Lääketieteellinen tiedekunta

 

Recent Submissions

  • Tjahjadi, Mardjono (Helsingin yliopisto, 2017)
    Objective Vertebrobasilar (VB) aneurysms remain considered as a significant challenge for both microneurosurgical and endovascular neurosurgeon/interventional neuroradiologists. The nature of the aneurysm formation and growth, as well as the tortuosity and geometry of the vessels in many cases, has reduced the efficacy of final clinical and radiological outcome of endovascular therapy. On the other hand, microsurgical treatment for VB aneurysms has also been reported to have a relatively high morbidity and mortality rate. The need to effectively treat the VB aneurysms was essentially based on the clinical fact that they have a higher rupture rate and worse prognosis than the anterior circulation group. Reducing the morbidity and mortality rate while increasing the aneurysm occlusion rate and its durability is the ultimate goal of aneurysm treatment. Our aim is to evaluate simple surgical techniques and their clinical and radiological results that have been used to treat VB aneurysms in department of neurosurgery of University of Helsinki and Helsinki University Hospital. Patients and Methods We analyzed surgical techniques that have been used in department of neurosurgery of University of Helsinki and Helsinki University Hospital during ten year period. The pre-operative clinical scale and final clinical and radiological outcomes were assessed to evaluate the efficacy of the surgical approaches. We used a defined subgroup of the surgical corridors into anterolateral, lateral, and posterolateral corridors to treat five levels of VB aneurysms. The five levels of VB aneurysms were divided based on their level to the clivus bone, which are above, upper, middle, lower, and lowermost. Results Above clivus level of VB aneurysm defined as more than 6 mm above the posterior clinoid process (PCP) was effectively treated by LSO approach, a simple modification of pterional approach which has anterolateral surgical corridors. Specifically for BB aneurysm, the wide P1 (first segment of PCA) angle was also a determined factor for the selection to use LSO. Upper clivus level defined as within 6 mm above and 8 mm below the PCP was simply treated with a subtemporal approach,at a lateral corridor to reach the lesion. This approach was a workhorse to treat theupper clivus level aneurysm because of shorter distance, more “straight to the point,”and better visibility of posterior basilar perforators. Middle clivus level aneurysms,defined as more than 8 mm below the PCP to the level of internal acoustic meatus (IAM) were commonly treated with a simplified presigmoid approach. This posterolateral corridor offered a wider and better exposure of VB artery and its surrounding neural structures. VB aneurysm which is located at lower clivus level, defined as more than 10 mm above the foramen magnum to the level of IAM, was effectively treated with simple lateral suboccipital approach or tic craniotomy. If the aneurysm is located very low or defined as less than 10 mm above the foramen magnum, a modification called “enough-lateral” approach was recommended. Conclusion These five simple surgical approaches (LSO, subtemporal, presigmoid, lateral suboccpital, and “enough-lateral”) were effective approaches to treat five different levels of VB aneurysm according to the clivus bone. The pre-operative clinical gradingscale and the large – giant size of aneurysm were the most consistent and determinant factors for unfavorable outcome in this study.
  • Jääskeläinen, Iiro (Helsingin yliopisto, 2017)
    Background. Skin and skin structure infections (SSSI) are among the most frequent indications for antimicrobial treatment both in the hospital and outpatient settings. SSSI is generally considered as complicated (cSSSI) if it involves deep subcutaneous tissues, needs surgery in addition to antimicrobial therapy or affects a patient with severe co-morbidity, like diabetes. CSSSIs are among the most frequently studied indications for new antibiotics and early treatment response has been suggested for assessment of drug efficacy. Study population. The patient material (n=460) of this population-based retrospective observational study consisted of all adult residents from Helsinki, Finland and the Gothenburg area, Sweden, who were hospitalized due to cSSSI in 2008–2011. Results and conclusions. In our study, as compared to previous studies on cSSSI, high levels of bacteraemia (13% of patients), treatment failure (38%) and initial antibiotic treatment modifications (39%) were detected, but a switch to narrow-spectrum antibiotic treatment (streamlining) was rare (5%). Staphylococcus aureus (21%) and streptococci (16%) were the most common aetiologies in monomicrobial infections. In multivariable analysis, late (≥4 days) treatment response was significantly associated to admission to ICU (OR 10.1), posttraumatic wound infection (OR 3.17), bacteraemia (OR 3.09), surgical intervention after diagnosis (OR 2.64), diabetes (OR 2.33) and initial broad-spectrum antibiotic therapy (OR 3.03). Early treatment response (≤3 days) was associated with previous hospitalization (OR 0.47) and empirical antimicrobial therapy covering the initial pathogens (OR 0.38). These observations suggest that time to treatment response depends not merely on treatment related factors. Furthermore, patients with early treatment response had eventually shorter hospital stay and antimicrobial treatment than those who stabilized later. After exclusion of patients with diabetic foot infection, no difference was detected in the microbiological aetiology of cSSSI between diabetics and nondiabetics. Yet, diabetes was the only baseline characteristic associated with broad-spectrum antimicrobial use and long (≥17 days) antibiotic treatment duration. Remarkable differences in the management of cSSSI were revealed between the two Nordic cities. Patients in Helsinki, as compared to those in Gothenburg, were treated more often with antimicrobials covering also Gram-negatives (96% vs. 47%), had more treatment modifications (mean 4.3 vs. 2.7) and longer median duration of antimicrobial therapy (29 vs. 12 days) and longer in-hospital stay (17 vs. 11 days). Most importantly, 57% of patients in Helsinki visited more than one department during their hospital stay, while in Gothenburg 85% of patients were treated in only one department. The findings suggest that cSSSI could be treated more often with a narrow-spectrum antibiotic and with a shorter treatment time and that unnecessary surgery and transfer of patients between wards should be avoided.
