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  • Medvedovsky, Mordekhay (Helsingin yliopisto, 2015)
    During the last years magnetoencephalography (MEG), has become an important part of the pre-surgical epilepsy workup. Interictal activity is usually recorded. Nevertheless, the technological advances now enable ictal MEG recordings as well. The records of 26 pharmaco-resistant focal epilepsy patients, who underwent ictal MEG and epilepsy surgery, were reviewed. In 12 patients prediction of ictal onset zone (IOZ) localization by ictal and interictal MEG was compared with ictal intracranial EEG (icEEG). On the lobar surface level the sensitivity of ictal MEG in IOZ location was 0.71 and the specificity 0.73. The sensitivity of the interictal MEG was 0.40 and specificity 0.77. The records of 34 operated epilepsy patients with focal cortical dysplasia (FCD) were retrospectively evaluated. The resected proportion of the source cluster related to interictal MEG was evaluated in respect to postoperative seizure outcome. 17 out of 34 patients with FCD (50%) achieved seizure freedom. The seizure outcome was similar in patients with MR-invisible and MR-visible FCD. With MEG source clusters and favorable seizure outcome (Engel class I and II) the proportion of the cluster volume resection was 49% - significantly higher (p=0.02) than with MEG clusters but unfavorable outcome (5.5% of cluster volume resection). Median nerve somatosensory evoked MEG responses were processed by movement compensation based on signal space separation (MC-SSS) and on spatio-temporal signal space separation (MC-tSSS). MEG was recorded in standard and deviant head positions. With up to 5 cm head displacement, MC-SSS decreased the mean localization error from 3.97 to 2.13 cm, but increased noise of planar gradiometers from 3.4 to 5.3 fT/cm. MC-tSSS reduced noise from 3.4 to 2.8 fT/cm and reduced the mean localization error from 3.91 to 0.89 cm. The MEG data containing speech-related artifacts and data containing alpha rhythm were processed by tSSS with different correlation limits. The speech artifact was progressively suppressed with the decreasing tSSS correlation limit. The optimal artifact suppression was achieved at correlation of 0.8. The randomly distributed source current (RDCS), and auditory and somatosensory evoked fields (AEFs and SEFs) were simulated. The information was calculated employing Shannon's theory of communication for a standard 306-sensor MEG device and for a virtual MEG helmet (VMH), which was constructed based on simulated MEG measurements in different head positions. With the simulation of 360 recorded events using RDCS model the maximum Shannon's number was 989 for single head position in standard MEG array and 1272 in VMH (28.6% additional information). With AEFs the additional contribution of VMH was 12.6% and with SEFs only 1.1%. To conclude, ictal MEG predicts IOZ location with higher sensitivity than interictal MEG. Resection of larger proportion of the MEG source cluster in patients with FCD is associated with a better seizure outcome, however, complete resection of MEG source cluster is often not required for achievement of favorable seizure outcome. The seizure outcome is similar in patients having MR-positive and MR-negative FCD. MC-tSSS decreases the source localization error to less than 1 cm, when the head is displaced up to 5 cm; however, it is reasonable to limit use of movement compensation for no more than 3-cm head displacement to keep the head inside sensor helmet. The optimization of the tSSS correlation limit to about 0.8 can improve the artifact suppression in MEG without substantial change of brain signals. MEG recording of the same brain activity in different head positions with subsequent construction of VMH can improve the information content of the data.
  • Pemovska, Tea (Helsingin yliopisto, 2015)
    Adult acute myeloid leukemia (AML) effectively illustrates the challenges of contemporary cancer drug discovery and development, as molecularly targeted therapies have not yet been translated in clinical practice. In fact the standard therapy (cytarabine and an anthracycline) for AML has not been changed in over 40 years. As a consequence, outcome remains poor with overall survival of 30-40%. The genetic alterations that are associated with AML have been mapped, but the underlying disease mechanism is poorly defined due to large inter-patient heterogeneity. In contrast, chronic myeloid leukemia (CML) is strictly driven by BCR-ABL1 and drugs targeting the ABL1 kinase activity have paved the way for oncoprotein targeting drugs in the treatment of cancer. In CML the main clinical challenge is instead the emergence of resistance to ABL1-directed therapy. This resistance typically occurs through point mutations in the kinase domain of ABL1 such as the clinically challenging T315I mutation. Hence, in both leukemia types there is an unmet need for novel therapeutic strategies. This study focused on development and implementation of an Individualized Systems Medicine (ISM) platform to identify novel therapeutic strategies for leukemia patients. The ISM strategy incorporated functional ex vivo drug sensitivity and resistance testing (DSRT), deep molecular profiling and clinical information to facilitate identification of personalized therapy approaches. A large number of approved and investigational anti-cancer compounds were tested and individualized selective responses were quantified with drug sensitivity scores (DSS). RNA and exome sequencing data was used to identify genetic alterations that enabled associating drug sensitivities with genetic alterations and biomarkers. The DSRT approach enabled functional taxonomy of AML patient samples based on drug responses, provided insights into disease biology, and identified effective drugs and drug combinations for individual patients and thus facilitated drug repurposing. In addition, integration of DSRT and molecular data identified phenotype to genotype links that has a potential for rapid translation of results. Clinical implementation of ISM data was plausible in approximately 80% of relapsed and refractory AML patient cases, and meaningful and evaluable responses were achieved in approximately 40% of cases. Notably, emergence of in vivo resistance to targeted therapy was mirrored in the DSRT profile of the relapsed samples, highlighting a solid correlation between ex vivo and in vivo drug responses. Finally, this study identified a number of kinase inhibitors that can be repositioned for specific subtypes of AML and CML, such as dasatinib in combination with a FLT3 inhibitor for AML patients with FLT3-ITD mutations and axitinib for patients with BCR-ABL1(T315I)-driven leukemia. The results of this thesis demonstrate how unbiased drug sensitivity profiling of patient-derived cancer cells is a powerful way to discern unforeseen drug-disease and drug-target links with clinical implications and provides a workable concept that can be implemented in routine clinical care of cancer patients in the future.
