Lääketieteellinen tiedekunta


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  • Saarinen, Aino (Helsingin yliopisto, 2018)
    This study investigated i) the relationship of temperament and character with paranoid ideation over age in adulthood ii) the association of explosive temperament profile with the development of character dimensions self-directedness and cooperativeness, and whether this association is modified by social support and attachment security iii) the co-occurrence of depressive symptoms with paranoid ideation from late adolescence to middle age in the general population. The participants (n = 2028, 2137, and 2109 in Studies I‒III) were selected from the prospective Cardiovascular Risk in Young Finns Study, which started in 1980. Paranoid ideation and depressive symptoms were assessed at several time points over a 20-year follow-up in 1992‒2012. Temperament and character, social support, and attachment security were measured multiple times between 1997‒2012. We used multilevel models for repeated measurements, which were controlled for participants’ age, gender, and socioeconomic status both in childhood and adulthood. The results revealed that single temperament dimensions of high novelty seeking, high harm avoidance and low reward dependence and also explosive temperament profile (consisting of high novelty seeking, high harm avoidance, and low reward dependence) were related to a higher level of paranoid ideation in adulthood. These associations appeared to be mediated by character dimensions. Specifically, high self-directedness, high cooperativeness, and low self-transcendence could protect individuals with temperament-related susceptibilities from paranoid ideation. Explosive temperament was associated with lower self-directedness and cooperativeness as compared to other temperaments, but high social support and secure attachment had a positive influence on character development in individuals with explosive temperaments. Additionally, we found that depressive symptoms were linked with the course of higher paranoid ideation, especially in late adolescence and early adulthood. Regarding various depressive subsymptoms, high negative attitude and high performance difficulties were associated with the course of more severe paranoid ideation over age in adulthood, whereas the influence of somatic symptoms became significant only after early adulthood. Finally, depressive symptoms appeared to be more strongly related to the development of trait- than state-level paranoid ideation. Specific variants of single temperament dimensions and profiles represented susceptibilities for paranoid ideation. The presence of supportive and confidential relationships was linked with more mature character (i.e. higher self-directedness and higher cooperativeness), which appeared to have a protective role against paranoid ideation in individuals with risky temperaments. The co-occurrence between depressive symptoms and paranoid ideation was especially evident in late adolescence and early adulthood. Individuals, who have temperament-related susceptibilities for paranoid ideation, might benefit from interventions, which promote the abilities to form confidential and supportive social relationships. This might help them to internalize more mature concepts about the self and interpersonal relationships, which, in turn, could enhance the self-regulation of temperament-related susceptibilities and lower the risk for paranoid ideation. Individuals with co-occurring depressive symptoms and paranoid ideation might benefit from neurocognitive rehabilitation, social skills training, and community-based treatments in order to enhance interpersonal activities and metacognitive abilities.
  • Peräsaari, Juha (Helsingin yliopisto, 2018)
    Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 %. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA% value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13% (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48% and 26%, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.
  • Sammallahti, Sara (Helsingin yliopisto, 2018)
    Background: Preterm birth (before 37 weeks of gestation) is a major cause of infant mortality and morbidity worldwide, and preventing its burden is a health care priority. Even in adulthood, individuals who were born preterm perform, on average, worse on tests of cognitive functioning than term-born peers do, and may have more mental health problems. Early growth failure is common among preterm individuals, and some studies have suggested that those preterm individuals who grow poorly in infancy have more neurodevelopmental problems later on in childhood. It is unclear whether these associations persist into adulthood and whether they extend beyond the smallest and most immature of preterm infants, to the majority of preterm infants who are born late preterm (at 34-36 completed weeks of gestation). It also remains unknown whether early postnatal growth patterns predict mental health outcomes - some partly conflicting evidence suggests that intrauterine growth restriction at least associates with mental health problems. The mechanisms explaining the associations between growth and neurodevelopment are also unclear. Early growth reflects a number of intertwined early-life environmental factors and individual characteristics, and while altering neonatal nutrition can affect growth, it is not known whether changes in nutrition can improve long-term neurodevelopmental outcomes. It has even been suggested that faster growth and higher nutritional intakes during the early postnatal period can present a trade-off between improved neurodevelopment and increased cardiovascular risk. Methods: The 157 participants of the Helsinki Study of Very Low Birth Weight Adults (HeSVA, birth weight <1500g) and the 108 participants of the Arvo Ylppö Longitudinal Study (AYLS, gestational age 34-36 completed weeks) examined in this thesis were born in Finland between 1978 and 1986. They were invited to adult follow-up visits between 2004 and 2012. Among these young adults, I examined whether growth in weight, length, and head circumference between different early growth periods (between preterm birth, term age, and 12 months of corrected age in HeSVA, and between late preterm birth, 5 and 20 months of corrected age, and 56 months of age in AYLS) was associated with performance in neuropsychological tests, with self-rated symptoms of depression, attention deficit hyperactivity disorder, and other mental health problems, or with diagnosis of mental disorder based on a psychiatric interview in adulthood. In the AYLS cohort, the participants also reported final grade point average and special education in comprehensive school. I further examined whether daily intakes of energy in total, of energy from human milk, and of