Browsing by Title

Introduction: Patients with rheumatoid arthritis (RA) have disturbances in the hypothalamic-pituitary-adrenal (HPA) axis. These are reflected in altered circadian rhythm of circulating serum cortisol, melatonin and IL-6 levels and in chronic fatigue. We hypothesized that the molecular machinery responsible for the circadian timekeeping is perturbed in RA. The aim of this study was to investigate the expression of circadian clock in RA. Methods: Gene expression of thirteen clock genes was analyzed in the synovial membrane of RA and control osteoarthritis (OA) patients. BMAL1 protein was detected using immunohistochemistry. Cell autonomous clock oscillation was started in RA and OA synovial fibroblasts using serum shock. The effect of pro-inflammatory stimulus on clock gene expression in synovial fibroblasts was studied using IL-6 and TNF-a. Results: Gene expression analysis disclosed disconcerted circadian timekeeping and immunohistochemistry revealed strong cytoplasmic localization of BMAL1 in RA patients. Perturbed circadian timekeeping is at least in part inflammation independent and cell autonomous, because RA synovial fibroblasts display altered circadian expression of several clock components, and perturbed circadian production of IL-6 and IL-1b after clock resetting. However, inflammatory stimulus disturbs the rhythm in cultured fibroblasts. Throughout the experiments ARNTL2 and NPAS2 appeared to be the most affected clock genes in human immune-inflammatory conditions. Conclusion: We conclude that the molecular machinery controlling the circadian rhythm is disturbed in RA patients.

Objective: The choice of patient outcomes in clinical quality registries is crucial for comparable and relevant data collection. Ideally, a uniform outcome framework would guide the assessment of outcomes. We set out to find a suitable published framework and validate it in clinical quality registries. Study design and Setting: A literature review was conducted to find an outcome framework that is patient-centric, easy-to-use, shared with clinical research, and allows registry evaluation. Chosen outcome framework was validated by extracting and classifying outcomes from 63 clinical quality registries at HUS Helsinki University Hospital, Finland. Results: COMET taxonomy was chosen from 23 published frameworks. HUS Clinical quality registries showed great variation in outcome domains and in number of measures. Physiological outcomes were present in 98%, resource use in all, and functioning domains in 62% of the registries. Patient-reported outcome measures were found in 48% of the registries. Conclusions: The COMET taxonomy was suitable for evaluating the choice of outcomes in clinical quality registries while some improvements are suggested. HUS Helsinki University Hospital clinical quality registries exist at different maturity levels showing room for improvement in life impact outcomes and in outcome prioritization. This article offers a comparison point for other registry evaluators.

Patients with inflammatory bowel disease (IBD) are at increased risk for developing symptomatic Clostridium difficile infection (CDI) with worse clinical outcomes, including mortality, as compared with the general population. IBD-patients are also more susceptible to have recurrences of CDI. At present, predisposing factors for CDI in IBD-patients are poorly established. To characterize IBD-related CDI, a retrospective cohort from HUS register was gathered. Patient characteristics were compared with two control groups: IBD-patients with CDI and CDI-patients. According to our results, there was no statistically significant difference in mortality rate between IBD- and CDI-patients in contrary to previous reports. We detected corticosteroid consumption in IBD patients with CDI to be greater than in patient with IBD alone. It could be considered as a risk factor for CDI. Clarifying risk factors for CDI could lead to better understanding of optimal treatment for CDI in IBD patients.

Epithelial Ovarian cancer remains to be one of the leading causes of cancer-related deaths in women, and 70-80% of EOC-related deaths are attributed to High-Grade Serous Ovarian Cancer (HGSC). The 5-year survival rate of HGSC remains concerning at 50%. Approximately 50% of HGSC patients exhibit impaired Homologous Recombination (HR) DNA repair, a high-fidelity double-stranded DNA damage repair mechanism. Patients with Homologous Recombination Deficient (HRD) tumors exhibit better responses to DNA-damaging platinum agents and Poly (ADP-ribose) polymerases (PARP) inhibitors. The success of these treatments is attributed to the inability of HRD tumors to repair DNA damage, ultimately leading to cell death. It is expected that Homologous Recombination Proficient (HRP) tumors have functional repair mechanisms to eliminate this damage. Therefore, they derive no durable benefit from DNA-damaging agents and PARP inhibitors, resulting in a poor prognosis. DNA damage can be identified by the presence of pHistoH2AX (phosphorylated H2AX protein). This protein is formed at an early stage in response to the presence of Double-Strand Breaks (DSBs), and its interaction with MDC1 is critical for the recruitment of subsequent DNA repair proteins. Interestingly, Immuno-Fluorescent Imaging has revealed the presence of pHistoH2AX in chemo naïve HRP tumors. This raises questions about the origin of this endogenous DNA damage in HRP tumors and whether it signifies underlying vulnerabilities that could be exploited for therapeutic purposes. To address these questions, my thesis aimed to identify the co-expression markers of pHistoH2AX. To achieve this objective, I analyzed existing data from Cytometry by Time of Flight and Cyclic Immunofluorescence experiments to identify interesting molecular candidates. These experiments gave rise to several interesting candidates including pSTAT3, PDL1, pAkt, pEGFR, Cyclin E1 and Vimentin as potential co-expressed markers in HRP tumors. I further validated the co-expression of pSTAT3 and pHistoH2AX in HGSC patient tissue sections by immunofluorescence staining. This study holds significant relevance for identifying alternative molecular targets that could potentially improve the survival outcomes of patients with HRP HGSC. Future studies, encompassing larger cohorts of HRP patients, may unveil suitable subpopulations that could benefit from targeting these identified proteins, paving the way for the development of more effective therapeutic strategies in the management of HRP HGSC.

