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  • Göhre, Felix (Helsingin yliopisto, 2016)
    Objective: Aneurysms of the posterior cerebral artery are rare vascular lesions. The overall incidence is less than 1%, representing around 7% of posterior circulation aneurysms. Due to this low incidence, most of the institutional series on PCA aneurysms are small and contain less than 25 patients. Only one other series comparable in scope to ours has been previously published. The presented study analyzes and describes the characteristic features of PCA aneurysms as well as investigates the relevant treatment strategies and their outcomes. A particular focus is in the description and analysis of PCA aneurysms treated from a subtemporal approach and the pres - entation of an associated aneurysm treatment from a lateral supraorbital approach. Patients and Methods: We reviewed 121 patients diagnosed with 135 PCA aneurysms, all of whom were treated between 1980 and 2012 at two Finnish neurosurgical units (Department of Neurosurgery at the University of Eastern Finland, Kuopio and Department of Neurosurgery at the University of Helsinki). Additionally, twelve historical (pre-1980) cases were presented. Detailed analyses of cerebral angiographies were conducted for 93 PCA aneurysms in 81 patients. A further subgroup analysis of 34 patients diagnosed with 37 PCA aneurysms treated via subtemporal approach was also performed. Results: Of the 121 patients with 135 PCA aneurysms, 52 (39%) aneurysms were ruptured and 83 (61%) unruptured . The following distribution along the PCA segments was observed: P1 segment (n=53), P1/2 junction (n=39), P2 segment (n=28), and P3 segment (n=15); no P4 segment aneurysms were found. Saccular aneurysms were more common than fusiform PCA aneurysms (76% vs. 24%). The detailed angiographic analysis showed that the median aneurysm size was 7 mm for ruptured PCA aneurysms and 4 mm for unruptured aneurysms. Saccular aneurysms (n=69, 74%) had a characteristic dome projection for each location: P1 segment, upward (67%); P1/P2 junction, anterior/upward (80%); P2 segment, lateral (67%); and P3 segment, posterior (50%). The following treatment results at 1-year follow-up were achieved for patients with: unruptured PCA aneurysms (n=19; 12 good outcomes, 63%; 6 moderate, 31%; 1 poor, 5%), ruptured PCA aneurysms (n=27; 10 good, 37%; 9 moderate, 33%; 8 poor, 30%), and patients with complex neurovascular pathologies and PCA aneurysms (n=96; 42 good, 43%; 40 moderate, 42%; 14 poor, 15%). Analyzing the subtemporal approach we found that most complications were not related to the subtemporal approach itself but to the specific nature of the PCA aneurysms treated and the chosen strategy. The most common (12 out of 34; 35%) serious complication in this series was an ipsilateral PCA infarction after parent vessel occlusion. Conclusion: PCA aneurysms are infrequent vascular lesions that are often associated with other vascular pathologies. Most ruptured PCA aneurysms are smaller than 10 mm and distally located. The saccular PCA aneurysms have a typical dome orientation at each PCA segment. Microsurgery and endovascular treatment are effective options for the occlusion of PCA aneurysms. As a result, individual treatment strategies are required. Despite commonly adequate vessel collateralization of the distal PCA territory, preservation or reconstruction of the parent vessel is crucial for favorable treatment outcomes. The subtemporal approach is favorable for the treatment of PCA aneurysms in proximity to the tentorium. Frontolateral approaches allow the treatment of proximal PCA aneurysms and ipsilateral anterior circulation aneurysms inside the Circle of Willis.