carbohydrates, protein, and fats during the initial hospitalization, which were relatively low compared to modern recommendations, predicted adult cognitive functioning (HeSVA). As growth variables, I used standardised residual change scores from linear regression models where weight, length, and head circumference z scores were regressed on corresponding measures at previous time points, creating uncorrelated residuals that reflect growth conditional on previous history. These growth variables were then used as independent variables in linear and logistic regression models to predict the outcomes, while taking into account several potential confounders including child and parental background characteristics and neonatal morbidity. Results: Faster growth during the first months of life was associated with better adult cognitive functioning in both cohorts. The size and direction of the effects were similar: for each SD faster growth in weight, head circumference, and length between birth and term age, the HeSVA participants had 0.23-0.41 SD higher general intelligence quotient, executive functioning component, and visual memory scores. For each SD faster weight gain and head growth from birth to 5 months, and head growth from 5 to 20 months, the AYLS participants had 0.19-0.41 SD higher general intelligence quotient and executive functioning component scores and grade point average. Those who grew faster also had lower odds of having received special education at school. Growth after these time periods did not predict cognitive functioning or school outcomes. In contrast, there were no consistent associations between early growth and adult mental health in either cohort. Even when taking into account several important neonatal complications and illnesses, the associations between early growth and adult cognitive functioning could not be wholly explained. Neonatal morbidity however seemed to largely account for the associations between higher energy intake between the first six weeks of life and better cognitive functioning among the HeSVA participants. Conclusions: Faster growth during the first weeks and months of life after preterm birth is associated with better cognitive functioning, and these associations persist into adulthood. The mechanisms explaining these associations are largely unclear, but seem outcome-specific. Early intakes of nutrition may reflect or possibly even mediate the effects of neonatal morbidity on neurodevelopment, however the neonatal morbidities commonly associated with preterm birth do not wholly account for the associations between early growth and long-term neurodevelopment. Keywords: premature birth; infant, very low birth weight; gestational age; birth weight; cognition; intelligence; executive functioning; memory; mental health; depression; attention deficit disorder with hyperactivity; substance-related disorders; anxiety disorders; education; growth; weight gain; body height; cephalometry; energy intake; milk, human; infant; adult; risk factors; follow-up studies; longitudinal studies; developmental origins of health and disease
  • Parkkonen, Eeva (Helsingin yliopisto, 2018)
    Despite advances in acute treatment of stroke, over third of the patients suffer from a disability, most often upper-limb paresis, still five years after stroke. To improve rehabil- itation, further understanding of stroke-induced plasticity is required. During the plastic period, cortical excitability increases, likely promoting cortical reorganization. Afferent input modulates the rolandic 20-Hz rhythm. The modulation, reflecting motor- cortex excitability, is observable as the activation-associated suppression and inhibition- associated rebound of the 20-Hz rhythm. In this Thesis, motor-cortex excitability was monitored by applying two different afferent inputs while recording the 20-Hz rhythm with magnetoencephalography (MEG), first in healthy controls and then in stroke patients in a one-year longitudinal study. Study I, comprising 22 healthy controls, focused on the modulation of the 20-Hz rhythm to tactile stimulation and passive movement as proprioceptive stimulation. The suppres- sion of the rhythm was similar to both stimuli whereas the rebound was stronger to pas- sive movement. Thus, passive movement could better serve in studying motor-cortex excitability changes. In Studies II and III, modulation of the 20-Hz rhythm to afferent input was measured in 23 patients having their first-ever stroke in the territory of the middle cerebral artery and related upper-limb paresis. Passive movement of the index finger (Study II) and tactile stimulation (Study III) were applied during MEG recordings in the acute (T 0 ; 1–7 days), subacute (T 1 ; one month) and chronic (T 2 ; 12 months) phases after stroke onset in conjunction with clinical testing of hand motor performance. The results showed that in the acute phase, the rebound was strongly diminished to both stimuli compared to the controls and increased significantly during the first month. During the follow-up period, the rebound strengths to both stimuli correlated with motor performance of the impaired hand. The bilateral weakness of the rebounds in the acute phase indicate hyperexcitability of both hemispheres after stroke. The subsequent increase in the rebound strength during the first month, reflecting an increase in motor-cortex inhibition, is in line with earlier studies in animals and humans suggesting a sensitive and motor-recovery-related plastic period immediately after stroke. The rebound strength to impaired-hand stimulation correlatedwith hand motor performance across the follow-up indicating that adequate integration of afferent input with motor functions is important for motor recovery. During the follow- up, the 20-Hz rebound to both tactile and passive-movement stimuli increased similarly. However, the rebounds to tactile stimuli recovered to the level of the controls whereas those to proprioceptive stimuli did not. This might indicate that proprioception did not recover fully in our patients. It would be most important to be able to predict and evaluate the progress of an individual patient during recovery from stroke to intensify and tailor rehabilitation for individual needs. Though, the efficacy of rehabilitation may be evaluated with different neuroimag- ing methods and clinical tests in a group level, so far there are no objective biomarkers to evaluate rehabilitation in an individual level. The results of this Thesis indicate that the 20-Hz rebound magnitude strongly reflects motor-cortex excitability and thus could serve as a robust noninvasive marker of stroke-induced neurophysiological processes that are relevant for motor recovery. Such a biomarker may enable to assess the efficacy of new therapeutical methods in stroke rehabilitation in both group and individual levels.