Objective: Accumulating research has shown that severe illness and ICU care seem to affect the cognitive functioning of ICU survivors in many different patient populations. So far, there seems to be little research focusing on the cognitive functioning of circulatory shock patients. The purpose of this thesis was to investigate the cognitive functioning of circulatory shock patients during the first three months after ICU care. The study aimed to compare the level of cognitive functioning of circulatory shock patients with control subjects at the time of ICU discharge and three months thereafter. Further, a temporal viewpoint was added to explore the recovery of cognitive functioning within the first three months following ICU care. Methods: This study is part of the ASSESS-SHOCK 2 project. The sample (N = 99) included 51 circulatory shock patients and 48 control subjects. The cognitive functioning of circulatory shock patients was assessed at ICU discharge and 3 months thereafter with the MoCA test. The assessment 3 months after ICU discharge also included a comprehensive domain-specific neuropsychological evaluation including 23 tests. The control subjects were assessed once with the same methods. Both the performance means, and frequency of cognitive impairment were considered in the analyses. Group differences were studied with general linear models and analysis of covariance, with age and level of education as factors and covariates. The temporal change was studied with a general linear mixed model, with age, level of education, delirium, and severity of illness as factors and covariates. Results and conclusions: This study was one of the first to focus on the post-ICU cognitive functioning of all types of circulatory shock patients. As hypothesised, circulatory shock patients had a lower level of overall cognitive functioning at ICU discharge than the control subjects. The prevalence of cognitive impairment was 77% for the patients at ICU discharge and 43% three months thereafter, compared to 33% for the control subjects. The significant cognitive differences between the two groups disappeared during the first three months after ICU discharge, as the patients’ cognitive functioning seemed to recover during that period. A closer look at the performance on different cognitive domains revealed, however, that circulatory shock patients still seemed to perform worse than the control subjects in the domains of executive functions and attention, and visuomotor and visual functions at the 3-month follow-up. Based on the results, circulatory shock patients seem to be particularly vulnerable to experiencing cognitive difficulties after ICU care. The findings of this study highlight the importance of screening for post-ICU cognitive difficulties in patients treated for circulatory shock. Identifying the cognitive difficulties already at the hospital could help to set up rehabilitation programs, ensuring that the patients would receive the support needed for the best possible recovery.

Objective: Both stress-related exhaustion and depression have previously been associated with a decline in cognitive performance, but there is a lack of evidence on whether these conditions have different associations with different cognitive domains and whether they have additive effects on cognitive performance. Furthermore, very little is known about the cognitive effects of chronic stress-related exhaustion. Consequently, the aims of this study were to 1) examine the associations between current stress-related exhaustion and cognitive performance, 2) investigate whether different developmental trajectories of stress-related exhaustion are differently associated with cognitive performance, 3) compare the association between stress-related exhaustion and cognitive performance to the relationship between depressive symptoms and cognitive performance, 4) examine if individuals with comorbid stress-related exhaustion and depression have lower cognitive performance than individuals with at most one of these conditions (i.e., whether clinical stress-related exhaustion and clinical depression might have additive effects on cognitive performance). Methods: The data used in the study was a Finnish population-based sample of six cohorts born between 1962 and 1977 from the Cardiovascular Risk in Young Finns Study. Stress-related exhaustion was assessed using the Maastricht Questionnaire, depressive symptoms with the Beck Depression Inventory, and cognitive performance with four subtests of the Cambridge Neuropsychological Test Automated Battery, measuring visuospatial associative learning, reaction time, sustained attention, and executive functions. Cognitive performance and depressive symptoms were assessed in 2012, and stress-related exhaustion in 2001, 2007, and 2012. Participants were 35 to 50 years old in 2012. Linear associations between stress-related exhaustion and cognitive performance (N = 905) and depressive symptoms and cognitive performance (N = 904) were examined by conducting multivariate regression analyses. Age, sex, socioeconomic status, and parents’ socioeconomic status were controlled in the regression models. Additionally, multivariate analyses of variance were performed to investigate the different developmental trajectories of stress-related exhaustion and their relation to cognitive performance (N = 541) and the associations of comorbid stress-related exhaustion and depression with cognitive performance (N = 1273). Results and conclusion: The main finding was that high stress-related exhaustion is associated with slower reaction times, but not with performance in spatial working memory, visuospatial associative learning, or executive functions. Ongoing, chronic stress-related exhaustion was more strongly associated with slower reaction times than short-term exhaustion experienced years ago. Compared to depressive symptoms, high stress-related exhaustion was associated with slower reaction times also when subclinical cases were included, whereas only clinical levels of depressive symptoms had an association with slower reaction times. There were no differences in cognitive performance between individuals with only stress-related exhaustion or depression and those with comorbid stress-related exhaustion and depression, which supports the notion that these conditions do not have additive effects on cognitive performance. These findings add to the existing evidence of the cognitive effects of stress-related exhaustion in the general population and have several practical implications. Further research is needed on the topic, preferably with longitudinal designs, more comprehensive cognitive measures, and clinical assessment of the psychiatric symptoms.