  • Laulajainen-Hongisto, Anu (Helsingin yliopisto, 2016)
    Acute otitis media (AOM) is an infection that is particularly common in children. The bacterial etiology of AOM, in both children and adults, affects its clinical picture. While in some cases the infection can simply be carefully monitored without treatment, antimicrobials are often prescribed. Caution is required, however, when prescribing antimicrobials as their excessive use has led to antimicrobial resistance; this resistance has been seen among some of the causative pathogens for these infections. Before the development of antimicrobial treatment, complications due to middle ear infections were common, potentially causing severe symptoms or even death. Some middle ear infections spread into surrounding structures, leading to intratemporal or extratemporal (extracranial or intracranial) complications. This thesis focuses on complicated otitis media and the causative factors of its complications. In the first two studies, we evaluated the medical records of all (n=100) children (0-16 years old) hospitalized at the Department of Otorhinolaryngology in the Helsinki University Hospital from 2003 to 2012 for acute mastoiditis (AM) or AOM, as well as the infection s bacteriology in relation to the patient s clinical findings and treatment. Using this information, we analyzed the differences in the etiologies and clinical pictures of those children hospitalized due to AOM compared to AM. In our third study, we examined the medical records of all (n=166) patients hospitalized at our institution from 1970 to 2012 due to intracranial abscesses (IA), including those of otogenic background (oIA). In the fourth study, we evaluated the bacteriology in relation to the patients clinical findings and treatment in all (n=160) adult patients treated at our institution from 2003 to 2012 for AOM or acute mastoid infection. In adults, acute mastoid infection was subclassified into AM, latent mastoiditis (LM), and AM following chronic middle ear infection (AMc). The clinical picture of AM in children differed according to the causative pathogen. Streptococcus pneumoniae (Pnc), especially its resistant strains, caused severe symptoms and often led to mastoidectomies. Pseudomonas aeruginosa (Ps) typically affected older children with prior tympanostomy tubes and generally caused milder symptoms. Furthermore, the bacteriological etiology of hospitalized AOM and AM patients was different compared to outpatient AOM. Two of the typical AOM pathogens, Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc), were uncommon among the hospitalized patients. Pnc, especially its resistant strains, was less common in children hospitalized for AOM compared to AM, and less common in adults than children. Streptococcus pyogenes (StrA) and Ps were both linked to otorrhea and were found only in older children. Over our 42 year study period, oIAs became less common and typically developed following chronic middle ear infections, often in connection with cholesteatoma. In adults, the bacteriological etiology and clinical picture of AMc differed from AOM as well as the other acute mastoid infection types (AM, LM). AOM and AM led to less surgical procedures than the more prolonged forms of acute mastoid infection (LM, AMc). In children, the hospitalized cases of AOM and AM differed from outpatient AOM. In adults, severe AOM, AM, and LM seem to compose a continuum that may lead to chronic otitis media and its acute complications, including oIAs. Otogenic IAs are quite rare, however, and became less common over our study period.
  • Markkula, Niina (Helsingin yliopisto, 2016)
    Depressive disorders are a major public health concern worldwide due to their pervasiveness, often chronic or recurrent course and serious adverse outcomes. These include psychosocial disability, reduced quality of life, physical health problems and increased mortality. This study examined prevalence, predictors and different adverse outcomes of depressive disorders (major depressive disorder and dysthymia) in a general population setting. Specifically, the study aimed to establish the prevalence of depressive disorders in Finland in 2011 and assess possible changes over the past decade; to examine risk factors for new-onset depressive disorders; to investigate the long-term prognosis of depressive disorders and its determinants; and to assess excess mortality associated with depressive, anxiety and alcohol use disorders. A large longitudinal study of the Finnish population, consisting of the Health 2000 and Health 2011 Surveys, was used to investigate these questions. The survey data was complemented with data from the Care Register for Health Care and the Finnish Causes of Death Statistics. The results show that one in 10 adults in Finland suffered from a depressive disorder in 2011, and the prevalence increased from 2000 to 2011, particularly among women. Methods to account for non-participation also showed that the non-participation of people with depressive disorders in population studies significantly biases prevalence estimates. People who were younger, had a history of multiple childhood adversities, lower trust axis of social capital, or an anxiety disorder or subclinical depressive symptoms at baseline, had a higher risk of developing depressive disorders. In addition, having three or more physical diseases was a risk factor for dysthymia. Among people with depressive disorders at baseline, 34-43% still had some depressive, anxiety or alcohol use disorder after 11 years, and 48-61% had clinically significant depressive symptoms. Unmarried people and those with more severe initial symptoms had a higher risk of persistent course. People with depressive disorders had a twofold mortality risk, whereas the risk was 1.7-fold in alcohol use disorders and was not increased in anxiety disorders, when adjusted for other risk factors. This study confirms that depression is an increasing public health concern in Finland, and that depressive disorders have serious long-term consequences. To reduce the burden of depressive disorders, it is of key importance to develop primary prevention efforts and measures to reduce the negative health and social consequences of depression.