  • Manninen, Otto (Helsingin yliopisto, 2015)
    Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B (CSTB). However, the disease processes leading to the observed symptoms are currently unclear. Clinical magnetic resonance imaging (MRI) of the brain has shown neurodegenerative changes and computed tomography data have suggested a bone phenotype. This thesis examined the disease processes and the background of the pathological changes in the brain and the bone, utilizing modern imaging methods and image analysis methodology complemented with experimental data in the mouse model (the Cstb -/- mouse) of the disease. In order to gain a comprehensive picture of the disease progression in the brain, we performed a longitudinal imaging study in the Cstb -/- mouse. Animals were studied from the pre-symptomatic to fully symptomatic disease stages (1-6 mo). For studying atrophic changes, in vivo MRI volumetry was preformed once a month from 1 to 6 months of age. For investigating white matter (WM) changes, ex vivo diffusion tensor imaging (DTI) was performed at 2, 4 and 6 months. The fractional anisotropy (FA) maps derived from DTI data were analysed using track based spatial statistics (TBSS) that provided us with a hypothesis-free analysis of white matter changes. In vivo volumetry showed progressive volume loss in Cstb-/- mice over time, the rate of which was neither spatially nor temporally uniform over the brain. TBSS revealed progressing FA decrease, suggesting severe and widespread WM damage, with most drastic changes in the cerebellum and the thalamus. Subsequently the congruence of the observed WM changes between the mouse model and EPM1 patients were evaluated. In vivo DTI data from fully symptomatic adult patients and ex vivo data from fully symptomatic (6 mo) Cstb-/- mice were analysed using TBSS with matching protocols. The results revealed extensive changes with a pattern of chronic WM degeneration in EPM1 patients, with similar alterations detected in Cstb-/- mice. Furthermore, previously unknown brain regions were shown to be affected both in patients and in mice. The imaging data were then used to guide tissue level analyses in mice. The microstructural counterpart of the areas with decreased FA in mice was characterized by immunohistochemistry and transmission electron microscopy. Based on the tissue level findings, the extensive changes identified by DTI in both EPM1 patients and in Cstb-/- mice are probably a consequence of widespread WM loss upon axonal degeneration, and likely contribute to the motor disturbances present in the disease. Finally, we characterized the bone changes underlying the observed skeletal phenotype in EPM1 patients by performing microtomography (µCT), histology, and in vitro cell culture experiments with the Cstb-/- mouse. Analysis of bone microstructure in Cstb-/- mice using μCT revealed structural changes. Moreover, histology confirmed both structural and functional alterations. The basis of these findings was investigated by studying the functionality of bone resorbing osteoclasts differentiated in vitro from bone marrow. In resorption pit formation assays, less and smaller resorption pits were formed by Cstb-/- osteoclasts, indicating decreased resorptive capacity, likely due to a decrease in osteoclast numbers. These data imply that the skeletal changes in Cstb-/- mice and EPM1 patients are a result of CSTB deficiency leading to altered osteoclast function, and the results would indicate that CSTB has a more substantial role as a modulator of bone metabolism than previously thought. Our results showed high correlations of the atrophy, WM and bone phenotypes between EPM1 patients and Cstb-/- mice and provided information about brain and tissue level changes present in these pathologies. High correlation between the mouse model and the findings in patients provided further affirmation for the use of the mouse model in EPM1 research. Furthermore, the results provided new insight both into the progression of brain pathology and the processes underlying the bone changes present in the disease. Finally, our research introduced new methodologies for research in mouse models of neurodegenerative diseases, and raised the prospects of future research.
  • Demir, And (Helsingin yliopisto, 2015)
    This study was undertaken to assess the feasibility of non-invasive sampling and assay of urinary gonadotropins for clinical evaluation of pubertal development. In the first study, the concentrations of LH and FSH in concurrent serum and first-morning-voided (FMV) urine samples of 820 children (486 boys and 334 girls, age 0-17 years) were determined with time-resolved immunofluorometric assay (IFMA). The detection limit of IFMA was 0.018 IU/L for FSH, 0.015 IU/L for LH and 0.012 IU/L for LHspec. It was possible to measure the low prepubertal LH and FSH concentrations reliably in these samples due to the high sensitivity and low detection limits of IFMA. The correlation between serum and urinary gonadotropin values was high (r=0.751; p < 0.001 for FSH and r=0.720; p < 0.001 for LH), and the urinary and serum concentrations were close to each other. Correcting urinary gonadotropin concentrations on the basis of urinary density or creatinine did not improve the correlation. Age-related changes in urinary LH and FSH (U-LH and U-FSH) were examined. The concentrations of U-LH and U-FSH decreased from birth until the child was a few months old, after which the upper range of the U-LH levels of girls remained stable at below 0.5 IU/L until age 9 years and of boys below 1.0 IU/L until age 11 years. The upper range of the U-FSH levels of girls remained below 3.0 IU/L until age 10 years and of boys below the same concentration until age 12 years. The median U-LH concentration during the prepubertal period was about 0.06 for girls and 0.07 for boys. For the boys, this figure rose 10-fold by age 11, 40-fold by age 12 and 50-fold by age 13-14. The overall increase in the median U-LH concentrations was 75-fold from 5 to 15 years and 35-fold from Tanner stage G1 to G5. The corresponding figures for girls were 30-fold by age 11, 70-fold by age 12 and 90-fold by age 14; the overall increase in median U-LH concentrations was 90-fold from 5 to 15 years and 40-fold from Tanner stage B1 to B5 times. These finding indicate that the U-LH concentrations of FMV samples obtained from clinically prepubertal children reflect pubertal levels. The age-related changes in U-FSH concentrations were similar for boys and girls; the only difference was that the levels were generally higher for girls, in particular between ages 2 8 years. U-FSH reached a 5-fold level compared to prepubertal levels by the end of the puberty in both sexes. FMV U-LH, U-FSH and their ratios correlated well with the corresponding basal and GnRH-stimulated serum concentrations (P < 0.001). Receiver operating characteristic (ROC) curve analyses of urinary and serum LH and FSH concentrations showed that FMV U-LH and U-LH/U-FSH performed equally well as the GnRH test for differentiating early puberty (Tanner 2) from prepuberty (Tanner 1) [area under the curve (AUC) 0.768-0.890 vs. 0.712-0.858]. FMV U-LH and U-LH/U-FSH performed equally well as basal S-LH for predicting a pubertal GnRH test result (AUCs 0.90 0.93). Among the tests studied, only FMV U-LH differentiated the transitions from Tanner stage 1 to 2 and Tanner stage 2 to 3 (p < 0.001 for boys and p-0.003 for girls). Again, this corroborates that FMV U-LH is the most reliable tool for evaluation of pubertal development. Therefore, FMV urinary LH determinations, which are non-invasive and, at most, minimally stressful for the child patient, can be used for preliminary diagnostic evaluation of pubertal development. It reduces the need for S-LH determinations and the GnRH stimulation tests, both invasive procedures.