  • Turunen, Mikko (2017)
    Clonal selection events are the driving force of tumorigenesis. Because of the rapid development of efficient methods for detecting disease linked genetic alterations, we are now faced with the problem that many of the newly identified genetic alterations lack a functional mechanistic characterization. In my thesis, I have focused on mechanistic characterization on 4 (I-IV) different, globally significant, clonal selected events in colorectal cancer (CRC) and in uterine leiomyoma (UL). I.  Uterine leiomyomas (ULs) are one of the most common human tumors. The most frequent genetic alteration in ULs are somatic missense mutations detected in codons 36, 43 and 44 in the exon 2 of Mediator subunit 12 (MED12), which are found in ~70% of all tumors. Affinity purification-mass spectrometry revealed that these oncogenic mutations specifically disrupt the MED12-CyclinC binding interface, which diminishes the ability of MED12 to interact with CyclinC-CDK8/19 thereby causing reduced kinase activity of the whole transcriptional coactivator Mediator complex. These results suggest that the impaired kinase activity of the Mediator could be the cause of the leiomyoma phenotype. II. Apart from somatic mutations, one of the main ways to introduce cellular alterations is to alter gene dosage. This often occurs through copy-number alterations (CNA) and allelic imbalance (AI) of different size genomic fragments within cells. By analyzing 1699 tumor samples, we were able to identify the common AI regions in CRC. Using systematic CRISPR-Cas9 and CRISPRa-dCas9 screens we were able to identify the plausible target genes of these AI events. These results indicate that apart from known CRC drivers, which are often somatically mutated, CNA / AI regions contain lots of genes, whose altered dosage can alter cellular proliferation, providing cancer cells with a proliferative advantage for clonal selection. III. SNPs are the most common type of genetic variants among people. Some of the variant carrying alleles are clonally selected during diseases, such as cancer. The G variant in rs6983267 located in 8q24 is known to cause more cancer related mortality than any other inherited human genetic mutation or variant. ChIP assay demonstrated that rs6983267-site functions as TCF7L2 transcription factor (TF) binding site, whereby the risk G allele causes a stronger binding of the protein to this binding site in CRC cells. The genomic location of rs6983267 was shown to function as transcriptional enhancer element with the proto-oncogene CMYC as probable target gene. IV. Somatic mutations are the dominant mechanism for inactivating tumor suppressors and activating oncogenes in Microsatellite instable (MSI) colorectal cancers. The circadian rhythm regulator gene CLOCK was identified as the most down regulated, and one of the most frequently mutated genes in MSI tumors. The identified mutations result in a truncated protein product, which was able to bind DNA, dimerize with BMAL and weakly activate transcription, but according to ChIP-seq, had lost its DNA binding specificity, and thus the ability to regulate the circadian target genes. By this way truncated CLOCK could function in dominant negative manner. These results suggest that mutations affecting the regulators of circadian rhythm can be frequently found in cancer, and therefore could help to understand the well-known linkage from epidemiologic studies between disrupted circadian rhythm and cancer incidence.
