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In our study, we examined the effects of early-life stress on sleep, depressive behaviour and neurophysiological factors common for depression and sleep disturbances. As a model for early-life stress we used cross-fostered (CF) adolescent and adult, male and female rats. In spontaneous sleep, we found an increase in NREM and REM time in light period and an increased number of REM onsets in light and dark period in CF group. Baseline adenosine expression and BDNF levels in basal forebrain were decreased in CF animals. In the behavioural tests there were no detectable differences, nor in recovery sleep. This thesis will concentrate on the scientific background of the project, further discuss the findings in our study and demonstrate the writer’s personal role in the project.

Abstract Objectives. Despite the convincing evidence of efficacy of psychotherapy, its mechanisms of change in therapy are still unclear raising questions on what constitutes psychotherapy. In this work, the common and specific factors of cognitive behavioral therapy and psychodynamic psychotherapy were inspected by exploring psychotherapy manuals, which has not been previously studied in therapy research, using machine learning methods. The aim of this work was to gain understanding of the theoretical frames of different psychotherapy approaches and explore their distinguishability as well as semantic features. Methods. Textual psychotherapy manuals representing psychodynamic psychotherapy (n=4) and cognitive behavioral therapy (n=4) were analyzed using latent Dirichlet allocation topic modeling. The number of topics was pre-defined as 2, based on the number of therapy approaches. Additionally, a Bayesian method was used, defining the best fitting number of topics for the data. Logistic regression was performed for both solutions regarding the selection of the number of topics to observe the associations of textual topics with the therapy approaches. Two models were compared in their ability to correctly discriminate between the therapy approaches. Results and conclusions. The models consisting of 2 and 24 topics proved excellent in distinguishing the therapy approaches thus pointing towards the differentiable nature of these two approaches. The discriminative power of the model with 24 topics was based on few perfectly discriminative topics yet the model also included topics common for both therapy approaches. Based on this work, the approaches differed regarding relational and agency emphasis whereas shared expectations appeared as common factor.

In diagnosis of many viral and some other microbial infections, measurement of IgG avidity is a globally emerging approach for identifying primary infections and estimating the time of clinical onset. While many calculation methods have been introduced for conversion of the raw data into a numerical avidity value, little information exists on their comparison and whether the complex and laborious ones show superior performance. We here compare diverse approaches for avidity calculation, and introduce for clinical use a new, highly sensitive and specific one. Enzyme immune assay (EIA) absorbance data from 135 parvovirus B19 IgG-positive sera were analyzed in parallel with the new and two reference methods (Avidity1.2 software representing gold standard methodology; avidity index (AI) widely used due to its simplicity). When sample dilutions were selected on the basis of optimal EIA absorbances, all three approaches performed equally (receiver operating characteristic area-under-curve, AUC, discriminating primary infection from past immunity 0.969-0.971). When the samples were reanalyzed at either lower or higher absorbance levels, avidity status (low, borderline or high) was altered, on the average, in 3.7 % of the samples with the new method, in 5.6 % with Avidity1.2 and in 28 % with AI. The new approach was further validated with extensive serum panels for cytomegalovirus, Toxoplasma gondii, rubella and Epstein–Barr virus (AUC 0.990-1.000). It allows for accurate measurement of antimicrobial IgG avidity even from samples with low IgG level, while the globally popular AI approach provides an alternative for samples with sufficiently high IgG level.