  • Almangush, Alhadi (Helsingin yliopisto, 2015)
    Histopathological predictors of early stage oral tongue cancer Oral tongue cancer constitutes the majority of malignancies of the oral cavity. In Finland during 2013, the age-adjusted incidence rates of oral tongue cancer were 1.7 per 100,000 in males and 0.8 per 100,000 in females. Staging of the clinical status of tumor size, lymph node, and metastasis (cTNM staging) is a widely accepted system for classification of many cancers including oral squamous cell carcinoma (OSCC). However, this staging system failed to prognosticate the outcome of early stage oral tongue squamous cell carcinoma (OTSCC). Numerous studies designed to introduce prognostic parameters and/or models to complement the insufficiency of cTNM staging and to predict the patient outcome have been carried out. Many of these prognostic models (or systems) were based on histopathologic parameters. However, all of the previously introduced models showed little or no predictive power in early stage (cT1-2N0) OTSCC. Thus, the identification of markers that predict the outcome of patients with early stage OTSCC is still necessary in order to apply effective individualized treatment. In this international collaborative study, we have examined the prognostic impact of several predictive factors in large patient cohorts from 7 institutions located in 3 geographic regions (Finland, Brazil, and USA). Moreover, we have introduced a new simple predictive model (BD score) for histopathologic classification and prognostication of early OTSCC. We suggest that this model could possibly be easily applied during the surgical resection, so patients with aggressive OTSCC could benefit from elective neck dissection (END) during the same procedure. This model could offer a step forward toward the personalized management of OTSCC. However, additional validation in different patient cohorts is still required.
  • Vattulainen-Collanus, Sanna (Helsingin yliopisto, 2015)
    Pulmonary arterial hypertension (PAH) is one of the most severe vascular diseases. In addition to increased vasoconstriction there are significant histopathological changes in small pulmonary arteries of PAH patients. These histopathological changes include endothelial cell (EC) injury, vascular inflammation, medial hypertrophy, intimal hyperplasia, and plexogenic arteriopathy. Changes in EC phenotype are suggested to play an important role in the development of occlusive vascular lesions. This phenotypic switch involves apoptosis-resistance, hyperproliferative capacity, and changes in energy metabolism. Somatic genomic abnormalities have also been identified in vascular lesions from patients with PAH. Mutations in bone morphogenetic protein receptor 2 (BMPR2) have been tightly linked to the pathogenesis of PAH. The genetic landscape of PAH-associated mutations in Finnish population is poorly understood. In this study, we utilized a novel targeted next-generation sequencing approach called Oligonucleotide-Selective sequencing (OS-Seq) to evaluate the role of known PAH genes, confirming a relatively high incidence of BMPR2 mutations among analyzed Finnish PAH-patients. Pulmonary ECs from the patients with PAH are identified with severe somatic chromosomal abnormalities. The role of genomic instability during pathogenesis of PAH and the mechanisms behind these changes in ECs are yet unknown. The genomic instability in IPAH patient ECs and the occlusive vasculopathy resemble a neoplastic process. In this study we revealed that loss of BMPR2 in pulmonary ECs leads to increased susceptibility to DNA damage and establish a link between Breast cancer 1 and BMPR2. BMPR2 deficiency-associated loss of DNA damage control could play a role in PAH -associated EC dysfunction, genomic instability and altered cellular phenotypes. One of the critical transcription factors downstream of BMPR2 is peroxisome proliferator-activated receptor gamma (PPARγ). In mice the TIE2 promoter mediated EC-specific loss of functional PPARγ (TIE2CrePPARγflox/flox) leads to dysregulation of EC genes such as apelin and development of PAH. The role of PPARγ in vascular regeneration or angiogenesis has remained poorly understood. We show that dysfunctional PPARγ in ECs leads to attenuation of angiogenic capacity and migration defect. Purinergic signaling is one potential modulator of pulmonary vascular homeostasis. ATP is known to regulate a variety of cellular processes, including vascular remodeling. In response to cell damage, ATP is released into extracellular space and through several physiological mechanisms cells can regulate their basal ATP niche contributing to the growth and microenvironment of the cells. The role of ATP in vascular modulation is well-known yet its association with pathophysiology of PAH is still undefined. In ECs the CD39 enzyme is the most prominent ATP hydrolyzing enzyme. We showed that PAH patients manifest suppression of CD39 leading to excess ATP niche in vascular wall. Our results suggest that attenuated CD39 activity is tightly linked to vascular remodelling and phenotypic switch of ECs.
  • Bramante, Simona (Helsingin yliopisto, 2015)
    Despite the numerous advances in cancer therapy over the past 50 years, cancer still remains the major cause of mortality worldwide, and thus new and more efficient treatments are needed. Oncolytic viruses have shown promising results in preclinical and clinical studies for the treatment of solid tumors, but their efficacy often remains low. A multitude of viral strains, such as adenovirus, have been engineered to become tumor-selective and to stimulate the immune system against the tumors. One example of oncolytic virus is Ad5/3-D24-GMCSF, a tumor-selective 5/3 chimeric oncolytic adenovirus armed with the immunostimulatory granulocyte-macrophage colony-stimulating factor (GM-CSF). In this thesis, we studied the utility of Ad5/3-D24-GMCSF in the treatment of sarcoma, melanoma and breast cancer. The virus showed strong oncolytic potential in vitro and antitumor efficacy in immunodeficient animal models. Furthermore, replication-linked GM-CSF production stimulated the differentiation of human monocytes into macrophages, important for induction of antitumor immune responses. In immunocompetent Syrian hamsters with soft-tissue sarcoma (STS) tumors, Ad5/3-D24-GMCSF reached non-injected tumors through vascular circulation, suggesting its utility for the treatment of metastatic disease. We showed that combining Ad5/3-D24-GMCSF with chemotherapeutics that possess immunogenic properties (doxorubicin and ifosfamide) and that selectively reduce circulating regulatory T-cells (cyclophosphamide), enhanced adenoviral replication and induced immunogenic cell death, setting the stage for clinical testing of combination regimens. Finally we reported safety and possible signs of efficacy in 40 patients with advanced sarcoma, melanoma and breast cancer, who were treated in the context of an Advanced Therapy Access Program (ATAP). Treatments were overall well-tolerated, and objective signs of treatment benefits were also observed. Therefore, our results confirm previous good data regarding Ad5/3-D24-GMCSF as a promising agent for treatment of cancer. Furthermore, our data may prove useful for clinical development of oncolytic adenoviruses combined with low-dose chemotherapy for the treatment of advanced sarcoma, melanoma and breast cancer, and may help to design optimal clinical trials.
