Lääketieteellinen tiedekunta

 

Recent Submissions

  • Salo, Heini (Helsingin yliopisto, 2017)
    This study presents the materials, methods, and results of the economic evaluations of 7-valent pneumococcal conjugate vaccination (PCV7) programme, influenza vaccination programme and human papillomavirus (HPV)-associated cost of illness study, all of which were used in the vaccine adoption decision-making process in Finland in 2001 2011. Vaccinations of all children aged 6 36 months with influenza vaccine were accepted into the NVP in 2007, infant pneumococcal vaccinations in 2010 and HPV vaccinations of all girls in 2013. When a new vaccine is considered for inclusion into the NVP in Finland the expected public health benefit, the safety of the vaccine for an individual, the safety of the vaccination programme at the population level, and the cost-effectiveness of the vaccination programme are evaluated. An economic evaluation is needed to support the decision-making process. The decision-makers have not specified an explicit range of cost-effectiveness threshold values below which an intervention would automatically be accepted and lead to funding. In the first economic evaluation of the infant PCV7 vaccination programme (excluding indirect herd effects) the cost per QALY gained was EUR 54 600. In the economic re-evaluation, including the indirect herd effects of the vaccination programme in older age groups reduced the cost per QALY gained to EUR 20 600. The influenza vaccination programme of healthy children was found to yield cost savings from the health care provider perspective even though the indirect herd effects and influenza-associated deaths were excluded. The vaccination programme was estimated to save annually EUR 7.6 per vaccinated child aged 0.5 4 years when the assumed vaccine efficacy was 60%. In Finland, there is a considerable annual disease burden of HPV-related genital disease in the female population. Most of it is detected by the 446 000 annual screening tests, 55% of which are carried out as opportunistic tests. The opportunistic tests account for 71% of the total of EUR 22.4 million screening costs. Further diagnostics, management and treatment of HPV-related genital disease resulted in an additional cost of EUR 22.3 million, of which the costs of less severe HPV-related disease manifestations were EUR 15.5 million. Considering all tests taken both within and outside the organised programme, the 5-year coverage of Pap testing in Finland was 87% among women aged 25 69 years. At present, the successful reduction in the cervical cancer incidence and mortality is due to tests taken both within and outside organised screening. Opportunistic Pap testing both substitutes and overlaps with the tests taken within the organised programme. Overlapping tests stem from the lack of coordination and result in over-management of reversible lesions. In order to be able to coordinate organised and opportunistic Pap testing without losing the high coverage, it is essential to establish a nationwide Pap test register. Furthermore, such a register is necessary for the effective and cost-effective secondary prevention of cervical cancer, which will be needed in both unvaccinated and vaccinated populations.
  • Kaskinen, Anu (Helsingin yliopisto, 2017)
    Congenital heart defects (CHD) are classified as acyanotic and cyanotic. In cyanotic CHD, a mixing of deoxygenated in oxygenated blood reduces arterial oxygenation and the child may be cyanotic, i.e., bluish. Many children with CHD need cardiac surgery. Congenital cardiac surgery often aims to restore normal circulation and correct the defect as seen in vast majority of pulmonary atresia with ventricular septal defect (PA+VSD), but palliative surgery may also be needed or may be the only possible treatment strategy. After congenital cardiac surgery excessive extravascular lung water (EVLW) may appear and impair optimal gas exchange. Effective clearance of EVLW and lung edema rests on active airway epithelial Na+ transport. Postoperative lung edema after congenital cardiac surgery has principally been assessed by chest radiography (CXR), which may be inaccurate and causes irradiation. Excessive EVLW promotes appearance of artifacts called B-lines in lung ultrasound (US), whereas lung compliance associates negatively with increased EVLW. In this thesis the effect of chronic hypoxemia on lung liquid transport was studied in children with CHD. Second, feasibility of lung US and lung compliance in assessment of EVLW and in predicting short-term clinical outcome was tested after congenital cardiac surgery. Third, the long-term survival of a cyanotic CHD was retrospectively evaluated in patients with PA+VSD. According to our findings, the airway epithelial Na+ transport was impaired in profoundly hypoxemic children with cyanotic CHD. After congenital cardiac surgery, lung US B-line score and static lung compliance correlated with CXR lung edema assessment. However, ventilator-derived dynamic lung compliance may not reflect the state of lung parenchyma similar to static compliance. Furthermore, both early postoperative lung US B-line and CXR lung edema scorings predicted short-term outcome interpreted as length of postoperative mechanical ventilation and intensive care. Among factors affecting the long-term survival of PA+VSD the primary anatomy of pulmonary circulation and achievement of repair were most important. In summary, our results emphasize the effect of postoperative pulmonary complications on short-term outcome after congenital cardiac surgery. Our data suggests that hypoxemia may attenuate the constitutional mechanism of the lung to prevent excessive lung liquid accumulation. To detect this, lung US can be used to complement CXR when assessing EVLW in children undergoing cardiac surgery. This may be particularly useful in profoundly hypoxemic children with cyanotic CHD and may promote early recognition of postoperative pulmonary complications. Although primary anatomical factors affect long-term outcome of PA+VSD, an important form of cyanotic heart disease, the treatment should aim for corrective surgery in all PA+VSD patients.