  • Savolainen, Mikko (Helsingin yliopisto, 2018)
    Tämä tutkimus käsittelee kallon saumojen ennenaikaisen sulkeutumisen (kraniosynostoosi) leikkaushoitoa. Perinteiseen leikkausmetodiin avoimeen kallon uudelleen kokoamiseen (kranioplastia) liittyy useita haasteita: leikkauksessa syntyvät luupuutokset jäävät joskus luutumatta,kestävän luiden välisen liitoksen saavuttaminen on haastavaa, toimenpide on hyvin invasiivinen henkeä uhkaavine komplikaatioineen. Uuteen vähemmän invasiiviseen hoitomuotoon kallon venytykseen liittyy myös tällä hetkellä usein ongelmia kuten luun venyttimien hajoamista tai irtoamista. Tutkimuksessa etsittiin ratkaisuja näihin ongelmiin.18:sta kraniosynostoosipotilaalle avoimen kranioplastian aikana luupuutosten peitoksi oli laitettu demineralisoitu luulevy (DML). Nämä luupuutokset osoittivat parempaa luutumista (74%) kuin vastaavat tyhjät luupuutokset (54%) saman potilaan kallossa. Vertailu tehtiin viikko ja vuosi leikkauksen jälkeen otetuista tietokonetomografia kuvista. DML osoittautui turvalliseksi ja hyödylliseksi materiaaliksi luuputosten peitoksi. Aalto-yliopiston kanssa yhteistössä kehitettiin metodi, jotta kallon venytyshoidossa syntyvät voimatpystytään määrittämään. Mittauksissa todettiin venytystä vastustavan voiman kasvavan jyrkästi venytyksen aikana ja laskevan tämän jälkeen merkittävästi (keskimäärin 69.9%). Keskimääräinen venytyksen aloitusvoima oli 20.4 N ja lopetusvoima 57.6 N. Tutkimuksesta voidaan päätellä, että kallon venytyshoidon komplikaatioita voidaan vähentää jakamalla venytys useampiin lyhyempiin venytys kertoihin. Aalto-yliopiston kanssa yhteistyössä tehdyssä laboratoriokokeissa todettiin, ettei kahdella erilaisellabiohajoavalla luun kiinnitysmekanismilla, perinteisellä ruuvilla ja ultraäänellä aktivoitavalla pinnillä, ole kliinisti merkittävää kestävyys eroa. Toisessa samantyyppisessä laboratoriokokeessa testattiin kolmen erilaisen biohajoavan kiinnitysmekanismin soveltuvuutta kallon luun venyttimen kiinnittämiseen. Tutkimuksessa todettiin, että luun venytin voidaan kiinnittää kalloon 8 biohajovallaruuvilla tai 12:sta biohajoavalla lämmöllä aktivoitavalla pinnillä. Biohajoavalla kiinnityksellä voidaan mahdolisesti vähentää hoitoon liittyviä komplikaatioita ja vähentää luun venyttimen poistoleikkauksen laajuutta.
  • Achuta, Venkat Swaroop (Helsingin yliopisto, 2018)
    Fragile X syndrome (FXS) is the most common cause of genetically acquired intellectual disability and is strongly associated with autism spectrum disorders. FXS is an X-linked neurodevelopmental disorder, with an incidence of approximately 1 in 5000 males and 1 in 8000 females. It is primarily caused by a trinucleotide repeat expansion in the Fragile X mental retardation 1 (FMR1) gene leading to epigenetic silencing and loss of FMR1 protein (FMRP). Studies using Fmr1-knockout (Fmr1-KO) mice, modelling FXS, revealed that alterations in glutamatergic signaling play a central role in the aberrances of developmental processes in FXS brain. Tissue plasminogen activator (tPA) is a serine protease that potentiates signaling mediated by glutamate receptors. This thesis explored the effects of tPA and glutamate receptor signaling during early differentiation of FXS neural progenitor cells (NPCs). The differentiation of human and mouse FXS NPCs was characterized using calcium imaging, live cell imaging and immunostaining. Expression of tPA was increased in NPCs and brain of Fmr1-KO mice. The increased tPA was involved in altered neuronal migration and activity-dependent changes in FMRP-deficient mouse NPCs. NPCs were functionally characterized based on their responses to activation of type 1 metabotropic and ionotropic glutamate receptors. Increased differentiation of subpopulations of glutamate-responsive cells was observed in FXS NPCs. Treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), rescued abnormal differentiation of glutamate-responsive cells in both human and mouse FXS NPCs. In addition, MPEP treatment corrected morphological defects and migration of Fmr1-KO cells. Finally, an increased differentiation was evident for cells expressing calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in FXS NPCs and reduced GluA2 expression resulted in increased calcium permeability of AMPA receptors. In summary, this study provides insight into the molecular mechanisms involved in early aberrant differentiation of FXS neuronal cells and will pave the way to develop new therapeutic approaches and biomarkers for FXS.