  • Markula-Patjas, Kati (Helsingin yliopisto, 2015)
    Children with juvenile idiopathic arthritis (JIA) are predisposed to compromised bone health and alterations in body composition because of chronic inflammation, nutritional and hormonal disturbances, limited physical activity and glucocorticoid (GC) therapy. Compromised bone health may present as pathological vertebral compression fractures, but data on their prevalence and risk factors in children are limited. Excess fat, and especially adipose tissue-derived adipokines leptin and adiponectin, may also contribute to impaired bone health. Furthermore, adipokines modulate immunity and inflammation in adults with rheumatic diseases, but their role in JIA has not been explored. We evaluated bone health in patients with severe JIA and investigated body composition and adipokines and their contribution to bone health and disease activity in JIA. We recruited two cohorts of patients for cross-sectional studies. The Severe JIA Cohort comprised 50 patients with severe polyarticular or systemic JIA. The GC-treated Cohort included 50 patients with JIA with mostly mild to moderate disease severity and at least three months' exposure to systemic GC. The results were compared with those of sex-and age-matched healthy controls. The study protocol included clinical and laboratory assessments, evaluation of bone mineral density (BMD) and body composition by dual-energy X-ray absorptiometry (DXA), spinal radiography and spinal magnetic resonance imaging (MRI). Spinal radiography showed vertebral compression fractures in 22% of the patients with severe JIA. Patients with fractures had higher weight-adjusted cumulative GC dose, higher disease activity and higher body mass index than those without fractures. Bone age-corrected BMD Z-scores for lumbar spine and whole body were similar between those with and without fractures. On spinal MRI, altogether 28% of patients with severe JIA showed vertebral fractures and several other vertebral changes, including end plate irregularities in 26%, anterior vertebral corner lesions in 16% and disc changes in 46%. Based on concentrations of bone turnover markers, the patients with severe JIA had increased bone resorption, but normal bone formation. Further, patients with severe JIA had increased body adiposity, and their serum leptin was increased even independently of fat mass. Leptin showed an inverse association with bone turnover markers in patients, while in controls the association was dependent on fat mass. In the GC-treated Cohort, fat mass, lean mass and serum leptin and adiponectin were similar to those of controls, but patients had slightly lower BMD values than controls. Those patients with lumbar spine BMD Z-score -1.0 tended to have higher serum leptin values than those with higher BMD Z-scores, but in regression analysis leptin was not associated with BMD. Adipokines did not correlate with current disease activity in either patient cohort. Patients with severe JIA have compromised bone health based on high prevalence of compression fractures. Risk factors include high GC exposure, high disease activity and high body mass index. BMD, as measured by DXA, is unable to differentiate between those with and without compression fractures. According to spinal MRI findings, patients with severe JIA have, besides compression fractures, several other changes involving intervertebral discs and vertebral end plates; the clinical relevance of these remains uncertain. Patients with severe JIA are prone to high adiposity, whereas those with less severe disease have normal body composition despite previous GC exposure. Leptin may negatively contribute to bone metabolism in severe JIA, but larger and longitudinal studies are needed to prove causality and to evaluate whether these preliminary findings are generalizable to other JIA groups. We did not observe a correlation between leptin or adiponectin and disease activity in either JIA cohort. The possible role of adipokines as a modulator of immunity and inflammation in JIA remains to be evaluated.
  • Siikamäki, Heli (Helsingin yliopisto, 2015)
    Study I analyzed Finnish travellers health problems abroad during 2010 2012. Information was drawn from a database kept by an assistance organization of insurance companies covering 95% of Finnish cases requiring aid abroad. The study included 50 710 cases. These data were compared to numbers of Finnish travellers from the Official Statistics of Finland to calculate incidences of illness and injury at various destinations. The most common diagnostic categories proved to be infections (60%) and injuries (14%); the most frequent diagnoses were acute gastroenteritis (23%) and respiratory infections (21%). Incidence was high in Africa, southern Europe plus the eastern Mediterranean, and Asia. Pre-travel counselling appears advisable also for visitors to southern Europe. Means for preventing gastrointestinal and respiratory infections are needed. Study II explored the final diagnoses of returning travellers with fever. This retrospective investigation comprised 462 febrile adults returning from malaria-endemic areas admitted to the Helsinki University Central Hospital emergency room during 2005 2009. The most common diagnostic categories were acute diarrhoeal disease (27%), systemic febrile illness (15%), and respiratory illness (15%). One traveller in four had a potentially life-threatening illness; septicemia proved as common as malaria (5% vs. 4%); one in ten had more than one diagnosis. The results suggest that the diagnostic protocol in tertiary hospital should in addition to malaria smears comprise blood cultures, influenza rapid test, and HIV test. Study III analyzed surveillance data on malaria cases reported to the National Infectious Disease Register 1995 2008 totalling 484 cases, and related them to travel statistics and antimalarial drug sales. The number of visits to malaria-endemic areas increased, whereas malaria cases did not, and a decreasing trend appeared in antimalarial drug sales. Infections were mostly acquired in Africa (76%). The most common species was Plasmodium falciparum (61%). Of all cases, 42% proved of foreign origin; in 89%, the infection was contracted in the region of birth, implying that immigrants visiting friends and relatives constitute a risk group with a particular need for pre-travel advice. Study IV analyzed in detail the background information on malaria cases diagnosed in Finland 2003 2011. The data included 265 cases, 54% of whom were born in malaria-endemic countries, and 86% currently lived in non-endemic regions. Of those born in non-endemic regions, 81% had received pre-travel advice, but only 20% of those born in endemic ones. Among travellers infected with P. falciparum, 4% reported regular use of appropriate chemoprophylaxis, yet individual rechecking by interview revealed that none had been fully compliant. These data suggest that, if taken conscientiously, mefloquine, atovaquone/proguanil, and doxycycline are effective as chemoprophylaxis against P. falciparum malaria.