  • Smeds, Eero (Helsingin yliopisto, 2017)
    Accurate control of motor performance requires close co-operation between the motor and sensory functions of the human nervous system. Proprioceptive information about the positions and movements of one s own body parts needs to be carefully monitored to allow fine-tuning of motor output. At the same time, the brain needs to block the influence of distracting external stimuli, such as movements of other persons and various sounds, on the ongoing movements. My thesis focuses on the cortical processes related to these phenomena. In the first studies of this thesis, we explored motor stability by recording brain and muscle activity with magnetoencephalography (MEG) and electromyography, respectively, from healthy adults who were maintaining a steady finger pinch. We analyzed the effects of simple auditory and visual distractors as well as observed movements of another person on the functional state of the primary motor (MI) cortex. All studied stimuli caused transient enhancement of the coupling between cortical and muscular activity at ~20 Hz, reflecting the maintenance of stable motor output. As expected based on earlier studies, movement observation also caused mirror activation in the MI cortex of the viewer, demonstrated by MEG-power suppression at ~7 and ~15 Hz. Importantly, these two simultaneous but opposite processes occurred at distinct frequency bands, suggesting that they were mediated by different populations of MI neurons. The results might explain how the human brain blocks the effects of external distractors on motor behavior and prevents unintentional imitation of observed movements. The latter part of my thesis focuses on cortical activity evoked by proprioceptive afference in adults and newborns. In adults, we recorded MEG responses to proprioceptive input elicited by passive finger extensions and flexions. The amplitudes of the ~70-ms (extension) and ~90-ms (flexion) responses in the primary somatosensory cortex increased by a factor of ~3 and ~6, respectively, when the interstimulus interval was prolonged from 0.5 to 8 s. These findings suggest an optimum interstimulus interval of 1.5 3.0 s for future applications in research and in the clinic. Finally, we showed using electroencephalography that proprioceptive stimulation with continuous passive hand movements elicits a prominent cortical response already at the neonatal phase. Such a passive-movement-based stimulation method could help assess the integrity of somatosensory pathways in neurologically impaired newborns. This thesis improves understanding of the cortical mechanisms essential for proper motor control. The gained knowledge can ultimately benefit diagnostics, treatment, and follow-up of motor-system impairments ranging from movement disorders to neonatal cerebrovascular problems.
  • Myntti, Tarja (Helsingin yliopisto, 2017)
    Chorioamnionitis, the main single cause of preterm delivery, can be subdivided into clinical and subclinical forms. The latter is more common and includes intra-amniotic infection (IAI), inflammation, and histologic chorioamnionitis (HCA). Amniotic fluid (AF) biomarkers can help in diagnosing subclinical chorioamnionitis, which is necessary for optimal timing of delivery. The aim of the study was to evaluate AF biomarkers in the diagnosis of intra-amniotic infection. The study population comprised 155 cases with a suspicion of IAI or preterm prelabor rupture of the membranes (PPROM) and 46 controls. Amniocentesis was performed in 105 cases between 22+0 and 36+5 weeks of gestation and in 46 controls. AF was obtained vaginally from 53 cases. In such AF samples, AF-lactate dehydrogenase (AF-LD) and AF-Glucose concentrations were determined. Determination in amniocentesis samples was of AF-LD, AF-Glucose, AF-matrix metalloproteinase (MMP)-8, AF-cathelicidin, AF-MMP-9, AF-myeloperoxidase, AF-interleukin-6, AF-neutrophil elastase (HNE), AF-elafin, AF-MMP-2, AF- tissue inhibitor of matrix metalloproteinases -1 (TIMP-1), AF-MMP-8/TIMP-1 molar ratio, and AF-C-reactive protein (CRP) levels. AF-MMP-8 measurement was by an immunoenzymometric assay, AF-LD and AF-Glucose by immunochemiluminometric assays, and others by commercial ELISA. Microbiological analyses were based on molecular microbiology and culture techniques. Placental histopathologic examination was performed. The most optimal cut-off value based on the ROC-curve for AF-LD in vaginally obtained AF against HCA was 1029 IU/L with a sensitivity of 65% and specificity of 69%. In such samples, glucose concentrations did not differ between women with or without HCA. In amniocentesis samples, AF-LD and AF-Glucose correlated with HCA and MIAC, and the most optimal cut-off values for both end-points were a respective 429 IU/L and 0.7 mmol/L. When AF-LD and AF-Gluc concentrations were adjusted by gestational age at amniocentesis, the association disappeared. AF-MMP-8, AF-cathelicidin, AF-MMP-9, AF-MPO, AF-IL-6, AF-Elafin, AF-HNE, and AF-TIMP-1 were associated with MIAC, but AF-MMP-2 and AF-CRP were not. The results were similar also when adjusted by gestational age at amniocentesis. Neutrophil-produced biomarkers were associated with IAI. In conclusion, the accuracies of AF-LD and AF-Glucose were quite poor, and better biomarkers for IAI diagnostics are essential. None of the other biomarkers studied out-performed others. IAI seemed, however, to be associated with neutrophil activation. The usefulness of each biomarker for clinical purposes depends more on local circumstances and laboratory method availability than on exact differences in accuracy.