The purpose of this study was to assess the best way to measure carpal alignment. The study compared computer-based measurements and manual measurements of the carpal alignment. The subjects of comparison were the methods of measuring the radioscaphoid, radiolunate, radiocapitate and radiometacarpal angles. 30 cone beam CT scans of healthy, uninjured, wrists were analyzed by automated software (Disior ltd) and by hand surgeons using lateral radiographs reconstructed from the CT scans. Six hand surgeons were given instructions on how to take the measurements. They analyzed both reconstructed radiographs in which the wrist bones were partially overlapping due to summation, and reconstructed radiographs, where overlapping of the wrist bones had been digitally removed. In addition, seven different hand surgeons were not given instructions on the measurement methods. They analyzed only the reconstructed radiographs with wrist bones overlapping. In manual measurements, the inter- and intra-observer reliability of the results varied from good to excellent (ICC: 0.77–0.99), both in the instructed and in the uninstructed group. Inter-observer reliability was better in the group instructed in the methods of measurement. Reliability was further improved in reconstructed radiographs where the overlapping of the carpal bones had been digitally removed. Intra-observer reliability was very similar in both the instructed and uninstructed groups, and improved when bony overlapping was removed. The software provided excellent intra-observer reliability (ICC 0.94-1.00) and result, that were highly comparable the instructed manual measurements from radiographs with no bony overlapping (mean difference range 1°-7°). Although statistically significant differences were seen between manual measurements and software measurements, the differences are too small to be clinically significant. The research shows that accurate and repeatable computer-aided measurements of the carpal alignment can be made from CT scans, thereby minimizing observational errors. Key words: Carpal alignment, measurement, reliability, computer-aided, digitally reconstructed radiographs

Background Since the ground-breaking phase III MPACT trial showed clear benefit of gemcitabine-nab-paclitaxel, this regimen has emerged as the standard of care for advanced pancreatic adenocarcinoma (PAC). Prior to this study, few studies have shown how results from randomized controlled trial translate to the real world. This study investigated how patients fared in the real world. Methods This single-centre, retrospective study was conducted in the Vaasa Central Hospital, Finland. 148 patients with PAC (ICD-10 C25) between 1/2011-12/2016 were identified with resectable, locally advanced or metastatic disease. Information about the basic characteristics, treatment regimens and adverse effects (AEs) were extracted from patient files and analysed. Results The median overall survival (OS) was 10.4 months for treated and 2.8 months for untreated patients. For metastatic disease OS was 4.9 months, for locally advanced 9.1 months. Patients who received 3 or more treatment lines had OS 19.1 months, while those who received 2 or 1 line had 11.3 and 6.2 months, respectively. The following grade 2-4 haematologic toxicities occurred: anaemia (n=19), leukopenia (n=49), neutropenia (n=55) and thrombocytopenia (n=9). Febrile neutropenia occurred 7 times. A total of 12 grade 5 AEs were recorded in 7 patients, and 3 other patients died of unknown complications. Conclusion This study shows that active treatment is worth pursuing in most PAC patients and study results from this real-world data study differ from randomized controlled trials. Special caution should be applied when continuing chemotherapy in patients with ECOG 2 and who are older than 70 years.

Johdanto Suomen Syöpärekisteri ylläpitää rekisteriä kaikista Suomessa todetuista syöpätapauksista. Väestöpohjainen syöpätapausten rekisteröinti tarjoaa kattavan ja luotettavan tietokannan syöpätutkimuksessa käytettäväksi. Rekisteröinnin kattavuuden ja rekisteröidyn tiedon oikeellisuuden puutteilla voi kuitenkin olla suuri vaikutus erityisesti harvinaisten sairauksien insidenssi- prevalenssi- ja elossaoloarvioihin. Tutkimuksessamme pyrimme tarkentamaan aiempaa arviota lapsuussyövän rekisteröinnin kattavuudesta Suomen Syöpärekisterissä (Leinonen ym. 2017). Materiaalit ja menetelmät Poimimme Syöpärekisteristä sekä Hoitoilmoitusrekisteristä kaikki 0–14-vuotiaiden syöpätapaukset vuosina 2009–2013. Tarkastimme jokaisen Syöpärekisteristä puuttuneen tapauksen syöpädiagnoosin oikeellisuuden joko lähettämällä potilasta hoitaneeseen sairaalaan täytettävä lomake tai tarkastamalla potilastiedot potilastietoarkistoista. Laskimme Syöpärekisterin rekisteröinnin kattavuusarviot 95 %:n luottamusvälein tauti- sekä ikäryhmittäin. Tulokset Vuosina 2009–2013 Syöpärekisteriin oli rekisteröity 741 uutta lapsisyöpätapausta. Hoitoilmoitusrekisteriin syöpätapauksia oli rekisteröity 1072. Virheellisten syöpädiagnoosien karsimisen jälkeen vahvistimme 49:n syöpätapauksen puuttuvan Syöpärekisteristä. Syöpärekisterin kattavuudeksi arvioimme 94% (95% luottamusväli 91.9¬–95.4); 92% (95% luottamusväli 89.1–94.2) kiinteiden ja 97% (95% luottamusväli 94.1–98.4) ei-kiinteiden kasvainten osalta. Retinoblastooman rekisteröinnin kattavuus oli huomattavan matala, 54% (95% luottamusväli 36.4–71.9). Myös luusto- ja keskushermostosyöpien kattavuusarviot olivat matalat. Lymfoomien ja munuaissyöpien rekisteröinnin kattavuusarvio sen sijaan oli 100%. Diskussio Suomen Syöpärekisteri tuottaa korkealaatuista tietoa lapsuusajan syövistä. Ei-kiinteiden syöpien rekisteröinti on kattavampaa kuin kiinteiden syöpien. Syöpäilmoituksia Syöpärekisterille on puuttunut erityisesti potilaista, joiden tautia ei aina varmenneta histologisesti, kuten silmä- ja keskushermostosyöpäpotilaista.

