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  • Vatanen, Anu (Helsingin yliopisto, 2016)
    Long-term ovarian function was retrospectively evaluated after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence. Cardiovascular risk factors, arterial morphology and stiffness, left ventricular (LV) mass and function, physical fitness and frailty were investigated in adult and adolescent survivors of high-risk neuroblastoma (HR NBL) after autologous HSCT in childhood. The first study population included a cohort of 92 female long-term survivors who were less than 20 years of age when treated at the Children s Hospital, Helsinki University Hospital, or Karolinska University Hospital, Huddinge, between 1978 and 2000. The follow-up data included signs of spontaneous puberty, age at menarche, the use of hormone replacement therapy, pregnancies, and information about pubertal or postpubertal serum FSH levels. The second study population included the Finnish national cohort of 19 long-term HR NBL survivors treated between 1980 and 2000, and 20 age- and sex-matched controls. Clinical examinations included 24h ambulatory blood pressure (BP), very-high-resolution vascular ultrasound, 3D echocardiography and Tissue Doppler Imaging ultrasounds, body composition, physical performance tests and interview. Older age at HSCT and total body irradiation and busulfan-based conditionings were risk factors for early ovarian aging. Leukemia survivors with previous cranial radiotherapy or transplanted after disease relapse were at high risk of premature ovarian failure. The HR NBL survivors showed increased carotid intima-media thickness, plaque formation and stiffness, increased radial artery intima thickness, and increased cardiovascular risk profile when compared to the controls. They had increased LV mass, decreased systolic and diastolic LV function when compared to the controls. Poor LV function associated with cardiac biomarkers, poor physical performance and increased BP. The survivors showed shorter telomere length and increased frequency of frailty phenotype when compared to the controls. The frailty phenotype associated with cardiovascular health and chronic inflammation. In conclusion, our study shows that the adult survivors after HSCT in young age are at risk of early reproductive and vascular aging and frailty. The survivors of pediatric HSCT require regular follow-up in adulthood and interventions for declining ovarian function, cardiovascular risk factors, high BP, subclinical signs of atherosclerosis and decreased cardiac function. Since lifestyle choices can influence cardiovascular health and frailty status, a healthy non-smoking lifestyle and physical activity should be advocated among all survivors who have received HSCT in childhood.
  • Leppilahti, Jussi (Helsingin yliopisto, 2016)
    Matrix metalloproteinases (MMP) and especially MMP-8 is one of the most widely reported oral fluid biomarkers and a promising target candidate for periodontal point-of-care (POC) diagnostics. Periodontitis is associated with increased oral fluid MMP-8 levels, which typically decrease after conventional periodontal treatments. Employing the measurement of oral fluid MMP-8 levels diagnostically, however, is complicated due to high variability. Chronic periodontal inflammation can induce MMP-8 expression in a wide array of cell types, although a great extent of the MMP-8 detected from the gingival crevicular fluid (GCF) originates from polynuclear neutrophil granulocytes (neutrophils). MMP-8 mediates periodontal tissue breakdown by processing extracellular matrix (ECM) proteins with a wide substrate specificity. There is also increasing evidence that MMP-8 contributes to inflammatory signaling cascades and has a protective role in periodontitis and cancer. Thus, it is important to define and differentiate a (statistical) range of physiological fluctuations in the oral fluid MMP-8 POC diagnostics, from the pathologically high MMP-8 levels. The aim of this study was to study methodological and biological reasons for the large variability of GCF MMP-8 and further to evaluate the utility of GCF MMP-8 for POC diagnostics and its ability to predict the treatment outcome after the conventional scaling and root plaining (SRP) treatment and during the supportive maintenance period. Different laboratory and POC MMP-8 detecting methods were compared to study methodological reasons of variability in the GCF MMP-8 levels. In addition, correlations between different inflammatory GCF biomarkers and MMP-8 were compared. The MMP-8 levels measured with laboratory methods or POC tests/devices based on the same monoclonal antibody were clearly in agreement and correlated significantly. There was surprisingly large variability in MMP-8 levels, however, when measured with different assays based on different antibodies. The comparison of different GCF biomarkers revealed highly discriminating properties, especially for myeloperoxidase (MPO) and MMP-8, to differentiate both healthy and gingivitis sites from moderate to advanced chronic periodontitis sites. The longitudinal variability in GCF MMP-8 response patterns was explored and the prognostic utility of GCF MMP-8 was studied. Distinct response patterns during the maintenance period could be found via cluster analysis, especially among smoking patients. High MMP-8 levels at baseline and especially the high-responding pattern among smokers during the maintenance period predicted the compromised treatment outcome. The utility of the GCF MMP-8 levels in the prognostic POC diagnostics was further studied within a heterogenic population by combining different independent datasets. Continuously high MMP-8 levels, at baseline and during the maintenance period, predicted an increased risk for compromised treatment outcome for both non- smoking and smoking patients. Low MMP-8 levels decreased the risk respectively. Overall, the different MMP-8 antibodies can have a quite large difference in affinities to different MMP-8 isoforms, causing variability to the measured levels. If researchers fail to use the same detection methods in different studies, result comparisons may be complicated. GCF MMP-8, however, is a promising candidate as a prognostic biomarker to identify sites with an increased risk for compromised treatment outcome. This study also strongly supports the evidence that MMP-8 can diagnostically differentiate between periodontitis and healthy or gingivitis sites and can also be used for the quantitative, therapeutic monitoring of treatment outcome. Different GCF MMP-8 cutoff levels should be applied for smokers and non-smokers in the MMP-8 based POC diagnostics, however.