  • Moisala, Mona (Helsingin yliopisto, 2017)
    Executive functions are pivotal in our everyday lives, as they form the basis for complex and goal-directed behavior. For example, the ability to maintain information in memory while making a decision requires executive processes. Whether or not executive functions can exhibit experience-dependent changes is still a topic of debate, but generally accepted principles of brain plasticity suggest that environmental factors can have an impact on cognitive processes and the activity and structure of their respective brain networks. One such environmental factor is the increasingly ubiquitous daily interaction with technology, which has been suggested to affect mental faculties such as the ability to maintain focus on a single task or to actively maintain information in short-term memory. The aim of the present thesis was to study activity in cortical networks of attention and working memory. In addition, we investigated whether any associations could be found between the recruitment of these networks or performance speed and accuracy in working memory and attention tasks, and the extent of daily technology-mediated activities reported by adolescent and young adult participants. In all studies, functional magnetic resonance imaging (fMRI) was used to record brain activity during task performance. By using novel experimental paradigms, the present results shed more light on the specific cortical networks recruited by different executive functions by showing that both common and specific brain regions are recruited by auditory and visual selective attention, divided attention and working memory processes. Furthermore, they demonstrate that during division of attention between two concurrent tasks (listening to speech and reading text), competition for neural resources in regions shared by the component tasks is a major contributor to performance limitations observed during multitasking. Importantly, the results of the present thesis also demonstrate that detectable associations exist between different types of daily technology use and cognitive functioning already in adolescence. More specifically, the results demonstrate that a tendency to use several media simultaneously (i.e., media multitasking) is related to increased distractibility. The extent of computer gaming in daily life, in turn, is associated with enhanced working memory functioning. These findings are of great importance, since it is vital to understand how the increasing amount of on-screen time might affect or interact with the cognitive and brain functioning of the current youth.
  • Salmiheimo, Aino (Helsingin yliopisto, 2017)
    Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Options for treatment are limited, and the only possibility of cure is radical surgery combined with chemotherapy. Inflammation and tumor stroma are important mediators in PDAC progression. Tumor-associated macrophages (TAMs), among other cells, create an immunosuppressive microenvironment and enhance tumor progression. Because they pivotally participate in tumorigenesis, TAMs are a potential target for therapeutic intervention. The aim of these studies was to explore inflammation and TAMs in PDAC. Three of the studies were conducted in cell cultures, and one was a retrospective clinical study. We polarized macrophages in cell cultures towards inflammatory M1 and anti-inflammatory M2 phenotypes and assessed the changes in the signaling pathways and the effect they had on pancreatic cancer cell migration. We studied the association of preoperative systemic inflammatory response (SIR), based on laboratory data, with the outcome of 265 patients with resectable PDAC. Tumor-associated anti-inflammatory M2 macrophages promoted pancreatic cancer cell migration in co-cultures by activating their MMP9 and ADAM8 expression. Support of the pro-inflammatory M1 phenotype causes these macrophages to inhibit cancer cell migration. Several intracellular STAT pathways and the NFkB pathway were activated by the interactions of cancer cells and macrophages. In preoperative laboratory data, patients elevated C-reactive protein (CRP), an indicator of SIR, predicted worse postoperative survival. Moreover, low levels of albumin, the most abundant protein in human blood circulation, as well as elevated tumor markers CA19-9 and CEA, were associated with worse survival. These studies provide novel insight into the interaction of TAMs and PDAC. The results encourage further research into TAMs and exploration of the possibilities of skewing macrophage polarization toward the inflammatory M1 phenotype. Development of SIR seems detrimental for patients with PDAC and predicts worse outcome. Preoperative CRP, in combination with albumin and tumor markers and clinical data, could prove useful when evaluating patients prognosis.
  • Nyberg, Solja (Helsingin yliopisto, 2017)
    Work is a common source of stress in modern societies. Job strain is the most widely used definition of work stress referring to a condition in which an employee has simultaneously high psychological job demands and a low level of work control. The aim of this study was to examine the extent to which job strain might increase the risk of incident type 2 diabetes and is associated with diabetes risk factors, such as obesity and physical inactivity. Data were obtained from the cohort studies participating in the European IPD Work Consortium. The analyses were based on individual-level data from 19 studies and up to 170 000 participants. Job strain and lifestyle factors were assessed by questionnaires and biological risk factors were measured in a biomedical examination in eight studies. Incident type 2 diabetes was ascertained from electronic health and mortality registers, repeated glucose-tolerance tests during the follow-up, or annual questionnaires. Operationalized definitions of job strain, lifestyle and covariate variables were harmonised before any analysis of the associations or linkage to outcome data. In harmonisation analyses, abbreviated scales, that were comparable to the complete scales, were developed. Job strain was associated with diabetes and its risk factors. After adjustment for age and sex, the odds ratio of having job strain was 1.19 (95% CI 1.13-1.25) times higher for class-I obese participants (BMI 30 to less than 35km/m2), and 1.30 (95% CI 1.16-1.46) times higher for the combined class II and III obesity groups (BMI at least 35 kg/m2), compared to normal-weight participants (BMI 18.5 to less than 25 kg/m2). Job strain was also associated with physical inactivity (odds ratio 1.36, 95% CI 1.25-1.48). The risk of incident diabetes was 1.15 (95% CI 1.06-1.25) times higher among the participants who reported job strain than among those who did not. This association was also observed in the subgroups, including those with and without lifestyle risk factors, and before and after adjustment for lifestyle factors including obesity and physical inactivity. According to cross-sectional analysis adjusted for age, sex and socioeconomic position, the odds for diabetes were 1.33 (95% CI 1.13-1.56) higher among participants with job strain as opposed to those without. In conclusion, these findings show a robust association between job strain, diabetes and its key risk factors. Nonetheless, the effect size was modest, suggesting that interventions to reduce job strain would not be very effective in combating diabetes on the population level.
