Faculty of Medicine

 

Recent Submissions

  • Purhonen, Janne (Helsingin yliopisto, 2020)
    Mitochondrial disorders are rare diseases but collectively the most frequent group of inborn errors of metabolism. These disorders are genetically and phenotypically heterogenous and can manifest in any organ of the body with onset at any age. Mitochondrial functions are also diverse with the ATP production via the oxidative phosphorylation (OXPHOS) being the most notable. At the center of the OXPHOS machinery is the respiratory complex III (CIII, cytochrome bc1 complex). CIII deficiency in GRACILE syndrome belonging to the Finnish disease heritage causes a neonatal-lethal hepatorenal disease. The primary cause of GRACILE syndrome is a c.A232G (p.S78G) mutation in the BCS1L gene, which encodes a translocase required for Rieske Fe-S protein (RISP, UQCRFS1) incorporation into CIII. Homozygous Bcs1lp.S78G mice bearing the GRACILE syndrome mutation recapitulate the human syndrome, but unlike the patients they have a short asymptomatic period and relatively longer lifespan giving a window for therapeutic interventions. In this thesis project, we studied two potential therapies aiming to improve dysfunctional mitochondria in Bcs1lp.S78G mice: ketogenic diet and NAD+ repletion. We also utilized an alternative oxidase (AOX) transgene to bypass the electron-transfer blockade at CIII. Ketogenic diets are low-carbohydrate high-fat diets causing nutritional ketosis. They have been proposed to induce a beneficial starvation-like adaptive mitochondrial response involving increased mitochondrial biogenesis. Bcs1lp.S78G mice tolerated the carbohydrate restriction of ketogenic diet, were able to utilize dietary fat as the main energy source and developed ketosis. Ketogenic diet attenuated the hepatic CIII assembly defect, increased CIII activity and corrected mitochondrial structural aberrations. Our results suggested that these changes were not due to increased mitochondrial biogenesis. In line with the improved CIII function, Bcs1l mutant mice showed attenuated hepatopathy as shown by delayed liver fibrosis, inhibited stellate cell activation and hepatic progenitor cell response, decreased cell death and plasma liver enzyme activities. Liver transcriptomics and subsequent histochemical analyses suggested altered macrophage activation and a normalizing effect by ketogenic diet. In the second study, we characterized NAD+ metabolism in Bcs1lp.S78G mice. We found transcriptionally repressed NAD+ de novo biosynthesis and decreased hepatic NAD+ concentration. Changes in NAD+ consuming processes did not explain the decreased NAD+ levels. Aiming to replete the NAD+ levels, we fed the Bcs1lp.S78G mice a NAD+ precursor nicotinamide riboside (NR). In contrast to previous studies on mitochondrial myopathy models and mouse models with secondary mitochondrial dysfunctions, the hepatic NAD+ depletion of Bcs1lp.S78G mice was refractory to NR supplementation and the disease progression was unaltered. Cellular NAD+ levels regulate mitochondrial functions via sirtuin deacetylases, which are the main targets of NAD+ repletion therapies. Investigation of the upstream effectors of sirtuins showed that a starvation-like metabolic state of Bcs1lp.S78G mice is linked to AMP kinase and cAMP signaling, which likely counterbalances the repressive effect of decreased NAD+ levels on the activity of SIRT1 and SIRT3. In the third study, we introduced Ciona intestinalis AOX transgene into the Bcs1lp.S78G mice. AOXs are non-mammalian enzymes that can bypass a blockade of the CIII-CIV segment of the respiratory electron transfer. The AOX-expressing Bcs1lp.S78G mice were viable, and their CIII-deficiency stimulated AOX-mediated respiration in isolated mitochondria. AOX expression tripled the median lifespan of Bcs1lp.S78G mice from 200 to 600 days. The extension of the lifespan was predominantly due to the complete prevention of late-onset cardiomyopathy. The effects of AOX were tissue specific. In the heart of Bcs1lp.S78G mice, it preserved normal tissue structure and function, mitochondrial morphology, respiratory electron transfer, and wild-type-like transcriptome. In contrast, AOX only minimally affected the late-stage liver disease. Whereas, in the kidneys, AOX normalized an atrophic kidney phenotype and some histological lesions but it did not normalize kidney function or cause global normalization of transcriptome changes. Our results suggest tissue-specific thresholds of CIII deficiency for in vivo AOX-mediated respiration in CIII deficiency. Moreover, our study demonstrates the value of AOX as a research tool to dissect the pathogenesis of CIII deficiency. During our investigations, we observed approximately 5-fold difference in the lifespan of the Bcs1lp.S78G mice on two closely related congenic backgrounds. In the fourth study, we tracked the difference to a spontaneous homoplasmic mitochondrial DNA (mtDNA) variant (mt-Cybp.D254N) in an isolated congenic Lund University mouse colony. The variant changes a highly conserved negative amino acid residue in the only mtDNA-encoded subunit of CIII, cytochrome b (MT-CYB). A crossbreeding experiment utilizing the maternal inheritance of mtDNA verified the novel variant as the determinant of the survival difference. Functional studies showed that the variant exacerbated complex III deficiency in all assessed tissues. In otherwise wild-type mice, it also decreased cardiac CIII activity, caused a slight disturbance in mitochondrial bioenergetics, and decreased whole-body energy expenditure. Molecular dynamics simulations and their verification in isolated mutagenized Rhodobacter capsulatus cytochrome bc1 complex showed that the mt-Cybp.D254N variant restricts the mobility of RISP head domain movement. In summary, these studies provided novel mechanistic and therapeutic insights into CIII deficiency at genetic, molecular, and metabolic level. The results highlight the importance of knowing the underlying tissue-specific pathology and metabolic adaptations when designing therapies for mitochondrial diseases. The genetic epistasis between Bcs1lp.S78G and mt-Cybp.D254N also highlights the role of mitochondrial DNA background as a modifier of mitochondrial disease phenotypes.
  • Haavisto, Anna-Kaisa (Helsingin yliopisto, 2020)
    Eye injuries cause inconvenience at least and permanent disability at worst. Yet most of the injuries are preventable. Therefore, it is essential to have updated information on the circumstances leading to eye injuries. By reporting on the causes and contexts, we can promote proper eye protection and safe behaviour to reduce the number of accidents. In this thesis, the focus of analysis was leisure-time eye injuries; injuries in children and those caused by toy guns, sports and wooden projectiles in Southern Finland. Patients were gathered from all new eye trauma patients (n = 1151) taken into care at the Helsinki University Eye Hospital during a one-year period in 2011-2012. The follow-up time was three months and patients injured by toy guns were examined also five years after the eye injury. Children comprised 18 % (n = 202/1151) of all patients. Eye injury was most likely at the age of 13-16, and the leading causes were a hit of a sporting equipment (15 %), contact with the human body (12 %) and superficial foreign body (11 %). The main diagnosis was mild ocular or periorbital trauma (50 %). Six open globe traumas were caused by fireworks, tools, ski pole and a gun. Permanent disability was estimated for 9 % (n = 19) of children. Toy guns caused 1 % (n = 15/1151) of all eye injuries, consisting of 12 airsoft guns, 2 peashooters and 1 paintball gun. The main diagnosis was contusion (87 %). At the five-year follow-up, 47 % (n = 7) had subjective impairment, and 53 % had (n = 8) abnormal clinical findings. Sports caused 13 % (n = 149/1151) of all eye injuries. Floorball, football and tennis were the main sports to come up in the study. Floorball eye injuries decreased from 45 to 32 % of all sports-eye injuries from the season 2002-2003. The main diagnosis was contusion (77 %). Regarding participants, rink bandy had the highest risk. Permanent disability was diagnosed in 11 % of patients and was more common (p = 0.033) in ice hockey than in other sports in the number of injuries. Wooden projectiles caused 6 % (n = 67/1151) of all eye injuries. Males aged 51-67 were at the highest risk. The most common activity during the accidents was playing (27 %), gardening (18 %) and forest work (16 %). In relation to time spent in the activity, the risk of eye injury was the highest in gardening, forest work and woodwork. Permanent disability was diagnosed for 10 % due to various activities. Children should be guided safe play with sticks, and fireworks and tools should be avoided among children. The sale of toy guns should be more restricted and put under the Firearms Act to increase awareness of the risk. The use of eye protection in floorball is recommended for all age groups, and in ice hockey, the use of visors should be emphasised. In gardening, forest work and woodwork, the use of protective eyewear should be enhanced.
