Lääketieteellinen tiedekunta


Recent Submissions

  • Karjalainen, Riikka (Helsingin yliopisto, 2019)
    Acute myeloid leukemia (AML) is a clonal disease of immature hematopoietic cells. Treatment of AML patients is based on conventional chemotherapy and stem cell transplantation, but the majority of patients still suffer from relapse and poor overall survival. A growing body of evidence suggests that the BM microenvironment plays an important role in protecting leukemic cells from drug-induced apoptosis, which consequently leads to accumulation of residual leukemic cells and eventual relapse. Although several factors are involved in leukemic cell-BM interactions, the exact mechanisms of these interactions and comprehensive knowledge of their impact on the activity of different drug classes is lacking. Better understanding of the molecular mechanisms of drug resistance could facilitate the development of improved treatment strategies, and means to monitor patients who are at risk for developing drug resistance. Modern technologies, such as RNA sequencing and proteomics, are widening our possibilities to learn more about the molecular basis of AML and to discover predictive biomarkers for therapy resistance. In study I, we evaluated the effect of stromal cell secreted soluble factors on ex vivo drug responses in AML. We comprehensively evaluated how mononuclear cells (MNCs) collected from AML patients respond to 304 different inhibitors in stromal cell-conditioned medium compared to standard cell culture medium. From this study, we discovered that the stroma-derived factors altered response to 12% (36/304) of the drugs. Amongst the drugs, sensitivity to BCL-2 inhibitor venetoclax was significantly reduced by the stromal conditions. In follow-up experiments, we found that this effect could be overcome by inhibition of activated JAK/STAT signaling. In study II, we investigated gene expression profiles that were associated with resistance to BCL-2 inhibitor venetoclax. Ex vivo and in vitro analyses of AML showed that high expression of S100A8 and S100A9 calcium binding family genes correlates positively with venetoclax resistance. In contrast, BET (bromodomain and extraterminal) inhibitor OTX-015 acted synergistically with venetoclax in resistant AML cell lines and patient samples. In study III, our aim was to determine the applicability of proteins in biomarker discovery. We compared marker panels from proteomic and microarray transcriptomic assays using reproducibility optimized test statistic (ROTS) in the context of AML dysregulated processes and networks. The analysis led to discovery of protein markers specific for AML using LC-MS/MS derived data. In summary, this thesis shows that JAK/STAT inhibitors can counteract BM stroma-mediated resistance to the BCL-2 inhibitor venetoclax. Furthermore, we discovered a gene expression profile that correlates with ex vivo venetoclax resistance in AML and provide evidence of AML-related biomarkers from a proteomics dataset.
  • Sundholm, Johnny (Helsingin yliopisto, 2019)
    Very-high resolution ultrasound (VHRU, 25-55MHz) is a recently developed method for non-invasive assessment of vascular structures. With its increased ultrasound frequency, the method allows for noninvasive examination of the vascular wall in vivo with an axial resolution in the range of tens of micrometers. These characteristics make it a feasible method to determine vascular dimensions of superficial arteries and arteries in the pediatric population. The aim of this thesis was the following: 1. To study the application of a semi-automatic border detection software to improve measurement characteristics of the arterial wall layers, 2. To assess accuracy, precision and feasibility of the VHRU method in assessing superficial arterial wall layers in preterm and term neonates, 3. To validate the VHRU method to assess age-related intimal thickening of the arterial wall, and 4. To determine the potential to implement the method as a noninvasive tool in the bedside diagnosis of giant-cell arteritis of the temporal artery. This Thesis shows that there is no significant difference in the technical precision or bias of arterial wall layer dimension measurements using a semi-automated border detection software compared to electronical calipers, but time of analysis is significantly shorter using the automated border detection software. VHRU is feasible, accurate and precise in the measurement of arterial layer thickness (intima-media and intima-media-adventitia thickness) of proximal conduit arteries, such as carotid, brachial and femoral, in preterm and term neonates. The resolution of VHRU is insufficient in the assessment of more peripheral conduit arteries such as the radial artery. VHRU is feasible and able to detect a thickened intimal layer, seen as a four-line pattern of the arterial far wall in the ultrasound image, in superficial peripheral muscular conduit arteries with intima thickness >0.06mm. Measurements leading-to-leading edge of the intimal layer are accurate compared with histological thickness. VHRU is feasible, accurate and precise in assessing transmural inflammation related intimal thickening in patients with giant-cell arteritis of the temporal artery. The method was however not useful in patients with inflammation limited to the adventitia or without inflammation on histology. In conclusion, very-high resolution ultrasound is an emerging method for the assessment of superficial vascular wall layer structures. The harmless and non-invasive method can detect near-microscopical changes in the vascular wall in human subjects from the newborn stage to old age. Very-high resolution ultrasound has a clinical potential in the non-invasive assessment of vascular health and disease related pathology.
  • Hallamies, Sanna (Helsingin yliopisto, 2019)
    Breast cancer is the leading cause of cancer deaths and the most common cancer in women worldwide. Most patients are postmenopausal women. Breast cancer in men and young women is rare, and risk factors and tumour biology in these patients differ from that of postmenopausal women. Breast cancer in young women is known to be more aggressive and survival poorer than in breast cancer patients in general. Of the several genetic risk factors of female breast cancer, mutations in BRCA1, and especially BRCA2, are also known susceptibility genes of male breast cancer. The contributing role of other breast cancer genes to the genetic background of male breast cancer is unclear. The aim of this work was to characterize breast cancer in Finnish men and young women and to report the treatment results at Helsinki University Hospital of men diagnosed 1981–2006, and young women diagnosed 1997–2007. We also screened known genetic risk variants of female breast cancer in Finnish male breast cancer patients to detect possible risk factors of male breast cancer. We used immunohistochemistry techniques to profile further the breast cancer tumours of young women, especially in the triple-negative subgroup, to find possible prognostic biomarkers. We found that imaging studies were seldom used to diagnose breast cancer in male patients. Treatment delay was longer than in breast cancer patients in general, and the tumours were more often locally advanced. The five-year overall survival had improved from the previous report in our institution in 1982 from 44% to 75%. CHEK2 c.1100delC mutation was found in 5.9% of male breast cancer patients, and mutations were significantly more frequent amongst male breast cancer patients compared to population controls. In young women, an excess of adverse prognostic markers was detected. The five-year overall survival of 80% was lower compared with 89% for breast cancer patients in general. Breast cancer recurrences were more common in patients with hormone receptor-positive tumours compared to patients with hormone receptor-negative tumours. A total of 10% of patients with local disease at diagnosis experienced a locoregional recurrence. Of these, 40% of the women had been treated with mastectomy, and only one (13%) had received postmastectomy radiation therapy. Androgen receptor-positive tumours in young female breast cancer patients were associated with a significantly shorter overall and disease-free survival compared to patients with androgen receptor -positive tumours. The subgroup of patients with quadruple-negative (triple-negative and androgen receptor -negative) tumours showed a trend of having the best prognosis. Our results suggest that inclusion of CHEK2 c.1100delC mutation analyses as part of genetic testing of male breast cancer patients should be considered. Awareness of male breast cancer should be raised both amongst the general public and healthcare professionals. Our results provide insight into the prognostic effect of the androgen receptor, specifically in young breast cancer patients with triple-negative tumours. Larger studies with a longer follow-up time on this subject are warranted.