  • Rintala, Jukka (Helsingin yliopisto, 2017)
    Chronic allograft injury is a multifactorial process mediated by both immunological and non-immunological factors, leading to organ dysfunction and humoral and cellular rejection. Currently, no specific treatment is available for chronic allograft injury. Pathological growth factor expression is observed before the development of end-stage renal disease (ESRD), and several growth factors (e.g., PDGF, TGF-β, EGF, and VEGF) are induced during the rejection process. This increased growth factor expression is induced by multiple pathways that are unaffected or partly induced by modern immunosuppressive medication. Individual growth factors induce their own expression and, via interactions, the expression of other growth factors. This cascade may lead to prolonged growth factor expression and subsequent chronic allograft injury. Many growth factors exert their effects through specific receptor tyrosine kinases (RTKs). RTKs can be inhibited by novel tyrosine kinase inhibitors (TKIs), which are orally administered and clinically used to treat several malignancies. In our experiments, we tested the efficacy of four different drugs with RTK-inhibition activity on chronic rejection in a rat transplantation model. First, we investigated FK778, an analogue of the active metabolite of leflunomide, which inhibits T- and B-cell proliferation and functions by interfering in de novo pyrimidine biosynthesis. FK778 also inhibits PDGF-RTK both in vitro and in vivo. In our experiments, FK778 decreased acute rejection in a dose-dependent manner and had additive effects with both cyclosporine and tacrolimus, decreasing both acute and chronic rejection. FK778 also decreased post-transplant PDGF and TGF-β expression. In our second study, we investigated short-term imatinib treatment in a chronic rejection model. According to our results, short-term (i.e., 30-day) treatment with PDGF-inhibiting TKI imatinib is sufficient to decrease subsequent chronic rejection changes at day 90. This short-term imatinib treatment also decreased post-transplant PDGF and TGF-β expression and restored allograft function. In the third study, we used erlotinib, a specific EGF-inhibiting TKI. We showed that, when combined with cyclosporine, erlotinib prevents chronic rejection changes and maintains better graft renal function. Erlotinib also decreased post-transplant EGF expression. In our fourth study we tested a potent, PDGF- and VEGF-inhibiting TKI, sunitinib, in combination with cyclosporine. Our data showed that sunitinib decreased early arterial expression of VEGF and PDGF as well as chronic expression of both PDGF and VEGF. Sunitinib decreased chronic rejection and maintained better graft function after transplantation. Taken together, our results show that growth factor inhibition via the inhibition of tyrosine kinases is a potent pathway to prevent chronic rejection and maintain graft function in the transplanted kidney. Our finding that even short-term imatinib treatment is sufficient to prevent chronic rejection indicates that life-long treatment may not be mandatory and early post-transplant events are crucial in mediating chronic rejection changes. TKIs imatinib, erlotinib, and sunitinib are well tolerated when combined with cyclosporine and prevent chronic rejection in an experimental kidney transplantation model. In addition, these drugs maintain better graft function after transplantation. Therefore, they could have beneficial effects in clinical transplantation.
  • Isokuortti, Elina (Helsingin yliopisto, 2017)
    Non-alcoholic fatty liver disease (NAFLD) often coexists with obesity and metabolic syndrome and is characterised by insulin resistance (IR). NAFLD may also be due to common gene variants in PNPLA3 at rs738409 and TM6SF2 at rs58542926. It is unclear whether these forms of NAFLD are related to IR. Liver fat content may be assessed using liver histology, imaging tools or biomarkers. This thesis was undertaken to better understand the pathogenesis of NAFLD and to improve currently available diagnostic tools. Subcutaneous (SC) adipocyte hypertrophy is related to IR, but it is unknown whether SC adipocyte size is independently associated with liver fat content. In study I, mean adipocyte size was determined from SC adipose tissue obtained from 119 non-diabetic subjects, whose liver fat content was measured using proton magnetic resonance spectroscopy (1H-MRS). SC adipocyte size significantly associated with liver fat content independent of age, gender, body composition and PNPLA3 genotype (R2=54%, p<0.0001). In study II, a systematic review was performed to investigate whether ‘PNPLA3 NAFLD’ and ‘TM6SF2 NAFLD’ are associated with IR. In 12 of 14 studies, the carriers of the PNPLA3 I148M variant had higher liver fat content than the non-carriers without an increase in IR, while in 5 of 7 studies, the carriers of the TM6SF2 E167K variant had higher liver fat content than the non-carriers without an increase in IR. A systematic review was also performed to compare how normal liver fat content is defined by liver histology and currently available imaging tools. These definitions were found to be variable and not inter-relatable. In study III, a reference value for HOMA-IR, a surrogate marker of IR, was determined, its use in the diagnosis of NAFLD evaluated and inter-laboratory variation determined. The study cohorts included two population-based studies, the FINRISK 2007 (n=5024) and the FIN-D2D (n=2849), and 368 non-diabetic subjects who underwent measurement of liver fat content (1H-MRS). In the healthy subjects of FINRISK (n=1167) and FIN-D2D (n=459), the upper reference limits of HOMA-IR (95th percentile [95% CI]) were 1.9 (1.8–2.0) and 2.0 (1.9–2.1), respectively. The former corresponded to the optimal HOMA-IR cut-off for diagnosing NAFLD (AUROC 0.88). The latter matched with a HOMA-IR corresponding to normal liver fat content (5.56%). Inter-laboratory variation of HOMA-IR was determined by simultaneously analysing samples from 10 subjects in 7 European laboratories. The coefficient of variation of HOMA-IR was high, 25%. In study IV, we determined whether serum pIGFBP-1, produced mainly by the liver, helps in the estimation of liver fat content independent of other known predictors. Fasting serum pIGFBP-1 was measured in 378 subjects who underwent measurement of liver fat content (1H-MRS). Serum pIGFBP-1 significantly associated with liver fat content independent of age, waist-to-hip ratio, and fasting ALT, glucose and insulin. This ‘% Liver fat equation' was significantly worse if pIGFBP-1 was removed (p<0.05) and significantly better than liver enzymes ALT and AST (p<0.0001). SC adipocyte size contributes independently to variation in liver fat content.‘Genetic NAFLD’ seems not to be characterised by IR despite higher liver fat content. Definitions of normal liver fat depend on the diagnostic imaging method used and are not inter-related. The upper reference limit of HOMA-IR corresponds to normal liver fat, but high inter-laboratory variation must be considered. Measurement of pIGFBP-1 may help in non-invasive diagnosis of NAFLD.