  • Savonius, Okko (Helsingin yliopisto, 2020)
    Bacterial meningitis remains a significant cause of childhood morbidity and mortality, despite reductions to the global meningitis burden resulting from immunisations against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Meningitis poses a threat to child health especially in resource-limited settings, where mortality rates can reach up to 50%, even with the use of effective broad-spectrum antibiotics. The extent of the host’s immune response associates with bacterial meningitis outcomes. Consequently, new treatment modalities have focused on controlling the initial inflammatory burst. This doctoral thesis project evaluated the use of a continuous antibiotic infusion, in contrast to conventional boluses, combined with paracetamol as a treatment for childhood bacterial meningitis. In addition, this research attempted to identify new prognostic markers in the cerebrospinal fluid (CSF) of children with meningitis and examined the impact of children’s vitamin D status on disease outcomes. The use of a continuous four-day cefotaxime infusion combined with oral paracetamol was evaluated in a prospective, randomised, double-blind parallel-group trial conducted at the Paediatric Hospital of Luanda in Angola between 2012 and 2017. The control intervention consisted of conventional cefotaxime boluses four times daily and an oral placebo, using mortality by day 7 from treatment initiation as the primary outcome. The prognostic role of matrix metalloproteinases (MMPs), myeloperoxidase (MPO) and the antimicrobial protein cathelicidin in the CSF and vitamin D levels in serum were analysed retrospectively using a cohort from Latin America of children with bacterial meningitis. Our prospective clinical trial showed no benefit from using a continuous cefotaxime infusion combined with paracetamol as a treatment for childhood bacterial meningitis in Angola. By day 7, 61 of 187 (32.6%) children in the intervention group and 64 of 186 (34.4%) children in the control group died (absolute risk difference 1.8%, 95% confidence interval -7.8% to 11.4%). Similarly, no differences emerged between the study groups in terms of neurological sequelae. In addition, the retrospective studies identified MMP-8 as a promising prognostic marker for bacterial meningitis: upon admission, a CSF MMP-8 level greater than the median value increased the odds of death 4.9-fold. The other analysed MMP, MPO and cathelicidin were also expressed in the CSF of children with bacterial meningitis, but did not predict disease outcomes to a similar extent. Furthermore, children’s vitamin D status upon admission did not associate with survival. In conclusion, the prognosis of childhood bacterial meningitis in Angola could not be improved by using a continuous cefotaxime infusion and oral paracetamol. Many of the children in our study were severely ill when presenting at hospital, likely contributing to the poor outcomes and warranting further attention. CSF MMP-8, however, presented as a potential prognostic marker for the disease.
  • Hänninen, Ulrika (Helsingin yliopisto, 2020)
    Colorectal cancer (CRC) is the third most common cancer and the second main cause of cancer mortality worldwide. The colorectum and the small bowel are part of a continuous passageway called the gastrointestinal (GI) tract, however, the cancer incidence varies greatly between these two organs. Although the small bowel constitutes three quarters of the length of the GI tract, only 3% of GI cancers are located in the small bowel. These cancers develop due to both somatic and inherited germline mutations. Thus, characterizing the genetic events that drive tumorigenesis is crucial to provide ways to improve prevention and clinical management of the disease. The general aim of this thesis was to gain new insights into the molecular genetic backgrounds of CRC and small bowel adenocarcinoma (SBA). The first aim of the thesis was to characterize the somatic mutation patterns of the AT-Rich Interaction Domain (ARID) family genes in CRCs with microsatellite instability (MSI). Approximately 15% of CRCs display MSI which arises due to a defective DNA mismatch repair system. These tumors accumulate a high number of mutations, especially small insertions and deletions in repetitive genomic areas called microsatellites. The ARID gene family comprises 15 members, including a known tumor suppressor gene ARID1A. We utilized exome sequencing data of 25 MSI CRCs and their corresponding normal tissues and identified 12 of the ARID genes to display mutations with a frequency of 4-52%. Four genes were selected for further analysis in 21 additional MSI CRCs. We found that, in addition to ARID1A, also ARID1B, ARID2, and ARID4A were frequently mutated and might play a role in MSI CRC. However, additional studies are warranted to further scrutinize the function of these mutations in MSI CRC genesis. The second aim of the thesis was to identify novel oncogenes in MSI CRC. These tumors represent a sensitive system for studying the generation and selection of oncogenic mutations. In contrast to many reported MSI target genes, few oncogenes are known in MSI CRC and they often display specific mutation hotspots. Thus, we used the exome sequencing data of 25 MSI CRCs and their corresponding normal tissues to search for genes with recurrent somatic missense mutations. We identified 33 novel candidate oncogenes of which the following fourteen genes displayed hotspot mutations also in the validation set of 254 MSI CRCs: ANTXR1, CEP135, CRYBB1, MORC2, SLC36A1, GALNT9, PI15, KRT82, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1, and TTPAL. This work revealed a variety of novel recurrent candidate oncogene mutations that might potentially be used to develop personalized therapies. Further research is still needed to confirm their pathogenic role and detailed function in tumorigenesis. The third aim of the thesis was to study the genetic overlap within synchronous CRCs (SCRCs). Approximately 4% of CRC patients display multiple simultaneous primary cancers in the colorectum. Understanding whether SCRCs within a patient are genetically similar or distinct is essential when designing personalized treatments. Exome sequencing data of 23 SCRC pairs and their corresponding healthy tissues revealed that the paired tumors shared a maximum of only a few somatic mutations. This indicated that the tumors have independent origins. Furthermore, paired tumors favored different somatic mutations in known CRC genes and signaling pathways. Variation was observed among clinically relevant genes, such as the discordant KRAS mutation status in a quarter of patients. Tumors within pairs also displayed variation in their mutational signature content suggesting that, regardless of the shared environment, some pairs might have undergone different mutational processes. Finally, by analyzing immune cell counts, we observed that the intratumor immune response varied within most tumor pairs. This was not explained by mutation burden or clinicopathological variables. Overall, this work revealed major diversity within SCRCs and highlights the need to evaluate all synchronous lesions within an individual for optimized therapeutic approach. Additional studies are still required to further elucidate the reasons underlying tumor multiplicity. The fourth aim of the thesis was to characterize the somatic mutation content in SBA. Due to its rarity, knowledge on the genetic background of SBA has remained somewhat elusive. We conducted the first large exome sequencing effort of 106 population-based SBAs representing all three small bowel segments. This work revealed significantly mutated genes previously associated with SBA (TP53, KRAS, APC, SMAD4, and BRAF), as well as novel candidate drivers, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We identified clear mutation hotspot patterns in ERBB2 and BRAF. Interestingly, we observed no V600E mutations, the most common BRAF mutation hotspot in CRC. Other clinically relevant aspects included mutations in ERBB family genes in over a quarter of SBAs as well as mutations in multiple genes that could predict anti-EGFR treatment resistance. We performed the first comprehensive mutation signature analysis on SBA that highlighted four signatures: 1A, 6, 17, and U2. Comparison of the three small bowel segments unveiled some variation in tumor characteristics. Further studies are needed to robustly clarify these differences and their clinical relevance. This comprehensive characterization provided further evidence that SBA is a distinct tumor type and singled out many potential therapeutic targets that could be utilized in SBA treatment development.
  • Evälahti, Marjut (Helsingin yliopisto, 2020)
    The amount, velocity, timing, and sensation of growth of the craniofacial complex are of interest to clinicians, researchers, and individuals alike, with different populations around the world exhibiting variation. The aims of this study were: to generate population-standard values for craniofacial growth and development in Finns from 4 to 25 years of age as well as to investigate population-specific features regarding growth timing and velocity. This work was based on the prospective Helsinki Longitudinal Growth Study conducted between 1967 and 1994. At the end of the study, when the subjects were examined as a group for the last time, 190 participants, young adults at the time, had remained in the study. Most of them were then aged 24 to 25, the youngest ones being 19 to 20 years of age. After the exclusion of children treated for orthodontics, 105 subjects, 50 boys and 55 girls, formed the final study group of untreated healthy individuals. The present study is based on 551 cephalograms taken from these individuals between the ages 4 to 25 years. This equated to 3 to 8 lateral skull radiographs of each child, with an average 5.2 radiographs per child. These radiographs were analyzed with a computer program specially developed for this study. Tables, growth curves, growth velocity curves, and change curves were created for reference values of Finnish children to describe their size, shape, dimensions, and respective changes. Findings are that Finnish children have a strong closing growth pattern and square facial form when compared to those of other populations, notably British children. Sexual dimorphism appeared in the findings, with males showing more pronounced closing in their pattern of growth and a more distinct mandibular pubertal growth spurt than females. Late or residual growth between ages 20 and 25 years occurred in many variables, especially in males. It is hoped that these data will be useful to clinicians, researchers, and individuals as a reference sample for Finnish normal craniofacial growth.