Breast cancer is now globally the most frequent cancer and leading cause of women’s death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phe- notype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three- dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions.

The aim of the study. Working memory (WM) is a cognitive function that relies on the neurotransmitter dopamine. WM has multiple subfunctions: maintaining relevant information, ignoring distractors, and updating the information when needed. Information maintenance and ignoring irrelevant stimuli are associated with brain activity in the prefrontal cortex and updating information with the striatum. A connection between polymorphisms within the dopaminergic genes COMT (COMT Val158Met polymorphism) and DRD2/ANKK1 (Taq1A polymorphism), and WM performance has been established in previous studies, and these genes seem to impact dopamine signaling in the prefrontal cortex and striatum, respectively. The present study investigates associations between dopaminergic gene polymorphisms and WM performance. The main research questions include the main effects and interactions that the genes have to WM on performance overall and WM stability and flexibility in particular. The study investigates also whether obesity, diet, and age affect WM performance, as there are indications for these from previous studies. Methods. Data from three separate cross-sectional studies with a total of 244 participants was used. A computer-based visual working memory task was used to assess the WM performance measures accuracy and reaction time. Other measurements included blood measures, Body Mass Index (BMI), and the Dietary Fat and free Sugar Questionnaire (DFS). Results and conclusion. In WM accuracy analyses, there was a significant main effect for the task condition as well as interactions between the COMT*task condition and COMT*Taq1A*task condition. In the three-way interaction analysis for WM accuracy, the most beneficial combination was Met/Met & A1- in the task condition measuring the stability, and Val/Met & A1+ in the task condition measuring the flexibility. This result gives support for established knowledge about how Met/Met combined with A1- is beneficial especially for WM stability and maintenance. Also, the inverted-U shape theory and previous studies' results of A1+ being beneficial in executive functions updating tasks, give support to the result regarding WM flexibility. In the three-way interaction reaction time analysis, the combination of Val/Met & A1+ was the fastest in every task condition. However, the significant differences were mainly between A1- and A1+ genotypes when combined with Val/Met and between Met/Met and Val/Met genotypes when combined with A1-. The two-way interaction between COMT Val158Met and task condition did not remain significant in pairwise comparisons. In reaction time analyses, COMT Val158Met and Taq1A had a significant main effect where reaction times followed the order: Met/Met < Val/Val < Val/Met, with Val/Met being significantly slower than the others and in Taq1A A1+ < A1-, with a significant difference. Adding age, BMI, and DFS to the analyses did not affect the significant/non- significant main effects or interactions in the analyses. The results of this thesis converge with the previous knowledge about these genotypes having an interacting effect on working memory stability and flexibility. However, these effects are complex to interpret as the results and their directions differed between the task conditions and outcome measurements. In the main outcome variable (accuracy), the result regarding the WM stability is well in line with previous literature about the Met/Met & A1- combination being beneficial to WM performance, and the result about Val/Met & A1+ being beneficial for WM flexibility gets preliminary support from executive function studies, but also opens new research avenues regarding the WM flexibility subfunction.