  • Salava, Alexander (Helsingin yliopisto, 2018)
    The skin microbiome – Investigations on skin malignancies and preterm newborn skin Skin disorders have been associated with specific microbiome changes and raised an interest in developing new diagnostic methods and treatments. Our object was to investigate the microbiome in skin cancer (melanoma) and inflammatory skin disorders (parapsoriasis) and to explore the skin microbiome in very low birth weight infants in intensive care and possible association to neonatal sepsis. Microbiome samples were taken of 15 cutaneous melanomas and 17 benign melanocytic nevi, of 13 patients with parapsoriasis and 12 very low birth weight infants during treatment in intensive care. Sequencing was carried out on 454 GS-FLX Titanium and Illumina MiSeq platforms and the data was analyzed by bioinformatics. There were no significant differences in the microbiome of melanomas, melanocytic nevi and controls. Additionally, the microbiome showed no significant differences between parapsoriasis and the same patient’s healthy skin. We observed a high cutaneous microbial diversity in most of the infants at birth and there was a decrease in diversity during the first three weeks of life. There was no association between microbiome changes and neonatal sepsis. The results suggest that microbiome swab sampling may not be helpful in diagnostics of melanoma or parapsoriasis. Moreover, microbiome changes seem not to play a role in parapsoriasis. We could demonstrate that very low birth weight infants in intensive care have a high cutaneous microbial diversity during the first days of life regardless of the way of delivery, prematurity causes or perinatal infections. The diversity decreases during the first weeks of life possibly due to intensive care treatment and antibiotics. Neonatal sepsis is not linked to microbiome changes and it is likely that other factors play a role, e.g. skin injury by medical devices and concomitant infections.
  • Hannus, Sinikka (Helsingin yliopisto, 2018)
    Developmental language disorders in children are common and constitute a common reason for support in both health care and school system. Specific language impairment (SLI) is diagnosed in Finland in accordance with the ICD (International Classification of Diseases) with either F80.1 or F80.2 diagnoses. The terminology related to SLI is not internationally unambiguous. Studies indicate that SLI may entail more extensive difficulties than those related purely to language and, also, that SLI in childhood persists into adulthood. SLI has been studied very little within the Finnish service system. The present study explored SLI in the primary health care of one Finnish town. The children participating in the study belonged to the multidisciplinary SLI in Vantaa study group. SLI in Vantaa consisted of all the Finnish speaking children born in 1998 and 1999 who had been diagnosed with the diagnosis F80.1 or F80.2 in the secondary health care, and their matched controls. The first data set assessed the test use of the speech and language therapists (SLTs). In the second data set, the test performance of the children diagnosed with SLI was compared to that of their matched controls. The third study analysed the prevalence of the diagnosed SLI in the SLTs’ statistics over a period of eleven years. The fourth study compared the home activities of the children with SLI with those of their matched controls. The tests that were considered to be the best in separating the children with SLI from their peers were the same ones that the SLTs had most confidence in and that they most frequently used. On the other hand, the SLTs used some tests to assess also other constructs of language than those for which these tests were originally devised. The prevalence of SLI remained lower than the internationally reported level, even though it did increase during the study period. The low prevalence raised the possibility of under-diagnosing of SLI. When comparing the peer groups in home activities, similarities outnumbered differences. The existing differences seemed to be related to something else than language difficulties. Unifying and developing the assessment procedures of SLI is needed in Finland. Organising the future studies in collaboration between the researchers and the clinicians may benefit the children with language disorders in the best possible way.
  • Forsgård, Richard (Helsingin yliopisto, 2018)
    Intestinal permeability is a key measure of gastrointestinal function and studies have associated increased intestinal permeability with several different pathologies. Clinically, increased intestinal permeability could contribute to disease pathophysiology by allowing unwanted substances to enter circulation and stimulate inflammatory processes. Thus, a better understanding of the factors and mechanisms that affect intestinal permeability could offer new insights on how to manage these diseases and disorders. The aim of this thesis was to investigate intestinal permeability changes under three separate settings. Chemotherapy-induced gastrointestinal toxicity is a major complication of cancer treatment and we examined if measuring intestinal permeability to iohexol could be used to assess the severity of this complication. We also hypothesized that chemotherapeutics affect the composition of intestinal microbiota and the global metabolome and studied how these alterations relate to increased intestinal permeability. In another study setting, we investigated whether intestinal permeability changes explain individual’s susceptibility to gastrointestinal symptoms during exercise. Finally, we treated intestinal tissue segments with a deoxycholic acid (DCA) concentration associated with high-fat feeding and examined the mechanisms by which it affects macromolecular permeability. Our results show that commonly used chemotherapeutics, running at a challenging pace for 90 min, and DCA concentration associated with high-fat feeding increase intestinal permeability. The observed increase in intestinal permeability after chemotherapy also correlated with the severity of gastrointestinal toxicity. Chemotherapy-induced gastrointestinal toxicity was also associated with unfavorable changes in the composition of intestinal microbiota which may play a role in the pathophysiology of intestinal complications during chemotherapy. Running-induced increase in intestinal permeability seems to result from intestinal ischemia but it did not explain the occurrence of gastrointestinal symptoms during the running test. The DCA-induced increase in macromolecular permeability appears to stem from direct interaction with the mucosa. However, we also observed evidence that DCA affects the intestine via a neural mechanism. Overall, these results demonstrate how different stressors can impair intestinal barrier function and possibly lead to various symptoms and complications.