  • Savolainen, Irina (Helsingin yliopisto, 2020)
    People who can not speak may use different communication aids, such as communication books (CB) and speech-generating devices (SGD), for replacing their lack of speech. The communication aids effect non-speaking and speaking participants’ practices in conversations. Within the framework of conversation analysis (CA), this dissertation follows four aided communicators between the ages of 7 and 18 years old and examines their conversations with their mothers, peers, and speech-language therapists. The focus is on the participants’ co-construction practices and the social action of turns produced by CBs or SGDs. The database consists of 21 video-recorded conversations, in which the participants engage in a typical interactive situation without a specific goal and discuss their topics of choice. The present study aims to extend our understanding of the co-construction process in aided conversations. As logopedic research (speech-language therapy), the aim is also to offer implications that aided communicators and their partners could utilize to facilitate their conversations. Each of the three original studies of this dissertation focus on the progress of aided conversations during the participants’ co-construction process. The research phenomena are turn-transitions, participants’ multimodal practices, and several interactional resources for co-construction of the social actions. The data proved to be a unique possibility to study mostly fluent aided conversations, in which aided communicators were active participants. It offers a view of the essential features of successful aided conversations, such as slowness, the co-constructed nature, and the role of the communication aid. The current study also shows how several aided communicators’ affect the flow of conversations by using many means similar to their speaking partners. The synthesis of the three studies’ results, as well as those of previous studies, offer an overall view of the co-construction process of aided turns. The co-construction model and the different structures of multimodal turns help us to see how aided and spoken conversations differ. The critical points are the transitions between turns and symbols and participants’ practices in coping with insufficient linguistic and prosodic resources of aided turns. The results illuminate participants’ multimodal and synchronized actions during transitions and their practices in utilizing several interactional resources in the co-construction of social actions. The present study also demonstrates how the concept of aided conversation is a general term that can refer many kinds of interaction. The amount of co-operation that aided conversations demand depends on, for example, the communication aid and the form of utterance. Aided conversations are often (but not always) slower than spoken conversations. The long silent moments, however, do not mean that conversations are not proceeding, or participants consider them to be a challenge. The results of the current study are useful for video-assisted guidance in speech-language therapy, during which aided communicators and their partners observe and develop their conversational practices. It offers a list of questions that are useful for video guiding. The large scope of the present study helps to point toward gaps in the present knowledge of aided conversations and give ideas for future research.
  • Sarajuuri, Jaana (Helsingin yliopisto, 2020)
    Traumatic brain injury (TBI) has a critical public health impact worldwide because of its high incidence, prevalence, and socioeconomic consequences. The common neuropathology following TBI contributes to a myriad of diverse interacting impairments in cognitive, behavioral, emotional, and motor functioning. Many people with TBI experience ongoing long-term, lifelong and also evolving symptoms that impact their general health, psychosocial outcomes, and overall well-being. Over the last three decades, standards of care, rehabilitation interventions, and research for TBI patients have developed, yet robust evidence for effective practices and evidence-based guidelines do not exist for most interventions. The effectiveness of postacute neuropsychologically oriented multidisciplinary comprehensive-holistic rehabilitation programs (CHRPs) in enhancing psychosocial adjustment and outcome has been supported by several studies, but controlled studies are scarce. Moreover, there is a shortage of research examining the associations between cognition and motor functions, particularly in patients with TBI, although such associations may have clinical implications for neurorehabilitation. Recently, awareness has increased of the need to supplement rehabilitation outcome assessment of TBI patients by subjective measures, which may have important implications for the allocation of different rehabilitation interventions and to enhance outcomes. The studies of this thesis investigated the psychosocial outcomes of an application of CHRP (Study I) and the relationship between the objective outcomes and their subjective self-appraisals in adults with postacute TBI (Study III) as well as the association between cognitive and motor functions for benefits in multidisciplinary neurorehabilitation after TBI (Study II). In Study I, the productivity of 19 consecutive adult patients with postacute moderate to severe TBI who underwent CHRP in a nationwide neurorehabilitation center setting was compared with that of 20 matched controls who received conventional clinical care and rehabilitation. After a six-week CHRP, the patients were followed up for two years and then evaluated for long-term outcome. The status of their productivity was judged as productive (defined as working, studying, or participating in volunteer activities) or nonproductive by two blinded and independent raters, and evaluated with structured questionnaires filled in by the patients and their significant others. In Study II, cognitive and motor functioning of 34 physically well-recovered men with postacute moderate to severe TBI was assessed. Cognitive functioning was measured in the domains of information processing, attention, and executive functions, particularly in regulation of voluntary movements. Motor performance was measured in postural balance, agility, and gross motor rhythm coordination. Study III comprised 54 adults with chronic moderate to severe TBI who had resumed working at various levels of competence following CHRPs running in two neurorehabilitation centers in two countries. The objective outcome measure was the level of work competence that participants had attained postrehabilitation. The subjective outcome measure was participants’ subjective self-appraisal of their rehabilitation outcomes by rating six measures: effort during rehabilitation, meaning in life, productivity, acceptance, social life, and intimate relationships. Study I showed that at the end of follow-up 89% of patients in the CHRP group were productive compared with 55% of controls. CHRP was found to be significantly predictive of a productive status at follow-up, and other factors did not explain the better productivity of the CHRP group. Moreover, the findings of Study III indicated that the levels of work obtained after a CHRP were not associated with the areas of subjective self-appraisals other than the ability to establish intimate relationships. Overall, the patients were found to be largely satisfied with the areas of wellness after CHRPs. The explorative Study II analyzing the relationship between cognitive and motor functions in postacute TBI found associations of measures of information processing, attention, and executive functioning with agility and dynamic balance. The fluency of information processing and executive functioning was reflected in the speed of walking/dynamic balance and running, and vice versa. The present results give evidence that the CHRP approach improves outcomes for individuals with moderate to severe postacute TBI even many years after injury (Studies I and III). The findings support the presumption that CHRPs facilitate achievement of a successful outcome through establishing a meaningful and satisfactory life after TBI in the face of persisting deficits. In line with the few previous studies, the findings of Study II support the interplay between cognition and motor performance supporting the possible multimodal effects of TBI rehabilitation and encouraging use of comprehensive multidisciplinary neurorehabilitation to enhance outcomes. Finally, the results of Study III are consistent with earlier studies that have noted a dissociation between functional outcomes and subjective well-being, especially in chronic TBI. Community functioning and the related satisfaction seem to be distinct aspects of participants’ experience that must be considered in the evaluation of rehabilitation outcomes following TBI. These findings may have implications for rehabilitation service provision and allocation, encouraging a move towards CHRP models in rehabilitation of individuals with TBI to improve their psychosocial outcomes and subjective well-being.