  • Backlund, Michael (Helsingin yliopisto, 2016)
    The renin-angiotensin system is a key regulator of blood pressure and electrolyte homeostasis. Most hemodynamic responses to angiotensin II are mediated via angiotensin II type 1 receptor (AT1R). The 3 -untranslated region (3 UTR) of AT1R mRNA is important in posttranscriptional regulation of AT1R expression. It contains multiple adenylate-uridylate-rich elements that are recognized by various RNA-binding proteins (RNBP) affecting the stability, conformation, subcellular localization, and translation of their target mRNAs. The aim of this study was to identify novel AT1R 3 UTR-binding RNBPs and understand their physiological role in AT1R function. AT1R 3 UTR-associated RNBPs were isolated from human vascular smooth muscle cells by protein affinity purification using AT1R 3 UTR as a probe. Mass spectrometric identification of the isolated proteins led to identification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Hu antigen R (HuR) and TIA1 cytotoxic granule-associated RNA-binding protein (TIA-1). GAPDH was identified as a novel AT1R mRNA-binding protein that suppresses AT1R translation. GAPDH binds to a hairpin-structure rich in adenosine and uridine in the proximal region of AT1R 3 UTR. Hydrogen peroxide-induced oxidative stress increased AT1R expression by dissociating GAPDH from AT1R 3 UTR and relieving it from the GAPDH-mediated suppression. Insulin-induced increase in AT1R expression was shown to be posttranscriptionally mediated by HuR. Insulin stabilized AT1R mRNA in a 3 UTR-dependent manner and HuR was shown to bind AT1R 3 UTR. Insulin induced nucleocytoplasmic translocation of HuR to cytoplasm and increased HuR binding to AT1R 3 UTR. This increased AT1R expression via stabilization of AT1R mRNA. AT1R avoids the endoplasmic reticulum (ER) stress-mediated translational suppression. Binding of TIA-1 to AT1R 3 UTR was shown to suppress AT1R expression. TIA-1 normally colocalized with AT1R mRNA in the cytoplasm. However, during ER stress TIA-1 was dissociated and directed to translationally silenced stress granules, while AT1R mRNA remained excluded from them. Thus, AT1R mRNA avoids aggregation to SGs and TIA-1-mediated translational suppression during ER stress. In conclusion, oxidative stress, insulin, and ER stress regulates AT1R expression posttranscriptionally by affecting the binding of GAPDH, HuR, and TIA-1 to its mRNA 3 UTR.
  • Lassenius, Mariann (Helsingin yliopisto, 2016)
    Around one-third of patients with type 1 diabetes develop diabetic nephropathy. Even though the pathogenesis of diabetic nephropathy is not fully understood, the process involves several environmental factors. Low grade inflammation has been linked to many metabolic diseases and is also evident in patients with type 1 diabetes, especially in the presence of nephropathy. Bacterial lipopolysaccharides (LPS) are powerful triggers of inflammation, but whether low grade inflammation is caused by these components is an open question. The aim of this thesis was to examine the relationship between LPS and the development of diabetic nephropathy, inflammation, vascular function, lipid metabolism, and intestinal homeostasis in patients with type 1 diabetes. The studies are part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane), a nationwide, multicenter study that aims to identify genetic and environmental risk factors for the development of diabetic complications in patients with type 1 diabetes. Study I was a follow-up study, and Studies II IV were cross-sectional in their design. Renal status was verified at follow-up by laboratory data and a review of all available medical files (Study I). Study II included, in addition to patients with type 1 diabetes, patients with IgA glomerulonephritis and non-diabetic control subjects. The participants in Studies III and IV had three consecutive high-fat meals and were followed for 10 hours postprandially. Factors associated with endotoxemia, vascular function, inflammation, and lipid metabolism were investigated. For all studies, LPS was measured by the limulus amebocyte lysate (LAL) assay from serum samples. In the patients with type 1 diabetes, high serum LPS activity at baseline was associated with the development of microalbuminuria during the follow-up. High serum LPS was also associated with features of the metabolic syndrome in both the patients with type 1 diabetes and the overweight non-diabetic controls. Of note, no accumulation of LPS in the circulation was evident in response to three high-fat meals. However, the patients with type 1 diabetes showed altered postprandial lipid metabolism and vascular response. Moreover, factors associated with gut homeostasis were altered in the patients with type 1 diabetes compared to the non-diabetic controls. We show that high serum LPS is associated with the development of diabetic nephropathy and features of the metabolic syndrome. The metabolic syndrome is associated with insulin resistance, and it is a risk factor for both diabetic nephropathy and cardiovascular disease. Endotoxins may affect the development of diabetic nephropathy through the direct disruption of the filtration barrier, but also through insulin resistance at both the tissue and systemic levels. In response to acute high-fat feeding, no evidence for LPS accumulation was seen. However, unfavorable changes in lipid metabolism and vascular response in patients with type 1 diabetes may render them at higher cardio-metabolic risk. This risk may be further enhanced by adverse changes in both inflammatory and protective factors in the gut, leading to a possibly higher gut permeability and an increase in circulating endotoxins.