  • Jouhi, Lauri (Helsingin yliopisto, 2018)
    Head and neck cancers constitute the seventh most common cancer group worldwide. Their incidence has been declining in the Western world, along with the decrease in tobacco smoking. The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising over the last two to three decades in many Western countries. This trend is attributed to human papillomavirus (HPV), which is responsible for the majority of OPSCC cases, whereas, the incidence of HPV-unrelated OPSCC has decreased. HPV-positive OPSCC differs from the HPV-negative form in various aspects: Patients are younger, and they typically have less tobacco and alcohol consumption. They tend to have smaller primary tumors but more advanced disease in the neck. Patients with HPV-positive tumors have better odds of survival, but their post-treatment lifetime may be harmed by major treatment-related morbidity. Many prospective randomized trials delivering de-intensified treatment for this OPSCC patient group are currently ongoing. Validated predictive biomarkers could aid in the treatment individualization of OPSCC. The only well-validated prognostic biomarkers in OPSCC are HPV and protein p16, reflecting HPV involvement. Toll-like receptors (TLRs) are receptors, which initiate immunological cascades. In HPV-associated cervical carcinoma, alteration in the expression of TLRs has been observed. These receptors are also expressed in an altered pattern when HPV infection persists in the cervix. Therefore, these receptors could have a role in HPV-associated OPSCC. The first part of the present study analyzed the treatment and outcome in two patient series treated over a ten-year period. Study I included all OPSCC patients treated at the Finnish university hospitals, and Study II focused on the management of the neck in cN+ disease of patients treated at the Helsinki University Hospital. The cohort included 674 patients, and during the study period, the incidence of this disease increased, which mainly occurred in the group of patients carrying a HPV-associated tumor. The outcome of lateral-wall OPSCC (tonsil) remained similar compared to an earlier Finnish nationwide report, but the outcome of anterior-wall disease (base of tongue) slightly improved. Study II revealed that the relative rate of neck dissections had decreased while the delivery of definitive oncological treatment had increased. However, the regional control rate had not worsened. Regional failures occurred in patients with class cN2b or higher and they often developed on the contralateral side of the neck, including in patients with an ipsilateral primary tumor. The second part of this thesis study (Studies III and IV) evaluated the role of TLRs in OPSCC. As a pilot study, we analyzed TLR 2, 3, 4, 5, 7, and 9 expression, p16 expression, and HPV status in 35 OPSCC samples. TLR 5, 7, and 9 expression varied according to p16 and HPV status. Based on these results, we evaluated the association of TLR 5, 7, and 9 with clinicopathological and outcome data in a cohort of 202 OPSCC patients. The findings indicated that high TLR 5 expression and low TLR 7 expression were related to poor disease-specific survival in the group of HPV-positive OPSCC patients.
  • Malmi, Hanna (Helsingin yliopisto, 2018)
    The incidence and complications of peptic ulcer disease (PUD) have declined during the last decades in Western countries. The Helicobacter pylori (H.pylori) infection and the use of non-steroidal anti-inflammatory drugs are the two main risk factors for peptic ulcer disease. Despite the use of H.pylori eradication therapy and gastroprotective agents, mortality associated with PUD has not decreased as assumed. The aims of this thesis were to evaluate time trends in the incidence of PUD and its complications in hospitalised patients, their short- and long-term mortality, risk factors for mortality. Moreover, the prevalence of PUD among patients suffering from acute gastrointestinal bleeding (GIB) symptoms in the beginning of the 21st century in the capital area of Finland was studied. In the retrospective epidemiological cohort study, data on adult patients hospitalised and diagnosed with PUD was collected from the Hospital District of Helsinki and Uusimaa patient register during 2000-2008. The data was linked with Prescription Register of the Finnish Social Insurance Institution allowed detailed individual medicine purchase data and all patients were followed in the National Cause of Death Register until the end of 2009. In the prospective observational cohort study, data on hospitalised patients referred for acute upper endoscopy during 2012-2014 in Meilahti and Jorvi hospitals were collected. The incidence of peptic ulcers decreased significantly from 121/100000 in 2000-2002 to 79/100000 in 2006-2008. The rate of severe complications was also reduced, mainly due to a reduction in bleedings. The one-year cumulative incidence of recurrent peptic ulcers was 13%. The use of several drugs indicating comorbidity was associated with an increased risk for recurrence. No change in standardized mortality ratio was seen; 3.7% of patients died within 30 days, and 11.8% within 1 year in the retrospective cohort. Both the short- and long-term survival was significantly impaired in women presenting with perforated duodenal ulcer. The main causes of death at one year were malignancies and cardiovascular diseases. Interestingly, previous use of statins was associated with significant reduction in all-cause mortality. Of all patients admitted for acute upper endoscopy during 2012-2014, 23% had PUD. Other specific diagnoses in acute upper endoscopy were oesophagitis (12%), oesophageal or gastric varices (10%), 10% gastroduodenitis (10%), Mallory-Weiss lesion (8%), and malignancy (5%). Of the PUD patients, 31% were H.pylori positive. The 30-day mortality was very low 0.7%. This is most probably explained by the exclusion of unstable or otherwise fragile patients who were not able to give written informed consent at the admission. The one-year mortality was 12.9% which is in line with results of the retrospective study. Comorbidities were associated with decreased survival (p=0.029) and obesity (BMI>=30) was associated with better survival (p=0.023). Of all individual patients referred for endoscopy, the source for acute bleeding or severe anaemia was not evident in 19% of patients. In further examinations, the diverticular disease of the colon was regarded as the most probable source of bleeding in 39% of patients of these patients. In conclusion, both the incidence and complications of PUD have markedly decreased in Finland. However, the one-year mortality associated with PUD remained high with no change. PUD is still the most common cause of acute gastro-intestinal bleeding.