  • Heinonen, Annu (Helsingin yliopisto, 2020)
    Cervical cancer is the fourth most common cancer in women worldwide. It develops through precancerous stages that can either regress spontaneously or progress into cancer. Human papillomavirus (HPV) infection is a necessary but not alone sufficient factor in development of cervical cancer. Almost 200 HPV types have been identified and 13 of them are considered high-risk oncogenic types for cervical cancer. The prevalence of HPV is highest among young women and most infections are transient. Persistent infection may lead to precancerous lesions called cervical intraepithelial neoplasia (CIN). Efficient screening programs with effective treatment of the precancerous lesions prevent 80 % of cervical cancer. Treatment of CIN aims to remove or destroy the lesion. This is most commonly done in an outpatient setting using a Loop Electrosurgical Excision Procedure (LEEP), in which an electrically charged loop wire is used to excise the lesion. The treatment is efficient but also has adverse effects on reproductive health. After treatment for CIN, women remain at a higher risk for recurrent CIN or cervical cancer for at least 20 years and need proper follow-up. The aim of this thesis was to provide extensive information on the treatment of CIN: its adverse reproductive effects, post-treatment follow-up and the psychological burden and Quality of Life. LEEP has been associated with an increased risk for preterm birth. In our studies, we wanted to clarify this association further and assess the role of CIN itself. We studied the effect of severity of CIN and the time between LEEP and subsequent birth. In both studies regarding preterm birth, we formed large study cohorts using data from the Hospital Discharge Register (HDR) and the Medical Birth Register (MBR). In the first study the study population had 547 (7.2%) preterm singleton births compared to 30151 (4.6%) in the control population (OR 1.61, 95% CI 1.47–1.75). Repeated LEEP increased the risk almost threefold. The risk for preterm birth did not increase with increasing severity of CIN and the time between LEEP and subsequent delivery did not affect the risk for preterm birth. In the second study, we included women diagnosed with CIN1 and compared preterm birth rates among women with LEEP to those not treated. We also compared both groups to the general population (MBR) and each woman’s deliveries before and after their CIN1 diagnoses. The risk for preterm birth was increased among women treated with LEEP for CIN1 compared to those in the MBR (OR 1.45, 95% CI 1.02–1.92). For CIN1 patients not treated with LEEP, the risk for preterm birth was not increased compared to women in the MBR. The risk for preterm birth was also increased after CIN1 diagnosis and LEEP (OR 1.47, 95% CI 1.05–2.06), whereas after only CIN1 diagnoses without LEEP, the risk was not increased (OR 0.90, 95% CI 0.71–1.13). There was no significant difference in the risk of preterm birth when comparing CIN1 patients with treatment to CIN1 patients without treatment (OR 1.31, 95% CI 0.94–1.83). Adjustments did not change the results. We also repeated analyses for primiparous and multiparous deliveries, but it did not change the results. In Finland, colposcopy is still widely used in the follow-up of women after treatment of CIN. This consumes both time and resources. We wanted to study the role of colposcopy in post-treatment follow-up and assess different tests as predictors of treatment outcome. The study was part of a large prospective trial at the Helsinki University colposcopy unit. In this study the study population consisted of 419 women with LEEP for high-grade lesion and a follow-up visit six months after treatment. Overall, 2.4% of cases developed a recurrent disease. Colposcopy was a poor indicator of recurrence among these women (Sensitivity 0%, specificity 97%, PPV 0% and NPV 98%) and should be omitted in the primary follow-up. High-risk Human Papilloma virus (hrHPV) performed best with a sensitivity of 100%, a specificity of 85%, an NPV of 100% and a PPV of 12%. The negative psychological effect of abnormal cytological findings and consequent examinations is widely acknowledged. We studied the general Health-Related Quality of Life (HRQoL) in women referred to colposcopy for abnormal cytology, and we further assessed different dimensions of their HRQoL and anxiety with questionnaires. The study comprised a prospective arm of patients from everyday clinical practice (n=238) and a retrospective arm where women treated eight years earlier were sent questionnaires (n=208). The general HRQoL score was not significantly different in patients than in the general population, meaning no effect on general HRQoL. However, patients scored significantly less on mental dimensions of the HRQoL tool. The severity of lesions did not affect results, but the negative psychological effect persisted for the 12-month follow-up period. In the retrospective arm, HRQoL was similar in patients and the general population except for a mildly lower score on the dimension of sexual activity. In conclusion, our results are in line with previous studies confirming that LEEP is associated with an increased risk for preterm birth. Severity of the lesion or time between LEEP and subsequent birth had no effect on the increased risk. Colposcopy should be omitted in the follow-up of women after treatment for CIN, and hrHPV has been proven to be a reliable tool in detecting women at risk for recurrent disease. Our study confirms the psychological burden of abnormal cytology and referral to colposcopy. The general HRQoL was not affected in our study.
  • Halavaara, Mika (Helsingin yliopisto, 2020)
    Diagnosis and treatment of bloodstream infections (BSIs) and infective endocarditis (IE) remain a challenge to treating physicians. Determining the microorganisms responsible is of major importance. New microbiological methods have emerged in the diagnosis of these entities with blood cultures remaining as a cornerstone. Changing epidemiology of IE and its risk groups pose a challenge to their treatment. BSIs and IE both contribute to a major morbidity and mortality. Hence, optimal treatment of these entities is imperative. Study I evaluated the impact of new microbiological method, short incubation matrix assisted laser desorption/ionization time-of-flight mass spectrometry (si-MALDI-TOF), on the antimicrobial treatment of BSIs caused by Pseudomonas aeruginosa, Enterococcus spp. and AmpC-producing Enterobacteriaceae when introduced into a routine clinical setting. Patients were treated at Helsinki University Hospital (HUS) between February 2014 and March 2015. A total of 124 BSI episodes were included. In 69 episodes si-MALDI-TOF identified the causative agent and in 55 episodes conventional identification methods were used. Identification by si-MALDI-TOF lead to 12.8% increase in episodes in which patients received appropriate antimicrobial treatment within 48 hours after the blood culture draw, which was the primary endpoint. In BSIs caused by Enterococcus spp. (n=62) the observed increase in appropriate antimicrobial treatment was 22.4% (87.9% vs 65.5%, P=0.038). In a subgroup of patients with immunosuppression si-MALDI-TOF method was observed to offer a significant benefit. Implementation of si-MALDI-TOF into a routine clinical setting was associated with an increased proportion of patients with appropriate antibiotic treatment within 48 hours after blood culture draw, especially in case of enterococcal BSIs. Study II explored bacteremia in patients with complicated skin and skin structure infections (cSSSI) in a population-based study including 460 patients with cSSSI from Helsinki, Finland and Gothenburg, Sweden. Blood cultures were positive in nearly one-fourth of those 258 patients from whom they were obtained. Diabetes, symptom duration less than two days and higher CRP level were associated with more frequent blood culture sampling, whereas surgical wound infection and peripheral artery disease were associated with less frequent blood culture sampling. None of the factors associated with blood culture drawing were found to be associated with blood culture positivity. Alcohol abuse was the only distinct patient characteristic associated with blood culture positivity. Patients with bacteremia had antibiotic treatment streamlined more often compared to non-bacteremic patients, which demonstrates a clear benefit of the information acquired from positive blood cultures. Given the high percentage of bacteremia amongst those from whom blood was cultured, difficulties in predicting patients with bacteremia and benefit of the information acquired from positive blood cultures, clinicians should order blood cultures from patients with cSSSI with low threshold. Study III evaluated the impact of pre-operative antimicrobial treatment duration on the yield of valve cultures and bacterial 16S PCR obtained during surgery for IE and the diagnostic value of PCR. The study cohort included 87 surgically treated IE patients from HUS between years 2011-2016 and from whom valve culture and PCR sample from resected endocardial material were obtained. None of the patients with preoperative antimicrobial treatment duration longer than two weeks had positive valve cultures. PCR positivity was 91% in those patients with antimicrobial treatment duration less than two weeks and 53% in those with more than two weeks. In PCR positive cases preoperative antimicrobial treatment duration was significantly shorter than in PCR negative cases. PCR sampling had a diagnostic impact in one-sixth of the cases. Pre-operative treatment duration was shown to have a negative effect on the yield of both valve cultures and PCR. PCR sampling had added diagnostic value, especially in blood culture negative cases. Study IV was a population-based study including all adult patients diagnosed with IE in Helsinki University Hospital Area between 2013 and 2017. The objective of this study was to describe the epidemiology, the spectrum of the microorganisms responsible for IE, clinical picture and the treatment and outcome of IE in the study region. Another objective was to determine the proportions of IE episodes according to the source of infection (i.e., mode of acquisition) and to define the characteristics of these groups and compare their differences. In all, 313 episodes of IE originating from 291 patients were included in the study cohort. Staphylococcus aureus was the leading cause accounting for one-third of the cases, followed by viridans group streptococci and Enterococcus spp. Equal proportions of community-acquired IE, health care-associated IE and drug use-related IE were observed, each accounting about for one-third of the cases. Distinct features of these entities were described and also different outcomes. Health care-associated IE was associated with more underlying diseases, prosthetic valve involvement, enterococcal etiology and higher mortality than community-acquired IE. Intravenous drug use-related IE was associated with more frequent right-sided and bilateral involvement, Staphylococcus aureus as etiology but no difference in mortality compared to community-acquired IE. High proportion of health care-associated IE and intravenous drug use-related IE pose a challenge for treatment, but also an opportunity for selected preventive strategies. In areas with common drug use, concomitant IE may account for a substantial proportion of all IE episodes, equal to that of health care-associated IE.