  • Ilander, Mette (Helsingin yliopisto, 2016)
    Chronic myeloid leukaemia (CML) is caused by a translocation between chromosomes 9 and 22. As a result of the translocation Philadelphia chromosome that contains a malignant oncogene is born. Tyrosine kinase inhibitors (TKIs) target the malignant oncokinase that is produced from the oncogene and drives the development of CML. The prognosis of CML patients has improved significantly after the emergence of the TKIs. Some patients can even stop the treatment without imminent disease relapse. However, it has been shown that patients who stay in remission without any treatment still have leukemic cells left. We hypothesized that the immune system is able to keep these cells under control and studied the mechanisms behind immune surveillance by analysing the immune cell phenotype and function in CML patients. The results of this thesis show that the immune system plays a role in the successful discontinuation of the treatment. The results from 3 separate studies suggested that natural killer cells are important in successful treatment discontinuation in CML, and that they might be capable of activating T cells and adaptive immunity to keep leukaemia under control. We further studied the effects of 2nd generation TKI dasatinib, known to have immunomodulatory effects. We observed that dasatinib treatment increased the number of Granzyme B expressing memory CD4+ helper and CD8+ cytotoxic T-cells, which were highly active by secreting interferon γ (IFN-γ). We hypothesized that these cells may have a role in the anti-leukaemia activity, as IFN-γ is known to be important in tumour control. The dasatinib induced antitumour immune effects were confirmed in a B16.OVA mouse melanoma model. We were able to demonstrate that dasatinib treatment increases the amount of tumour-infiltrating CD8+ cytotoxic T cells and induces a tumour size reduction dependent on the presence of functional T cells. Taken together, this thesis work illustrates the significance of an active immune system in successful treatment discontinuation in CML. Based on our results it would be important to combine immune activating agents in the future treatment strategies of CML in order to increase the number of patients who are able to successfully discontinue the treatment and be cured.
  • Äyräs, Outi (Helsingin yliopisto, 2016)
    Background: Increased nuchal translucency (NT) has been used as a screening method for fetal aneuploidies since 1990s. It is also known to be associated with a wide variety of structural defects and genetic syndromes. Long-term studies with a large cohort about the neurodevelopmental outcome of euploid children with increased fetal NT are sparse and the neurodevelopment is worth further study. Aim: The primary aim of this study was to collect data on the pregnancy outcomes, long-term neurodevelopmental and overall outcomes in a large cohort of fetuses with increased NT from singleton pregnancies in order to improve parental counselling. Material: All singleton pregnancies referred to the Department of Fetal Medicine at the Helsinki University Hospital due to increased NT in the first-trimester screening during 2002 2007 were studied. The outcome data were retrieved from hospital databases and national registers. Results: There were 1063 fetuses with increased NT in the first-trimester screening. Abnormal karyotype was observed in 224 fetuses (21%) and adverse pregnancy outcome occurred in 322 (30%). Termination of pregnancy was performed in 209 (20%) and there were 43 (4%) miscarriages and perinatal deaths. Of the 834 euploid fetuses 74 (9%) had structural defects or genetic disorders. Favourable pregnancy outcome became less likely by increasing NT: favourable outcome occurred in 92% in the lowest NT group (95th percentile 3.4 mm) and in 18% in the highest NT group (≥ 6.5 mm). Of the euploid fetuses with normal second-trimester ultrasound examination 96% were healthy at the discharge from the delivery hospital. During the follow-up (mean 6.5 years) neurodevelopmental impairment was detected in 29 (4.2%) and it was severe in 12 (1.7%). Major structural defects, severe neurodevelopmental impairment, or genetic disorders were detected in 54 cases (7%). Conclusion: One in five fetuses with increased NT (≥ 95th percentile) has chromosomal abnormalities and one in ten of the euploid fetuses has structural defects or genetic syndromes. Major health impairment (major structural defect, severe neurodevelopmental impairment, or genetic syndrome) is likely to be detected in 7% of euploid children with increased NT in the first-trimester screening but normal findings in the second-trimester screening. These results are helpful in counselling the parents when increased NT is detected.
