ToppFun and R/Bioconductor tool gage (Generally Applicable Gene-set Enrichment for Pathway Analysis) for Gene Ontology (GO) and KEGG pathway analysis. My analysis revealed several shared GO and KEGG pathways that compose of differentially expressed genes with opposite expression patterns in Wilms tumor and MAPK/ERK deficient renal progenitors. The identified pathways include those previously validated by the host laboratory and some interesting new pathways that will be studied further in the future. The most interesting novel pathways affected in both Wilms tumor and MAPK/ERK deficient kidneys were related to the extracellular matrix (ECM) and chromatin. ECM related GO terms were specifically altered in nephron progenitors and Wilms tumor suggesting that Wilms tumor transformation involves dysregulation of ECM possibly downstream of MAPK/ERK pathway. MAPK/ERK pathway also mediates chromatin level regulation which is also demonstrated by my results. Chromatin related GO terms were upregulated in Wilms tumor and downregulated both in ureteric bud epithelium and nephron progenitors. The second aim of my thesis is to verify the observed gene expression changes by utilizing mouse embryonic kidney cultures and qPCR. The validation was only initial trial and requires further optimization. It did not show significant downregulation in selected validation genes that were chosen for validation. Future goal of my research is to carry out similar analysis in chemotherapy naïve dataset and at different Wilms tumor stages. This will allow avoiding possible chemotherapy induced changes in the outcome and better sorting of tumor progression and its correlation with specific renal progenitor types. In summary, my current results suggest both ECM and chromatin regulation as promising fields for future research.

Pehmytkudossarkoomat (PKS) ovat ryhmä syöpäsairauksia, jotka saavat alkunsa mesenkymaalisista kantasoluista ja esiintyvät tyypillisesti raajoissa ja vartalonseinämässä. Radiokemoterapia (RKT) on aggressiivinen hoitoprotokolla, jolla pyritään entistä säästävämpään kirurgiseen hoitoon sekä parantamaan paikallista tautikontrollia. Aggressiivinen hoitomuoto on toisaalta raskas potilaille sekä sisältää riskin hoitokomplikaatioista. Näihin lukeutuvat hoidon jälkeinen raajajäykkyys sekä leikaushaavojen post-operatiiviset komplikaatiot. Kirjallisuudessa on raportoitu samankaltaisten, mutta ei identtisten protokollien käytön tuloksista. Tämän tutkimuksen päätavoitteina oli tutkia potilaiden selviytymistä ja pitkäaikaiskomplikaatioiden määrää. Tutkimuksessa analysoitiin 89 korkean riskin PKS-potilasta, jotka hoidettiin vuosina 1998-2016 Helsingin yliopistollisessa sairaalassa pehmytkudostuumoriryhmän toimesta. Käytetty RKT-protokolla koostuu kuudesta lomitetusta doksorubisiini-ifosfamidi-solunsalpaajajaksosta sekä jaksotetusta hyperfraktioidusta sädehoidosta. TULOKSET: Potilaista 99 %:lla oli korkean riskin tauti. Hoitomyöntyvyys oli tutkimuksessa hyvä ja suurin osa potilaista sai suunnitellun hoidon kokonaisuudessaan. Paikalliskontrolli 5,4 vuoden seurannassa oli 81 % ja raajan säästävä kirurgia oli mahdollinen 93 %:lla potilaista. DISKUSSIO: Paikalliskontrolli on tyydyttävä aiempiin löydöksiin verrattuna, mutta metastaasiton selviytyminen oli vain 50,3 % kolmen vuoden seurannassa. Aiempien löydösten perusteella säästävä kirurgia ei aina johda parempaan selviytymiseen. Pehmytkudossarkooma on harvinainen ja haastava tauti, jonka hoidosta on vaikea tehdä tilastollisesti vahvaan tutkimusnäyttöön pohjautuvaa suositusta. Tämä tutkimus tuo lisää näyttöä RKT-protokollan hyödyllisyydestä korkean riskin potilaiden hoidossa satunnaistettujen kontrolloitujen hoitotutkimusten puuttuessa. Heikko kokonaisselviytyminen puoltaa uusien hoitomahdollisuuksien tutkimusta sekä kokeilua.