  • Ylivinkka, Irene (Helsingin yliopisto, 2017)
    Glioblastoma is the most malignant brain cancer. Currently no cure has been established. The lethality of glioblastoma is a consequence of its extremely invasive nature: it rarely metastasizes outside the nervous system but effectively spreads throughout the brain parenchyma. This property, in addition to its challenging location makes it impossible to remove surgically. Furthermore, the tumors are heterogeneous and contain cells that are resistant to radiation therapy as well as to the only currently approved chemotherapy, temozolomide. Netrins are secreted extracellular matrix proteins. They were initially identified as proteins essential for the correct axonal wiring of both vertebrates and invertebrates. Later, they were observed to regulate the branching morphogenesis of various organs including mammary gland, lungs and pancreas. During recent years increasing number of studies have linked netrins to various forms of cancer. For example, netrin-1 induces the invasion of pancreatic, colorectal and hepatocytic cancers and medulloblastoma and promotes the survival of breast and lung cancer and neuroblastoma. Netrin-4 can modulate tumor growth, angiogenesis and metastasis. In the current work, we analyzed how netrins contribute to glioblastoma growth. We discovered that both netrin-1 and -4 regulate the malignancy of glioblastoma via independent pathways. Netrin-1 expression was upregulated in glioblastoma whereas netrin-4 was downregulated. However, both were associated with poor patient prognosis. The signaling pathways mediating the effects of these proteins were systematically explored. First, our results revealed a new mechanism where netrin-4 controls glioma cell proliferation via UNC5B and ITGB4 receptors. During normal cell culture conditions netrin-4 is abundantly expressed, and it binds to both UNC5B and ITGB4 receptors that counteract each other and keep glioma cell proliferation in balance. However, during glioma progression netrin-4 expression is decreased and the signaling is shifted towards ITGB4. This led to increased cell proliferation and tumor growth. Second, we discovered a mechanism through which netrin-1 promotes cell invasion. Netrin-1 expression associated with astrocytomas which are invasive glioma subtype. In glioblastoma cells it interacted with Notch2 and Jagged1 and facilitated the activation of the signaling. Subsequently, this led to an increase in cell invasion in vitro and in vivo. Furthermore, a unique invasion pattern was characterized where netrin-1 expressing cells were promoting the motility and stemness of the invasion leading stem-like cells. Third, we designed and engineered a recombinant peptide that had the capacity to inhibit netrin-1 signaling. This peptide was able to overcome the effects of the full-length netrin-1 and specifically inhibited the invasiveness of the stem-like glioblastoma cells in vitro and in vivo. This peptide may prove out to be of therapeutic value in GBM treatment.
  • Strien, Leena (Helsingin yliopisto, 2017)
    Sentinel node biopsy limits axillary lymph node resection to breast cancer (BC) patients with metastases in the sentinel node (SN). The reduced number of nodes allows detailed histopathologic assessment, followed by detection of foci < 2 mm size (micrometastases) or isolated tumor cells (ITC) ≤ 0.2 mm in size, with contradictory metastatic nature and prognostic significance. The aim was to investigate the malignant nature of smaller metastases by comparison analyses of altogether 1074 BC primary tumors (PT) and corresponding SN metastases, including macrometastases (≥ 2 mm in size), micrometastases and ITCs. This was performed by morphometry on 95 PTs and corresponding metastases and an analysis of MTA-1. Preoperative diagnostic needling as a possible cause for ITCs was investigated. HER-2 amplification analyzed by in situ hybridization was evaluated in 29 HER-2 amplified and 36 HER-2 non-amplified PTs and metastases, including ER and PR. Fifty-two BCs separated by Ki-67 ≤ 14% into luminal A and B subtypes for immunohistochemic CXCR4-, CCR7-, and Maspin-, and FOXP3-expression, all linked to more aggressive tumor behavior. Prevalence and risk factors for nonsentinel node (NSN) metastases in 484 patients with SN micrometastases and ITC were analysed. Statistical analyses were mostly descriptive. Factors between PTs and metastases were analysed by Chi square- and Mann-Whitney U -test and logistic regression analysis for NSN metastasis- associated factors as a nomogram. Morphometric analysis of ITCs showed similar atypia with the PTs. ITC prevalence was unrelated to PT biopsy methods. Concordance between PTs and ITCs in ER, PR, and HER-2 expression was high. HER-2 remained amplified in the metastases including the 3 cases with ITC. MTA-1, Maspin and CXCR4 expression pointed to more benign disease, no differences appeared between ITC and larger metastases. CCR7 expression and FOXP3-positive tumors showed some tendency toward more aggressive features; and combined CXCR4 and CCR7 seemed to suggest more aggressive disease. Factors associated with NSN metastases in patients with SN micrometastases an ITC were larger tumor size and multifocality. Only 7.2% had additional NSN metastases pointing to a low risk group. In the light of these studies, ITCs seem to represent malignant cells like micro- and macrometases, but their invasive character cannot be confirmed by these investigations. The expression of factors associated with invasion, metastasis, and poorer survival were expressed in ITCs as in their larger counterparts equally and seem to show connections with factors that may be associated with circulating tumor cells or tumor dormancy.