  • Nummi, Vuokko (Helsingin yliopisto, 2019)
    Von Willebrand disease (VWD) is an inherited bleeding disorder due to quantitative or qualitative defect of von Willebrand factor (VWF). The bleeding symptoms of affected patients range from mild spontaneous mucocutaneous bleeds to severe gastrointestinal, intra-articular, trauma- and surgery-associated bleeds. The reasons behind this intriguing variance of bleeding tendency are not well understood. This thesis aims at characterizing VWF in a cohort of VWD patients by means of phenotypic and genotypic studies and global coagulation tests, with specific focus on platelets and their VWF-dependent functions. These features were characterized in two patient groups: type 3, the most severe form of VWD with absent VWF (studies I to III), and in a group of patients who carry a historical diagnosis of any type of VWD (study IV). In study I, we reported the clinical features and focused on the molecular analysis of the VWF gene in 10 Finnish patients with type 3 VWD. In study II, type 3 was further characterized in 9 patients in the laboratory by evaluating the clotting capacity by thrombin generation assay in the presence and absence of platelets before and after VWF therapy. Finally, platelet expression of P-selectin and phosphatidylserine were investigated by means of flow cytometry. To cover the spectrums of treatment challenges encountered in VWD, a case report of a patient with anti-VWF alloantibodies and its management in an acute setting is presented (study III). Study IV included 83 subjects who carried a historical diagnosis of VWD. All patients were evaluated according to present guideline recommendations and additionally, we assessed whole blood platelet aggregation using Multiplate® and function using PFA-100®. In study I, we discovered that two main mutations of VWF, c.2435delC and c.4975C>T, account for 85% of the genetic defects of our Finnish type 3 VWD. Even though the genetic background was homogenous, the clinical expression varied. Among our patients, some had severe bleeding tendency and received regular VWF prophylaxis while others had only low spontaneous bleeding rates. Out of patients included, 30% (study I) and 44% (study II) had relatively mild bleeding phenotype and received only occasional on-demand therapy. In study II, we showed that these type 3 patients expressed less than 50% of normal thrombin generation (TG) capacity in plasma, and TG was dependent on FVIII levels. However, in platelet-rich plasma, TG was close to normal, suggesting a compensatory role for platelets. Study III describes the management of a 49-year old woman with type 3 VWD and a history of anti-VWF alloantibodies. Following an elective colonoscopy with biopsy, she suffered from extended life-threatening gastrointestinal bleeding. The administration of intravenous immunoglobulin infusions appeared to eliminate the alloantibody, and the patient was successfully treated with VWF therapy. In study IV, the historical VWD diagnosis was confirmed 93% of type 2 and 3 cases, but only in 26% of type 1. Laboratory results indicated low VWF for 26% of our historical type 1 patients. However, 47% of historical type 1 patients had currently normal VWF and FVIII. As a conclusion, the bleeding symptoms of patients who carry historical type 1 VWD diagnosis are not always explained by VWF deficiency. VWD was associated to abnormal platelet aggregation and function, associating also to the severity of bleeding symptoms. With these rapid methods, confirmation of VWD diagnosis can be performed promptly in the laboratory.
  • Lääveri, Tinja (Helsingin yliopisto, 2019)
    Travellers’ diarrhoea (TD) is the most common disease encountered by travellers to the (sub)tropics: it affects 20–70% of travellers annually. Although the disease is mostly mild and seldom requires hospitalisation, among children living in developing regions, the same pathogens may cause growth retardation and cognitive impairment and attribute to over 500,000 deaths each year. While the aetiology of TD has been widely studied, the results of these investigations are not fully reliable since with traditional culture-based methods the aetiology remains open in up to half of travellers with TD. Diarrhoeagenic Escherichia coli are the most common pathogens, but they often remain unidentified. The introduction of PCR-based diagnostic methods into TD research have brought a need to reassess our knowledge based on older investigations and new studies are needed. We developed a novel multiplex real-time quantitative reverse transcription PCR (RT-qPCR) assay that identifies the following diarrhoeal pathogens: enterotoxigenic (ETEC), enteroaggregative (EAEC), enteropathogenic (EPEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC) E. coli as well as Campylobacter, Shigella, Salmonella, Yersinia and Vibrio cholerae. The study groups in this thesis included 459 travellers recruited at a travel clinic pre-travel consultation and a group of 45 travelling together to Benin, West Africa. The travellers provided stool samples and questionnaires before and after travel. The aim of this thesis was to apply the novel molecular method on the aetiology of TD in various geographic regions, compare the impact of different definitions for TD and No TD on pathogen findings and analyse the association of pathogen findings to experienced symptoms. A pathogen was detected in 17% of stool samples when employing culture-based methods while the multiplex RT-qPCR assay detected a pathogen in 76%. Moreover, multiple pathogen findings were common: among the group travelling to Benin, two or more pathogens detected in 78% of stools. Furthermore, in the group of 459 travellers recruited at the Travel Clinic, a pathogen was detected in half of those remaining asymptomatic and those with antibiotic use during travel. In earlier studies, ETEC has been the most frequently identified pathogen in all regions other than Southeast Asia where Campylobacter predominate. In our study, EAEC and EPEC outnumbered these pathogens in all regions. This difference is mainly explained by the better coverage and higher sensitivity of the method applied. In TD research, either classical or WHO definition have been used for TD. Our results showed that both definitions are applicable. By contrast, defining control groups had greater impact: If the classical definition was used, control groups may have included not only the fully asymptomatic, but also those with mild or resolved symptoms. Moreover, if the control group included travellers with mild and resolved symptoms, the difference between those with TD and the control group would not have appeared significant for EAEC and Campylobacter. This thesis applied a novel PCR-based method with broad coverage to study the aetiology of TD. The results have changed our perception on the pathogen findings and their role in TD. When designing new studies on TD special emphasis should be given on defining control groups. PCR-based methods not only open up new possibilities into TD research but also show that the role of each pathogen should be re-evaluated.