There has been little developmental research on individual differences in rationality and cognitive biases. Prior research shows that the same environmental factors predict the development of life history strategies as well as working memory capacity (WMC), a major determinant of capacity for rational reasoning. I hypothesized that those environmental factors would also predict cognitive miserliness – lazy reasoning accompanied by susceptibility to cognitive biases. In a laboratory study of 71 library-users, I measured life history strategy (K-factor), retrospective childhood unpredictability, WMC, cognitive reflection, belief-bias, denominator neglect, and outcome bias. My results did not support the hypothesis postulated. I did not observe an association between either life history strategy or unpredictable childhood and any of the cognitive variables. Due to limited sample size and methods, further research is warranted. Furthermore, a failure to conceptually replicate the previous findings that childhood adversity predicts lower working memory capacity suggests a need for conceptual clarification of these existing results.

Purpose: The perception and interpretation of how other people move their body is an important component of adaptive social interaction. Children are known to distinguish between body motion (biological motion) and non-biological motion at an early age, but their ability to interpret body motion has received little scientific attention. Music and dance-related movement activities have been found to positively influence social interaction in children. The purpose of the current study was to investigate the effect of three classroom-integrated interventions (movement MO, music MU, movement-music MOMU) on social cognition in children. Since two of the interventions were movement-based, a test measuring the ability to recognise social interaction based on body motion was used in the current study. Based on previous research findings, the hypothesis was that children who received any of the interventions would improve more than a control group (no intervention) in sensitivity to social interaction. In addition, the children’s performance was compared with that of adults’. Methods: Video displays of two point-light human figures either interacting with each other or moving separately were used to measure the ability to recognise social interaction based on body motion. The test included 94 displays (47 interaction situations and 47 no interaction situations). Children aged 10–11 (3 intervention groups and 1 control group, n = 59) completed the test twice, pre and post intervention. In addition, nine adults (n = 9) completed the test. The theory of signal detection was utilised in the analysis of performance, with discriminability d′ reflecting sensitivity to social interaction and criterion c reflecting response bias. Results: Adults performed better than children at baseline. Children who received any of the interventions improved significantly in their ability to recognise social interaction post intervention, whereas the difference between the pre and post measurement did not reach statistical significance in the control group. Conclusions: Children were able to recognise social interaction based on body motion. Children who received a movement, music or movement-music intervention improved in the test, suggesting that all interventions had a positive impact on the ability to recognise social interaction based on body motion. This suggests that movement and music interventions conducted by elementary school teachers may support children’s ability to interpret body motion, an important aspect of social interaction.