  • Jansson, Anu (Helsingin yliopisto, 2020)
    Loneliness increases the risk of admission to long-term care facilities and is associated with various adverse health outcomes. In previous studies the prevalence of loneliness has been even higher in these settings than among community-dwelling older people. Despite the adverse health outcomes, loneliness has received surprisingly little attention in long-term care facilities. The aim of this study was to explore loneliness in long-term care facilities: its prevalence, associated factors and prognosis (Study I), as well as temporal trends over time (Study II). The aim also included exploration of how loneliness was experienced by older people in long-term care facilities (Study III). Furthermore, we aimed to assess the effectiveness of a group intervention process among lonely residents in long-term care facilities (Study IV). In addition, we aimed to investigate how this group model, “Circle of Friends” (CoF) has been implemented over ten years in Finland, and what is its fidelity and feasibility (Study V). The current work involved the use of both quantitative and qualitative methods complementing each other in order to explore loneliness. Cross-sectional interviews and assessments (Study I) among all residents (n=2072) in Helsinki long-term care facilities explored the prevalence of loneliness, its associated factors and prognostic significance over a 3.6-year follow-up period. Repeated cross-sectional interviews and assessments (Study II) in 2011 and 2017 among all residents (n=1563 and n=1367, respectively) in Helsinki long-term care facilities were used to explore the temporal trends of loneliness. Loneliness was inquired about thus: “Do you suffer from loneliness?” (seldom or never/sometimes/often or always). In both studies participants with severe dementia were excluded. The associated factors explored included demographic factors, diseases, functioning, psychological well-being (PWB) and nutrition (MNA). The qualitative studies (Studies III and IV) involved a multi-method approach among six cognitively impaired (MMSE score 15–23) and seven cognitively intact participants. Individual and focus-group interviews, observations on CoF group processes, and group facilitators’ field-diaries were used as data. Study V was based on survey data collected from participants (n=1041) and facilitators (n=319) of the CoF group intervention in Finland in 2006−2016. In Study I, 35% of the respondents suffered from loneliness at least sometimes. Loneliness was associated with poor self-rated health, dependency in activities of daily living and mobility, higher cognitive function and poor psychological well-being. Loneliness predicted mortality. In Study II there was no change in the prevalence of loneliness over time in cross-sectional samples in 2011 and 2017: propensity score-adjusted loneliness was 36% at both time points. Feeling depressed was the only independent variable associated with loneliness in a multivariate logistic regression model. The prevalence of loneliness among respondents feeling depressed was 55%, and among those not feeling depressed, 24%. Study III gave voice to older people who suffered from loneliness and described their experiences. Loneliness proved to be a severe and idiosyncratic experience, anchored in time and location of the long-term care facilities. The respondents described loneliness in varied ways, richly, often using figurative metaphors. Loneliness was dependent on time of day, day of the week, and season. Passing lonely time was meaningless and full of waiting, stagnation and nothingness. In place-dependent loneliness, respondents felt mentally homeless: none of them named their apartment as home, but instead they used coarse descriptions, such as hospital or prison. The respondents had to spend long periods of time in their apartments and their desire to get out, get away from their loneliness, was not met. Respondents felt themselves invisible, and others in the facilities unknown, distant; some even unapproachable. A facilitated CoF group process (Study IV) with clear progressing steps, meaningful activities and mutual interaction revealed lonely older people’s capability to groupwork, despite their frailty and cognitive impairment. Loneliness was reflected upon and ventilated among peers in versatile ways. The goal-oriented group acknowledged participants’ own expectations and made them visible. The group empowered the participants to self-direction, which in the cognitively impaired happened sooner than in the cognitively intact. Study V showed that facilitators of older people’s CoF groups have maintained the key elements, objectives and structure of the original model over ten years. CoF training has been essential in achieving its aims: alleviation of loneliness and participants’ continuing meetings on their own in a high proportion of participants. Of the facilitated groups, 67% continued on their own after the official group meetings. It seems that this model is beneficial and also feasible in long-term care facilities, along with rigorous training of the professionals. Loneliness among older people in long-term care facilities is linked to health, well-being and mortality. It should be recognized in a work routine by asking about and documenting experiences. Interventions and their means should address loneliness in long-term care facilities. To be heard, feel visible, be connected, socially attached to the place, and recognized as persons should be a priority in daily practices in long-term care facilities. Older people in these facilities have faced a major event in their recent past, moving from a “real”, meaningful home. Many older people are also aware of another major event in the near future, approaching death. It is obvious that the time remaining should be made as good as possible. Knowing the harmful effects of loneliness, it is the ethical duty of professionals to prevent and alleviate it.
  • Leo, Vera (Helsingin yliopisto, 2020)
    The prevalence of stroke increases in the ageing population entailing an enormous economic and societal burden. This has raised the need for motivating, effective and easily applicable rehabilitation tools to enhance recovery and neuroplasticity. Music is an important source of enjoyment and well-being across life and it provides a multidomain stimulus that is both pleasant and rewarding, and engages the brain extensively. Previous evidence suggests that daily music listening can enhance cognitive recovery and mood and induce functional and structural neuroplasticity changes after stroke. Songs may also function as a verbal learning aid in healthy subjects. The aim of this thesis was to further explore the specific role of vocal (sung) music as a tool to aid verbal learning and long-term recovery after stroke. In Studies I and II, stroke patients (N = 31) performed a verbal learning task where novel narrative stories were presented in both spoken and sung formats, and underwent MRI at acute and 6-month post-stroke stages. Study I showed that stroke patients, especially those with mild aphasia, learned and recalled the stories better when they were presented in sung than spoken format at the 6-month stage. Exploring the cognitive and neural mechanisms underlying this effect, Study II further showed that non-aphasic patients exhibited more stable recall, indicated by reduced serial position effects, whereas aphasic patients showed a larger recency effect and enhanced chunking in the sung than spoken task. Diffusion tensor imaging and voxel-based morphometry results indicated that these effects were coupled with greater volume of the left arcuate fasciculus in non-aphasics, and with greater volume of the right inferior fronto-occipital fasciculus and grey matter in a bilateral network of temporal, frontal, and parietal regions in aphasics. In Study III, data was pooled from two randomized controlled trials where stroke patients (N = 83) received an intervention involving daily listening to self-selected vocal music, instrumental music, or audiobooks during the first three months after stroke. The recovery was assessed with neuropsychological tests and a mood questionnaire at acute, 3-month and 6-month stages, and structural MRI and functional MRI (fMRI) at acute and 6-month stages. Compared to audiobooks, listening to music enhanced the recovery of language skills and verbal memory and reduced negative mood. Vocal music had the strongest rehabilitative effect on both language and verbal memory, and the positive effects of music listening on language recovery were seen especially in patients with aphasia. Results from voxel-based morphometry and resting-state, and task-based fMRI analyses showed that vocal music listening selectively increased grey matter volume in left temporal areas and functional connectivity in the default mode network from acute to 6-month stage. The findings of the present thesis provide further evidence that listening to vocal music is a useful tool to support cognitive and emotional recovery after stroke and to enhance early language recovery in aphasia. The rehabilitative effects are driven by both structural and functional plasticity changes in temporoparietal networks, which are crucial for emotional processing, language and memory.
  • Ortiz, Rebekka (Helsingin yliopisto, 2020)
    Dystonia is a movement disorder with distinguishable abnormal postures and movements. However, the non-motor symptoms are now being understood to be part of the disease. Deep brain stimulation (DBS) has established as secondline treatment for the medically refractory dystonia. In this dissertation, the prevalence, comorbidities and retirement in dystonia was assessed in the years 2007-2016 in Finland. Moreover, the utilization of DBS in dystonia was evaluated. The contact prevalence of adult onset isolated dystonia was 405 per million. Especially the prevalence of adult-onset isolated cervical dystonia (CD) was high being 304 per million. The prevalence of other dystonia types varied from 1-33 per million. The highest prevalence within mainland Finland was recorded in its eastern parts. The good coverage of patients in the study might account for the difference, but genetic or exogenous geographical factors cannot be excluded. Altogether 585 DBS operations were made in the studied period, 37 of them with a dystonia indication. The motor scores had improved 55% on average at twelve months. The most common adverse events were postoperative infections. The role of DBS in dystonia as a safe and effective treatment was reinforced. However, the number of operations was relatively small and performed during a late stage of illness. DBS should be offered as a treatment more frequently. Anxiety and depression were the most prominent comorbidities in CD. However, their prevalence was less than expected, and it is likely that they are underdiagnosed in CD. The working ability in CD is reduced causing earlier retirement and the co-occurrence of psychiatric diseases that further emphasise the difference. More health-care resources should be devoted to support the working ability of CD patients. The active screening of non-motor symptoms, particularly the psychiatric comorbidities in CD treatment should be emphasised.