  • Kesävuori, Risto (Helsingin yliopisto, 2019)
    The median sternotomy has been the gold standard approach for cardiac surgical procedures since 1957, when the superiority of the median sternotomy over different thoracotomy approaches for cardiac surgery was first described. In the sternotomy approach, surgical access to the heart is achieved after longitudinal division of the sternum. Less invasive methods for cardiac operations were introduced in the late 1990s to avoid the large incisions and sternal trauma caused by the median sternotomy. These minimally invasive techniques have evolved, and totally endoscopic robotically assisted cardiac operations have been performed recently through small ports in the intercostal spaces. This study’s objective was to evaluate the safety and effectiveness of minimally invasive cardiac surgery in a university teaching hospital with respect to learning curve, quality of life, and mid-term outcomes. It also describes a radiological classification for unilateral pulmonary edema (UPE) and evaluates the risk factors for UPE, as well as evaluating in detail a minimal volume ventilation method that aims to reduce pulmonary dysfunction after minimally invasive cardiac surgery. A total of 244 patients who underwent minimally invasive cardiac surgery between 2009 and 2017 at the Helsinki University Hospital were retrospectively reviewed for this study. The safety and efficacy of the robotic myxoma and mitral valve operations were comparable to the outcomes of the sternotomy operations: high repair rates and low complication rates were observed with the robotic and sternotomy approaches. Although intra-operative times and total ventilation times were longer with the robotic approach, intensive care unit stay was shorter after robotic mitral valve operations when compared with the sternotomy approach. Notably, a significant decrease of intra-operative times and ventilation times was observed during the learning curve of the robotic mitral valve operations. The 5-year survival and freedom from reoperation were similar after robotic and sternotomy mitral valve operations. Minimal volume ventilation during cardiopulmonary bypass (CPB) was associated with shorter ventilation times and lower postoperative arterial lactate levels compared with operations with no ventilation during CPB. The grading system for UPE correlated with the postoperative ventilation parameters: patients who had grade I UPE had lower PaO2/FiO2 values than patients who did not develop UPE, and total ventilation times among patients with grade II UPE were longer than with grade I UPE or no UPE. Also, substantial radiological interobserver agreement of the UPE grading was observed. This study showed that the robotic approach is a safe and effective method for mitral valve and myxoma surgery in a university teaching hospital setting. However, a significant early learning curve was observed with the robotic approach. Minimal volume ventilation during cardiopulmonary bypass was beneficial in terms of total ventilation times and postoperative arterial lactate levels, but larger prospective and randomized studies are needed to verify any possible benefits of minimal volume ventilation during minimally invasive cardiac operations. The UPE grading associated with total ventilation times and postoperative PaO2/FiO2 levels. These findings suggest that the grading system is reproducible and associates with clinical outcomes: grade I UPE has a measurable effect and grade II UPE a significant impact on postoperative pulmonary function.
  • Sibolt, Gerli (Helsingin yliopisto, 2019)
    Cerebral small-vessel disease (CSVD) is a common disease causing slowly progressive disability and earlier death. In CSVD, the destruction of subcortical networks leads to cognitive impairment, mood disorders, gait instability, and motor deficits. All those weaken the ability to be independent of help. Imaging features of CSVD can be visible on brain scans years before the first clinical symptoms. The imaging features are: cerebral white matter lesions (WML), cerebral microbleeds (CMB), perivascular spaces, brain atrophy, and lacunar infarcts. The aim of this thesis was to investigate the features of cerebral small-vessel disease and their association with long-term outcome in ischaemic stroke patients. The six publications were sub-studies of the Helsinki Stroke Aging Memory (SAM) study. The SAM cohort consists of 486 consecutive patients aged 55 to 85 years with ischaemic stroke who were admitted to Helsinki University Central Hospital. At 3 months, comprehensive clinical, neuropsychological, psychiatric, and radiological data were acquired. The cohort had a follow-up 21 years later using extensive national registers. The findings of the six publications can be summarised as follows: In post-stroke patients, the presence of WMLs was an indicator of ischaemic stroke recurrence up to 5 years after a first-ever ischaemic stroke and indicated a high risk of serious traumatic injuries, especially hip fractures requiring hospital treatment. After ischaemic stroke, patients with severe WMLs spent fewer days at home and became permanently institutionalised earlier, especially within the first 5 years. In post-stroke patients, depression and especially depression-executive dysfunction syndrome were associated with a shorter interval to ischaemic stroke recurrence. Post-stroke dementia predicted the recurrence of ischaemic stroke at the long-term follow-up. Post-stroke dementia was a robust predictor of institutionalisation. Imaging and clinical features of CSVD were associated with unfavourable outcome events, like earlier recurrent stroke, traumatic injuries, and earlier permanent institutionalisation.
  • Siuko, Mika (Helsingin yliopisto, 2019)
    Optic neuritis (ON) is caused by immune-mediated demyelination of the optic nerve. In ON the visual acuity of the patient usually decreases in one eye. Common additional symptoms include impaired colour vision, pain with eye movements, and pupillary dysfunction. While ON may present as a single episode, in about 20% of patients it is the first symptom of multiple sclerosis (MS). Approximately half of patients with MS are affected by ON at some stage of the disease. MS typically causes demyelination in the optic tract, cerebrum, brainstem, and spinal cord; MS symptoms are therefore extensive. With the revised diagnostic criteria of MS, the diagnosis of MS may sometimes be confirmed already after the first episode of ON. In addition to MS, another demyelinating disease associated with ON is neuromyelitis optica (NMO), also known as Devic disease. As the diagnostic criteria for this disease have recently evolved the most common term is neuromyelitis optica spectrum disorders (NMOSD). NMOSD is characterized by demyelinating changes in the spinal cord and an increased aquaporin-4 (AQP4) antibody index. There are currently no treatments that improve the prognosis of ON. However, high-dose corticosteroids may reduce the duration of symptoms and some medications may reduce the risk of MS development among patients with ON. The diagnosis of ON is demanding as the diagnosis is based on exclusion of other causes. Little is known about the factors that affect the natural course of ON. Severe visual impairment may result after multiple recurrences. We analysed the natural course of ON and its differential diagnosis, clinical findings, incidence, and connection to MS in Southern Finland during the period from 2008 to 2012. In addition, we studied the prevalence of NMO associated with ON in southern Finland and the development of NMO diagnostics. We also analysed genetic mutations by exome sequencing in NMO patients in Southern Finland. We observed that the incidence of ON in Finland has increased. This may be due to improved diagnostic methods and because diagnostic delay is briefer as patients nowadays actively seek medical attention with even minor symptoms. The seasonal variation in the number of ON diagnoses was also confirmed. The challenges in diagnosing ON were notable, as over one third of patients with suspected ON at onset were later diagnosed with a disease other than ON. Our study confirmed that ON occurs more frequently in women (F:M ratio 3:1) and most cases is related to MS. Both bilateral ON (1.6%) and NMO (1%) are rare in Finland. The natural course of ON showed good recovery; approximately 70% of patients achieved visual acuity >0.8 (average follow-up time of 38 days). When analysing the factors that affect prognosis for patient visual impairment, our data suggest that in addition to baseline visual acuity, optic disc swelling and lesions in the optic nerve on magnetic resonance imaging (MRI) are associated with poorer prognosis. Nearly one-third (30%) of patients were already diagnosed with MS before diagnosis of ON. Among patients with their first ON, 82% were diagnosed with demyelinating changes in brain MRI. Demyelinating changes in brain MRI were a significant risk factor for MS; 54% of ON patients with early-stage demyelination in brain MRI developed MS (average follow-up time of 7 years). Only 5% of those without demyelinating changes in brain MRI developed MS. The practice of performing MRI before any medical treatment was also supported by our finding of six intracranial compressive lesions (2%) as mimickers of ON. We investigated the sensitivity and specificity of the AQP4 antibody assay in the diagnosis of NMO in our ON patient cohort. The number of patients with NMO was very low (n=2). The AQP4 antibody test sensitivity was only 1/2 and had a positive predictive value of 1/3. The exome sequencing study of patients with NMO (n=5) was the first published study of this kind in this disease. No genetic variants common to all patients were found. Four of the mutations were shared by two patients with NMO (C3ORF20, PDZD2, C5ORF47, and ZNF606). Another PDZD2 variant was also found in a third patient. Additionally, two rare, probably functional variants in the non-coding region of DNA were found in two patients. The significance of these findings cannot yet be evaluated. However, as extensive research in this field is ongoing we assume that the role of these variants will be revealed in the future.