  • Arpalahti, Leena (Helsingin yliopisto, 2018)
    The ubiquitin-proteasome system (UPS) is the major cellular pathway for controlled protein degradation, and, together with the autophagy-lysosome pathway, it is a central player in maintaining protein homeostasis. The catalytic core of the UPS is the proteasome, a complex holoenzyme composed of multiple different subunits with varying functions. Disruptions in the UPS are associated with many pathological conditions, including aging-related neurological diseases (such as Alzheimer's, Parkinson's, or Huntington's disease), as well as different cancers. Proteasome inhibitors (e.g. Bortezomib) are in use as cancer therapeutics (e.g. in refractory multiple myeloma and mantle cell lymphoma), but dose-limiting toxicities, drug-resistance and other adverse side-effects have created an acute need for identifying alternative targets that modulate the UPS. Yet, despite its wide-ranging importance, it remains to be defined how UPS is regulated, especially in vivo. The purpose of this thesis was to provide new information on UPS modulation in a living, multicellular organism, with the help of the model organism Caenorhabditis elegans. Further, the aim was to investigate the potential role of an identified proteasome regulator UCHL5/UBH-4 as a biomarker in three gastrointestinal cancers: colorectal cancer (CRC), gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC). In the first part of the study, it was established that UCHL5/UBH-4, a proteasome-associated deubiquitinating enzyme (DUB), modulates proteasome activity in C. elegans, and additionally increases the degradation of proteotoxic proteins in human cancer cells. In C. elegans, UBH-4 expression was demonstrated to be regulated by the ageing-regulating Insulin/IGF-1 signaling (IIS) pathway through the transcription factor DAF-16 in a tissue-specific manner. Further, minor knockdown of ubh-4 resulted in a short lifespan extension without affecting progeny amounts. In the second part of the study, the role of UCHL5 was investigated in various gastrointestinal cancers. UCHL5 tumorexpression was scored with immunohistochemistry from representative patient tumor samples in CRC, GC and PDAC. UCHL5-immunoexpression correlated with increased survival in the subgroup of patients with lymph node-positive (Dukes C/stage III) rectal cancer. In addition, both positive nuclear and high cytoplasmic UCHL5-immunoexpression associated with better prognosis in PDAC. Positive UCHL5-immunoexpression was also linked to enhanced survival in the subgroups of gastric cancer patients with small tumors (<5 cm) or stages I-II of the disease. This thesis identified UCHL5/UBH-4 as a new proteasome modulator, and further UCHL5 as a novel prognostic marker with potential clinical relevance. In the future, the recognized significance of UPS in the development and progress of different diseases is only likely to grow. Therefore, understanding the underlying regulatory mechanisms of UPS function is of fundamental importance.