  • Sundström, Mira (Helsingin yliopisto, 2017)
    In Finland, the number of problem opioid and amphetamine users lies between 18,000 and 30,000, whereby only 20% receive treatment for their dependence. Annually illicit or medicinal drugs are found in the blood samples of more than 6,000 drivers, and approximately 500 fatal poisonings result from drugs. Drug testing attempts to unravel the role of psychoactive substances—whether used for therapeutic purposes or abused—under various circumstances. Such occasions requiring drug testing include treatment for drug users and poisoned patients, patient compliance, driving under the influence of drugs, and post-mortem toxicology. Although various techniques are available for the determination of a range of psychoactive substances, few methods provide cost-efficient means to detect the wide range of abused drugs. Many conventional methods remain too narrow in scope, complicated, or lead to false-positive or false-negative results. A current challenge for drug testing laboratories is the wide and changing panel of abused drugs. New psychoactive substances (NPS) continually emerge on the drug scene, requiring analytical methods not necessary ten years ago. These chemically diverse substances typically remain undetected by common drug testing methods, whereby reference standards are often insufficiently available further impeding method development. NPS are manufactured to mimic the effects of conventional drugs, while circumventing narcotic laws and drug testing. Due to their rapid appearance and disappearance, NPS display a challenging group of analytes to detect. A comprehensive drug testing method based on ultra-high performance liquid chromatography/high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-HR-QTOFMS) in the positive ionization mode was developed for hundreds of drugs. The coverage of the method appeared more extensive than for most previous methods, enabling sensitive and cost-effective drug testing in a single analytical run from a single urine sample. Due to the utilization of mass fragmentation, isotopic pattern, and metabolite pattern, the method produced testing results with an identification reliability comparable to dedicated target analysis. The method outperformed immunoassay drug testing as well as a pretargeted QTOFMS approach performed on the same platform in terms of specificity, sensitivity, and scope. The study of drug abuse patterns revealed a high prevalence of multiple drug abuse among all study subjects regardless of their treatment status. In particular, it was common among those subjects not routinely attending medical treatment for their drug problem. The most common set of abused substances consisted of buprenorphine, benzodiazepines, amphetamine, and cannabis. Other drugs of abuse always accompanied NPS findings, and NPS were most commonly identified in samples from individuals not receiving treatment. The analytically confirmed drug profiles of problematic Finnish drug users are reported here for the first time with a substantial accuracy, and the findings suggest that treatment for drug dependence helps reduce drug abuse. It is anticipated that the urine drug testing method presented in this thesis will find additional applications in future forensic and clinical toxicology contexts.