  • Hyvönen, Maija (2016)
    Gliomas, malignant brain tumors, are among the most aggressive cancers in adults. Due to their invasive growth, resistance mechanisms and tendency to relapse, the prognosis of high-grade glioma patients is very poor. Therefore, to improve therapeutic strategies it is essential to study molecular mechanisms underlying the progression of gliomas and identify novel, glioma-specific proteins that could be therapeutically targeted. In this study we first mapped vascular markers of malignant gliomas to find potential candidates for tumor targeting. By using in vivo phage display method we identified a peptide, CooP, which, after systemic delivery, specifically homed to brain tumor satellites and their vasculature in mice. Coop was successfully used in tumor imaging and targeted drug delivery. We also identified mammary-derived growth inhibitor (MDGI) as an interacting partner for CooP in the brain tumor tissue and tumor-associated vasculature. Homing peptide-conjugated nanocarriers have shown great potential in targeting various tumors, including gliomas. Therefore, we estimated the potential of CooP peptide in the surface functionalization and targeted delivery of porous silica nanoparticles in vitro and in vivo. CooP-functionalized particles were shown to be stable, non-toxic and suitable for targeting MDGI expressing subcutanous xenografts. In the last part of this study we characterized the expression and function of MDGI in gliomas. Our immunohistochemical analyses revealed abundant MDGI expression in clinical brain tumor specimens and patient-derived gliospheres. In lower-grade glioma patients MDGI expression correlated with poorer overall survival. Importantly, also endothelium-associated expression of MDGI in the clinical samples was observed. Functional in vitro and ex vivo assays demonstrated that MDGI overexpression enhanced the aggressive growth of glioma cells, whereas even more striking changes occurred when MDGI was genetically silenced. MDGI silencing compromised the growth of human gliospheres, altered the expression of stress-related proteins, disrupted mitochondrial function and eventually caused apoptotic cell death. In addition, mass spectrometric analyses revealed significant changes in the intracellular metabolites after MDGI silencing. Together our results show that the glioma-specific CooP peptide can be utilized both in glioma imaging and targeted drug delivery as well as in biofunctionalization and targeting of nanoparticles in vivo. In addition, MDGI, the interacting partner of CooP, is abundantly expressed in malignant gliomas and essential for glioma cell survival. Since MDGI is reachable via intravenously injected agents, it could be a potential candidate for the targeted treatment of gliomas.
  • Yukin, Alexey (Helsingin yliopisto, 2016)
    This Thesis addresses fundamental mechanisms of brain disorders that occur in preterm infants or during early childhood. To this end, we have developed animal models to mimic disorder-specific pathological conditions in the brain. During critical periods of development of the mammalian brain, cell migration and synapse formation are crucially important to set up newly developed neuronal circuits that will support complex network activity. A particular set of cells, the subplate neurons, is the first to mature during the earliest stages of cortical development. These neurons act as transient relay and processing station for signals coming from subcortical structures to the cortex. Their high dependence on oxygen supply makes them vulnerable to injuries that take place during pregnancy. In the present work, conditions of this kind were mimicked by specific toxin-based ablation of subplate neurons. At a more advanced stage of brain development, a very common type of brain disorder is febrile seizures (FS). They represent convulsive events in humans that are promoted by respiratory alkalosis during febrile illness. The global incidence of FS is estimated from 2 to 14 % (depending on ethnicity) of all children in the age of 6 months to 5 years. Using an animal based on 13-14 day old rats exposed to hyperthermia, we show that a pro-excitatory action of GABA based on the neuron-specific carbonic anhydrase (CA) isoform VII is crucially involved in the generation of these seizures. Finally, while it is widely assumed that FS are limbic in origin, this Thesis provides new evidence that the brainstem can have an independent and prominent role in the generation of FS, and also of convulsions induced by kainic acid, which so far, have been considered prototypical in studies of limbic seizures. As a whole, this work demonstrates the high utility and heuristic value of custom-designed animal models in studies of basic mechanisms and consequences of disorders in the developing brain.
  • Rozov, Stanislav (Helsingin yliopisto, 2016)
    The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.