  • Orivuori, Laura (Helsingin yliopisto, 2015)
    ABSTRACT Allergies have become a major public health problem in recent decades. Approximately 60 million people in Europe, and one billion worldwide, are affected by allergies. In Europe, approximately 30% of the population suffers from allergic rhinoconjunctivitis, approximately 20% from asthma, and 15% from allergic skin conditions. The farming environment has been shown to protect against allergies. In the present thesis, we studied the development of Immunoglobulin E (IgE) sensitization, allergic diseases, gut permeability and inflammation in children from farming and non-farming environments who participated in the PASTURE project (Protection against allergy: study in rural environments). Our results showed that early-age inflammation, measured with serum high-sensitivity C- reactive protein (hs-CRP) at the age of 1 year, was associated with decreased risk of IgE-sensitization at the age of 4.5 years. Our findings suggest that poor inflammatory response at infancy may predispose to IgE-sensitization. The allergy-protective effect of breastfeeding is debated. Our findings illustrated that increased breast milk soluble immunoglobulin A (sIgA) levels were associated with decreased risk of atopic dermatitis (AD) up to the age of 2 years. When the ingested dose of sIgA during the first year of life was considered, it was associated with decreased risk of AD up to ages of 2 and 4 years. Elevated sIgA levels in breast milk were associated with environmental factors indicating increased environmental microbial load. Serum immunoglobulin A (IgA) and immunoglobulin G (IgG) against cow s milk β- lactoglobulin (BLG) and wheat gliadin are induced by the antigen exposure, but the antibody levels are also affected by the gut permeability and inflammation. Elevated serum IgA or IgG antibody levels against BLG at the age of 1 year increased the risk of sensitization to at least one of the measured allergens or food allergens at the age of 6 years. Elevated levels of IgG against gliadin at the age of 1 year increased the risk of sensitization to any, at least one inhalant, or at least one food allergen at the age of 6 years. Our findings suggest that an enhanced antibody response to food antigens reflects alterations in mucosal tolerance, such as altered increased gut permeability and/or microbiota, which is later seen as sensitization to allergens. Fecal calprotectin is a marker of intestinal inflammation. We studied the association of early-infancy fecal calprotectin levels to the later development of allergic diseases in children from farming and non-farming environments, and further evaluated the effect of gut microbes on the levels of fecal calprotectin. Infants from a farming environment had higher levels of fecal calprotectin at the age of 2 months when compared to the infants from a non-farming environment. However, farming did not explain the very high levels of calprotectin, i.e. the levels above the 90th percentile. The infants with remarkably high fecal calprotectin levels at the age of 2 months, i.e. levels above the 90th percentile, had an increased risk of developing AD and asthma/asthmatic bronchitis by the age of 6 years. Infants who had high fecal calprotectin concentrations had less Escherichia in their feces. Our findings suggest that strong intestinal inflammation at early infancy represents a risk of allergic diseases, and the colonization with Escherichia coli is an important regulator of the inflammation implicating long-term health effects mediated by early intestinal colonization. In conclusion, the findings in this thesis show that the environmental microbial load plays an important role in the development of the immune system in infants and ultimately may affect the risk of developing allergic diseases. In addition to the direct effects on the infant, the effects of the environmental microbial load are also mediated indirectly through alterations in maternal milk composition. Interestingly, we found that an early intestinal inflammation is associated with the later risk of allergic diseases and gut colonization indicating a crucial role of gut colonization in the development of allergy. Keywords: Allergy, antibody, asthma, atopic dermatitis, farming environment, fecal calprotectin, IgE-sensitization, inflammation.
  • Knaster, Peter (Helsingin yliopisto, 2015)
    Chronic pain is a long-lasting burdensome condition. Comorbid psychological symptoms are common in chronic pain patients and they tend to worsen the treatment outcome. The aim of this cross-sectional study was to assess the prevalence of psychiatric comorbidity in chronic pain patients and to assess the associations between chronic pain, anxiety, anger, and depression. The study participants in the study were one hundred consecutive chronic pain patients referred to the Meilahti Pain Clinic of Helsinki University Hospital. The subjects were interviewed with the Structured Clinical Interview for DSM-IV for Axis I disorders (SCID-I). In addition self-report questionnaires were used in the assessment. Most (75%) patients had at least one lifetime mental disorder. The prevalence of major depressive disorder (MDD) was 37% and of a specific anxiety disorder 25% over the past 12 months. The psychiatric comorbidity was associated with increased pain intensity, measured by Visual Analogue Scale (VAS). The majority (77%) of the anxiety disorders had their onset before the onset of pain, whereas only 37% of the mood disorders preceded pain onset. The Harm Avoidance (HA) scale of the Temperament and Character Inventory (TCI) of Cloninger was associated with pain-related anxiety measured with Pain Anxiety Symptom Scale-20. The pain intensity influenced the strength of the association between the Harm Avoidance HA4 subscale and pain-related anxiety. Higher pain intensity was associated with stronger association between the variables. Likewise, pain intensity influenced the association between anger management and depression. A tendency to inhibit angry feelings was associated the somatic and physical symptoms of depression, measured by a two-factor model of the Beck Depression Inventory (BDI). The association was stronger in patients with higher pain intensity. Chronic pain patients with current MDD scored higher in both the somatic and cognitive-emotional subscales of the BDI compared with those without MDD. However, the somatic-physical-related items were more strongly associated with the diagnosis of MDD. Psychiatric disorders are common in chronic pain patients. Because of their influence on the chronic pain treatment and outcome, their thorough assessment is important. The linking mechanisms between chronic pain and the psychiatric disorders and symptoms are complicated and there is an overlap between the constructs. Clear boundaries between pain, anxiety and depression can be difficult to draw, which can be a reflection of the common background mechanisms such as common neural circuits and neurotransmitters.
  • Louhimo, Riku (Helsingin yliopisto, 2015)
    Cancer is one of the leading causes of death in industrialized nations and its incidence is steadily increasing due to population aging. Cancer constitutes a group of diseases characterized by unwanted cellular growth which results from random genomic alterations and environmental exposure. Diverse genomic and epigenomic alterations separately and jointly regulate gene expression and stimulate and support neoplastic growth. More effective treatment, earlier and more accurate diagnosis, and improved management of cancer are important for public health and well-being. Technological improvements in data measurement, storing and transport capability are transforming cancer research to a data-intensive field. The large increases in the quality and quantity of data for the analysis and interpretation of experiments has made employing computational and statistical tools necessary. Data integration - the combination of different types of measurement data - is a valuable computational tool for cancer research because data integration improves the interpretability of data-driven analytics and can thereby provide novel prognostic markers and drug targets. I have developed two computational data integration tools for large-scale genomic data and a simulator framework for testing a specific type of data integration algorithm. The first computational method, CNAmet, enhances the interpretation of genomic analysis results by integrating three data levels: gene expression, copy-number alteration, and DNA methylation. The second computational method, GOPredict, uses a knowledge discovery approach to prioritize drugs for patient cohorts thereby stratifying patients into potentitally drug-sensitive subgroups. Using the simulator framework, we are able to compare the performance of integration algorithms which integrate gene copy-number data with gene expression data to find putative cancer genes. Our experimental results indicate in simulated, cell line, and primary tumor data that well-performing integration algorithms for gene copy-number and expression data use and process genomic data appropriately. Applying these methods to diffuse large B-cell lymphoma, integrative analysis of copy-number and expression data helps to uncover a gene with putative prognostic utility. Furthermore, analysis of glioblastoma brain cancer data with CNAmet suggests that a number of known cancer genes, including the epidermal growth factor receptor, are highly expressed due to co-occuring alterations in their promoter DNA methylation and copy-number. Finally, integration of publicly available molecular and literature data with GOPredict suggests that treating patients with FGFR inhibitors in breast cancer and CDK inhibitors in ovarian cancer could support standard drug therapies. Collectively, the methods developed here and their application to varied molecular cancer data sets illustrates the benefits of data integration in cancer genomics.