Colorectal cancer is the third most common cancer in Finland. It is often diagnosed at a late stage, reducing patients´ prognosis and survival. Studies have shown that screening of colorectal cancer can detect cancer at earlier stage and reduce its incidence and mortality. The most effective way of preventing colorectal cancer is to remove the premalignant cells using endoscopically.a Screening for colorectal cancer became a part of the national screening programme in Finland in the beginning of 2022. Screening is carried out according to the guidelines of the Finnish Cancer Registry Syöpärekisteri, and based on the recommendations of the EU Cancer Screening Council. The aim of the gradually expanding screening programme is to cover the population aged 56-74 by 2031. The screening of the colorectal cancer is executed in two different stages. The first screening method is a faecal immunochemical blood test (FIT) that aims to detect microscopic blood in the patient faeces. Patients who test positive in FIT are invited to the second stage of the screening for further examination. The second stage consists primarily of a full colonoscopy with biopsies. The aim of this study was to find out more about the quality and quantity of the findings in the colonoscopies performed as a part of the colorectal cancer screening in Helsinki and Uusimaa hospital district. The second aim of this study was to examine the quality of the screening colonoscopy process. The study was conducted as a retrospective, systematic review on the topic. Data was collected by combining several different patient databases. The study included 400 patients from Helsinki, Espoo, Vantaa and Kerava regions who had undergone a screening colonscopy in early 2023. The study reinforced the perception that colorectal cancer screening colonoscopies have a high incidence of findings; the most significant being a relatively high incidence of cancer and especially its precursors. Most of the cancers found were of an early stage forms. Another observation of the study is that the endoscopical part of the screening of colorectal cancer in Helsinki and Uusimaa hospital district is of a high quality and well meets the criteria set.

Tausta: Komorbiditeettien eli muiden itsenäisten sairauksien vaikutusta myasthenia graviksen (MG) ennusteeseen ei tunneta. Muut autoimmuuni sairaudet on liitetty MG:een mutta niidrn rooli MG:n taudin kuvaan on kiistanalainen. Menetelmät: Tässä retrospektiivisessä yhden keskuksen kohorttitutkimuksessa seurasimme 154 suomalaista yleistynyttä MG:sta sairastavaa potilasta, joille oli tehty tymektomia eli kateenkorvan poisto. Keskimääräinen seuranta-aika oli 8,6 (±5.0 ) vuotta tymektomian jälkeen. Potilaiden komorbiditeetit oli diagnosoitu miltä tahansa ajanhetkeltä ja tiedot oli peräisin potilasasiakirjoista. Tautitaakka pisteytettiin käyttämällä Charlson comorbidity indexiä (CCI). Potilaat jaettiin alaryhmiin komorbiditeettien mukaan; MG ainoastaan (n=45) ja MG sekä mikä tahansa komorbiditeetti (n=109). Jälkimmäinen ryhmä jaettiin vielä; MG sekä muu autoimmuunitauti (n=33) ja MG sekä ei-autoimmuuni komorbiditeetti -ryhmään(n=76). Tutkimuksen päätetapahtumina oli täydellinen remissio (CSR), minimaalisen lääkityksen tarve (pyridostigmiini max 100mg/vrk) ja sairaalahoidon tarve. Tulokset: Potilaat joilla ainoastaan MG saavutti CSR useammin kuin MG sekä mikä tahansa komorbiditeetti –ryhmä (26.7% vs 8.3%, p = 0.004). Minimaalisen lääkityksen tarpeen saavutettiin useammin MG ainoastaan -ryhmässä kuin MG sekä ei-autoimmuuni komorbiditeetti –ryhmässä (p = 0.047 ). Sairaalahoidon tarve oli alhaisempaa potilailla joilla vain MG kuin potilailla oli MG sekä mikä tahansa komorbiditeetti (p = 0.046). Logistisen regressioanalyysin mukaan matala CCI kasvattaa todennäköisyyttä saavuttaa CSR (p = 0.033). Matala CCI oli yleisempää potilailla, joilla oli minimaalinen lääkitys tarve ja eivätkä tarvinnut sairaalahoitoa (p < 0.001) Johtopäätökset: Lähes 9 vuoden tymektomian jälkeisen seurannan aikana potilailla, joilla on yleistynyt MG ja komorbiditeettejä on huonompi ennuste kuin potilailla jotka sairastavat vain MG:tä. Autoimmuunisairaudet eivät huonontanut MG:n ennustetta enempään kuin muut komorbiditeetit.