  • Blom, Sami (Helsingin yliopisto, 2019)
    Prostate cancer (PCa) is the most common cancer in men. The substantial intra- and intertumoral heterogeneity of PCa at many levels is a challenge in terms of prognostic assessment and stratifying patients for treatments. Accumulating evidence suggests that PCa stroma has a significant role in tumorigenesis and in tumor progression, but the exact mechanisms of how the stroma and cancer cells regulate each other are still largely unknown. In order to better understand the heterogeneity of PCa and the role of stroma, assays allowing in situ molecular analyses in the intact spatial context of the tumors are needed. In this thesis, a multiplex immunohistochemistry (mIHC) platform was developed including tissue staining, imaging, and analysis methodology. The developed platform allowed simultaneous detection of six protein targets in formalin-fixed paraffin-embedded (FFPE) tissue samples, which was demonstrated by quantitative analysis of epithelial cells and immune cells in whole-sections of PCa tissues. The mIHC method was applied to study the effects of caveolin-1 (CAV1) and transforming growth factor beta 1 (TGF-beta), a pleiotropic cytokine secreted by stromal cells, in PCa. In vitro, integrin beta 1 (ITGB1) regulated caveolin-1 (CAV1) expression and CAV1 switched TGF-beta signaling from tumor-suppressive to tumor-promoting. In clinical PCa samples, mIHC analysis showed that CAV1 associated with ITGB1 expression and loss of E-cadherin. Lastly, characterization of PCa stroma by using the developed mIHC method revealed that fibroblasts associate with aggressive PCa and predict patient survival. The results indicate that in addition to cancer cells, the tumor stroma and especially fibroblasts are important in PCa progression. In conclusion, a multiplex IHC platform for quantitative analysis of FFPE tissues was developed. By using the developed platform, fibroblasts were shown to predict clinical outcome in PCa, which suggests that analysis of stromal features could improve prognostic assessment of PCa. Furthermore, CAV1-dependent TGF-beta response in PCa cancer cells provided a novel mechanism by which growth inhibitory TGF-beta signals switch to tumor promoting signals in PCa.
  • Tolonen, Matti (Helsingin yliopisto, 2019)
    Secondary peritonitis results from a breach in the gastrointestinal tract. The contents spilled into the peritoneum cause a local inflammation response. The inflammation may further advance into systemic circulation and cause sepsis with associated organ dysfunctions and a high risk of death, referred to as severe complicated intra-abdominal sepsis (SCIAS). The role of the intra-abdominal view (IAV) during surgery is mostly unknown. Severely ill patients may require open abdomen (OA) management with a temporary abdominal closure device. However, OA management entails some risks for the patient and not all abdomens are closed. The aims of this thesis were to analyze pre- and intraoperative prognostic factors for SCIAS and mortality as well as the applicability of vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) in the management of OA were evaluated. Studies I and II were retrospective studies and the data were collected from electronic patient records of Helsinki University Hospital. Study I comprised all consecutive patients with a diffuse secondary peritonitis in 2012-2013. Study II consisted of patients with a diffuse peritonitis and OA managed with VAWCM during 2008-2016. The patients with a secondary peritonitis for Studies III and IV were prospectively recruited during 2016-2018. Preoperative blood samples for cytokine analyses were obtained and the operating surgeon filled out a paper form to describe the IAV. In Study I, 223 patients were analyzed. The independent preoperative risk factors for SCIAS or mortality were acute organ dysfunctions, chronic kidney insufficiency, and pre-existing cardiovascular disease. Patients lacking these risk factors had no mortality. In Study II, 41 patients were analyzed. Delayed primary fascial closure rate among survivors was 92% (n = 33). In Study III, including 283 patients, independent risk factors for SCIAS or mortality in the IAV were fecal or bile exudate, diffuse peritonitis, diffuse substantial redness of the peritoneum, and a non-appendicular source of infection. Based on these results an IAV score was developed. In Study IV, consisting of 131 patients, interleukin-8 was the most competent marker associated with all the assessed variables. The risk for the development of SCIAS or death can be preoperatively effectively predicted based on readily available risk factors. Interleukin-8 showed the best overall performance of preoperative circulating cytokines. The IAV provides a rough estimate of the magnitude of the systemic inflammatory response and the IAV score serves as a simple method to quantify the response. The VAWCM technique in the management of OA in patients with peritonitis is highly effective.
  • Mohamed, Hesham E. Abdolhfid (Helsingin yliopisto, 2019)
    The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing in many Western countries. In Finland, the incidence increased from 32 cases in 1996 to 85 cases in 2006 to 193 cases in 2016. Globally, OPSCC is the 12th most common cancer and is frequently related to human papillomavirus (HPV) infection. The prediction of OPSCC prognosis is one of the main dilemmas for the clinicians. Although many parameters have been used to predict the prognosis, such as clinical factors of tumor size and invasion, lymph node and distant metastases (cTNM) staging, and other prognostic models based on histopathologic parameters; in addition to the patient-related and treatment-related factors, all of these parameters are of limited value in predicting prognosis. For this reason, assessing of the immunohistochemical markers as prognostic biomarkers was a target for many recent studies. Tolllike receptors (TLRs) play important roles in the development of carcinoma of different sites including the tongue, cutaneous, cervical and laryngeal squamous cell carcinoma, and colorectal adenocarcinoma. Hormone receptors play a crucial role in the pathogenesis and treatment of breast carcinoma and carcinoma of the male and female genital organs, in addition to their role in carcinomas of other organs including stomach, larynx, and salivary gland, but their role in OPSCC still poorly understood. During the epithelial to mesenchymal transition (EMT), the epithelial cells lose some of their essential epithelial characteristics and gain invasive and migratory characteristics, which are properties of the mesenchymal cells. In addition, HPV infection induces keratinocyte stem cells to behave like cancer stem cell (CSCs). Detection of more specific prognostic biomarkers would be beneficial on the clinical level. In this thesis project, we examined the prognostic value of TLR5, 7 and 9, sex hormone receptors: androgen receptors (AR), progesterone receptors (PR), and estrogen receptors (ER), EMT markers: β-catenin, E-cadherin, vimentin, and biomarkers expressed by stem cells: Bmi-1, HESC5:3, and HES77 in a cohort of 202 OPSCC patients. We also examined the correlations of these markers with HPV infection. We found that high TLR5, low TLR7, and high PR levels are associated with poor disease-specific survival (DSS) (p=0.002 and p=0.001 respectively). In addition, HPV-positive OPSCCs express higher levels of TLR7 (p<0.001), AR (p<0.001), HESC5:3 (p=0.016), vimentin (p=0.026), and cell membranous β-catenin (p=0.001), and lower levels of TLR5 (p<0.001), TLR9 (p<0.001), PR (p<0.001), and Bmi-1 (p=0.006) than the HPV-negative OPSCCs. From our findings, we conclude that high TLR5, low TLR7, and high PR expression levels may impact the prognosis of OPSCC. In addition, our results support the fact that HPV-positive and HPV-negative OPSCCs are different tumor entities.