  • Scheinin, Ilari (Helsingin yliopisto, 2017)
    Chromosomal copy number aberrations are one of the main mechanisms that give rise to the proliferative capabilities of cancer cells. These aberrations can be quantified with technologies that generate measurements genome-wide and with high resolution. Hence, they produce vast amounts of data, which requires tailored bioinformatic solutions for analysis and management. Two such high-resolution and genome-wide technologies are DNA microarrays, which are successively replaced by next-generation sequencing approaches. This dissertation describes three novel bioinformatic solutions for copy number analysis in cancer with these technologies. CanGEM is a publicly-accessible database solution for storage of raw and processed copy number data from cancer research experiments. The contents of the database can be queried based on clinical and copy number data. Clinical data is collected using appropriate controlled vocabularies. Copy number data is collected as raw microarray data and automated analysis identifies the locations of chromosomal aberrations. In order to allow integration of data measured with different microarray platforms, a copy number status is derived for every known human gene. CGHpower is a statistical power calculator for copy number experiments that compare two groups. It estimates genome complexity of a cancer type in question from a pilot data set of the sample series, and assesses the number of samples required to satisfy statistical requirements. It can be used either in the planning stages of experiments, including as a justification in grant applications, or to verify whether sufficient samples were included in past experiments. Performance of this bioinformatic solution is evaluated with real and simulated data sets. QDNAseq is a preprocessing solution to detect copy number aberrations from shallow whole-genome next-generation sequencing data. It corrects the observed sequencing coverage for known systematic biases and allows filtering of spurious regions in the genome. A new list of such problematic regions is derived from public data generated by the 1000 Genomes Project. Performance of the solution is evaluated relative to other similar published solutions and DNA microarrays, and also compared to theoretical statistical expectations. An application of the QDNAseq method is also presented in a translational research project with the aim to identify copy number aberrations in tumors of patients with low-grade glioma. Aberrations identified by shallow whole-genome next-generation sequencing and QDNAseq are used to evaluate associations with patient survival, and also to assess intratumoral heterogeneity and temporal evolution of these tumors. A loss in chromosome 10q is identified to be associated with poor prognosis, and the finding validated in two independent data sets. From the assessment of intratumoral heterogeneity and temporal tumor evolution, the well-characterized co-deletion of 1p/19q is found to be the only chromosomal aberration that is consistently present or absent across the entire tumor and possible future recurrences. This is compatible with the present view of its role as an early event in the development of these tumors. The text concludes with a discussion of lessons learned from the development process and application of the three described bioinformatic solutions. Better awareness of and adherence to established best practices from the software development field would have been useful, and together with more careful consideration of implementation decisions could have resulted…
  • Lahdensuo, Kanerva (Helsingin yliopisto, 2017)
    Prostate cancer (PC) is the most common non-cutaneous cancer in Western men. In Finland, 4500-5000 new cases are diagnosed annually. There is great variability in the clinical course of PC. Patients are therefore stratified into risk groups, reflecting how aggressive their PC is and how actively it should be treated and monitored. Currently, risk stratification is based on diagnostic prostate biopsies, the patient’s prostate-specific antigen level, and the disease’s clinical stage. This system has well-established limitations. The biggest uncertainty stems from prostate biopsies, which can be inaccurate. The current system also ignores prostate magnetic-resonance imaging (MRI), which is already widely used. Prognostic tissue markers from cancer samples could possibly improve the prediction of patients’ outcomes. This thesis study was carried out at the Department of Urology at Helsinki University Hospital during 2011-2016. The study looked into the safety (Study I) and diagnostic performance (Study II) of transrectal prostate biopsies, the value of prostate MRI in the follow-up of patients on active surveillance (AS) (Study III), and the correlation of tissue markers with clinical outcomes of patients following radical prostatectomy (RP) (Study IV). Study I: The incidence of severe infections following transrectal prostate biopsies has increased alarmingly in recent years. In Study I, we retrospectively evaluated the incidence of bacteremic post-biopsy infections in the Helsinki and Uusimaa hospital district during 2005-2013. A 2.4-fold increase was observed over the study period. In Study II, we retrospectively investigated in RP specimens of 96 men operated at our institution between 2009 and 2010 the performance of 12-core prostate biopsies in predicting tumor location and extent. We found biopsies to be inaccurate, which makes them a poor tool for detailed planning of radical or focal therapies. Study III was a prospective study investigating the value of prostate MRI in the follow-up of AS patients. In 2009-2011, 80 men at our institution underwent prostate MRI after being on AS for one year. We found prostate MRI to, at the time, add no value to the standard follow-up of AS patients. In Study IV, we retrospectively analyzed 815 men treated with RP between 1983 and 2005 at Helsinki University Hospital and at Turku University Hospital. The association of expressions of three PC tissue markers–ERG, PTEN, and AR–with clinical outcomes—requirement for secondary therapy after RP, disease-specific survival, and overall survival—were explored. Loss of PTEN expression appears to be a strong driver for disease progression, and its performance as a prognostic tool should be further studied in prospective settings.