  • Brinck, Tuomas (Helsingin yliopisto, 2017)
    Background: Trauma is responsible for an annual five million deaths worldwide, as well as for long-lasting morbidity and disability, especially in younger patients. In the acute care of severely injured patients, randomized controlled studies are practically impossible. Trauma registries collect detailed information on severe injuries, treatment, and outcome, and thus serve as an important tool in evaluating quality care. Aim: To evaluate severely injured patients’ treatment and outcome at a tertiary trauma centre (the trauma unit of Helsinki University Hospital, HUH Trauma Unit) by means of both internal and international trauma registry comparisons, and to explore roles, challenges, limitations, and possible future applications of trauma registries in benchmarking and quality control in Finland. Methods: This retrospective analysis is based on the trauma registry of Helsinki University Hospital (TR-THEL) and the German Trauma Registry (TR-DGU) and analyses injuries, treatment, and outcome of severely injured adult patients (New Injury Severity Score ≥16) treated at the HUH Trauma Unit and at German level-one trauma centres between 2006-13. It assesses a prognostic model for outcome adjustment by internal and external validation, and analyses the effect of a massive transfusion protocol (MTP) in the treatment and outcome of haemodynamically compromised trauma patients (systolic blood pressure <90 or base excess <-5.0 on admission) at the HUH Trauma Unit. Results: The German level-one trauma centres numbered 85. Study populations ranged from 354 to 15,306 patients. Differences in treatment between southern Finland and Germany were identifiable in pre- and in-hospital treatment: in Germany, patients were under the care of an emergency physician on scene and were intubated and then transferred to hospital by helicopter more often than were the Finnish patients, and the length of stays in Germany both in an intensive-care unit and in hospital were longer than in Finland. The standardized mortality ratio (SMR; observed/predicted mortality) at the HUH Trauma Unit was 0.79 (95% CI 0.69-0.90) and at German trauma centres 0.82 (0.79-0.85). In subgroup analysis, a poorer outcome emerged for Finnish patients with a penetrating head injury (SMR TR-THEL 2.35; 95% CI 1.30-3.50 vs. TR-DGU 1.06; 0.94-1.18) and in younger Finnish patients (≤60 years) with an isolated head injury (SMR TR-THEL 1.40; 0.99-1.81 vs. TR-DGU 1.01; 0.87-1.15). Factors explaining this outcome difference were identifiable: early treatment limitations due to very poor prognosis in the TR-THEL, and only modest discrimination of the prediction model in external validation (area under the curve [AUC] 0.76; 95% CI 0.71-0.82) in patients with isolated traumatic brain injury. The SMR of patients with haemodynamic compromise treated at the HUH Trauma Unit decreased (indicating better survival) over time from 0.97 (before MTP; 95% CI 0.71-1.23), to 0.87 (the implementation of MTP; 0.49-1.25), to 0.79 (post MTP; 0.46-1.11). Conclusion: The overall adjusted outcome results at the HUH Trauma Unit were similar to those of the German level-one trauma centres, despite the obvious differences in pre- and in-hospital treatment between southern Finland and Germany. The overall awareness of damage control fluid resuscitation and introduction of MTP at the HUH Trauma Unit had a positive effect on outcome. In the evaluation of isolated head injuries, traumatic brain injury (TBI) -specific prognostic models should be the recommendation, because of general trauma-prediction model limitations for TBI-severity assessment. Trauma registry comparisons have several pitfalls calling for acknowledgement. Such comparisons are, however, a feasible method for benchmarking and controlling the effect of changes made in the treatment of severely injured patients. Finland needs to establish a trauma-registry network covering all five university hospitals.