  • Vaahersalo, Jukka (Helsingin yliopisto, 2016)
    Aims The objectives of this study were to evaluate the incidence and neurological outcomes of out-of-hospital cardiac arrest (OHCA) patients in Finnish intensive care units (ICU). This study also investigated the use of therapeutic hypothermia (TH), arterial blood gas (ABG) pressures and different biomarkers association with one-year neurological outcome after OHCA. Materials and methods The FINNRESUSCI study was conducted in 21 out of 22 ICUs in Finland during a one-year study period. All adult patients after OHCA who were treated in ICU were included. Blood samples for biomarker evaluation were collected and neurological outcomes were determined 12 months after CA. All patients were included when evaluated the incidence, the implementation of TH and outcomes. In Study II, all ABG samples obtained from mechanically ventilated patients during the first 24h from ICU admission. In Study III and IV, biomarkers were measured from patients resuscitated from VF/VT. Main results FINNRESUSCI study included 548 patients, of whom 311 (56.8%) had shockable (VF/VT) and 237 (43.2%) non-shockable (PEA or asystole) as an initial rhythm. TH was induced totally in 311 unconscious patients 85.8% in VF/VT and 31.4% in PEA or asystole group. Good neurologic outcome was achieved in 58.0% patients with shockable rhythms and in 19.4% with non-shockable rhythms after TH treatment. The mean PaCO2 tension during the first 24-hour in ICU was an independent predictor of a good outcome with an odds ratio (OR) of 1.054, but the mean PaO2 tension was not. The time spent above PaCO2 45 mmHg was associated with good neurologic outcome and patients with the highest mean PaCO2 and PaO2 values had better neurologic outcome than predicted with an OR of 3.2 (95% CI 1.1-9.2). IL-6 and S-100B was associated with time to ROSC and poor neurological outcome (p less than 0.001). Admission IL-6 was associated with extra-cerebral organ dysfunction (p less than 0.001) and was an independent predictor of poor neurological outcome with an OR of 1.006 (95% CI 1.000-1.011). Hs-TnT levels were elevated in all of the patients, higher in patients with poor vs. good neurological outcome 739 vs. 334 ng/l (p=0.028), but there was no statistical difference in mortality. Conclusions TH is well implemented in clinical practice in Finnish ICUs. The majority of OHCA patients with shockable rhythms survive with good neurology, while the outcome of patients with non-shockable rhythms is poorer despite the TH treatment. There was no harmful association between hyperoxia and outcome, but instead mild hypercapnia combined with mild hyperoxia might be beneficial during the first 24 hours. IL-6 was associated with extra-cerebral organ dysfunction and predicted neurological outcome after OHCA-VF/VT, while hs-TnT does not give any additional prognostic information.
  • Kuhlefelt, Marina (Helsingin yliopisto, 2016)
    Smoking cessation and surgical planning decrease complications and compromised healing in patients undergoing orthognatic surgery Orthognatic surgery is surgery for the correction of discrepancies in the facial skeleton. The main aim of the thesis was to identify factors that increase complications and compromised healing in these patients. Medical records of orthognatic patients treated at the Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland were retrieved retrospectively for the first two studies. For the last two studies patients planned for bilateral sagittal split osteotomy (BSSO) were recruited at the Department before surgery and followed up for one year. The outcome variable in the first study was the removal of one symptomatic titanium miniplate, whereas in the second study it was a surgical site infection. The predictor variables were age, gender, smoking status, duration of operation, general diseases, dimensions of mandibular movement and osteosynthesis supporting material. The main outcome variable in the third study was neurosensory disturbance, whereas in the last study it was temporomandibular disorders at one year post-operative. The main predictor variable in the third study was the degree of manipulation of the mandibular nerve and in the last study TMD before surgery, evaluated by the Helkimo Dysfunction index. Explanatory variables age, gender, smoking status, mandibular advancement and duration of operation were also recorded for the statistical analyses. 19.0% of the inserted miniplates were removed in 153 BSSO patients. Plate-related reasons for removal were infection and screw-loosening. 9.1% of the patients (n= 286) in the second study had a surgical site infection. Smoking was the only significant predictor for infections or removal of osteosynthesis material. 90.2% BSSO patients (n= 41) reported altered sensations in the lower lip one year after surgery. The disturbance tended to increase the more the mandibular nerve was manipulated during surgery. Four patients had a visible nerve laceration and all of them experienced a major burden of the altered sensation. Two of these patients (4.9%) had neuropathic pain. Most patients were satisfied with the treatment, but the four patients with visible nerve lacerations were not. A substantial proportion (42.5%) of the patients in the last study had TMD as one of the reasons for seeking treatment. The TMD did not change after treatment in the majority of patients (60%), 30% improved and for 10% the situation impaired. The main finding was that smoking cessation will reduce infections and the need for removal of osteosynthesis material. Regarding neurosensory complications, the surgical technique does matter, and nerve manipulation and lacerations should be avoided at all costs. TMD symptoms improved for only 30% of patients undergoing BSSO. Thus BSSO is not a predictable treatment for TMD patients.