  • Ling, Jiaxin (Helsingin yliopisto, 2018)
    More than 60% of human emerging infectious diseases (EIDs) are zoonotic. Zoonoses are infectious diseases of animals (usually vertebrates) that can be transmitted to humans. Hantaviruses are emerging zoonotic pathogens that belong to the genus Orthohantavirus and family Hantaviridae in order Bunyavirales. Hantaviruses pose a serious threat to human health because their infection causes two highly fatal diseases: haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Rodents have been regarded as the main reservoir and evolutionary scene of hantaviruses. In the last three decades, our knowledge of hantaviruses has broadened significantly. In contrast to the initial assumption that hantaviruses are mainly carried by rodents, many novel hantaviruses have been detected in shrews, moles and bats during the last few years. These findings raise a number of significant questions about the evolutionary history of hantaviruses, their host association and adaptation, the role and frequency of spillover infections and host-switch events, and most importantly, their pathogenicity.   In Finland, Puumala virus (PUUV) has been regarded as the only rodent-borne hantavirus present in the country. To search for novel hantaviruses other than PUUV, various novel hantaviruses were molecularly identified in different species of Soricomorpha ("shrew-form"). Genetic analyses revealed that four soricomorph-borne hantaviruses circulate in Finland, including Boginia virus (BOGV) in Neomys fodiens and Asikkala virus (ASIV) in Sorex minutus. Common shrews (Sorex araneus) harboured two different hantaviruses: Seewis virus (SWSV) and an Altai-like virus, showing the first evidence of co-existence of two distinct hantavirus species circulating simultaneously in one host species population. This host sharing of two divergent hantaviruses in the European common shrews contradicts hantavirus-host specificity, further implying the complexity of hantavirus evolution.   After screening hundreds of S. araneus from all of Finland, we obtained a large data set of new SWSV sequences that enabled phylogeographic analyses of SWSV. The results demonstrated that this shrew-borne hantavirus is similar to rodent-borne hantaviruses, and the post-glacial spread of SWSV into Finland mirrors that of the host, S. araneus: these shrews colonized Finland from the east after the last ice age (12,000–8,000 years ago) and then subsequently spread along emerging land bridges towards the west or north.   Most new hantaviruses discovered in soricomorph and bat hosts instead of rodents have raised questions as to whether any of them will emerge as human pathogens. Therefore, to predict human exposure risk, novel laboratory techniques for molecular and serological hantavirus detection were developed. No evidence of SWSV infection was found among a panel of 486 patient serum samples; however, we demonstrated a cross-reaction of anti-PUUV serum with shrew-borne hantavirus nucleocapsid (N) protein.   This thesis focused on the diversity, host maintenance and cross-species transmission dynamics of soricomorph-borne hantaviruses. The study presented innovative methods to investigate this pertinent topic at the interface of wildlife diseases and human health. The results provided new insights about the ecology, evolutionary origins and phylogeography, and most importantly, the potential pathogenicity of soricomorph-borne hantaviruses. This knowledge in combination with future studies will hopefully lead to a better understanding of host-parasite relationships.
  • Karpov, Boris (Helsingin yliopisto, 2018)
    A high proportion of patients with mental disorders experience concurrent anxiety symptoms and substance abuse, which impacts the course and outcome of principal psychiatric disorders and increases the risk of physical morbidity and suicide. Another prominent problem that worsens outcome and increases healthcare costs, is poor adherence to psychiatric treatment. As a consequence of severe course and poor treatment adherence, mental disorders are highly disabling. Because of methodological variations in the studies on anxiety and substance use comorbidity, adherence, and functioning, it remains unclear whether such conditions share similar characteristics across schizophrenia spectrum and mood disorders. The Helsinki University Psychiatric Consortium Study was performed in the metropolitan area of Helsinki between 12.01.2011 and 20.12.2012, covering specialized psychiatric care units. For this study, patients were divided into three subgroups: schizophrenia or schizoaffective disorder (SSA, n=113), bipolar disorder (BD, n=99), and depressive disorder (DD, n=188). Anxiety symptoms were measured with the Overall Anxiety Severity and Impairment Scale; substance use was assessed with recorded substance use disorder diagnoses, Alcohol Use Disorders Identification Test, and original questionnaires; treatment adherence was assessed with patients´ self-reports; subjective level of functioning was assessed with the Sheehan Disability Scale; and data on objective work status were gathered from medical records. Nearly half of all patients felt severe anxiety frequently, but SSA patients less often than mood disorders peers. High neuroticism, symptoms of depression and borderline personality disorder were associated with co-occurring anxiety within all diagnostic groups. Almost half of the patients reported hazardous alcohol use or were daily smokers. Symptoms of anxiety and borderline personality disorder were associated with self-reported alcohol consumption. Outpatients were significantly more adherent than current inpatients. Non-adherence to outpatient visits was strongly associated with hospital setting and substance use disorder. Nearly one-third of mood disorder patients were employed, while in SSA patients this proportion was only 5.3%. Severe course of disease and current depressive symptoms were likely to affect work status and perceived functional impairment, respectively. Careful detection and treatment of harmful substance use and affective symptoms are necessary to enhance treatment adherence, and functional level of patients with mood or schizophrenia spectrum disorders.