  • Kliuchko, Marina (Helsingin yliopisto, 2017)
    Exposure to noise has a negative influence on human health, including an increased occurrence of cardiovascular diseases. Susceptibility to the harmful effects of noise can be further moderated by a personal trait called noise sensitivity (NS). It is not understood what makes some individuals more sensitive to noise than others. So far, the research on this topic has been largely limited to perceptual and population studies. The aim of this thesis was to broaden the understanding of NS by addressing its biological mechanisms. Thus, this thesis investigated the neuroanatomical correlates of NS and its effects on auditory processing. The thesis consists of three studies. The first study examines whether NS can be developed as the result of musical training (Study I). The other two studies investigate whether NS is reflected in the functioning of the central auditory system (Study II) and whether it is related to the morphology of cortical and subcortical brain structures (Study III). The research was conducted using questionnaires, combined magneto- and electroencephalography (MEG/EEG) and magnetic resonance imaging (MRI). The findings of this thesis suggest that NS moderates how and why individuals listen to music. However, NS is not associated with musical training and thus does not seem to relate to fine perceptual skills (Study I). An investigation of the central auditory processing in Study II, however, revealed compromised sound feature encoding and automatic discrimination skills in noise-sensitive individuals. Study III showed that NS is also associated with the structural organization of the brain. Noise-sensitive individuals were found to have enlarged volumes of the auditory cortical areas and hippocampus as well as thicker right anterior insular cortex. These results suggest that NS is related to the structures involved with auditory perceptual, emotional, and interoceptive processing. Overall, this thesis proposes that NS is not merely an attitudinal phenomenon but instead has underlying neuronal mechanisms.
  • Aronniemi, Johanna (Helsingin yliopisto, 2017)
    Venous malformations (VMs) are congenital vascular anomalies. They cause variable symptoms and are associated with blood coagulation disorders. Sclerotherapy has recently become the primary treatment for most VMs. This thesis aimed to investigate histology and imaging of VMs operated on for unsatisfactory sclerotherapy response, blood coagulation and fibrinolysis activity in pediatric VM patients, and safety aspects of sclerotherapy for trunk and extremity and head and neck VMs. We studied VM patients undergone sclerotherapy at Helsinki University Hospital between 2007 and 2013 and paediatric VM patients collected from the Helsinki Children's hospital outpatient registry. We analyzed histology and imaging findings of extremity VMs operated on for poor response to sclerotherapy (n=102), sclerotherapy complications of all sclerotherapy-treated patients (n=202), and coagulation abnormalities of the paediatric VM patients (n=62). Of the sclerotherapy-treated extremity VMs, 19% were operated on for insufficient sclerotherapy response. The histology of most intramuscular VMs was not consistent with common VM, corresponding instead to angiomatosis of soft tissue (AST). The imaging findings for common VM and AST were overlapping. Pediatric VM patients had significant abnormalities in leukocyte, antithrombin, FVII, FVIII, and FXIII levels, in addition to previously reported elevated D-dimer levels. Disseminated intravascular coagulation did not occur and platelets were generally normal. The sclerotherapy complication rate per procedure was 13% for trunk and extremity VMs and 10% for head and neck VMs. Superficial location and use of ethanol increased the risk for local complications. Blood coagulopathy was a predisposing factor for severe complications. Histology has an important role in the differential diagnostics of intramuscular VMs, as different histological entities require different treatment approaches. VMs are associated with specific abnormalities in coagulation biomarkers, implying a close interrelation between coagulation and angiogenesis. Sclerotherapy for both peripheral and head and neck VMs is generally safe, but entails a risk for severe complications.
  • Ala-Nikkola, Taina (Helsingin yliopisto, 2017)
    This study investigates the structure and organisation of Finnish mental health services. The study is related to REFINEMENT, a European multicentre study to investigate service costs and other effects. A cross-sectional sampling was conducted in 2012-2014 to map the substance abuse and mental health systems of the Hospital District of Southwest Finland as well as those under the special remit of Helsinki University Hospital region. The mapping utilised the European Service Mapping Schedule – Revised (ESMS-R), which contains 89 ‘Main Types of Care’ (MTC) divided into six branches. The existing service structures of the various catchment areas were reviewed for the most part comparatively in terms of qualitative and quantitative indicators. Diversity of care and the effect of population size were reviewed in depth, assessing whether any care-providers or branches of the classification tree was particularly sensitive to population size. Existing services were evaluated in relation to socioeconomic factors and needs indicators of the population. In the sample, population growth was linearly related to increased diversity of mental health and substance abuse services up to the level of 500,000 adult inhabitants. A quantitative review of personnel resources found that the more an area invested its planned personnel resources in outpatient activities, the smaller the amount of total planned resources was. In areas where psychiatry at the basic specialty care level was organised as an activity of the municipality itself, rather than of the municipal joint authority or of social and health services, the planned personnel resources were greater. Third-sector providers were the most responsive to changes in the size of the population base. Treatment and service activities, for their part, showed the greatest sensitivity to population growth in terms of 24-hour residential care. Contrary to expectations, diversity in outpatient care and personnel resources showed no effect on the areas’ bed occupancy allocations, which correlated with socioeconomic factors instead. Bed occupancy also correlated with the amount of alcohol sold in the area and with the area’s mental health index. Rather than using structural factors and socioeconomic needs indicators to connect bed occupancy to the mental health index, which describes the service needs caused by severe mental health problems, one may instead consider the connection in terms of well-targeted allocation of care. The result might be to describe areas as having achieved generally adequate levels of outpatient care. Local services that are low-threshold, available without referral or otherwise directly, are linked to smaller total personnel numbers. Based on the study, one cannot directly conclude whether deficiencies in specialised health care have the effect of increasing compensatory, low-threshold services produced mainly by the third sector. Mental health problems may relate to an area having a higher mental health index, higher scores being an indicator of consequences of severe mental health problems. A larger population base enables a more diversified offering of services. The effect may obtain also in population samples greater than those used in our study and in population bases of over 500,000 inhabitants.