  • Ghahramani, Abolfazl (Unigrafia, 2017)
    Occupational injuries are a major problem worldwide and affect all countries, particularly developing ones. In recent decades, the application of approaches such as the Occupational Health and Safety Management System (OHSMS) has led to the successful control of workplace injuries in high-income countries. The Occupational Health and Safety Assessment Series (OHSAS) 18001 as a world-recognized OHSMS has gained considerable acceptance by a large number of organizations. However, few studies have examined the effectiveness of OHSAS 18001 on safety performance in certified organizations. This study consisted of four sub-studies, and was conducted to explore the effect of OHSAS 18001 on the occupational injury, safety climate, and Occupational Health and Safety (OHS)practices in OHSAS 18001-certified companies compared with a control group in Iran. OHSAS 18001 practices were also examined in the certified companies, where interviews were conducted to explore the influencing factors on the effectiveness of OHSAS 18001. A negative binomial regression indicated no significant effect of OHSAS 18001 certification on the occupational injury rate. The second sub-study applied a new safety climate questionnaire, and a hierarchical regression indicated that the safety climate was influenced by the implementation of OHSAS 18001 and safety training. The third sub-study pointed to the better OHS practices of the certified companies compared with the control ones. The results also showed that adopting the OHSAS 18001 standard improved the documentation for the management of OHS, but did not lead to continuous improvement in the required practices. The evaluation of the collected evidence revealed the main reasons for a poor safety culture. The interviewees emphasized the internal and external influencing factors in the effectiveness of OHSAS including commitment of top management and the enforcement of OHS legal requirements. It can be concluded that the implementation of OHSAS 18001 in an organization is not a guarantee of improved safety performance and of the existence of a high-quality management system. This study suggests that certified companies should focus on proper improvement and maintenance of the implemented management systems by escalating their commitment to the requirements of the established management systems and by participating their employees in OHSAS 18001 practices. This study also emphasized the importance of providing safety training for employees who work in the certified companies. These efforts may help the companies in the creation of a good safety culture and the transforming the paper systems into effective management systems to make improvement in OHS performance.
  • Hautamäki, Asta (Helsingin yliopisto, 2017)
    Age-related macular degeneration (AMD) is the leading cause of visual impairment in developed countries. Geographic atrophy and exudative AMD, the advanced forms of AMD account for the majority of visual impairment. No evidence-based medical treatment exists for geographic atrophy, but the choroidal neovascularization (CNV) forming exudative AMD lesion can be targeted with therapy. Vascular endothelial growth factor (VEGF) has a crucial role in ocular neovessel formation. VEGF-inhibitors form the mainstay of present-day treatment of exudative AMD. Although response to anti-VEGF agents is usually good, marked individual variations exist in treatment outcomes. The reasons behind the variations are largely unknown. The aim of this study was to identify factors that predict treatment response during anti-VEGF therapy and affect activity of exudative AMD lesion. We analyzed the effects of CNV lesion characteristics, the effects of potential genetic predictors: variants of interleukin-8 (IL-8), VEGF, and erythropoietin genes, the effects of well-known risk factors for AMD: tobacco smoking, risk variants of complement factor H (CFH), ARMS2, and complement component 3 (C3) genes, and the variations in anterior chamber protein concentration (flare). Initial treatment response after the first injections of anti-VEGF agent bevacizumab was analyzed retrospectively in a material of 96 patients. Long-term treatment response and flare was studied in a prospective two-year follow-up of 50 patients treated with bevacizumab. Association of the genetic variant of IL-8 with earlier onset of exudative AMD was analyzed retrospectively using the medical records of 301 patients with exudative AMD, 72 patients with dry AMD, and 119 control subjects. The IL-8 (rs4073) promoter polymorphism has been associated with regulation of the production of IL-8, a potent mediator of inflammation and neovascularization. It was the only genetic factor in the analyses that had an association with the initial anatomic treatment response. It also had a marked cumulative effect on the long-term anatomic response together with the risk variants of VEGF and CFH genes. CNV lesion characteristics affected both functional and anatomic outcomes of initial treatment, but were less important in predicting long-term response. In the long term follow-up also the genetic variant of ARMS2 was associated with functional outcome. Flare reflected poorly the lesion activity and did not predict treatment response. However, the fellow eyes that developed exudative AMD later had higher flare values at the beginning of follow-up compared with the eyes that remained free of exudative AMD features. An association was also found between the variant of IL-8 and age of onset of exudative AMD. These findings support the hypothesis that IL-8 has a role in the process leading to CNV growth in exudative AMD and in the regulation of activity of exudative AMD lesion during anti-VEGF treatment.