  • Sahlman, Perttu (Helsingin yliopisto, 2019)
    The most severe manifestations of alcoholic liver disease (ALD) are alcoholic liver cirrhosis and alcoholic hepatitis (AH). The purpose of this study was to examine incidence, risk factors, prognosis and malignant comorbidities of ALD in a cohort of patients with alcoholic liver cirrhosis (n=7746) and AH (n=4127) as an inpatient diagnosis during years 1996-2012 identified from the national Hospital Discharge Registry and followed until death or incidence of cancer (41209 person-years). There was increase in incidence of alcoholic liver cirrhosis (by 66% among men and 75% among women) and AH (by 76% among men and 108% among women) during the study period. Survival of the patients was poor, 5-year relative survival rates for male and female alcoholic liver cirrhosis patients being 0.28 (95%CI 0.27-0.30) and 0.39 (95%CI 0.36-0.41), and for all patients with AH 0.46 (95%CI: 0.44-0.48) without difference between sexes. Majority of the patients died from alcohol-related causes. Risk for mortality from several other causes was increased: cancers (standardised mortality ratio [SMR] 6.82; 95%CI 6.35-7.29), digestive diseases (SMR 27.95; 95%CI 24.78–31.31), respiratory diseases (SMR 7.86; 95%CI 6.70–9.10) and circulatory diseases (SMR 6.13; 95%CI 5.74–6.52). The risk of accidental or violent death was increased (11.12; 95%CI 10.13-12.15), as well. Standardised cancer incidence among patients with advanced ALD was 2.86 (95%CI 2.69-3.03) There was increased risk for cancer of liver (SIR 59.20; 95%CI 53.11–65.61) pancreas (SIR 3.71; 95%CI 2.72-24.94), pharynx (SIR 9.25; 95%CI 6.05–13.56), mouth (SIR 8.31; 95%CI 4.84–13,29), tongue (SIR 7,21; 95%CI 3.60–12.89), oesophagus (SIR 7.92; 95%CI 5.49–11.07), larynx (SIR 5.20; 95%CI 2.77–8.89), lung (SIR 2.77; 95%CI 2.27– 3.32), stomach (SIR 2.76; 95%CI 1.79–4.07), kidney (SIR 2.69; 95 CI 1.84–3.79), colon (SIR 2.33; 95%CI 1.70–3.11), cervix uteri (SIR 4.93; 95%CI 1.34–12.63) and non-melanoma skin cancer (SIR 1.89; 95%CI 1.18–2.86) . Alterations in cholesterol metabolism in severe AH were studied among 24 hospitalised patients with severe AH treated with prednisolone and randomised to get either prednisolone alone or in combination with ciprofloxacin to identify potential prognostic factors to predict response to corticosteroid therapy at baseline. AH patients had a distinct profile of sterol metabolism compared to patients with primary sclerosing cholangitis and healthy individuals. Certain non-cholesterol sterols (i.e. plant sterols) putatively reflecting the nutritional status of the patients were related to response to corticosteroids. High serum level of ferritin at baseline predicted poor response to corticosteroid therapy. Potential risk factors besides alcohol for advanced liver disease were studied in a cohort of 41260 individuals comprised of persons participating Health2000 or FINRISK studies 1992-2012 without an underlying liver disease. Age, PNPLA3 haplotype and WHR increased the risk for advanced liver disease. There is synergism between alcohol intake and central obesity to the risk. Binge drinking poses an additional risk factor.
  • Vihonen, Hanna (Helsingin yliopisto, 2019)
    Background: Blood glucose disturbance is commonly seen in critically ill patients and it is associated with a poorer outcome. Aim of the study: To (a) describe how common blood glucose disturbance is in the prehospital setting and its association with short-term mortality and morbidity, (b) describe the very early mechanisms of stress-induced hyperglycaemia, and (c) examine whether blood glucose could be added as an additional parameter to a “track and trigger” scoring system for better discrimination of risk of death. Material and Methods: This study was conducted in areas of district of Helsinki and Uusimaa between 2006-2015 including one prospective and three retrospective sub-studies: 28 out-of-hospital cardiac arrest patients regardless of initial arrythmia type (III), 152 ST-elevation myocardial infarction patients (I), 3568 hypoglycaemic patients without diabetes from (II), and 27141 patients with all parameters to include in National Early Warning Score and a blood glucose measurement (IV). Results: Hyperglycaemia was common (76-93%) and hypoglycaemia less (2-11%), depending on the study design (I-IV). Of those, diabetes was not previously diagnosed in 62-71% (I, III, and IV). A greater change in blood glucose level during prehospital phase in ST-elevation myocardial infarction patients was associated with 30-day mortality (non-survivors +1.2±5.1 vs survivors -0.3±2.4 mmol/l [mean±SD], p=0.03) (I). When diabetes was not considered alcohol [41%, (CI95% 40-43)] was the most possible cause of hypoglycaemia episode encountered by emergency medical service (II). In out-of-hospital cardiac arrest patients hyperglycaemia was common (11.2 mmol/l, IQR 8.8-15.7) showing a decrease of 2.2 mmol/l, IQR -3.6 to -0.2 in blood glucose level from prehospital to hospital admission blood sampling 96 min (IQR 85-119) (III). Insulin (10.1 mU/l, IQR 4.2-5.2) and glucagon 141 ng/l, IQR 105-240 levels were low, and glucagon-like-peptide 1 level increased 2-8- fold (6.3 ng/ml, IQR 5.2-9.0) from fasting level (III). All studied biomarkers had great interindividual variation, and this was not associated with a change in blood glucose level (III). Blood glucose improved National Early Warning Score discrimination capability for risk of death at 24-hours and at 30-days Hyperglycaemia: 24-hour risk of mortality: OR 1.54, (1.11-2.12) and 30-day risk of mortality: OR 1.41, (1.20-1.66) and hypoglycaemia: 24-hour risk of mortality: OR 5.46, (2.87-9.64) and 30-day risk of mortality: OR 2.33, (1.47-3.52)  (IV). The association was improved according to likelihood ratio tests (p<0.001). Reclassification tests additionally confirmed the improvement of the model (continuous net reclassification index at 24-hours risk of mortality was 0.413, CI95% 0.281-0.545, p<0.001; at 30 days, it was 0.254, CI95% 0.197 -3.11, p<0.001; and integrated discrimination improvement was at 30 days risk of mortality 0.002, CI95% 0.001-0.003, p<0.001) (IV). Conclusions: Disturbance of blood glucose homeostasis was commonly observed already in prehospital surroundings and seemed to be associated with an elevated mortality. When added to the National Early Warning Score, especially when hypoglycaemia was present, discrimination of risk of short-term death seemed to be improved. In contrast with the insulin resistance and excess counterregulatory hormones typically seen in stress-induced hyperglycaemia, the initial physiological mechanisms of blood glucose disturbance seemed to differ because both insulin and glucagon levels were found to be initially low.