  • Peuralinna, Terhi (Helsingin yliopisto, 2015)
    This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40% of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.
  • Sivula, Mirka (Helsingin yliopisto, 2015)
    Disseminated intravascular coagulation (DIC) is common in critically ill patients. Patients with disturbed coagulation develop more organ dysfunction and have higher mortality. The pathophysiology behind the increased morbidity and mortality remains unclear. This study assessed the applicability of diagnostic tools for DIC: a modified score for overt DIC and thromboelastometry (TEM), a viscoelastic coagulation monitor. A further aim was to evaluate matrix metalloproteinase-8 (MMP-8), tissue inhibitor of metalloproteinase-1 (TIMP-1), nucleosomal histone-complexed DNA (hcDNA) and high-mobility group box 1 (HMGB1) protein levels in severe sepsis with disturbed coagulation and to assess their association with organ dysfunctions and outcome. Studies I-IV comprised 769 patients. Study I included 494 unselected critically ill patients in whom the incidence of DIC was studied by a modified score for overt DIC. Study II was a prospective pilot study with 28 patients with severe sepsis and ten healthy controls. TEM analyses were performed on admission to intensive care unit (ICU). Study III contained 22 patients with severe sepsis, in whom serum MMP-8 and TIMP-1 concentrations were measured repeatedly. Study IV was a sub-study of a large, prospective, observational, multicentre study conducted in 17 Finnish ICUs (FINNAKI Study). Admission levels of hcDNA and HMGB1 were analysed from 225 consecutive patients. In the university hospital ICU, incidence of DIC ranged from 31% (I) to over 40% (II, III). A multicentre study revealed a lower incidence (33%) of thrombocytopenia in severe sepsis patients. Components of the score discriminated patients with DIC well; only fibrinogen proved useless. Discriminative power of antithrombin was comparable to D-dimer and prothrombin time ratio. TEM trace was hypocoagulable in DIC patients as compared with other sepsis patients and healthy controls. Clot strength and clot formation parameters discriminated DIC patients well from those without DIC. In all patients fibrinolysis was inhibited. The markers speculated to contribute to coagulation disturbance and organ dysfunction, MMP-8, TIMP-1, hcDNA and HMGB1, were higher in patients with disturbed coagulation. HcDNA and HMGB1 were also elevated in patients with acute kidney injury and adverse outcome. HcDNA was an independent predictor of thrombocytopenia.
  • Kulovesi, Pipsa (Helsingin yliopisto, 2015)
    The tear film covers the cornea and conjunctiva providing nutrients to the corneal cells and protecting it from the external environment. Tear film is composed of three intermixed layers. Mucous matrix covers the epithelial cells and is gradually mixed with the aqueous layer which is covered by a thin lipid layer. The lipid layer consists of both polar and nonpolar lipids. Lipids are thought to prevent the collapse of the tear film onto the ocular surface and to retard evaporation from the tears. In this study several in vitro methods were used to study the surface properties and organization of different lipid mixtures resembling those in the tear film lipid layer. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), and freefatty acids (FFA) were used as the polar lipids and cholesterol oleate (CO), triglycerides (TG), and wax esters(WE) were used as the nonpolar lipids. Langmuir film technique was used to examine the behavior of the lipid films during compressions and de-compression. Brewster angle microscopy (BAM) and atomic force microscopy (AFM) were utilized for visualizing the films. Grazing incidence X-ray difraction was used for surface structure studies. The results of experimental studies were compared with coarse-grained molecular dynamics simulations. Custom built system was used to evaluate the evaporation retarding effect of several lipid mixtures containing wax esters. Compression isotherms showed one to two kinks in the compression curve that account for the rearrangement of the lipids in the film for all mixtures studied. Hysteresis was small meaning that these films are very stable and little, if any, solubilization of lipids into the aqueous phase takes place. All lipid films studied were more or less inhomogeneous when viewed with BAM, especially in higher surface pressures. This is most likely caused by the nonpolar lipids aggregating on the lipid film surface. This was also seen in the simulation studies where CO and TG formed circular aggregates on top of the polar lipids. Nonpolar lipids stabilized the films under high compression by arranging so that the lipid film could have a lower surface pressure than would be expected for small surface areas. However, an excess of nonpolar lipids caused the films to be more inhomogenous and to have less stable structure. Lipid mixtures that contained wax esters did not retard evaporation, which suggests that lipids' function in the tear film may have more to do with maintaining a thin tear film and preventing its collapse rather than preventing evaporation. The task of TFLL is still under debate, although it has been regarded to be the evaporation barrier, hindering the movement of water molecules out from the tear fluid. This, however has been questioned in this thesis project. Although some WEs have been shown to retard the evaporation of water, this effect is lost when different lipid species are mixed, as was done in this study where several WE species were mixed with PC, CO, and TG. No evaporation retarding effect was detected for any mixtures studied. Evaporation retarding lipid films must be very tightly packed but this is not possible for TFLL-like films because the tear film lipids must also be suitable for the environment they are in where they must adapt to fast changes in surface pressure and must also be fluid. This cannot be achieved by the films that have been shown to retard evaporation as these films are rather stiff and cannot be compressed.