  • Massinen, Satu (Helsingin yliopisto, 2017)
    Specific reading disorder (SRD), or developmental dyslexia, is defined as an unexpected difficulty in learning to read and write when intelligence and senses are normal. Hereditary factors are estimated to play a substantial role in the etiology of SRD, although the exact neurobiological mechanisms involved are rather poorly understood. In this thesis we have investigated the function of three SRD susceptibility candidate genes, DYX1C1, DCDC2 and ROBO1, with the aim of finding neurodevelopmental and molecular pathways that might shed light on the etiology of SRD. When research for this thesis began, knockdown of the rodent orthologs of DYX1C1 and DCDC2 had been shown to disturb radial neuronal migration in the developing cerebral cortex, but the function of human DYX1C1 and DCDC2 at the cellular level was still unclear. We discovered that both DYX1C1 and DCDC2 are involved in signalling pathways that are important in brain development; DYX1C1 is involved in estrogen signalling and DCDC2 is involved in ciliary signalling. We found that the effect of DYX1C1 on estrogen signalling was concerted through its interaction with estrogen receptors (ERs) in in the presence of the endogenous ligand, 17β-estradiol. We observed that DYX1C1 regulates the degradation of ERs, resulting in decreased transcriptional responses to 17β-estradiol. Our findings suggest that the effects of DYX1C1 on brain development may be at least partially mediated by ERs and that hormonal factors may play a role in SRD. We also observed DYX1C1 and ERα complexes in the neurites of primary rat hippocampal neurons, which suggests a role for DYX1C1 in rapid non-genomic ER signalling. The effect of DCDC2 on the ciliary signalling was such that the overexpression of DCDC2 was found to activate SHH signalling, whereas the downregulation of DCDC2 expression was found to enhance WNT signalling. We also observed that the DCDC2 protein localizes to the primary cilium in primary rat hippocampal neurons and is involved in regulating the length of the cilium through its role in stabilizing microtubules. DCDC2 was also found to interact with the ciliary kinesin-2 subunit KIF3A, a key molecule in function and maintenance of cilia. Consistent with a role in ciliary function, the overexpression of DCDC2 in C. elegans resulted in an abnormal neuronal phenotype that could only be observed in ciliated neurons. Our results were the first to suggest a role for DCDC2 in the structure and function of primary cilia. Later, others have reported more links between ciliary function and SRD candidate genes, most notably the putative role of DYX1C1 as a cytoplasmic assembly factor for ciliary dynein. ROBO1 has been discovered as a SRD susceptibility gene in a large multi-generation family, in whom a rare haplotype in the broad genomic area of ROBO1 is co-segregated with SRD. The expression of ROBO1 has been shown to be reduced from the SRD-associated haplotype, but the causal factor for the reduced expression was not known. In this thesis we have characterized genetic variation within the SRD-susceptibility haplotype by whole genome sequencing, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. We found several novel variants in the SRD susceptibility haplotype and tested transcription factor binding to four of the variants by EMSA. We did not detect transcription factor binding to three of the variants. However, one of the variants was bound by the LIM homeobox 2 (LHX2) transcription factor with increased binding affinity to the non-reference allele. Knockdown of LHX2 in lymphoblast cell lines extracted from subjects of the DYX5-linked family showed decreased expression of ROBO1 supporting the idea that LHX2 regulates ROBO1. Because the regulation of ROBO1 is likely to be complex and the effect of the novel variants was at the most very subtle in our experiments, it remains unknown if any of them are causal factors for the SRD susceptibility. The mouse ortholog of ROBO1 has been shown to have many functions in brain development: it is involved in neuronal migration of interneurons and pyramidal cells and in axonal guidance of major nerve tracts. The role of ROBO1 in mouse brain led us to test two hypotheses on two human populations: 1) We tested whether ROBO1 controls midline crossing of auditory pathways in the family with reduced expression of ROBO1 and 2) we tested whether in the normal population ROBO1 is involved in the development of the corpus callosum, the major axon tract connecting the cerebral hemispheres. The axonal crossing of the auditory pathways was studied using a functional approach, based on magnetoencephalography and frequency tagging. We found impaired interaural interaction in the subjects that had reduced ROBO1 expression supporting a defect in midline crossing of auditory pathways. Moreover, the deficit in interaural interaction depended on the ROBO1 in a dose-dependent manner. Our results suggest that ROBO1 controls midline crossing of the auditory pathways and were the first evidence of a SRD susceptibility gene being linked to a specific sensory function in the human brain. The role of ROBO1 in callosal development was assessed by studying whether polymorphisms in ROBO1 correlate with variation in the white matter structure in the corpus callosum. By using data acquired by both structural magnetic resonance imaging and diffusion tensor imaging we found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections from the body of the corpus callosum to the parietal cortical regions. Our results suggest that the human ROBO1 may be involved in the regulation of the structure and connectivity of the posterior part of the corpus callosum. Overall, our results support the idea that similarly as in mice, the human ROBO1 is likely to play many different roles in brain development. In conclusion, the results of this study have advanced the field of SRD research by suggesting new functions for SRD candidate susceptibility genes in cellular and developmental pathways that are highly relevant in the context of brain development. More studies will be needed to clarify the role of genes in the etiology of SRD and in the neurobiology of reading, but our results have provided clues that may be worthwhile to be investigated.