  • Karppinen, Helena (Helsingin yliopisto, 2019)
    The aim of this study was to explore older people’s wishes concerning their length of life, self-perceptions of their health, wellbeing and functioning, and lastly whether their documented living wills (LWs) are associated with care at the end of life. The study was based on random samples of 75–96-year-old community-dwelling people in Helsinki (HEVA [the Helsinki Aging Study 1989, 1999 and 2009] and DEBATE [Drugs and Evidence-BAsed medicine in The Elderly 2000–2010]). In the DEBATE study the association between baseline will-to-live (WTL) and survival in the next ten years was analysed in a follow-up study of 283 participants (Study I). A wish to live up to 100 years, with reasons for this wish was explored in a cross-sectional study (Study II) concerning 1405 participants in the HEVA 2009 study. Changes in self-rated health (SRH), psychological wellbeing (PWB) and disability were rated, comparing cohorts in 1989, 1999 and 2009 (Study III, with 4898 participants). The association between baseline LWs and end-of-life care of 207 deceased DEBATE participants with cardiovascular disease (Study IV) was evaluated in a ten-year follow-up study. A long WTL was more common in males, in younger people, and in those with good SRH. In a ten-year follow-up study, baseline WTL was a strong predictor of survival irrespective of age, gender and comorbidities (Study I). In Study II, 33% of the respondents were willing to become centenarians, some of them conditionally if functioning remained sufficient. A wish not to live extremely long was associated with fear of the future, negative attitudes and anticipation of diseases or disabilities. When comparing age cohorts over 20 years (Study III), SRH and PWB improved from 1989 to 2009, but levelling-off of previously detected improvements in physical functioning were worrisome. Living wills (Study IV) did not seem to affect the intensity of received care at the close of life. However, death occurred more often at home among those who had completed a LW at baseline, compared with those without a prior LW (17% vs. 6%). Even though self-perceptions have been regarded as increasingly important, studies on WTL among older people have been scarce. Treatment options and specific health conditions were not in the scope of the present study, but instead, the results emphasize the importance of listening to older people themselves when planning their treatment plans and when developing future preventive and rehabilitative measures to support their WTL, quality of life, and functioning. The results of the present work suggest that increasing psychological wellbeing and care more congruent with patient preferences is possible. However, levelling-off of improving physical functioning among older people and the oldest-old is a study result that may demand more resources in social and health services than previously predicted. Discussions about preferences, living wills and their documentation in health files is suggested to take place early in primary care, even before severe diseases or disabilities.
  • Friedmacher, Florian (Helsingin yliopisto, 2019)
    Congenital diaphragmatic hernia (CDH) is a prenatal defect in the integrity of the developing diaphragm, which results in pulmonary hypoplasia (PH) with alveolar immaturity. PH leads to life-threatening respiratory insufficiency at birth, thus remaining a major cause of neonatal mortality in CDH. Lipid-containing interstitial fibroblasts (LIFs) are crucial for fetal lung growth by stimulating alveolarization and surfactant phospholipid production in alveolar epithelial cells type II (AECII), which in turn increases alveolar maturation. Thymocyte antigen 1 (Thy-1) is a strongly expressed cell surface protein in LIFs, which plays a key role in alveolar lipid homeostasis by upregulating adipocyte differentiation-related protein (Adrp). Adrp is necessary for the intracellular uptake of neutral lipids into LIFs and their transport to AECII. Furthermore, LIFs express leptin (Lep), which binds to its receptor (Lep-R) on AECII, thus stimulating de novo synthesis and secretion of surfactant proteins. As Thy-1-/- knockout animals show a phenotype similar to PH in human CDH with impaired alveolar development and reduced proliferation of LIFs, the first objective of this study was to identify disruptions in Thy-1 signaling in hypoplastic rat lungs with toxicological induced CDH, which may have an adverse effect on the expression and lipid content of pulmonary LIFs. In addition, as it has been demonstrated that retinoids positively affect the proliferation of LIFs and expression of Lep and Lep-R in developing rat lungs, the second objective was to investigate if prenatal administration of all-trans retinoic acid (ATRA) may have the potential to attenuate PH in this rodent CDH model by improving fetal alveolarization and surfactant production. This study revealed that disruption of the Thy-1/Adrp signaling cascade in hypoplastic rat lungs leads to a reduction of pulmonary LIFs with significantly fewer cytoplasmatic lipid inclusions and impaired alveolar mesenchymal cell differentiation, which may contribute to decreased alveolar development and PH in the nitrofen-induced CDH model. Prenatal treatment with ATRA may therefore have a therapeutic potential in attenuating CDH-associated PH by increasing the overall number of LIFs and lipid droplets through an upregulation of Adrp transcripts and corresponding protein expression, and consequently enhances Lep-mediated surfactant phospholipid synthesis, which in turn stimulates fetal alveolarization, distal airway maturation and de novo surfactant production.