  • Haapio, Mikko (Helsingin yliopisto, 2016)
    Background and aims. Patients with end-stage renal disease and on chronic renal replacement therapy are at increased risk of death compared to a population of the same age without end-stage renal disease. Despite some improvement in prognosis of end-stage renal disease patients during recent decades, the expected outcome remains dismal. Several factors are associated with impaired survival of patients with end-stage renal disease: especially high age, low serum albumin, chronic inflammation, and comorbidities such as diabetes and heart failure. However, a major portion of factors behind impaired survival have been insufficiently identified, and their prognostic weight is largely unknown. We therefore targeted for further exploration and measurement of factors potentially associated with survival of patients on chronic renal replacement therapy. Study patients and methods. In the four studies of this thesis, we investigated the survival of cohorts of adult patients in Finland after the start of chronic renal replacement therapy. These cohorts were in Study I, 1,604 patients with type 1 diabetes and 1,556 with glomerulonephritis who started chronic RRT during 1980–2005; in Study II, 319 patients during one year (1998) preceding start of chronic renal replacement therapy and thereafter; in Study III, all 4,463 patients who started chronic renal replacement therapy in 2000–2009; in Study IV, all 6,103 patients who entered chronic dialysis in 2000–2012. Data on patient cohorts came from the Finnish Registry for Kidney Diseases, a database including comprehensive information on Finnish patients on chronic renal replacement therapy since 1964. In Study III, data also came from the Finnish Kidney Transplant Registry. The statistical methods mainly employed in our survival analyses were Kaplan-Meier curves, the log rank test, and Cox proportional hazards regression and binary logistic regression for multivariable modeling. Results. In Study I, we showed that survival of patients with type 1 diabetes receiving chronic renal replacement therapy has improved significantly and consistently over the years and in all age-groups. Patients entering chronic renal replacement therapy in 2000–2005 had a 77% lower risk of death than those entering in 1980–1984. Said another way, median survival time of patients with type 1 diabetes on chronic renal replacement therapy has increased from 3.6 years to more than eight. In Study II, we detected a significantly higher age-adjusted mortality in those on chronic renal replacement therapy whose decline in estimated glomerular filtration rate during the predialysis phase had been the fastest. Their mortality risk was 73% higher in the patient tertile of fastest decliners compared to the slowest. This association, however, proved not to be causal, but instead jointly caused by many confounding factors, especially age, end-stage renal disease diagnoses type 1 diabetes and amyloidosis, and the comorbidities myocardial infarction and cancer. In Study III, results of our primary adjusted analyses (intention-to-treat) indicated no significant difference in risk of death between patients on chronic renal replacement therapy who started with peritoneal dialysis compared to those who started with hemodialysis. Without adjustment, the relative risk of death of peritoneal dialysis patients was 0.65 (95% CI 0.58-0.73, p<0.001) compared to hemodialysis patients. With adjustment for 26 potentially confounding variables, the corresponding relative risk was, however, 1.07 (95% CI 0.94-1.22, p=0.33). Results from our secondary analysis method (as-treated) and further with full adjustment, however, indicated a 17 to 33% higher relative risk of death for patients exclusively treated by peritoneal dialysis compared to those treated by hemodialysis exclusively. In Study IV, we developed one- and two-year all-cause mortality prediction models for patients starting chronic dialysis. These models were based on a less recent training cohort and validated with a more recent validation cohort. As a result, area under the curve for the one-year model (with seven variables) reached 0.77 and for the two-year model (with six variables) 0.74. Because mortality in the more recent patient cohort was significantly lower than in the less-recent cohort, both models slightly overestimated mortality risk. Conclusions. Based on studies described in this thesis, survival of Finnish patients with type 1 diabetes and end-stage renal disease has significantly improved since the beginning of the 1980s, despite their conspicuous increase in age, and has improved relatively more in patients with type 1 diabetes than in patients with glomerulonephritis, suggesting progress both in dialysis therapy and overall management of patients with end-stage renal disease and, quite