  • Laine, Merja (Helsingin yliopisto, 2015)
    Cardiometabolic health among male former elite athletes Regular physical activity is one of the cornerstones in the prevention of chronic diseases. The aim of this study was to assess whether a former career as a male elite athlete associates with various cardiometabolic disorders and whether it has any effect on leukocyte telomere length in later life. The original study population (N=4136) consists of 2424 male former elite athletes and 1712 matched controls. Of those, 599 (392 former athletes, 207 controls) participated in a clinical study in 2008. The athletes were divided into three groups based upon their previous career: endurance, mixed and power sports. The clinical study in 2008 included a physical examination, laboratory tests, and several questionnaires. Data on use of medication was obtained from the Finnish Social Insurance Institution. Among the participants, the former elite athletes tend to have lower age-adjusted prevalence of type 2 diabetes compared with the controls (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.45-1.01). The male former athletes also had lower age-adjusted risk for hypertension (OR 0.69, 95% CI 0.49-0.98), metabolic syndrome (OR 0.57, 95% CI 0.40-0.81), and non-alcoholic fatty liver disease (OR 0.61, 95% CI 0.42-0.88) compared to the controls. The former athletes had significantly lower age-adjusted body fat percentage compared to the controls (p=0.021) whereas no significant differences in mean age-adjusted leukocyte telomere lenght between the athlete and control groups (p = 0.845) were observed. Moreover, with aging the former athletes maintained their physically active lifestyle better than their controls. A male former elite athlete career seems to protect from type 2 diabetes, hypertension, metabolic syndrome, and non-alcoholic fatty liver disease at older age. It was also associated with a more favorable body composition. The volume of current leisure time physical activity was inversely associated with these cardiometabolic outcomes.
  • Kupari, Jussi (Helsingin yliopisto, 2015)
    The Glial cell line-derived neurotrophic factor (GDNF) family ligands, which include GDNF, neurturin (NRTN), persephin (PSPN) and artemin (ARTN), signal through a glycosyl phosphatidyl inositol (GPI)-linked cognate-receptor (GFRα1-4) and the transmembrane receptor tyrosine kinase receptor RET. The members of the GDNF family play a particularly important role in the development of the peripheral nervous system (PNS). In the autonomic nervous system, GDNF and NRTN regulate important steps in the development of the enteric and parasympathetic nervous systems from migration and proliferation to soma size and target innervation, whereas ARTN takes part in the early phases of sympathetic nervous system development. In the sensory system, GFRα2 ¬ the co-receptor of NRTN has been shown to mediate trophic signaling for nonpeptidergic nociceptive neurons, and is also required for their innervation of the glabrous epidermis. However, several aspects of the role of GFRα2-signaling in normal PNS development and function remain poorly understood. Therefore, the aims of this study were to elucidate (1) the role of GFRα2-signaling in the development of parasympathetic neurons; (2) the role of GFRα2-signaling in two classes of somatosensory mechanoreceptor neurons and their target innervation; and (3) the role of GFRα2-signaling in the cholinergic innervation of the gastric mucosa and the role of this innervation in gastric secretion. We discovered that programmed cell death (PCD) is a normal part of parasympathetic neuron development in mice. GFRα2-signaling was found to regulate parasympathetic neuron survival in pancreatic and submandibular ganglia during late embryonic development; lack of GFRα2-mediated signaling resulted in the loss of intrapancreatic neurons through PCD. In argreement with previous studies, apoptosis in the ENS was found to be rare, and was not increased in the absence of GFRα2, implying that the normal number of enteric neurons is not determined by PCD. In the dorsal root ganglia (DRGs), we found that GFRα2 regulates the cell size, but not the peripheral innervation of hair follicles in both the large early-RET RA Aβ-class low threshold mechanoreceptors (LTMRs) and in the small C-LTMRs. In contrast, GFRα2 was found to regulate both the cell size and the epidermal innervation in the small Mrgprd+ C-nociceptors. We also found evidence that the RA Aβ-LTMRs downregulate GFRα2-expression at some point after birth, suggesting a possible switch in neurotrophic signaling pathways. In the enteric nervous system, we demonstrated that GFRα2-signaling via NRTN is required for cholinergic innervation of the gastric mucosa. Interestingly, this innervation was found to be unnecessary for maintaining the gastric mucosa and for gastrin secretion and basal acid secretion. Even though vagally-stimulated secretion is lost in the GFRα2-KO mice, their ability to secrete acid in response to direct parietal cell stimulation remains in the absence of gastric mucosal innervation.
  • Marinkovic, Ivan (Helsingin yliopisto, 2015)
    Intracerebral hemorrhage (ICH) represents the subtype of stroke carrying the most detrimental outcome and highest mortality. It is clearly underinvestigated and lacks an effective treatment except supportive management measures. The dismal outcomes of ICH are clearly associated with the mass effect of hematoma accompanied with dynamic perihematomal edema (PHE) and potential intraventricular bleeding (IVH), which is often complicated by development of hydrocephalus. In this thesis, we aimed to develop novel therapy modalities, which apart from experimental conditions, might be found effective in clinical scenario, and successfully implemented in ICH treatment clinical protocols in the future. In study (I), we utilized autologous blood injection model and magnetic resonance imaging (MRI) follow-up. Following the induction of deep right hemispheric hematoma of 75uL of volume, we performed decompressive craniectomy (DC) at 1 h, 6 h, and 24 h time points, aiming at diminishing high intracranial pressure (ICP) after the bleeding event. Control group did not undergo DC procedure. Decompressive craniectomy was found effective in reducing mortality and improving overall neurobehavioral outcome and mortality in all the 3 treatment groups. Effect of DC was most pronounced in the early craniectomy group (1 h). In study (II), we aimed to examine how deleterious is the influence of tissue plasminogen activator (tPA) in experimental ICH scenario, and whether the adverse tPA effects could be antagonized by the clinically safe mast-cell stabilizer chromoglycate. Animals were divided in four groups. We utilized intrahemispheric collagenase injection rat ICH model and MRI follow-up imaging up to 72h. Group 1 received tPA only, whereas Group 2 and Group 3 besides tPA received chromoglycate in single or double dose. Group 4 was used as a control having ICH, but receiving saline only. TPA-treated animals did not have significantly larger hematomas or hemispheric expansion even though been characterized by worse overall outcome. Application of chromoglycate in high dose mitigated detrimental outcomes present in the group being treated with tPA only, and diminished the extent of hemispheric expansion. This encourages further research to potentially establish "blind" thrombolysis concept coupled with concomitant application of MC inhibitors, as we could show that injurious tPA effects were successfully abolished by concomitant MC stabilization in experimental ICH scenario. In the third study (III), we decided to develop a novel combined ICH + intraventricular hemorrhage (IVH) model in the rat as such a model does not exist besides the fact that approximately 40% of all ICHs in human patients are complicated by presence of intraventricular hemorrhage which is known to worsen prognosis. We utilized different blood volumes of 100-250uL in modified autologous blood injection model to induce deep intrahemispheric ICH to establish a fully novel experimental approach of ICH followed by IVH. We performed 1-week MRI follow-up and consistent neurobehavioral evaluation at 24 h, 48 h, 72 h, and 1 week after hemorrhage. Using MRI, we identified the presence of hydrocephalus in all experimental subjects, and its progressive tendency during entire follow-up. The most prominent hemispheric expansion and the most pronounced hydrocephalus were present in experimental groups with >200uL blood injection. This model was reliable and highly reproducible, demonstrating promising initial point for ICH+IVH experimental research. These two novel treatment strategies established in our studies give promise for further refinements and potential applications in human patients. The novel ICH+IVH model we established in rat models may serve as an improved model for future experimental studies as it mimics human disease scenarios better than the existing models.