  • Liimatta, Heini (Helsingin yliopisto, 2019)
    Preventive home visits (PHVs) to support functioning and well-being of older people and to reduce the rates of institutionalization and hospitalization have been studied for decades. The importance of preventive evidence-based effective means increases as the proportion of older people in the population continues to grow. Preventive means to support independence are needed, as many older people wish to continue living at their homes as long as possible. At the same time there is an economic aim: cost-effective means are needed for assessing and managing early the illnesses and disabilities of older people to constrain the growing need for costly hospital care and long periods of institutionalization. PHVs might offer one such intervention. However, findings in PHV studies have been controversial. In this study, with four sub-studies, we explored the effects of PHVs targeted to home-dwelling older people. In Study I we systematically reviewed the evidence from randomized controlled trials (RCTs) on the effectiveness of PHVs targeted to community-dwelling older people on their functioning, well-being and health-related quality-of-life (HRQoL), mortality and use and costs of healthcare and social services. In Studies II–IV an RCT was carried out to investigate the effects of multiprofessional PHV intervention implementing comprehensive geriatric assessment (CGA) of independent home-dwelling older people in regard to their HRQoL (15-dimensional [15D] measure) and use and costs of healthcare and social services. A new intervention trial was performed due to the lack of studies on effects of multiprofessional PHVs on patient-preferred outcomes (HRQoL), and their cost-effectiveness. A systematic search of databases (PubMed, Ovid Medline, Cochrane Database, DARE, and Cinahl) supplemented with a manual search of references from earlier reviews was performed in Study I to identify RCTs reporting on the effects of PHV interventions targeted to unselected community-dwelling older populations. Study I review article included PHV trials with focus on use and costs of services and the literature review included a broader selection of RCTs on PHV interventions. Relevant studies were independently rated by three investigators as regards methodological quality and the extracted data was summarized descriptively. Most of the studies were of good or moderate methodological quality and 25 out of 33 studies reported some favourable effects of PHVs, mainly on functioning. These positive effects were produced cost-neutrally, as no differences in total costs between the intervention and control groups were reported. The present PHV intervention study is an RCT (n = 422) examining the effects of a three-visit multiprofessional PHV programme implementing CGA targeted to home-dwelling older people randomized into intervention (n = 211) and control (n = 211) groups. The participants in the trial were older people (75 years old or older) living in their homes with no regular home help or care in Hyvinkää municipality, Finland. The intervention group received three home visits delivered by a nurse, a physiotherapist and a social worker. In Study II we reported the baseline data and feasibility of the intervention. Randomization was successful, with the intervention and control groups being balanced at baseline. PHV intervention was found to be feasible among the home-dwelling older people. There were no drop-outs during the intervention and feedback at the one-year follow-up was mostly favourable. Only 13% of the responders found the home visits not to be beneficial. Study III concerned the effects of PHV intervention on the primary outcome of the trial. Measured using the 15D instrument, HRQoL in the intervention group declined significantly more slowly, the difference between groups in changes after one year being -0.015 (95% CI -0.029 to -0.0016; p = 0.028 adjusted for age, sex, and baseline value). However, the effect was diluted after the home visits were discontinued, and there was no significant difference between the groups at the two-year follow-up. There were no differences in mortality between the groups. Study IV concerned the use and costs of healthcare and social services of the participants and a cost-utility analysis. There were no significant differences in the use of healthcare and social services of the participants at baseline or during follow-up, or in the total costs of healthcare and social services. There were no significant differences in quality-adjusted life-years (QALYs) gained between the groups. However, the cost-utility analysis showed 60% of the incremental cost-effectiveness ratio (ICERs) in the “dominant” quadrant of the cost-effectiveness plane, suggesting that the intervention might be both more effective and less costly compared with usual care. There were no reported adverse effects of the intervention. To conclude, the available literature provides evidence for some positive effects of PHVs on functioning, HRQoL and mortality of older people, although these findings remain controversial. These favourable effects of PHV intervention were produced cost-neutrally. There is some evidence that PHV interventions are cost-effective, but more research is needed. A multiprofessional PHV intervention programme implementing CGA supported the HRQoL of older people during one-year of follow-up, although the effect became diminished once the visits were discontinued. No significant differences between the groups in costs of healthcare and social services were detected. Cost-utility analysis suggested that the intervention might be cost-effective without accruing increased costs.
  • Kavaja, Lauri (Helsingin yliopisto, 2019)
    In the natural course of shoulder instability, about half of the patients never experience a subsequent incident after the primary one, but also chronically unstable shoulders may eventually stabilize. The risk for recurrent episodes after primary dislocation is high among young and athletic men, and therefore, prompt surgery is often proposed for this group. Also, in treatment of chronic post-traumatic instability, surgery is often suggested. A significant increase in the total incidence and proportion of arthroscopic surgery has been widely reported during the last two decades. Network meta-analyses (NMAs) have not been previously published on traumatic shoulder instability. Shoulder capsular surgery incidence rates have not been studied in Finland. Glenohumeral osteoarthritis (OA) has previously been studied in the long run with non-anatomic or mixed surgical interventions with no special attention directed to arthroscopic anatomic fixation methods. This thesis aimed to evaluate the best available evidence in treatment of traumatic shoulder instability, trends in shoulder capsular surgery procedure incidences in Finland during 1999-2008 between open and arthroscopic procedures geographically, between different age groups, and between publicly and privately funded hospitals after a change in the reimbursement system of occupational and traffic insurance in 2005. We retrospectively analysed a group of patients after arthroscopic anatomic fixation methods in terms of radiological glenohumeral OA and condition-specific shoulder function. According to a moderate level of evidence, surgical treatment of primary traumatic shoulder dislocation seems to lead to fewer redislocations than non-surgical management, and according to a low level of evidence open anatomic fixation prevents redislocations more efficiently than arthroscopic anatomic fixation in treatment of chronic post-traumatic shoulder instability. The total incidence of shoulder capsular surgery procedures and the proportion of arthroscopic procedures increased significantly in Finland between 1999 and 2008 with notable geographical variation. Since 2005, the procedure incidences have slightly decreased in publicly funded hospitals, but have continued to increase in privately funded hospitals without a distinct change in trend. We commonly observed mild glenohumeral OA among patients treated with arthroscopic anatomic fixation method, but its impact on shoulder function was minor. Operative treatment reduced efficiently recurrent shoulder dislocations after primary traumatic shoulder dislocation, but routine surgical intervention can still be considered over-treatment in the typical patient population. In Finland, total incidence of shoulder capsular surgery procedures, proportion of arthroscopic procedures and geographical variation in procedures increased significantly, which might indicate differences in regional treatment practices or background incidence. The insurance companies may have referred patients to private hospitals for better availability of treating surgeons, faster access to treatment, and lower total expenses. In the long run, mild radiological glenohumeral OA was commonly observed, but the surgical method itself is probably not significant in the development of glenohumeral OA. The impact of glenohumeral OA on the patient’s shoulder function was minor, with few objective findings.