  • Viljakainen-Diop, Jannina (Helsingin yliopisto, 2020)
    Healthy eating habits, such as the consumption of fruits and vegetables and eating regular meals, reduce the risk of being overweight and obese in childhood as well as other noncommunicable diseases. However, eating habits have been examined only to a limited extent in Finland, such that further and updated information on eating habits and body mass is needed among adolescents. Healthy eating habits maintain health. Moreover, dietary choices and food timing shape the gut microbiota, although less is known about their relevance to saliva microbiota. This study aims to: 1) identify the eating habits of Finnish adolescents; 2) examine the associations between eating habits and body mass; and 3) examine the associations between eating habits and the saliva microbial diversity and composition. The study dataset consisted of 9- to 14-year-old Finnish adolescents participating in the Finnish Health in Teens (Fin-HIT) study between 2011 and 2014. Study I and study II consisted of 10 569 participants from 496 schools in 44 municipalities in southern, middle, and northern Finland. Study III included 842 randomly selected participants from the Fin-HIT study. These participants answered a web-based questionnaire on an electronic tablet. The questionnaire assessed lifestyle factors, such as diet and eating-related health behaviours. Participants also provided unstimulated saliva samples and trained fieldworkers measured their height and weight in a standardised way in school. Measurements used to calculate body mass index (BMI). BMI was categorised as underweight, normal weight and overweight or obese. The results from the current study identified three eating habit groups in adolescents: ‘healthy eaters’ (4 661; 44.1%), ‘unhealthy eaters’ (1 298; 12.3%) and ‘fruit and vegetable avoiders’ (4610; 43.6%). Healthy eaters most frequently ate a regular breakfast and other meals (lunch and dinner) and had parents with a high education level. Unhealthy eaters, however, most frequently ate breakfast and other meals irregularly and had parents with a low education level (study I). Avoiding fruits and vegetables was associated with a high risk of being underweight. Eating breakfast irregularly was associated with a high risk of being overweight and obese and a decreased risk of being underweight. Similarly, eating dinner irregularly was associated with a decreased risk of being underweight (study II). More diverse saliva microbiota composition was observed among regular breakfast eaters compared to irregular breakfast eaters. Similarly, a tendency for a higher diversity in the saliva microbiota was found among regular dinner eaters compared to irregular dinner eaters. More specifically, Prevotella was highly abundant among fruit and vegetable avoiders and irregular breakfast and dinner eaters (study III). The results presented here on eating habits emphasise that more attention must be devoted to adolescents’ eating habits, particularly to those who avoid fruits and vegetables and those who irregularly eat meals since they are at high risk for adverse health outcomes, such as being overweight and obese. Futhermore, the results here on eating habits and body mass will assist public health personnel in guiding adolescents regarding how to maintain a normal weight. The association between avoiding fruits and vegetables and eating irregular meals, respectively, and the abundance of Prevotella in saliva warrants further studies on Prevotella and eating habits.
  • Kasurinen, Aaro (Helsingin yliopisto, 2020)
    Gastric cancer is the second most common cause of cancer-related mortality worldwide. The poor prognosis largely results from late diagnosis, often occurring when disease is already at an advanced stage. At the time of diagnosis, treatment with curative intent is possible for less than half of all patients. Currently, the only curative treatment is radical surgery. Despite the decreased incidence of gastric cancer in developed countries given changes in lifestyle and the treatment of Helicobacter pylori (H. pylori) infection, prognosis remains poor. More precise knowledge regarding the underlying pathophysiology is needed in order to allow for earlier diagnosis and to improve prognosis. Chronic inflammation of the gastrointestinal tract mucosa predisposes individuals to cancer with several proteins contributing to the crosstalk between inflammation and cancer. Matrix metalloproteinases (MMPs) can promote cancer cell invasion and metastasis by degrading the extracellular matrix. In previous studies, a high expression of matrix metalloproteinase 14 (MMP14) associated with metastasized gastric cancer and a poor outcome. Prospero homeobox protein 1 (PROX1) is a transcription factor functioning in cell fate determination and organ development, and also expressing in various cancers. PROX1 acts context dependently either as an oncogene or as a tumor suppressor. PROX1 was recently shown to inhibit the transcription of MMP14 in several cancers, although it was not examined in gastric cancer. Toll-like receptors (TLRs) are pattern recognition receptors essential to innate immunity. They express in malignant diseases, activated by damage-associated molecular patterns. Tumor-associated trypsin-2 (TAT-2) and its inhibitor, tumor-associated trypsin inhibitor (TATI), can promote carcinogenesis by activating endothelial growth factor receptors, pro-urokinase, and MMPs. In addition, C-reactive protein (CRP) is a well-known and widely used inflammatory biomarker. Elevated preoperative CRP levels have been attributed to a poor outcome in colonic, pancreatic, and gastric cancers. Therefore, this study aimed to evaluate the significance of these potential prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated on between 2000 and 2009 for histologically confirmed gastric adenocarcinoma in the Department of Surgery, Helsinki University Hospital, Finland. Preoperative blood samples were collected from 240 patients with gastric cancer and from 48 control patients with benign disease. Tissue MMP14, PROX1, TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 expression levels were studied using immunohistochemistry. Soluble serum MMP14 levels were determined using an enzyme-linked immunosorbent assay. Serum TAT-2, TATI, and plasma CRP levels were determined using time-resolved immunofluorometric assays. A high MMP14 expression, whether in tissue samples or serum, predicted a poor outcome and a high serum MMP14 remained an independent prognostic factor in the multivariate survival analysis. A high tissue MMP14 predicted an unfavorable outcome, particularly among those with a low PROX1 level. Furthermore, a high tissue TLR5 expression predicted a better outcome. We also found that TLR1, TLR2, TLR4, TLR7, and TLR9 did not serve as prognostic biomarkers across the entire cohort. Nevertheless, TLR9 served as a prognostic factor among those with stage II disease and TLR7 among those with stage III disease. High serum TAT-2 and TATI both identified patients with poor prognoses, with TATI remaining significant in the multivariate survival analysis. Moreover, serum TAT-2 levels were higher among patients with gastric cancer than among controls. Interestingly, preoperative CRP did not serve as a prognostic biomarker in this cohort of gastric cancer patients. None of the biomarkers studied are currently in routine clinical use in gastric cancer. However, this thesis shows that several of the biomarkers examined hold potential as prognostic factors in gastric cancer and represent promising candidates for further investigation. In conclusion, survival seems worse among gastric cancer patients with a high tissue MMP14 expression, particularly with concurrent low PROX1 levels. Thus, a high serum MMP14 may serve as an independent unfavorable prognostic biomarker. Survival appears better among patients with a high tissue TLR5 expression. Additionally, high tissue TLR7 and TLR9 expressions appear to serve as favorable prognostic biomarkers in certain subgroups. In addition, a high serum TATI may serve as an independent unfavorable prognostic factor. Lastly, serum TAT-2 levels appear higher among patients with gastric cancer than among controls and a high TAT-2 may serve as a marker of an unfavorable prognosis.