  • Äyräs, Outi (Helsingin yliopisto, 2016)
    Background: Increased nuchal translucency (NT) has been used as a screening method for fetal aneuploidies since 1990s. It is also known to be associated with a wide variety of structural defects and genetic syndromes. Long-term studies with a large cohort about the neurodevelopmental outcome of euploid children with increased fetal NT are sparse and the neurodevelopment is worth further study. Aim: The primary aim of this study was to collect data on the pregnancy outcomes, long-term neurodevelopmental and overall outcomes in a large cohort of fetuses with increased NT from singleton pregnancies in order to improve parental counselling. Material: All singleton pregnancies referred to the Department of Fetal Medicine at the Helsinki University Hospital due to increased NT in the first-trimester screening during 2002 2007 were studied. The outcome data were retrieved from hospital databases and national registers. Results: There were 1063 fetuses with increased NT in the first-trimester screening. Abnormal karyotype was observed in 224 fetuses (21%) and adverse pregnancy outcome occurred in 322 (30%). Termination of pregnancy was performed in 209 (20%) and there were 43 (4%) miscarriages and perinatal deaths. Of the 834 euploid fetuses 74 (9%) had structural defects or genetic disorders. Favourable pregnancy outcome became less likely by increasing NT: favourable outcome occurred in 92% in the lowest NT group (95th percentile 3.4 mm) and in 18% in the highest NT group (≥ 6.5 mm). Of the euploid fetuses with normal second-trimester ultrasound examination 96% were healthy at the discharge from the delivery hospital. During the follow-up (mean 6.5 years) neurodevelopmental impairment was detected in 29 (4.2%) and it was severe in 12 (1.7%). Major structural defects, severe neurodevelopmental impairment, or genetic disorders were detected in 54 cases (7%). Conclusion: One in five fetuses with increased NT (≥ 95th percentile) has chromosomal abnormalities and one in ten of the euploid fetuses has structural defects or genetic syndromes. Major health impairment (major structural defect, severe neurodevelopmental impairment, or genetic syndrome) is likely to be detected in 7% of euploid children with increased NT in the first-trimester screening but normal findings in the second-trimester screening. These results are helpful in counselling the parents when increased NT is detected.
  • Ilander, Mette (Helsingin yliopisto, 2016)
    Chronic myeloid leukaemia (CML) is caused by a translocation between chromosomes 9 and 22. As a result of the translocation Philadelphia chromosome that contains a malignant oncogene is formed. Tyrosine kinase inhibitors (TKIs) target the malignant oncokinase that is produced from the oncogene and drives the development of CML. The prognosis of CML patients has improved significantly after the emergence of the TKI therapy. Some patients can even stop the treatment without imminent disease relapse. However, it has been shown that patients who stay in remission without any treatment still have leukemic cells left. We hypothesised that the immune system is able to keep these cells under control and studied the mechanisms behind immune surveillance by analysing the immune cell phenotype and function in CML patients. The results of this thesis show that the immune system plays a role in the successful discontinuation of the treatment. The results from 3 separate studies suggested that natural killer cells are important in successful treatment discontinuation in CML, and that they might be capable of activating T cells and adaptive immunity to keep leukaemia under control. We further studied the effects of 2nd generation TKI dasatinib, known to have immunomodulatory effects. We observed that dasatinib treatment increased the number of Granzyme B expressing memory CD4+ helper and CD8+ cytotoxic T-cells, which were highly active by secreting interferon  (IFN-. We hypothesise that these cells may have a role in the anti-leukaemia immune activity, as IFN- is known to be important in tumour control. The dasatinib induced antitumour immune effects were confirmed in a B16.OVA mouse melanoma model. We were able to demonstrate that dasatinib treatment increases the amount of tumour-infiltrating CD8+ cytotoxic T cells and induces a tumour size reduction dependent on the presence of functional T cells. Taken together, this thesis work illustrates the significance of an active immune system in successful treatment discontinuation in CML. Based on our results it would be important to combine immune activating agents in the future treatment strategies of CML in order to increase the number of patients who are able to successfully discontinue the treatment and be cured.