  • Puonti, Helena (Helsingin yliopisto, 2017)
    A beautiful, naturally-shaped and symmetrical breast mound will be created for a breast cancer patient after mastectomy using a free abdominal flap. The disadvantage with the breast reconstructed with this method is its lack of sensation, even some spontaneous reinnervation takes place from the surrounding tissues. The objective of the present study was to find and develope a method of dissecting and reconnecting nerves of the abdominal flap and the chest area in order to reconstruct a breast with sensation for the breast cancer patient. The first aim was to find out, which nerves in the chest and the flap, when coapted, would provide the best sensation to the reconstructed breast. The second aim was to investigate whether the dissecting of the nerves causes additional complications in the abdominal flap donor site. The third aim was to develop a better neurorrhaphy technique, using two nerve pedicles. The fourth aim was to assess and qualify the methods of sensory assessment employed in the study. Breast reconstruction with a free muscle-sparing transverse rectus abdominis myocutaneous flap (ms-TRAM flap) was performed in this study for 96 breast cancer patients in Savonlinna Central Hospital between 2001 and 2013. The reinnervation of the flap was performed in 44 patients with the novel dual neurorrhaphy technique and in 32 with single neurorrhaphy, and 20 breast reconstruction patients without flap reinnervation functioned as a control group. The contralateral healthy breasts of 38 breast reconstruction patients were used as the reference site, and 20 healthy volunteer women participated sensory testing of healthy abdominal skin. Skin sensation of the reconstructed breast was assessed two years after the surgery. In addition, between 2006 and 2013, sensory testing of the skin of the mastectomized breast was performed prospectively before the reconstruction surgery, and the healthy breast, abdominal skin and the reconstructed breast skin were also tested one year after the surgery. Sensory tests included clinical sensory examinations, quantitative sensory tests (QST), skin samples, and neurophysiological somatosensory evoked potentials (SEP). Additionally, a patient questionnaire of patients subjective sensory changes was carried out. Both neurorrhaphy techniques provided the reconstructed breast with better skin sensation than without neurorrhaphy, and dual neurorrhaphy resulted in better sensory recovery than innervation with single neurorrhaphy. All available tactile nerves in the chest area proved to be capable of restoring sensation to the ms-TRAM flap breast. No significant complications occurred in the abdominal wall in the flap donor site with either of the neurorrhaphy techniques. Nerve coaptations did not cause pain symptoms, and the increase in the operative time was insignificant. The function of large myelinated sensory fibres (i.e. vibration and tactile detection) recovered best. The poorest recovery took place in small unmyelinated sensory fibres (i.e. thermal detection and sharp-blunt discrimination). As a result of breast cancer treatment, tactile and thermal sensitivity of the mastectomized skin was reduced already before breast reconstruction surgery. All methods of sensory assessment employed in the study could detect the nerve damage caused by the surgery and measure nerve regeneration, with the exception of epithelial nerve fibre density (ENFD) testing, which could not identify nerve regeneration in the comparison of innervated and non-innervated breast reconstructions. Additionally objective SEP proved to be quite an insensitive method in diagnosing nerve damage, they might be suitable for follow-up of its recovery. QST and the clinical sharp-blunt discrimination test were the most sensitive tests both for the identification of sensory damage and nerve regeneration. Based on this study, we recommend dual neurorrhaphy of the ms-TRAM flap in breast reconstruction for use in clinical practice.
  • Vaara, Satu (Helsingin yliopisto, 2017)
    Coronary artery disease (CAD), acute coronary syndromes (ACS), and other conditions related to atherosclerosis are leading causes of death in developed countries. The incidence of CAD cannot be explained only by clinical risk factors, such as hypertension, dyslipidemia, diabetes and smoking; the genetics also matters. Major findings concerning the genetics of CAD have emerged during the last decade with many CAD-related risk variants found. This study evaluated the characteristics of the Corogene cohort of Finnish consecutive patients who underwent coronary angiography between 2006 and 2008. Furthermore, it evaluated the importance of clinical risk factors and genetic risk scores (GRS) formed of known CAD risk variants in predicting the ACS prognosis and sought for genetic differences between patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). The most common reason for coronary angiography in the Corogene Study during the study period was ACS. About half of all patients were finally revascularized either by percutaneous coronary intervention or coronary artery by-pass grafting. One-fourth of the patients had no signs of obstructive CAD in coronary angiography. GRS formed of 47 confirmed risk variants was found to be associated with recurrent ACS independent of clinical factors. Smoking and STEMI had an inverse association with the GRS. When compared to other studies evaluating GRS in recurrent ACS prediction, the GRS with 47 confirmed CAD variants included the greatest number of risk variants. As it did not improve the accuracy of prediction by clinical factors, the GRS has thus not yet proven useful in clinical practice. Smoking, having an inverse association with the GRS, may outweigh the genetic predisposition to CAD. Both clinical and genetic differences between STEMI and NSTEMI patients were studied and genome-wide association analysis revealed variants, including rs656843, at a locus near 1p13.3, to be associated nominally with NSTEMI. This finding could be replicated in another case-control sample of MI patients, but not in a prospective sample of FINRISK participants. The inverse correlation of the GRSs with STEMI, the finding of a genetic variant linked nominally to NSTEMI, and the fact that patients with NSTEMI and STEMI present with different clinical risk-factor profiles suggest that these two ACS subtypes may have somewhat different etiologies. The genetic variant conferring the risk for NSTEMI (rs656843) was also associated with peripheral artery disease (PAD) in ACS patients, but not in a general population sample of FINRISK individuals. The heterogeneity in PAD phenotypes and genetics may explain why the association could not be shown in a general population sample but only in a selected cohort of ACS patients.