  • Liu, Chengyu (Helsingin yliopisto, 2017)
    Cancer is one of the most lethal diseases. By 2030, deaths caused by cancers are estimated to reach 13 million per year worldwide. Cancer is a collection of related diseases distinguished by uncontrolled cell division that is driven by genomic alterations. Cancer is heterogeneous and shows an extraordinary genomic diversity between patients with transcriptionally and histologically similar cancer subtypes, and even between tumors from the same anatomical position. The heterogeneity poses great challenges in understanding cancer mechanisms and drug resistance; this understanding is critical for precise prognosis and improved treatments. Emergence of high-throughput technologies, such as microarrays and next-generation sequencing, has motivated the investigation of cancer cells on a genome-wide scale. Over the last decade, an unprecedented amount of high-throughput data has been generated. The challenge is to turn such a vast amount of raw data into clinically valuable information to benefit cancer patients. Single omics data have failed to fully uncover mechanisms behind cancer phenotypes. Accordingly, integrative approaches have been introduced to systematically analyze and interpret multi-omics data, among which network-based integrative approaches have achieved substantial advances in basic biological studies and cancer treatments. In this thesis, the development and application of network-based integrative methods are included to address challenges in analyzing cancer samples. Two novel methods are introduced to integrate disparate omics data and biological networks at the single-patient level: PerPAS, which takes pathway topology into account and integrates gene expression and clinical data with pathway information; and DERA, which elevates gene expression analysis to the network level and identifies network-based biomarkers that provide functional interpretation. The performance of both methods was demonstrated using biological experiment data, and the results were validated in independent cohorts. The application part of this thesis focuses on understanding cancer mechanisms and identifying clinical biomarkers in breast cancer and diffuse large B-cell lymphoma using PerPAS, DERA, and an existing method SPIA. Our experimental results provided insights into underlying cancer mechanisms and potential prognostic biomarkers for breast cancer, and identified therapeutic targets for diffuse large B-cell lymphoma. The potential of the therapeutic targets was verified in in vitro experiments.
  • Villa, Pia (Helsingin yliopisto, 2017)
    Prediction and prevention of pre-eclampsia Pre-eclampsia occurs in 2 to 8% of all pregnancies. Every year 70,000 women die due to pre-eclampsia and its complications. Most of these deaths occur in developing countries. In developed countries, the risk of maternal or fetal death is low, but the complications of pre-eclampsia may be severe. Early-onset disease may end in a very preterm birth, since delivery is the only treatment available. We studied prediction and prevention of pre-eclampsia in the PREDO cohort, which involved 947 pregnant women with risk factors of pre-eclampsia and 117 controls. Our study included also a meta-analysis showing that low-dose aspirin, 100 mg per day, prevents pre-eclampsia (risk ratio [RR] 0.6, 95% CI 0.37-0.83) and particularly severe (RR 0.3, 95% CI 0.11-0.69) pre-eclampsia, when the treatment is started before the 16th week of pregnancy in high-risk women. We estimated the risk using medical history and by measuring uterine artery flow with Doppler ultrasound. In our cohort, those women who had had pre-eclampsia or a small-for-gestational-age newborn in an earlier pregnancy, or who had chronic hypertension or type I diabetes mellitus had a high risk for developing early onset pre-eclampsia. The risk of pre-eclampsia increased exponentially with increasing number of risk factors. In the future, it may be possible to predict pre-eclampsia in early pregnancy with risk-estimating algorithms. In the midpregnancy, it is possible to predict pre-eclampsia by measuring serum placental growth factor (PlGF) and soluble vascular endothelial growth factor-1 (sFlt-1) concentrations. In our cohort, all women who developed early-onset pre-eclampsia could be identified, with no false positives, 4 to 6 weeks prior to the diagnosis with sFlt-1:PlGF ratio measurement. This may help to plan individual follow-up in at-risk women, and also help in the clinical decision-making among women with signs and symptoms of pre-eclampsia. Women with chronic hypertension are followed during pregnancy because of an increased risk of pre-eclampsia. We found that an increased albumin:creatine ratio predicts pre-eclampsia in early pregnancy in these women and may help in individual risk estimation. We showed that free fatty acid concentrations are significantly elevated in women with established pre-eclampsia compared to controls. This may underlie several characteristics of pre-eclampsia, for example endothelial cell dysfunction.