Goals Length of human lifespan is an important measure of societal welfare. Mortality is largely linked to physical health, but psychological well-being has also been shown to predict mortality, happier people living longer lives. Psychological well-being can be construed as both subjective well-being (SWB) and eudaimonic well-being (EWB), and measures belonging to both of these constructs have been shown to individually predict mortality. No study to date has, however, compared these differing measures of psychological well-being as predictors of mortality. This study compares measures of life satisfaction (a part of SWB) and purpose in life (a part of EWB) as predictors of mortality. Methods The data used in this study comes from the Midlife in the US (MIDUS) survey, a large-scale longitudinal study spanning almost 20 years. MIDUS includes measures for life satisfaction and purpose in life, as well as data on mortality and many health behaviors with a sample of N=3768. Effects of life satisfaction and purpose in life on mortality were analysed with multiple Cox proportional hazards models. Results Life satisfaction predicts mortality when modeled alone, as does purpose in life. When modeled together, only purpose in life predicts mortality. This finding stands when additional health behavior variables are controlled, but when the sample is stratified by sex, the relation between life satisfaction and mortality also reaches marginal significance for women but not men. Conclusions This study shows that purpose in life might be a better predictor of mortality compared to life satisfaction. The results also give preliminary support for a hypothesis that purpose, and by proxy EWB, is closer to the evolutionary and physiological core of psychological well-being.

Alzheimer’s disease (AD) is a neurodegenerative brain disorder in which the disease process may take decades until the symptoms become evident. To date, no ideal biomarker has emerged that would enable early detection of AD. Environmental and lifestyle factors are thought to affect the risk of developing AD, possibly through epigenetic mechanisms such as DNA methylation (DNAm). DNAm has been shown to differ in the blood and brain of subjects with AD compared with subjects without AD, suggesting that DNAm may be involved in the pathogenic process of AD. This study aims to detect the difference in blood DNAm at baseline between cases who later developed AD and controls who remained AD diagnosis-free during follow-up in a sample selected from a Finnish population-based cohort. Leucocyte genome-wide DNAm was profiled on approximately 850,000 CpG sites by using Infinium MethylationEPIC assay. Each CpG was regressed on the outcome of AD diagnosis during follow-up, controlling for subjects’ age at sampling, sex, smoking status, blood cell counts, working stress level, slide, and array. Specific differentially methylated positions (DMPs) were further explored using pathway analysis. Finally, the methylation level of the candidate gene (APOE) selected from the literature was compared with the sample of this study. After correction for multiple testing, the later diagnosis of AD was not significantly (adjusted p-value < 0.05) associated with methylation level at the baseline at any DNAm site. There was, however, a robust hypomethylation of DMPs among the cases, as 90.9% of the DMPs (p-value < 0.05) were hypomethylated in the case group. The 200 genes annotated by DMPs with the smallest p-values were involved in two neuronal pathways: “Axon guidance associated with semaphorins Homo sapiens” (p-value = 0.0058, adjusted p-value = 0.065) in Panther 2016 and “Semaphorin interactions Homo sapiens” (p-value = 0.00005, adjusted p-value = 0.078) in Reactome 2016. No significant difference existed in DNAm of the candidate gene (APOE) between cases and controls, while cg26190885 at the promoter region of APOE showed nominal significance (p-value = 0.04). In conclusion, no strong evidence was found to support the hypothesis that systemic changes in DNAm are involved in the pathogenesis of AD or that DNAm marks could be detected in blood before the symptoms become evident. A genome-wide pattern of hypomethylation measured by the Infinium MethylationEPIC assay was observed in the case group, serving as a venue for further investigations.