  • Gao, Jing (Helsingin yliopisto, 2018)
    Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable chronic airway disease (CAD) and is the fourth leading cause of illness and death worldwide. CAD represents a group of diseases with different clinical phenotypes, airway inflammation, obstruction and destruction of the lung parenchyma. COPD is a heterogeneous disease, which is characterized by persistent respiratory symptoms and airflow limitation and its prevalence varies considerably across populations. Asthma-COPD overlap syndrome (ACOS) had been reported in 2009 and recognised by Global Strategy for Asthma Management and Prevention (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2014. ACOS is identified by the features that it shares with both asthma and COPD. Inhaling tobacco smoke is the main risk for CAD, thus smoking cessation is not only the key step for prevention and maintenance therapy for COPD (GOLD 2017), but also it is encouraged in the patient with asthma and their families (GINA 2017). Smoking cessation, pulmonary rehabilitation, pharmacologic therapy and the other therapies for COPD may improve symptoms, health status and exercise ability and reduce frequency of exacerbations (GOLD 2017). At present, COPD is generally diagnosed by lung function measurement using spirometry, but not all individuals presenting with airflow limitation follow the paradigm. On the individual level spirometry may poorly correlate with symptoms, risk of exacerbation, prognosis and response to treatment in COPD. Due to disease heterogeneity, limitations of spirometry and lack of predictive molecular markers, the mechanisms underlying different COPD phenotypes are still unclear. Therefore, identification of the similarities and differences of COPD clinical phenotypes is important, as these phenotypes require different therapeutic approaches and have distinct clinical outcomes. We hypothesised that the potential biomarkers may play an important role and even predict the development of COPD. Accordingly, patients with asthma, COPD and ACOS would exhibit different biomarker profiles. Furthermore, distinguishing COPD phenotypes via distinct molecular and cellular pathways may facilitate the development of individualised diagnosis and precision medicine. The first goal of this study was to identify COPD-specific proteomic changes involved in disease onset and severity. The second goal was to identify novel biomarkers for the clinical COPD phenotypes in smokers and in patients with COPD, asthma and ACOS in cross-sectional and longitudinal studies. Those studies included the 6-year longitudinal cohort of adult smokers for early diagnosis of COPD studies, and the Finnish discovery cohort and Japanese validation cohort for ACOS studies. The third goal was to investigate whether the levels of these markers are associated with variables such as pack-years, lung function and sputum cell profiles. Finally, we aimed to evaluate the association of the biomarker levels with a longitudinal decline of lung function. We selected biomarkers identified in our non-hypothesis-based proteomic approaches for early COPD diagnosis, such as transglutaminase 2 (TGM2), bactericidal/permeability-increasing (BPI) fold-containing protein B1 (BPIFB1) and soluble receptor for advanced glycation end-products (sRAGE). Based on our previous results and non-hypothesis-based proteomic approaches, we developed two panels of potential biomarkers for ACOS: COPD-related biomarkers and asthma-related biomarkers. The four COPD-related biomarkers are neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), surfactant protein A (SP-A) and sRAGE. The three asthma-related biomarkers are chitinase-like protein (YKL-40), interleukin-6 (IL-6) and interleukin IL-13 (IL-13). For the early COPD diagnosis studies, induced sputum and plasma samples were categorised into 3 groups: non-smokers, smokers without COPD and smokers with COPD (stable stage I and stage II-III). Lung tissue samples were obtained from non-smokers, smokers without COPD, smokers with COPD and patients with idiopathic pulmonary fibrosis (IPF). For the ACOS studies, induced sputum and plasma samples were categorised into 5 groups: non-smokers, healthy smokers, patients with asthma, COPD and ACOS. Sputum cell counts were evaluated from sputum cytospins. TGM2 and BPIFB1 were assessed by Western blot analysis and by cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). BPIFB1 was further detected by immunohistochemistry and functional enzyme-linked immunosorbent assay (ELISA). TGM2, sRAGE, NGAL, MPO, SP-A, YKL-40, IL-6 and IL-13 levels were measured by commercial ELISA or magnetic human high sensitivity luminex assay (luminex assay). Our results showed that TGM2 levels in sputum and plasma were elevated in mild-moderate COPD and associated with lung function. Sputum BPIFB1 levels were elevated in smokers with COPD, whereas plasma sRAGE levels were decreased in smokers without COPD and smokers with COPD. Sputum BPIFB1 and plasma sRAGE levels were significantly associated with reduced airflow limitation over time in smokers with COPD. In the Finnish discovery cohort of the ACOS study, sputum MPO and plasma SP-A levels were significantly elevated in ACOS, whereas plasma sRAGE levels were decreased in ACOS. Sputum IL-13 levels were increased in ACOS when compared with controls. Sputum YKL-40 and IL-6 differentiated ACOS from COPD and asthma based on receiver operating characteristic (ROC) curve analysis. However, only sputum NGAL results could be repeated from the Finnish discovery cohort to Japanese validation cohort. Importantly, NGAL differentiated ACOS from COPD and independently correlated with forced expiratory volume in one second % (FEV1%-predict) in both cohorts. In conclusion, our findings support the hypothesis that monitoring of these biomarkers may be useful for differential diagnosis between the clinical phenotypes of COPD. TGM2 may be a potential diagnostic and therapeutic marker in COPD, which may relate to COPD onset and severity. BPIFB1 and sRAGE play vital roles in the pathogenesis of smoking-related COPD. High concentrations of sRAGE might be involved in the protective role of the airway. Patients with COPD and ACOS exhibit different NGAL profiles in sputum. These findings suggest that these potential biomarkers could be a novel diagnostic and therapeutic target for COPD. On the other hand, sputum biomarkers reflect both airway inflammation and tissue remodelling, and monitoring these biomarkers may be useful for differential diagnosis between asthma, COPD and ACOS.