  • Metsäniitty, Mari (Helsingin yliopisto, 2019)
    Assessment of an individual’s age has important applications in forensics. From developing countries, the possibility to gather reliable reference data for forensic age estimation may be difficult. The aim was 1) to analyse the validity of the Greulich and Pyle method (1959), and other skeletal and dental methods; 2) to analyse forensic age assessments of asylum seekers in Finland, and the Finnish legislation; 3) to compare a created Somali dental development model (SM) on lower left permanent teeth (PT) from 31 to 37 with the Willems et al. model (WM; 2001); and 4) to study whether the addition of information on the development of third molars (TM) with PT increases the accuracy of age assessment of young Somalis. Dental and skeletal radiographic age-assessment methods were compared using Finnish child victim data (N=47). Information on forensic age assessment was collected from Finnish legislation texts, EU statistics, and public statistics by Immigration Authorities on asylum seekers in Finland. Analysis was made of forensic age assessments in Finland in 2015. The dental development of Somalis, born and living in Finland, was analysed, staging the PT according to Demirjian et al. (1973) and TM according to Köhler et al. (1994). First, both SM and WM on PT were validated on 635 Somalis, aged 4–18 years. Secondly, the age prediction performances of PT and TM development were tested separately and combined on 803 Somalis, aged 3–23 years, using a Bayesian approach. Of the compared dental and skeletal methods, development of PT showed the smallest deviation from the chronological age. In 2015, 149 asylum seekers, originating most often from Afghanistan, Iraq, and Somalia, were assessed for age using methods authorised by the Finnish legislation. Comparing the performances of the WM and SM, small but statistically significant differences in mean error were detected: -0.07 years in males and 0.16 years in females. The approach combining PT and TM predicted the age with the highest accuracy. In conclusion, dental methods, except using only TM, override skeletal methods in accuracy. The current Finnish legislation on forensic age assessment has been successfully implemented in Finland. In age assessment, the WM performs well for Somali children. The age prediction performance improves by combining the information of PT and TM, especially in 12- to 15-year-olds, when both PT and TM are still developing.
  • Äyräväinen, Leena (Helsingin yliopisto, 2019)
    Background. Patients with rheumatoid arthritis (RA) suffer from an autoimmune disease with an increased susceptibility to extra-articular inflammation. The purpose of this study was to clarify the oral health in patients with early (ERA) and chronic (CRA) stage of RA. 53 ERA and 28 CRA patients were recruited to this prospective follow-up study at Helsinki University Hospital between 2005 and 2014. ERA patients were naïve to conventional disease- modifying antirheumatic drugs (cDMARDs). CRA patients had a long history of RA and currently an inadequate response to cDMARDs. CRA patients were starting biologic DMARDs mostly combined with cDMARDs. A group of 43 control subjects of age-, gender- and place of residence- matched volunteers was included. Methods. Dental and medical examinations were conducted twice (follow-up mean 16 months) in RA patients and once in controls. Dental examinations included evaluation of periodontitis, prevalence of periodontopathic bacteria from plaque samples, salivary and serum inflammatory biomarkers MMP-8, TIMP-1 and IL-6, saliva flow, Decayed Missing Teeth (DMFT), Decayed Missing Filled Surfaces (DMFS) and Total Dental Index. Dental data comprised also bite-wing and tomogram x-rays. Medical examinations consisted of clinical rheumatological status by disease activity score DAS 28 (28-joint count), total number of swollen (66) and tender (68) joints, blood tests [rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (CCPAb), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA) and antibodies for anti-SSA/SSB (anti-Ro/La) and ribonucleoprotein (RNPAb)], radiographs of hands and feet and general function by Health Assessment Questionnaire (HAQ). Results. At baseline RA patients had significantly more periodontitis: 78.8 % of ERA and 85.7 % of CRA patients vs. 44.1 % of controls suffered from periodontitis (p=0.001). Periodontal findings were more common in RA patients than in controls. Antirheumatic medication seemed to have no influence on periodontal parameters. Salivary inflammatory biomarker MMP-8 was associated with periodontal parameters. MMP-8 (p=0.010) and also IL-6 (p=0.010) in saliva were significantly increased in ERA patients compared with CRA patients and controls at baseline, while MMP-8 and IL-6 in serum were significantly elevated in CRA patients during the study. Salivary MMP-8 and MMP-8/TIMP-1 ratio associated with Periodontal Inflammatory Burden Index (PIBI) in CRA patients at baseline (MMP-8: p<0.001; MMP-8/TIMP-1: p<0.001) and after follow-up (MMP-8: p=0.002; MMP-8/TIMP-1: p=0.003). A similar association between MMP-8 and MMP-8/TIMP1 ratio in saliva was observed also in controls (MMP-8: p=0.010; MMP-8/TIMP-1: p=0.010). Total Dental Index (TDI) was significantly elevated in ERA and CRA patients vs. controls [ERA: 2 (2-3); CRA 2 (1-3); controls 1 (1-3), p=0.045]. RA disease activity (DAS28) associated positively with DMFT (p=0.002) and DMFS (p=0.001) in CRA patients at baseline and further after follow-up (DMFT: p=0.001; DMFS: p= 0.001), while in ERA patients such association was observed after follow-up (DMFT: p=0.016; DMFS: p= 0.038). Conclusions. RA patients even already at the early stage of disease had more periodontitis than control subjects. This was reflected also in elevated salivary inflammatory biomarker (MMP-8, IL-6) levels. Further DMFT and DMFS correlated positively with RA disease activity in CRA patients throughout the study.
  • Grotenfelt, Nora Elisabeth (Helsingin yliopisto, 2019)
    The global prevalence of gestational diabetes (GDM) is around 14%, with increasing numbers over the last decades. In 2017, 19% of all pregnancies in Finland were affected by GDM. Despite treatment, GDM is associated with several short- and long-term adverse health outcomes for both the mother and the child. The short-term effects include an increased risk of large-for-gestational-age babies, birth injuries, Caesarean sections, and neonatal hypoglycemia. The long-term consequences include an increased risk of type 2 diabetes for the mother, and an increased risk of overweight, obesity, metabolic syndrome, and type 2 diabetes for the offspring of GDM pregnancies. Over the recent years, several studies designed to reduce GDM have been published. So far the results are inconclusive. Moreover, there is a shortage of studies assessing the effects of prevention of GDM on the long-term health of the offspring. The aim of this study was to assess women at high risk for GDM considering their clinical characteristics, genetic variance, and time of GDM diagnosis, and to determine the effect of a lifestyle intervention aiming at GDM prevention on long-term offspring health outcomes. This thesis includes four studies. Studies I and II are substudies and Study II is a secondary study of the RADIEL GDM prevention trial, conducted in 2004-2008, assessing maternal outcomes until delivery. Study III includes assessment of neonatal data. In the original RADIEL trial, a total of 720 women with a body mass index (BMI) ≥ 30 kg/m2 and/or a history of GDM in a previous pregnancy were enrolled either before conception or in early pregnancy and allocated either to a lifestyle intervention or a conventional-care group. The intervention focused on both diet and physical activity. Study IV is a substudy of the RADIEL five-year follow-up study (2013-2017), into which all participants of the original RADIEL trial with a viable singleton pregnancy and at least one study visit during pregnancy were invited five years after delivery along with their children. We detected pronounced differences in GDM occurrence between participants with different clinical characteristics. In addition, the effect of the intervention on GDM occurrence differed according to genetic variance. The findings suggest that GDM is a heterogenous disorder, consisting of subgroups that differ markedly regarding both fenotype and genotype. Our lifestyle intervention, delivered by trained nurses to a heterogeneous group of high-risk women enrolled either in early pregnancy or before conception, was not associated with positive effects on metabolic health in the offspring. The value of these findings is the increased knowledge of GDM heterogeneity, useful when improving the screening of GDM and the targeting and cost-effectiveness of future interventions and treatment.

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