Congenital chylothorax is a rare disorder which may end up in stillbirth or neonatal death. Due to its rarity, no clear standards for optimal treatment have been established. Reports of long-term outcomes are scarce. This is a retrospective study of all cases of congenital chylothorax treated in Helsinki University Central Hospital 1999-9/2013. Information on the pregnancies and antenatal management, neonatal management an long term outcomes has been retreived from the patient records of Helsinki University Central Hospital. There were altogether 17 cases, no in-utero deaths and seven deaths in the neonatal period. 71 per cent of the patients underwent intrauterine thoracocentesis and there was one attempt of placing a thoraco-amnionic shunt. Factors such as fetal hydrops, early onset of congenital chylothorax, chromosomal and structural anomalies and prematurity seemed connected to higher mortality, as they have in earlier studies. In follow-up, three of seven patients have been diagnosed with asthma.

Maksan rasvoittumisen ajatellaan joskus olevan vain metabolisen oireyhtymän hyvälaatuinen maksamanifestaatio, vaikka se johtaa, erityisesti maksan fibrotisoituessa, kasvaneeseen kardiovaskulaarikuolleisuuteen ja pahimmillaan maksasyöpään. Tästä kansanterveydellisesti merkittävästä roolista huolimatta rasvamaksa on alidiagnosoitu ja sen patogeneettiset mekanismit ovat huonosti ymmärrettyjä, molemmat osin hyvien diagnostisten työkalujen puutteesta johtuen. Päätimme selvittää uusien non-lineaaristen kuvantamismodaliteettien soveltuvuutta rasvamaksan varhaisessa diagnostiikassa. Selvitimme 32 lihavuusleikkauspotilaan maksakudoskoepalojen kudosarkkitehtuurin perinteisin kudosvärjäysmenetelmin ja vertasimme tuloksia samojen potilaiden non-lineaarisesti kuvannettuihin näytteisiin. Kuvansimme minimaalisesti käsitellyistä jääleikkeistä coherent anti-Stokes Raman scattering (CARS) ja second harmonic generation (SHG) signaalit, joita hyödyntäen arvioimme näytteiden rasva- ja kollageenipitoisuuden. Kehitimme myös kuva-analytiikka-algoritmin, joka mahdollistaa kollageenisignaalin automatisoidun ja objektiivisen arvioimisen. Näytteistä mittaamamme SHG- ja CARS-signaalit korreloivat hyvin patologien arvioihin näytteiden fibrotisoitumis- ja rasvoittumisasteista, minkä lisäksi automatisoitu algoritmimme erotteli luotettavasti jopa varhaisen fibroosin normaalista kudoksesta. Myös terveiksi luokiteltujen näytteiden maksakudoksen keskellä esiintyi hienoa fibrillaarista SHG-signaalia. Tunnistamamme SHG-signaali oli spesifiä kolokalisoituen hyvin kollageeni-I- ja III-vasta-ainevärjäyksien kanssa. Tuloksemme osoittavat, että multimodaalisten kuvantamismenetelmien avulla voidaan tunnistaa maksan fibrillaarista kollageenia perinteisiä kudostutkimusmenetelmiä herkemmin. Kehittämämme kuva-analyysi-algoritmi puolestaan arvioi varhaisen fibroosin määrän nopeasti, objektiivisesti ja jatkuvalla skaalalla. Yhdessä nämä löydökset luovat edellytykset tutkia esimerkiksi maksan vähäisen fibroosin kliinistä merkitystä ja paranemistaipumusta isommissa potilasaineistoissa.