  • Viljakka, Timo (Helsingin yliopisto, 2020)
    Numerous surgical methods have been used in the treatment of Kienböck’s disease, methods based on either modification of the lunar load, improvement of the blood flow of the lunate, or are based on removal of the damaged lunate and its replacement by various materials. Recent steps have been total wrist arthrodesis and proximal row carpectomy. The etiology of the disease is still unclear, with little research available on the natural course. No reliable comparison has been presented of the different treatment methods, and treatment options are based on the re-sults with various therapies at different stages of the disease. The purpose of our study was to discover the results in long-term follow-up from three different surgical procedures and prognosis for untreated patients. Surgical treatments included silicone implant arthroplasty, SLA (53 patients), radial shortening osteotomy, RSO (16 patients), and titanium implant arthroplasty (11 patients); the untreated group comprised 8 patients. The studies were retrospective and non-randomized. RSO was done for ulna minus variance patients. The degree of disease was in all groups mainly Lichtman -Degnan stages IIIA-IIIB. The follow-up times were 27 years for silicone patients, 25 years for osteotomies, 11 years for titanium implants, and 18 years for untreated patients ( mean 27 years from onset of symptoms). In SLA the result was impaired by silicone-induced synovitis and bone cyst formation in 78% of patients. Revisions were maid for 22%. In osteotomies, the progression of the disease led to two revisions (12%) and four osteotomies (25%) had poor results. With a titanium implant, poor results were associated with two implant dislocations. Silicone-implant patients and untreated patients had the highest incidence of pain at rest and during exertion ( VAS during exertion 5.2 in both). Full pain-relief ranged from 0% (untreated) to -21% (osteotomy). Range on motion (ROM) and grip strength imp-roved in all groups but remained generally significantly worse than on the healthy side. In the osteotomy group, ROM (88%) and grip strength (95%) were the best. Radiological changes progressed in each treatment group. In silicone-patients, arthrosis existed in 91%, and our arthrosis index was the highest, 7.7/15. Wrist collapse increased as well. In osteotomies, arthrosis existed in 71% and for titanium-implant patients in 45% with an index of 4.4 in both. With untreated, arthrosis was in 89% and an index 5.4. However, untreated disease did not lead to severe arthrotic changes. Functional ability remained good according to the DASH score: in osteotomies 6.1, with titanium implants 9.6, and for those untreated 11.3, while in silicone-implant patients it was 25.4. The corresponding result was in terms of working ability: in silicone-implant patients, 21% were incapacitated and for osteotomies this was 7%. Of the untreated patients, 25% had switched to lighter work, as had 9% of titanium-implant patients. The results according to Mayo wrist scoring were similar, with the best score for osteotomies, 79, and the worst for silicone-implant patients, 54.8. Osteotomy yielded a clear benefit for 75% of the patients in long-term follow-up, although the failure rate was high, 25%. The functional result of untreated patients was moderately good, although their wrist degenerative changes increased. The result from titanium implant was skewed by two dislocations, and the operative technique currently do not completely eliminate this problem. Moreover, treatment indications require further attention. In future, prospective studies would be needed to better assess the role and importance of surgical treatments. Similarly, the natural course of the disease should also become better known, so that the actual effect of these treatment methods on the course of the disease would become clear.
  • Maasalo, Katri (Helsingin yliopisto, 2020)
    Emotional symptoms are symptoms of anxiety and depression that are included in the broad dimension of internalising symptoms encompassing feelings and behaviours such as fearfulness, worry, sadness, and withdrawal. Elevated levels of emotional symptoms are prevalent in children and often a precursor of adolescent and adulthood mental health disorders, such as major depression, one of the leading causes of disability in Finland and worldwide. The prevention of depression is a global challenge. Although major depression is a relatively rare condition in childhood, the more common emotional symptoms and subthreshold conditions of depression in childhood have been identified as possible targets for preventive action in the battle against depression. Results of studies involving adolescent participants suggest that examining the precursors of depression at the symptom level could aid in recognising individuals at risk for escalation to more severe disorders. Depressed mood, an emotional symptom that is one of the core symptoms of depression, has been associated with a future risk of psychopathology and may also cause current impairment, increasing the importance of early detection. However, there has not been much research on depressed mood in children. The present study examined the associations between emotional problems and depressed mood and three suggested risk factors for emerging, prolonging, and escalating emotional symptoms: inhibitory control, sleep problems, and co-occurring behaviour problems. The aim of the study was to provide data that would aid in the early recognition and prevention of emotional problems. Cross-sectional questionnaire data from the Strengths and Diffculties Questionnaire (SDQ) and the Quality of Life Questionnaire 17D were used in studies I–III, and the go/no-go task was used to assess children’s inhibitory control in the longitudinal study IV. The first study examined the prevalence of emotional problems and depressed mood in a population-based sample of 1,714 children aged 4–12. The associations of emotional problems and depressed mood with conduct problems and hyperactivity, as well as with child and family factors were also examined. In the population-based sample, 5.8% of the children had emotional problems and 16.0% had depressed mood. Both emotional problems and depressed mood were associated with sleep problems, illness or disability in children, and not living with both parents. Emotional problems and depressed mood were both significantly associated with conduct problems and hyperactivity. Of the emotional symptoms, depressed mood had the strongest association with both conduct problems and hyperactivity. The second study examined the prevalence of emotional problems and depressed mood in a child psychiatric outpatient sample of 862 children aged 6–12 and the associations of emotional problems and depressed mood with conduct problems and hyperactivity. The impact of depressed mood on children’s global functioning was also assessed. In the clinical sample, 13.1% of the children had emotional problems, and 59.4% had depressed mood. Emotional problems and depressed mood were signi􀂿cantly associated with conduct problems but not hyperactivity. Irrespective of diagnosis, depressed mood was consistently associated with poorer global functioning. The third study examined the associations of child-reported sleep problems and emotional symptoms in a child psychiatric outpatient sample of 432 children aged 6–12. Child-reported sleep problems were the most common among children with depression or anxiety, and sleep problems were significantly associated with depressive disorders. Even among children with attention-deficit/hyperactivity disorder or oppositional de􀂿ant or conduct disorder, sleep problems were associated with emotional symptoms, suggesting that child-reported sleep problems are indicative of subthreshold emotional problems in these children. The fourth study assessed the association between inhibitory control skills and internalizing symptoms in a sample of 2,874 children aged 7–9 using a longitudinal design with a statistical model that distinguishes within-person variance from between-person variance between the constructs. Over the course of the study, the association between inhibitory control and internalizing symptoms was explained at the between-person level. This 􀂿nding supports the hypothesis that among children at this developmental stage, inhibitory control and emotional symptoms are associated as trait-like constructs. However, no cross-lagged associations suggesting a potential causal relationship were found. The findings of these four studies suggest that depressed mood is associated with similar risk factors as emotional problems in general. When emotional problems are associated with conduct problems or hyperactivity, this association is mostly explained by depressed mood. The global functioning level was poorer among child psychiatric patients with depressed mood than among those with normal mood. The findings also suggest that when a child has a sleep problem, it is useful to evaluate the presence of emotional problems and depressed mood. The association between emotional problems and inhibitory control suggests they could have a shared background.
  • Jakkula, Pekka (Helsingin yliopisto, 2020)
    Aims The objective of this study was to determine the feasibility of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2), normoxia or moderate hyperoxia, and low-normal or high-normal mean arterial pressure (MAP) in comatose patients after out-of-hospital cardiac arrest (OHCA) and successful resuscitation. In addition, we assessed the effects of the two different levels of PaCO2, arterial oxygen tension (PaO2) and MAP on markers of neurological and myocardial injury, cerebral oxygenation, and epileptic activity. Moreover, we investigated the association between cerebral oxygenation and the extent of cerebral injury as assessed with markers of brain injury and neurological outcome. Materials and methods In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial with 23 factorial design, 123 patients resuscitated from OHCA with a shockable initial rhythm were randomly assigned to targeting low-normal (4.5–4.7 kPa) or high-normal (5.8–6.0 kPa) PaCO2, normoxia (PaO2 10–15 kPa) or moderate hyperoxia (PaO2 20–25 kPa), and low-normal (65-75 mmHg) or high-normal (80-100 mmHg) MAP during the first 36 h in the intensive care unit. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest (CA). Secondary endpoints included NSE concentrations at 24 and 72 h after CA; S100 calcium-binding protein B (S100B) and cardiac troponin T (TnT) concentrations at 24, 48, and 72 h after CA; clinically significant changes in continuous electroencephalography (EEG), results of frontal regional oxygen saturation (rSO2) measured with near-infrared spectroscopy (NIRS) during the first 48 h of intensive care; and neurologic outcome at 6 months (Studies II-III). In a post hoc analysis, we evaluated the association between frontal rSO2 and NSE concentration at 48 h, and the association between frontal rSO2 and good (Cerebral Performance Category [CPC] 1-2) and poor (CPC 3-5) neurological outcome (Study IV). In another post hoc analysis, we combined data from a subgroup of patients with acute myocardial infarction (AMI) and vasopressor dependent hypotension with data from a comparable subgroup of another trial (Neuroprotect) to evaluate the association between MAP and myocardial injury assessed with the area under the 72-hour TnT curve (Study V). Main results We observed a clear separation between the study groups in PaCO2, PaO2, and MAP during the 36-hour intervention period. However, there was no difference in serum NSE concentrations between the intervention groups at any of the studied time points. S100B and TnT concentrations, EEG findings, and neurological outcome at 6 months were comparable between the groups. High-normal PaCO2 and moderate hyperoxia significantly increased frontal rSO2, but MAP level did not. No significant association between frontal rSO2 and NSE or neurological outcome was observed. In a subgroup of patients with AMI and vasopressor dependent hypotension, combined from the two trials (COMACARE and Neuroprotect), myocardial injury was significantly lower in patients assigned to the higher MAP group. The risk of new-onset CA or arrhythmias was not increased despite significantly higher doses of noradrenaline and dobutamine in the higher MAP group. Conclusions Targeting low-normal or high-normal PaCO2, normoxia or moderate hyperoxia, and low-normal or high-normal MAP was feasible in comatose patients after OHCA and successful resuscitation. None of the studied interventions affected the extent of the developing brain damage as measured with biomarkers of neurological injury. High-normal PaCO2 and moderate hyperoxia resulted in increased cerebral oxygenation, but this was not associated with the extent of brain injury. In patients with AMI and vasopressor dependent hypotension, targeting a MAP between 80/85-100 mmHg was associated with smaller myocardial injury without clinically significant side effects.