  • Soini , Tuuli (Helsingin yliopisto, 2017)
    Heavy menstrual bleeding (HMB) is a common problem affecting up to one-third of women in their reproductive years. Modern intrauterine treatment modalities for HMB, namely levonorgestrel-releasing intrauterine system (LNG-IUS) and endometrial ablation, have changed significantly the management of HMB and resulted in a marked decrease in the number of hysterectomies in many countries. Despite the increasing popularity of these treatments, little is known about the cancer risks among women treated with these methods. Also, some women need a later hysterectomy after endometrial ablation, but factors predisposing to that are insufficiently known. In this thesis, cancer risks among Finnish women treated for HMB with LNG-IUS (93 843 women) or endometrial ablation (5 484 women) at ages 30-49 years, were assessed. Also, the risk factors for postablation hysterectomy were evaluated. The studies were based on nationwide register data. The use of LNG-IUS for HMB was associated with an increased risk of breast cancer, but a decreased risk of both endometrial and ovarian cancer. This means 2-4 excess cases of breast cancer per 1 000 LNG-IUS users followed for ten years. Also, this means 3-6 prevented endometrial cancers, and 3-6 prevented invasive ovarian cancers per 10 000 LNG-IUS users followed for ten years. Among women with endometrial ablation, the incidence of endometrial cancer or breast cancer after endometrial ablation was similar to that of the general population. Over 80% of endometrial ablation treated women did not need a later hysterectomy. The risk factors for postablation hysterectomy were leiomyomas, young age, and a history of two or more cesarean deliveries or sterilization. The results of this thesis revealed new information on the cancer risks among women treated for HMB with LNG-IUS or endometrial ablation. Both these methods for treatment of HMB are effective, but an individual risk–benefit assessment is important to do when deciding the treatment for HMB.
  • Fogarty, Christopher (Helsingin yliopisto, 2017)
    Type 1 diabetes (T1D) is a disease characterized by the autoimmune destruction of insulin-producing pancreatic β cells. Diabetic nephropathy is a life-threatening complication of T1D, characterized by the progressive loss of kidney function. Approximately one-third of all patients with T1D develop diabetic nephropathy. Bacterial DNA and bacterial lipopolysaccharides (LPS) are two categories of bacterial remnants that are known to induce inflammation. Inflammation and elevated levels of bacterial remnants have previously been shown to be associated with the development of diabetic nephropathy, and there is evidence in mice that these factors play a causal role in disease progression. The general aim of this thesis is to identify biological factors that modulate bacterial remnant-mediated inflammation in patients with T1D. Specifically, we aimed to better understand the composition, origin and consequences of bacterial remnants in circulation in the context of T1D by (1) evaluating the presence of bacterial DNA in the sera of patients with T1D and controls (Study I) and (2) measuring LPS activity, inflammation, inflammatory potential and gut-related factors in the context of multiple high-fat meals given to patients with T1D and healthy controls (Studies II & III). Study I found a higher frequency of Pseudomonal (Pa) DNA in circulation as well as elevated anti-Pa IgA levels in patients with T1D. These Pa-specific IgA antibodies correlated with higher C-reactive protein, a marker for inflammation, suggesting that patients with T1D undergo recurrent or chronic Pseudomonal exposure and potentially explaining the chronic inflammation in patients with T1D. Contrary to our hypotheses, study I found no correlation between LPS activity and either bacterial DNA composition or antibodies against identified bacterial species. This may be attributable to differences in the half-lives and host clearance mechanisms of bacterial remnants. However, it is also possible that the entry mechanisms and points of entry for LPS and bacterial DNA are different. The identification of numerous bacteria known to be present in the oral cavity suggests that one possible point of entry is the oral cavity. Another possible point of entry for bacterial remnants is the gut. Circulating LPS was previously shown to increase after the ingestion of high-fat meals by healthy adults. Study II found a pronounced increase in serum markers of inflammation after multiple high-fat meals; however, our data suggest this inflammation was not attributable to increases in circulating LPS. Indeed, circulating LPS levels appeared to have no effect on immune cell activation or systemic inflammation. This led us to investigate factors related to intestinal homeostasis, particularly focusing on factors such as alkaline phosphatases, which might affect the potency of intestinally derived LPS. In Study III, we found a general disturbance in factors related to gut homeostasis in patients with T1D. Specifically, low levels of fecal alkaline phosphatase found in patients with T1D contributed to increased LPS potency in the intestine, which in turn boosted intestinal inflammation. These studies help shed light on the potential routes of entry for bacterial remnants and the possible mechanisms underlying the inflammatory response induced by high-fat meals.