  • Vatanen, Anu (Helsingin yliopisto, 2016)
    Long-term ovarian function was retrospectively evaluated after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence. Cardiovascular risk factors, arterial morphology and stiffness, left ventricular (LV) mass and function, physical fitness and frailty were investigated in adult and adolescent survivors of high-risk neuroblastoma (HR NBL) after autologous HSCT in childhood. The first study population included a cohort of 92 female long-term survivors who were less than 20 years of age when treated at the Children s Hospital, Helsinki University Hospital, or Karolinska University Hospital, Huddinge, between 1978 and 2000. The follow-up data included signs of spontaneous puberty, age at menarche, the use of hormone replacement therapy, pregnancies, and information about pubertal or postpubertal serum FSH levels. The second study population included the Finnish national cohort of 19 long-term HR NBL survivors treated between 1980 and 2000, and 20 age- and sex-matched controls. Clinical examinations included 24h ambulatory blood pressure (BP), very-high-resolution vascular ultrasound, 3D echocardiography and Tissue Doppler Imaging ultrasounds, body composition, physical performance tests and interview. Older age at HSCT and total body irradiation and busulfan-based conditionings were risk factors for early ovarian aging. Leukemia survivors with previous cranial radiotherapy or transplanted after disease relapse were at high risk of premature ovarian failure. The HR NBL survivors showed increased carotid intima-media thickness, plaque formation and stiffness, increased radial artery intima thickness, and increased cardiovascular risk profile when compared to the controls. They had increased LV mass, decreased systolic and diastolic LV function when compared to the controls. Poor LV function associated with cardiac biomarkers, poor physical performance and increased BP. The survivors showed shorter telomere length and increased frequency of frailty phenotype when compared to the controls. The frailty phenotype associated with cardiovascular health and chronic inflammation. In conclusion, our study shows that the adult survivors after HSCT in young age are at risk of early reproductive and vascular aging and frailty. The survivors of pediatric HSCT require regular follow-up in adulthood and interventions for declining ovarian function, cardiovascular risk factors, high BP, subclinical signs of atherosclerosis and decreased cardiac function. Since lifestyle choices can influence cardiovascular health and frailty status, a healthy non-smoking lifestyle and physical activity should be advocated among all survivors who have received HSCT in childhood.
  • Koskinen, Anni (Helsingin yliopisto, 2016)
    Background: Chronic rhinosinusitis (CRS) is a multifactorial inflammation of the nose and paranasal sinuses. It is diagnosed by typical symptoms lasting more than 12 weeks and/or a computed tomography scan (CT) and/or endoscopic changes. In Europe the prevalence of CRS has been found to be 10.9% 1. The treatment of CRS is primarily conservative, with nasal saline irrigations and topical intranasal corticosteroids. Antibiotics are used primarily only during exacerbations. Comorbidities such as asthma and allergy should be treated efficiently as they can predispose to CRS. Immunodeficiency can also be discovered behind CRS or vice versa. Especially defects in humoral immunity are thought to be more prevalent among CRS patients than healthy controls 2. If conservative treatment of CRS fails, surgery is indicated. Endoscopic sinus surgery (ESS) is a well-established strategy in the treatment of patients with CRS refractory to maximum medical therapy. During the last decade balloon sinuplasty has partly replaced ESS in the treatment of CRS. In balloon sinuplasty the natural ostium of the sinus is dilated without removing mucosa or bone. Methods: First we performed a retrospective controlled study in which we compared humoral immunity between chronic- or recurrent rhinosinusitis patients and healthy controls. Immune responses to tetanus and diphtheria vaccines were evaluated by measuring specific antibody levels of the serum samples of 25 CRS patients and 30 control patients. Next we performed a retrospective controlled study in which we compared ESS and balloon sinuplasty in the treatment of CRS. In this study 208 patients with CRS without nasal polyps underwent either balloon sinuplasty or ESS of maxillary sinuses. Forty-five ESS patients and 40 balloon patients met the inclusion criteria. These patients were sent a postal questionnaire approximately 28 months postoperatively. Patient history factors, number of exacerbations, and a visual analog scale (VAS) scoring the change in symptoms between preoperative and postoperative status were evaluated. We also analysed intra- and early postoperative factors, such as operation time, anesthesia method and complications among the same patients treated either with ESS and balloon sinuplasty. To investigate the long-term efficacy and satisfaction among these patients we performed a phone-interview on average six years after the primary surgery. Patients were asked to compare present symptom status with the symptoms before the operation. Number of exacerbations and need for revision surgery were also evaluated. Results: We were able to show that after vaccination patients with chronic- or recurrent rhinosinusitis had on average 4.08-fold lower responses to diphteria toxoid than healthy controls recruited from hospital personnel. Antibody levels