  • Hartwall, Linnea (Helsingin yliopisto, 2020)
    Type 1 diabetes is an autoimmune disease caused by T-cell-mediated destruction of the insulin-producing beta cells of the pancreas. The exact mechanisms leading to type 1 diabetes are still mostly unknown, but genetic and environmental factors are involved. This doctoral study aimed at characterizing novel immune responses associated with the development of type 1 diabetes. We were interested in peripheral immunological responses in T helper cells. One environmental factor we focused on was vitamin D, since epidemiological data have associated it with type 1 diabetes and it has a direct effect on T cells. The aims of this study were to investigate the role of vitamin D during the fetal period for type 1 diabetes by analyzing first-trimester serum samples from mothers of healthy and diabetic children. A low concentration of serum 25-hydroxyvitamin D (25(OH)D) during the first trimester of pregnancy was not associated with type 1 diabetes in the offspring. Furthermore, we investigated the possible protective role of vitamin D in beta-cell autoimmunity in young children from Finland and Estonia, two countries differing in the incidence of type 1 diabetes, standards of living, and vitamin D fortification of foods at the time of the study. We did not find differences in the vitamin D status or active hormone levels (1,25-dehydroxyvitamin D (1,25(OH)₂D)) of vitamin D between the study groups. Estonian children had lower 25(OH)D concentrations than Finnish children, but their 1,25(OH)₂D concentrations were at the same sufficient level. Additionally, we investigated the timing of upregulation of T helper (Th)17 immunity and the role of Th17 plasticity in the development of type 1 diabetes in prediabetic children. Stimulated peripheral blood mononuclear cells (PBMCs) from children with multiple beta-cell autoantibodies and impaired glucose tolerance revealed upregulation of Th17 immunity and increased mRNA expression of interferon-γ (IFN-γ) and interleukin-9 (IL-9). These children also had higher IFN-γ mRNA expression in FACS-purified Th17 cells. We observed that Th17 immunity, and increased plasticity of Th17 cells is associated with advanced beta-cell autoimmunity and it correlated with clinical parameters. Finally, we examined peripheral cytokine, chemokine, and growth factor profiles in healthy children from Russia, Estonia, and Finland, countries with different incidences of type 1 diabetes and standards of living. We observed that Finnish children had a lower concentration of epidermal growth factor (EGF) and soluble CD40 ligand (sCD40L) in their blood. We observed higher mRNA expression of interleukin-22 (IL-22) in circulating memory T helper cells of Estonian children. We also noted that Th17 and Th1 immunity-related cytokines were upregulated in the blood of Finnish children. To conclude, vitamin D is not a direct protective factor in the development of beta-cell autoimmunity or type 1 diabetes. Th17 immunity and plasticity associate with type 1 diabetes disease progression from advanced beta-cell autoimmunity to clinical disease. These data may provide new tools for improved disease development monitoring, for identifying high-risk individuals and for developing disease-preventing methods. The low EGF and sCD40L levels in the blood of Finnish children may modulate the epithelium of the intestine and hence result in altered immunological responses favoring the development of immune-mediated diseases such as type 1 diabetes in Finland. Keywords: Type 1 diabetes, T cell, Vitamin D, Th17 immunity, Epidermal growth factor
  • Strandholm, Thea (Helsingin yliopisto, 2020)
    Background. Personality disorders (PDs) among depressed adolescents are common, but there is little research on how PDs impact the course of depression and the long-term development from adolescence into adulthood. The objective of this study was to examine the association between depression and PDs in a one-year follow-up of adolescents and in an eight-year follow-up from adolescence to adulthood, PD symptom change during adolescence, and the associations of PDs with defense mechanisms, social support, and comorbid psychiatric disorders among depressed adolescents. Methods. This study was part of the Adolescent Depression Study (ADS), a prospective, naturalistic research project. The sample comprised originally depressed adolescent outpatients (N=218) aged 13–19 years, who were interviewed and diagnosed at baseline and at six-month and one-year follow-ups using K-SADS- PL for DSM-IV psychiatric clinical disorders and SCID-II for PD diagnoses. The subjects were further assessed in an eight-year follow-up using diagnostic interviews (SCID-I and -II) and self-report scales, and observer-report rating scales were used at every assessment point. Results. Of the participants, 67% presented at least one depression recurrence. At the eight-year follow-up, 36% had a mood disorder, and anxiety (48%) and PDs (26%) were also frequent.Over half of the patients suffered from a mood disorder 25% or more of the follow-up time from adolescence into adulthood. If presenting with comorbid depression and PD, the short-term outcome in psychiatric treatment was worse. Treatment breadth did not impact positively on the outcome for depressed adolescents with a PD, but those without a PD gained from a larger variety of treatments. Decrease in both depression severity and comorbidity rate correlated positively with PD symptom decrease. Higher perceived social support was associated with a decrease in PD symptoms in the PD categories narcissistic, schizotypal, and paranoid. Immature defense mechanisms predicted PDs in adulthood, while mature defense style did not associate negatively with a later PD diagnosis. Displacement, isolation, and reaction formation were the strongest predictors of a PD in adulthood, all considered mental inhibitions. Conclusion. These results show the seriousness of depression in adolescence and its long-term impact on outcome. In patients presenting with a comorbid PD, the short- and long-term outcomes of depression were generally worse. Social support and thus the ability to connect with other people might impact clinical symptoms, higher perceived social support being a possible protective factor for symptoms. There was covariation between symptoms of PDs and other psychiatric symptoms, all clinically relevant in treatment planning. Adolescents with PD should be treated with specialized treatments for PDs. In line with earlier studies, the results suggest defense styles should be a focus in treatment planning and content. Also, attention should be directed to separate defenses, especially those having to do with mental inhibition.
  • Mattila, Mikko (Helsingin yliopisto, 2020)
    Structural changes in the spine are the most common children's musculoskeletal abnormalities, as they cover 70% of all musculoskeletal disorders in children and adolescent. Idiopathic scoliosis is the most common of these structural changes. The congenital structural problems of the spine form an entity of their own. Changes in the development of the spine during fetal period range from changes in individual vertebral to being part of a wider developmental disorder. Careful follow-up and research are the basis of care. Genetically induced syndromes form a wide heterogeneous group that have vertebral problems often seen in cervical development and growth. There are a number of rare diseases in this group. One of the primary aims of this thesis was to assess whether en bloc vertebral column derotation provides an efficient control or correction of thoracic rib hump as compared with no derotation in adolescents with an idiopathic scoliosis. The outcomes of hybrid and total pedicle screw instrumentation were compared in children undergoing surgery for neuromuscular scoliosis or severe scoliosis. Within the rare bone dysplastia group, we studied the outcomes of upper cervical spine fusion in this heterogeneous group.We showed that en bloc derotation provides an effective initial correction of the rib hump,but the effect diminishes during two year follow-up. Comparing hybrid technique with total pedicle screw method we proved that surgery with pedicle screw technique is more effective in correcting neuromuscular and severe scoliosis. Blood loss was significantly smaller (2000 ml) and patients had better major curve correction (two year follow-up 75% vs 59%) with less need for anteroposterior surgery when comparing these techniques in the neuromuscular group. Pedicle screw instrumentation provided shorter operative time (1 hour 39minutes), diminished blood loss(1600ml), enabled better major curve correction (73% vs 59%) with less need for anteroposterior surgery as compared with hybrid constructs in patients with severe over 90degrees scoliosis. Feasibility of different techniques were investigated in the rare disease group. Cervical spine instability in the patients with rare bone dysplasia surgery was found effective.Although results are encouraging , risks and complications are common.Surgery has become an important part of treatment in many types of spinal disorders.Better techniques evolve from old methods and procedures only if these are studied meticulously. Keywords: scoliosis, pedicle, rib hump, total pedicle screw technique, coronalbalance, sagittal balance, rare bone dysplasia, cervical spine

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