evidently, also in management of diabetes. Furthermore, factors behind the rapid decline in estimated glomerular filtration rate during the year preceding the start of chronic renal replacement therapy, and effects of these factors on subsequent survival are now better characterized. Rate of decline in estimated glomerular filtration rate is not a causal factor for survival, but instead a marker of other factors associated with end-stage renal disease patients’ survival. In addition, based on this research, no overall difference appeared in survival regarding modality of dialysis. Patients starting chronic dialysis differ significantly between dialysis modalities with respect to many patient-level prognostic factors, but after comprehensive adjustment for these putative confounders, no survival advantage of one dialysis modality over another emerged. And lastly, important factors affecting one- and two-year mortality of Finnish patients starting chronic dialysis are now identified and their prognostic weight can be investigated. Based on these findings, we constructed two models for survival estimation hopefully to be implemented in individualized treatment-planning of patients approaching chronic renal replacement therapy.
  • Koskinen, Anni (Helsingin yliopisto, 2016)
    Background: Chronic rhinosinusitis (CRS) is a multifactorial inflammation of the nose and paranasal sinuses. It is diagnosed by typical symptoms lasting more than 12 weeks and/or a computed tomography scan (CT) and/or endoscopic changes. In Europe the prevalence of CRS has been found to be 10.9% 1. The treatment of CRS is primarily conservative, with nasal saline irrigations and topical intranasal corticosteroids. Antibiotics are used primarily only during exacerbations. Comorbidities such as asthma and allergy should be treated efficiently as they can predispose to CRS. Immunodeficiency can also be discovered behind CRS or vice versa. Especially defects in humoral immunity are thought to be more prevalent among CRS patients than healthy controls 2. If conservative treatment of CRS fails, surgery is indicated. Endoscopic sinus surgery (ESS) is a well-established strategy in the treatment of patients with CRS refractory to maximum medical therapy. During the last decade balloon sinuplasty has partly replaced ESS in the treatment of CRS. In balloon sinuplasty the natural ostium of the sinus is dilated without removing mucosa or bone. Methods: First we performed a retrospective controlled study in which we compared humoral immunity between chronic- or recurrent rhinosinusitis patients and healthy controls. Immune responses to tetanus and diphtheria vaccines were evaluated by measuring specific antibody levels of the serum samples of 25 CRS patients and 30 control patients. Next we performed a retrospective controlled study in which we compared ESS and balloon sinuplasty in the treatment of CRS. In this study 208 patients with CRS without nasal polyps underwent either balloon sinuplasty or ESS of maxillary sinuses. Forty-five ESS patients and 40 balloon patients met the inclusion criteria. These patients were sent a postal questionnaire approximately 28 months postoperatively. Patient history factors, number of exacerbations, and a visual analog scale (VAS) scoring the change in symptoms between preoperative and postoperative status were evaluated. We also analysed intra- and early postoperative factors, such as operation time, anesthesia method and complications among the same patients treated either with ESS and balloon sinuplasty. To investigate the long-term efficacy and satisfaction among these patients we performed a phone-interview on average six years after the primary surgery. Patients were asked to compare present symptom status with the symptoms before the operation. Number of exacerbations and need for revision surgery were also evaluated. Results: We were able to show that after vaccination patients with chronic- or recurrent rhinosinusitis had on average 4.08-fold lower responses to diphteria toxoid than healthy controls recruited from hospital personnel. Antibody levels to tetanus toxoid were on average 2.20-fold lower among CRS patients than in the healthy control group. Fourteen out of the 25 rhinosinusitis patients had antibody levels that did not reach the 95% normal distribution range of healthy controls after either diphteria or tetanus vaccination. In the retrospective study comparing ESS and balloon sinuplasty, the groups were identical in response rate and patient characteristics. The duration of sick leave was significantly longer in the ESS group. However, the duration of sick leave was only an estimate of the recovery time made by the operating surgeon and does not necessarily correlate to the true recovery time. Eight ESS operated patients were detected with adhesions, as no adhesions were