Tausta: Krooninen keuhkosiirteen toimintahäiriö (chronic lung allograft dysfunction, CLAD) on johtava kuolinsyy keuhkonsiirron jälkeen ja jakautuu kahteen pääfenotyyppiin, obstruktiota aiheuttava Bronchiolitis obliterans syndrome (BOS) ja restriktiota aiheuttava Restrictive allograft syndrome (RAS). RAS:lle ominaista on huomattava tilavuuden heikentyminen keuhkosiirteessä ja selvästi huonompi ennuste verrattuna BOS:iin. Loimme keuhkojen tietokonetomografiakuvista keuhkojen 3D-kuvan käyttäen tarkoitukseen luotua ulkopuolista ohjelmistoa. 3D-kuvan avulla ohjelmisto laski keuhkoille tilavuuden, jonka perusteella luokittelimme CLAD-potilaat keuhkotilavuuden avulla kahteen pääfenotyyppiin, tutkien fenotyypin vaikutusta potilaan ennusteeseen. Metodit: Vuosina 2003-2015 keuhkonsiirron Helsingin yliopistollisessa sairaalassa saaneet aikuispotilaat (n=167), arvioitiin retrospektiivisesti CLAD:n osalta. CLAD-potilaiden (n=71) keuhkotilavuudet analysoitiin ja potilaat luokiteltiin BOS:iin ja RAS:iin keuhkotilavuusmuutosten avulla. Potilaat luokiteltiin luokkaan BOSTT-volumetria, mikäli keuhkotilavuus CLAD-diagnoosihetkellä oli laskenut alle 15% verrattuna perusarvoon, ja luokkaan RASTT-volumetria, mikäli keuhkotilavuus laski yli 15% verrattuna perusarvoon. Määritimme TT-volumetrisesti määriteltyjen fenotyyppien kliinisen vaikutuksen ja analysoimme keuhkofunktioparametrien, radiologisten löydösten ja tilavuusmuutosten ennustearvon. Tulokset: 43%:lla (n=71) keuhkonsiirtopotilaista diagnosoitiin CLAD. 89% CLAD-potilaista luokiteltiin TT-volumetrian perusteella luokkaan BOSTT-volumetria ja 11% luokkaan RASTT volumetria. Keuhkosiirteen selviytymisennuste CLAD-diagnoosin jälkeen oli huomattavasti alhaisempi RASTT-volumetria-luokalle (mediaani 1.6 vs 9.7 vuotta, p=0.038). CLAD diagnoosihetkellä RASTT-volumetria-luokittelu (p=0.05), korkeampi keuhkosiirrekudoksen tiiviys (p=0.007) ja huomattavampi FEV1-lasku perusarvosta (p=0.004) olivat keuhkosiirteen ennustetta huonontavia tekijöitä. Yhteenveto: CLAD-potilaiden luokittelu keuhkotilavuusmuutosten avulla auttaa yksilöimään potilaita, joilla on korostunut riski keuhkosiirteen menetykseen. Tulokset tulisi validoida prospektiivisella tutkimusasetelmalla.

Aims of the study. The aim of this study was to examine normative development of sleep patterns and circadian rhythmicity during adolescence. Previous studies have found that sleep duration shortens across the lifespan, and especially adolescents’ sleep timing shifts later due to physiological and psychological factors. Sleep patterns in adolescence are connected to individual’s endogenous circadian rhythms, usually measured by delayed melatonin secretion in the evening. There is a lack of understanding how sleep patterns are related to circadian body temperature rhythms during adolescence. Methods. This study was part of SleepHelsinki! cohort study of the Sleep & Mind Research Group. Adolescents’ sleep patterns were measured with actigraphies, whereas circadian body temperature was measured from the skin surface. Circadian temperature rhythmicity was inspected by circadian period length, the mesor of skin surface temperature and the amplitude of daily changes within the rhythm. Baseline measurements were measured from 215 (71.6 % girls) adolescents aged 16–18 years. At one-year follow-up, 156 (76.3 % girls) adolescents were measured again. Mixed models for repeated measures were used to examine changes over the year in sleep patterns and endogenous circadian temperature rhythm, separately for both girls and boys. Sex differences were tested with one-way variance analysis. Linear and ordinal regressions were used to predict sleep and circadian rhythm over the year. Results and conclusions. Over the year, adolescents’ sleep duration became longer during the week, while weekend sleep shortened. However, this change was only significant for girls. Sleep schedule became more delayed for both girls and boys during the week, as sleep onset, midpoint and offset occurred at a later time. Circadian rhythm changed for boys, as their average skin surface temperature increased, and their circadian temperature amplitude became smaller. Boys also had significantly lower circadian temperature amplitude than girls at the follow-up. Compared to boys, girls were 5.85 times more likely to have a high circadian temperature amplitude at the follow-up measurement. Changes in sleep length during the week was moderated by temperature amplitude, with higher circadian amplitude predicting sleep duration to become longer. Still, the likelihood to have long sleep duration was affected by past sleep duration.