  • Sandboge, Samuel (Helsingin yliopisto, 2015)
    Background. A small birth size, an indicator of a suboptimal intrauterine environment, is a risk factor for several non-communicable diseases (NCDs), a risk that in many cases is modified by childhood growth patterns. Regional variation in NCD prevalence could partly have its origin in early development. Lifestyle factors further influence NCD prevalence. Aims. We aimed to explore the associations between early growth and adult resting metabolic rate (RMR), body composition, non-alcoholic fatty liver disease (NAFLD), and hypertension. We also studied the associations between fructose intake and NAFLD, and differences in birth size between Helsinki and the Åland Islands. Subjects and methods. The Helsinki Birth Cohort Study consists of 13345 individuals born in Helsinki in 1934‒44. Detailed records are available for all participants including information on maternal and birth characteristics and measurements of childhood body size. 2003 individuals participated in a clinical study in 2001‒04 and 1083 of these additionally participated in a follow-up study in 2006‒08. The Åland records include 1697 births for the years 1937‒44. Results. The association between birth weight and RMR was inverse among women and quadratic among men. A higher attained adult weight than expected, based on weight and height measurements before age 11 years and adult height, was associated with higher adult body fat content. The odds ratio (OR) for NAFLD was 18.5 (95% CI 10.1; 33.6) among those who belonged to the lowest BMI tertile at age 2 years and subsequently were obese as adults, compared to those who were still lean or normal weight as adults. NAFLD was most common among individuals with the lowest dietary fructose intake. Systolic blood pressure (SBP) and the presence of hypertension were inversely associated with linear (height) growth between ages 2 and 11 years. Relative weight gain after age 11 years was positively associated with SBP. Ålandic babies born 1937‒44 were 87 grams (95% CI 61; 111) heavier and 0.4 cm (95% CI 0.3; 0.5) longer than their Helsinki peers. Conclusions. A more pronounced increase in relative weight after age 11 years than would be expected from previous body size, was positively associated with body fat content, NAFLD, and hypertension. Conversely, several growth measurements before age 11 years were negatively associated with the outcomes studied. None of the studied individuals were obese in childhood. Instead, a larger relative childhood body size in this group most likely represents a more beneficial childhood environment. Contrary to previous findings, we found that individuals with the highest fructose intake were least likely to suffer from NAFLD. We found a small but significant difference in birth size between the Åland Islands and Helsinki for the years 1937‒44.
  • Lindahl, Jan (Helsingin yliopisto, 2015)
    Jan Lindahl: MANAGEMENT OF PELVIC RING INJURIES Unstable pelvic ring injuries are relatively rare injuries, but they constitute a major cause of death and disability in high-energy polytrauma patients Massive hemorrhage is the leading cause of potentially preventable death following a blunt pelvic trauma. The overall aim of surgical treatment for unstable pelvic ring injuries is to restore the pelvic anatomy and perform neural decompression, thus allowing normal function with a low rate of complications. This doctoral thesis was initiated to investigate the outcomes of acute and definitive management strategies for unstable pelvic ring injuries. The first study investigated the radiological and functional results of treating type B and C pelvic injuries with an anterior external fixation frame. The second study focused on identifying factors for early predictions of mortality-related outcome and prognosis in patients with pelvic fracture-related arterial bleeding that were treated with transcatheter angiographic embolization (TAE). The third study investigated the outcomes of type C pelvic fractures treated with standardized reduction and internal fixation methods. The fourth study evaluated outcomes and identified prognostic factors for operatively-treated, H-shaped sacral fractures with spinopelvic dissociation. Study I showed that an anterior external fixator failed to achieve and properly maintain reduction in 75% of type B open book injuries and in nearly all (95%) type C pelvic ring injuries. Therefore, an external frame is not a suitable method of treatment for the most unstable pelvic ring injuries as a definitive treatment. The current clinical applications of anterior pelvic external fixators comprise the resuscitation phase, initial fracture stabilization phase, and sometimes, in complex injuries (type C), the definitive phase for fixation of the anterior part of the pelvic ring, in conjunction with posterior internal fixation. Study II of pelvic fracture related arterial bleedings showed that the worst prognosis was related to exsanguinating bleeding from the main trunk of the internal or external iliac artery (large pelvic arteries) or from multiple branches of the internal or external iliac vasculature (high vessel size score). Definitive control of arterial bleeding was achieved with TAE in all patients. In massive hemorrhage with several bleeding arteries uni- or bilaterally, it is reasonable to use non-selective embolization by promptly occluding the main trunk of the internal iliac artery, either uni- or bilaterally. Study III of operatively treated type C pelvic fractures revealed that, internal fixation of injuries in the posterior and anterior pelvic ring provided excellent or good radiological results in 90% of cases. Additionally, because a reduction with displacement less than or equal to 5 mm was more often associated with a good functional outcome, that should be the goal of operative management. However, the prognosis is also often dependent on associated injuries, particularly a permanent lumbosacral plexus injury. The results favoured internal fixation of all the injured elements of the pelvis for improved stability and a more accurate anatomical result in the entire pelvic ring. The H-shaped sacral fracture with spinopelvic dissociation is a rare injury pattern. Study IV revealed that lumbopelvic fixation was a reliable treatment method. The study also showed that neurological recovery and clinical outcome were associated with the degree of initial translational displacement of the transverse sacral fracture component. Permanent neurological deficits were more frequent and the clinical outcome was worst in completely displaced transverse sacral fractures. An accurate operative reduction of all sacral fracture components was associated with better neurological recovery and clinical outcome. We conclude, that with appropriate treatment of unstable pelvic ring injuries, and associated injuries in other organs, it is possible to achieve better survival rates and functional results, and to reduce long-term disability.