found in the balloon sinuplasty group. In the first questionnaire study, patients in both groups experienced equal improvement of all asked symptoms. The balloon sinuplasty group reported a statistically significant higher number of maxillary sinus punctures and antibiotic courses during the last 12 months. According to the phone-interview study, enrolled approximately six years after the primary operation, both groups experienced improvement in all symptoms and were equally satisfied with the operation. The number of patient-reported acute exacerbations was again higher among the balloon dilated patients. Four patients in the balloon sinuplasty group underwent revision surgery. There were no revisions in the ESS group. These findings were statistically significant. Conclusion: A significant proportion of our study patients had reduced antibody responses to protein vaccines. This could indicate that CRS patients might have impaired humoral immunity predisposing them to chronic and/or recurrent infections. Responses to protein vaccines might be used to evaluate immune status of CRS patients. Results of our study comparing ESS and balloon sinuplasty showed that the techniques seemed comparable in terms of operation time, anesthesia method and low complication rate. The putative benefits of balloon sinuplasty might be lower adhesion formation, shorter recovery time and possibility to be performed in-office. Except the increased number of revisions in the balloon sinuplasty group, both techniques seemed to retain the efficacy and patient satisfaction in average two and six years after the surgery. Patients in our study were carefully selected with neither nasal polyposis nor severe sinonasal pathology. This should be borne in mind when applying these results in clinical practise. The role of balloon sinuplasty in the management of CRS patients with nasal polyposis or more extensive disease needs to be established by further studies.
  • Dudek, Mateusz (Helsingin yliopisto, 2016)
    Alcohol addiction is one of the most prevalent brain disorders in the world. A major hurdle for reducing alcohol-related harms and developing effective treatments is the poor understanding of neural processes responsible for the development of dependence and addiction. Alcohol has been shown to affect various neurotransmitter systems; however, the mesolimbic dopamine (DA) system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), has been thought to play a key role in producing the reinforcing effects of alcohol. The VTA region has also been suggested to be the anatomical site for the interaction of the dopaminergic system with the opioidergic and γ-aminobutyric acid (GABA) systems. Here, manganese-enhanced magnetic resonance imaging (MEMRI) and behavioral tests were used to study drug-induced alterations in brain activity of the alcohol-preferring AA (Alko Alcohol) and heterogeneous Wistar rats. MEMRI is based on the ability of paramagnetic Mn2+ ions to accumulate in excitable neurons, thus enhancing the T1-weighted signal in activated brain regions. Mn2+ ions can also be transported anterogradely and retrogradely in neurons, released to the synaptic cleft, and taken up by other neurons. These properties allow MEMRI to measure long-term changes in brain activity, as well as map neural pathways involved in acute and long-term drug actions, including drug reward and toxicity. The AA rats exposed to alcohol compared to water controls displayed a widespread and persistent activation in brain regions that have been previously linked with alcohol reinforcement. Similarly, activity in neural pathways originating in the NAc and projecting caudally to the midbrain was enhanced in alcohol drinking rats. Moreover, this alcohol-induced activation was blocked by systemic naltrexone (NLX) administration. Comparison of naïve AA and Wistar rats revealed a lowered basal activity in the caudal linear nucleus (CLi) of AA rats, which was restored by voluntary alcohol drinking. The intra-CLi γ-aminobutyric acid type A receptor (GABAA) agonist muscimol produced a dose-dependent increase in alcohol drinking, blocked by co-administration of the GABAA antagonist bicuculline, suggesting that the CLi GABAergic system is involved in the regulation of alcohol reward. MEMRI was also employed for assessing stimulant-induced toxicity. Methamphetamine and mephedron displayed disparate effects on brain activity, as methamphetamine produced widespread decreases in activity, whereas mephedron increased activity in limited brain areas. Taken together, the use of MEMRI for mapping alcohol- and stimulant-induced alterations in functional brain activity revealed networks and specific pathways that have potential for guiding further translational efforts to develop medications for drug abuse disorders, as well as for evaluating drug-induced toxicity.