Although lung transplantation has become a routine procedure and is optimal therapy for patients with end-stage pulmonary diseases, the lifespan of lung allografts is still shorter than that of other organ transplants. As acute allograft rejection is one of the main risk factors for the development of chronic lung allograft dysfunction (CLAD) which threatens the long-term survival rate of the recipients, it is crucial to predict and diagnose acute lung allograft rejection. However, there are no specific methods established so far to predict acute rejection (AR). Even though the histopathological evaluation of transbronchial biopsies (TBBs) is used as the gold standard to ensure the diagnosis of AR, it is essential to discover novel biomarkers for AR to overcome the limitations of the TBB-based invasive diagnostics. Recently extracellular vesicles (EVs) got noticed as potential biomarkers in various fields of medicine based on the findings that they exist in high concentration in body fluids and deliver functional genetic molecules which can modulate gene expression in target cells. In that regard, this preliminary study was designed with two different approaches; a time-point analysis and a case analysis of rejection and non-rejection episodes to validate their potentials as diagnostic and predictive biomarkers for acute lung allograft rejection. To discover biomarkers, EV RNA was isolated from the plasma of four patients that was collected at different time points, and whole EV mRNA transcriptome sequencing was performed on the Illumina platform to obtain at least 15 million reads. The time-point analysis showed that the mRNA contents of EVs changed according to the time points and clinical presentations of the patients. At the same time, gene expression profiles showed that mRNA molecules inside the EVs change from innate immunity to adaptive immunity related signatures with the time after transplantation. Furthermore, the case analysis identified that EVs contain RNA molecules that are closely related to the migration of leukocytes and adaptive immune system during acute rejection episodes. In conclusion, the profiles of EV RNA may reflect the immune responses that are taking place in the recipient’s body. Therefore, it is speculated that EVs may play an essential role in the development of AR by transferring functional mRNA molecules to the allograft, immune cells, and endothelial cells. On that account, EV transcriptome profiling could be used as a diagnostic tool for AR in the future, as well as a therapeutic tool by engineering EVs to target specific genes that may be involved in the development of AR. Keywords: extracellular vesicles, lung transplantation, transplantation immunology, RNA sequencing, acute lung allograft rejection, biomarkers

Objective: Cardiovascular disease is one of the leading causes of death in the world and elevated blood pressure is one of the major risk factors for cardiovascular disease. Health behavior such as alcohol use, smoking and physical activity as well as obesity are known to affect the risk for cardiovascular disease. Also temperament has been shown to be associated with the risk for cardiovascular disease in numerous studies. The exact pathway through which the association between temperament and the risk for cardiovascular disease is mediated is so far unknown. Temperament has been shown to be associated with elevated blood pressure but not much research on the subject has yet been conducted. The aim of this study was to examine if temperament is associated with elevated blood pressure, which factors mediate the association and how they mediate it. Methods: The participants of the study were from The Cardiovascular Risk in Young Finns Study (CRYFS) and the data from the follow-up carried out in 2007. The subjects were divided into groups of elevated blood pressure and normal blood pressure according to their blood pressure levels. Temperament was assessed using a self-report form of the Temperament and Character Inventory (TCI-9) which measures the temperament traits of Cloninger's psychobiological theory - novelty seeking, harm avoidance, reward dependence and persistence. Concerning mediating variables the subjects were asked to answer questions about their alcohol use, smoking and physical activity. Body mass index was calculated from measures of weight and height. Logistic regression and correlation analyses were used for the analyses. Results and conclusions: A high level of reward dependence was related to a lower risk for elevated blood pressure. Two health behavior variables, higher level of alcohol use and greater body mass index were related to an increased risk. A weak association between a higher level of persistence and a lower level of blood pressure was also found. The association between reward dependence and elevated blood pressure showed evidence for being independent of the health behavior variables. Behavioral styles based on temperament are suggested as the mediating mechanism behind the association. For example behavioral styles could affect a person's tendency to seek medical help and health care. The concept of personalized health care expanded with temperament related information should be considered as a valuable potential asset for preventive health care in the future.