to tetanus toxoid were on average 2.20-fold lower among CRS patients than in the healthy control group. Fourteen out of the 25 rhinosinusitis patients had antibody levels that did not reach the 95% normal distribution range of healthy controls after either diphteria or tetanus vaccination. In the retrospective study comparing ESS and balloon sinuplasty, the groups were identical in response rate and patient characteristics. The duration of sick leave was significantly longer in the ESS group. However, the duration of sick leave was only an estimate of the recovery time made by the operating surgeon and does not necessarily correlate to the true recovery time. Eight ESS operated patients were detected with adhesions, as no adhesions were found in the balloon sinuplasty group. In the first questionnaire study, patients in both groups experienced equal improvement of all asked symptoms. The balloon sinuplasty group reported a statistically significant higher number of maxillary sinus punctures and antibiotic courses during the last 12 months. According to the phone-interview study, enrolled approximately six years after the primary operation, both groups experienced improvement in all symptoms and were equally satisfied with the operation. The number of patient-reported acute exacerbations was again higher among the balloon dilated patients. Four patients in the balloon sinuplasty group underwent revision surgery. There were no revisions in the ESS group. These findings were statistically significant. Conclusion: A significant proportion of our study patients had reduced antibody responses to protein vaccines. This could indicate that CRS patients might have impaired humoral immunity predisposing them to chronic and/or recurrent infections. Responses to protein vaccines might be used to evaluate immune status of CRS patients. Results of our study comparing ESS and balloon sinuplasty showed that the techniques seemed comparable in terms of operation time, anesthesia method and low complication rate. The putative benefits of balloon sinuplasty might be lower adhesion formation, shorter recovery time and possibility to be performed in-office. Except the increased number of revisions in the balloon sinuplasty group, both techniques seemed to retain the efficacy and patient satisfaction in average two and six years after the surgery. Patients in our study were carefully selected with neither nasal polyposis nor severe sinonasal pathology. This should be borne in mind when applying these results in clinical practise. The role of balloon sinuplasty in the management of CRS patients with nasal polyposis or more extensive disease needs to be established by further studies.
  • Dudek, Mateusz (Helsingin yliopisto, 2016)
    Alcohol addiction is one of the most prevalent brain disorders in the world. A major hurdle for reducing alcohol-related harms and developing effective treatments is the poor understanding of neural processes responsible for the development of dependence and addiction. Alcohol has been shown to affect various neurotransmitter systems; however, the mesolimbic dopamine (DA) system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), has been thought to play a key role in producing the reinforcing effects of alcohol. The VTA region has also been suggested to be the anatomical site for the interaction of the dopaminergic system with the opioidergic and γ-aminobutyric acid (GABA) systems. Here, manganese-enhanced magnetic resonance imaging (MEMRI) and behavioral tests were used to study drug-induced alterations in brain activity of the alcohol-preferring AA (Alko Alcohol) and heterogeneous Wistar rats. MEMRI is based on the ability of paramagnetic Mn2+ ions to accumulate in excitable neurons, thus enhancing the T1-weighted signal in activated brain regions. Mn2+ ions can also be transported anterogradely and retrogradely in neurons, released to the synaptic cleft, and taken up by other neurons. These properties allow MEMRI to measure long-term changes in brain activity, as well as map neural pathways involved in acute and long-term drug actions, including drug reward and toxicity. The AA rats exposed to alcohol compared to water controls displayed a widespread and persistent activation in brain regions that have been previously linked with alcohol reinforcement. Similarly, activity in neural pathways originating in the NAc and projecting caudally to the midbrain was enhanced in alcohol drinking rats. Moreover, this alcohol-induced activation was blocked by systemic naltrexone (NLX) administration. Comparison of naïve AA and Wistar rats revealed a lowered basal activity in the caudal linear nucleus (CLi) of AA rats, which was restored by voluntary alcohol drinking. The intra-CLi γ-aminobutyric acid type A receptor (GABAA) agonist muscimol produced a dose-dependent increase in alcohol drinking, blocked by co-administration of the GABAA antagonist bicuculline, suggesting that the CLi GABAergic system is involved in the regulation of alcohol reward. MEMRI was also employed for assessing stimulant-induced toxicity. Methamphetamine and mephedron displayed disparate effects on brain activity, as methamphetamine produced widespread decreases in activity, whereas mephedron increased activity in limited brain areas. Taken together, the use of MEMRI for mapping alcohol- and stimulant-induced alterations in functional brain activity revealed networks and specific pathways that have potential for guiding further translational efforts to develop medications for drug abuse disorders, as well as for evaluating drug-induced toxicity.