  • Akinrinade, Oyediran (Helsingin yliopisto, 2016)
    Next generation sequencing (NGS) technologies provide the potential for developing high-throughput and low-cost platforms for medical research and diagnostics, which is expected to accelerate the findings of root causes and treatments of human diseases. In addition to short read lengths of NGS technology; another limiting factor to clinical applications of genomic NGS is downstream bioinformatics analysis. Several challenging computation problems have to be solved before we realize the full potential of NGS technology. These include management of large quantities of data, efficient analyses, fusion of data from various sources, and interpretation of identified variants. Endothelial cell (EC) dysfunction is a hallmark of several cardiovascular diseases (CVDs). Loss of functional peroxisome proliferator-activated receptor gamma (PPARγ) leads to EC dysfunction, and development of pulmonary arterial hypertension (PAH). However, the role of PPARγ in angiogenesis in the development of PAH is unknown. In this study, RNA sequencing and bioinformatic strategies were used to quantify and reveal global gene expression changes associated with loss of PPARγ, in a bid to unravel the mechanisms by which PPARγ modulates endothelial homeostasis, regulates angiogenic response, and could contribute to the pathobiology of human cardiovascular diseases. This study reveals, for the first time in an animal model, that loss of PPARγ leads to attenuated ECs migratory capacity and decreased angiogenic potential. Implemented bioinformatics approach revealed a novel molecular mechanism and novel downstream target gene for PPARγ. Furthermore, this study reports the first genetic analysis of dilated cardiomyopathy (DCM) patients in Finland; evaluates the efficacy of NGS in genetic diagnostics of DCM patients, and demonstrates the need for a rigorous and clinically oriented bioinformatics variant assessment and interpretation strategy. In addition, bioinformatics data mining approach was used to evaluate the significance of titin (TTN) truncating variants (TTNtv) in the pathogenesis of DCM. Mutations in genes encoding sarcomere proteins are the leading cause of DCM, with TTNtv accounting for ~21% of DCM cases. Clinical significance of variants in cardiomyopathy-associated genes is difficult to assess due to population genetic variation, and diagnostic yield of genetic testing is not well understood among DCM patients. Moreover, the genetic profile of DCM in Finnish population is poorly understood. In this study, a novel targeted resequencing approach, oligonucleotide-selective sequencing (OS-Seq), was used to investigate the genetic landscape of DCM among Finnish patients, and the approach enabled genetic diagnosis for 35.2% of the patients. Notably, 17.2% of Finnish DCM patients had TTNtv predicted to cause loss of function. Truncating TTN mutations, especially in A-band region, represent the most common cause of DCM. Clinical interpretation of these variants can be challenging, as these variants are also present in reference populations. Meta analyses of TTNtv reported in largest available reference population database, and those identified in accumulated DCM cohorts showed that 50 - 53% of TTNtv in the reference population were located in low transcript count regions, thus, possessing low likelihood of being disease-causing. On this basis, a variant assessment strategy that prioritizes TTNtv affecting at least five transcripts of the gene was developed.
  • Kyrklund, Kristiina (Helsingin yliopisto, 2016)
    Aims – To perform a detailed evaluation of the bowel functional outcomes of anorectal malformations (ARMs) after standardized treatment and systematic follow-up in relation to matched controls. To study the bowel habits of a large cohort of individuals from the general population to obtain a baseline for comparison to patients. Methods – A single-institution, cross-sectional study of all patients treated between 1983-2006 for anterior anus (AA, conservative or anal dilatations), perineal fistula (PF) males (anoplasty and/or dilatations) vestibular fistula (VF) or PF females (anterior sagittal anorectoplasty - ASARP) rectourethral fistula (RUF; posterior sagittal anorectoplasty – PSARP). Patients with significant cognitive impairment, total sacral agenesis/caudal regression syndrome, Currarino syndrome, or meningomyelocele were excluded. Participants answered a detailed questionnaire on bowel function by post. Parents of children <16 years assisted in responses. Case details were obtained from records. Patients were matched by age and gender to 3 individuals from the general population who had answered identical questionnaires. Ethical approval was obtained. Results – Our study of 594 individuals from the general population identified that minor aberrations in bowel function, especially soiling prevail in healthy individuals in an age-dependent manner. A total of 159 patients (72%; median age 12.5 (4-29) years) participated in the study on outcomes for ARMs (79 females: 45 AA and 34 VF/PF and 80 males: 46 PF/low ARM and 34 RUF males (35% bulbar, 53% prostatic, 12% bladder neck fistula). Fecal control in AA females and low ARM males was not significantly different from controls in the long-term (p=NS). In VF/PF in females, 68% of patients attained a functional outcome comparable to controls and 85% were socially continent (vs 100% of controls; p<0.001) Among RUF males, 76% of patients were social continent (vs 95% of controls; p<0.002). Despite some improvement in symptoms with increasing age, both soiling and fecal accidents among patients with VF/PF (65% and 24% respectively) and RUF (59% and 37% respectively) remained significantly higher than in controls in the long-term (18-26% for soiling and 4-6% for fecal accidents; p≤0.006 vs patients).The median BFS, the proportion with voluntary bowel movements and total continence decreased with increasing level of fistula in RUF. Constipation was an important sequel in all types of ARMs, affecting 31-44% of patients vs 2-13% of controls (p≤0.003 vs patients). Social restrictions affected a 15-36% of patients with severe ARMs (vs ≤5% of controls; p≤0.01). Conclusions - Our results support the appropriateness of sagittal repair methods for the treatment of VF/PF in females and RUF, and minor perineal procedures for mild ARMs. Patients with mild ARMs can generally be expected to develop bowel functional outcomes comparable to matched peers. In females with VF/PF and males with RUF, problems with fecal control persist at higher levels than controls into adulthood. However, the majority can be expected to achieve social continence with appropriate aftercare and effective management of constipation.
  • Savanheimo, Nora (Helsingin yliopisto, 2016)
    This study evaluated the dental general anaesthesia (DGA) process in Helsinki Public Dental Service (PDS). The aims were to describe the characteristics of the DGA patients, the parents descriptions of their children s previous dental care, to assess the dental care that precedes DGA, the reasons for having to resort to DGA, the treatments performed under DGA, and the long-term outcome of DGA. Three groups of DGA patients comprised the data. Study group 1 included all generally healthy (GH) patients aged 0 16 years treated under DGA in 2001 (n=102). Study group 2 included all GH patients aged 0 13 years treated under DGA in 2004 (n=199), and the study group 3 included all patients including those that were not GH treated under DGA in 2010 (n=349). The data were obtained from patient documents and from a questionnaire given to the parents of children treated under DGA in 2001. The three study groups were restricted to include 0 13-year-old GH patients for longitudinal comparisons. Most of the DGA patients in the Helsinki PDS were GH children in 2010. A comparison of the 0 5-year-old GH DGA children showed that the proportion of immigrants increased from 30% in 2004 to 51% in 2010. Conscious sedation had been used for more than half of the patients before DGA. Parents reported in 2001 that the first difficulties in the child s dental care were noticed when the child was younger than 3 years of age for 39% of that study group, and dental fear followed by pain were the most important reasons for previous unsuccessful dental care. The most frequent reasons for the referrals in 2004 and 2010 for DGA were extreme uncooperation, extreme dental fear and need for extensive treatments. The reason of avoidance of dental fear was introduced in 2010. Restorations, followed by tooth extractions, dominated the treatment-mix performed under DGA. The treatment need was extensive, even more for immigrants than for non-immigrants. The GH 0 13-year-olds that were treated under DGA in 2004 were followed-up for a mean of 47.6 (13.7 SD) months. The first visit of the patients to their home dental clinic after DGA generally occurred on a far later date than that recommended. The mean time elapsed to the first operative treatment need was 18.5 (14.1 SD) months. More than half (53%) of patients expressed dental fear and 54% were uncooperative during the follow-up. Familiarization in order to control dental fear was given to only 13% of the patients. Emergency treatment was given to 52% of the patients and 65% missed at least one appointment. DGA could probably be avoided for GH children. However, this requires earlier intervention. Special attention is needed with immigrant families. DGA is an essential part of the PDS care, even if there are some aspects of the DGA process that need more considerations and improvements.
  • Tarjanne, Satu (Helsingin yliopisto, 2016)
    Endometriosis is a common gynecological disease affecting women in their best reproductive years. Deep infiltrating form of the disease, rectovaginal endometriosis (RVE), causes pain via mechanisms that are partly unknown. In symptomatic patients not responding to hormonal therapies, surgery is needed. Surgical treatment of RVE is challenging, and may require bowel resection. Currently, a laparoscopic approach is used in most RVE operations, bowel resections included. Recurrence rates following surgery vary between 5-30%. This study was undertaken in order to acquire information on the long-term outcome of surgery for RVE, in particular factors affecting recurrence. Altogether 60 patients operated upon in 2002-2004 had a follow-up visit in our clinic, on average four years after the original operation. Symptom recurrence was evaluated by using symptom diaries. In addition, we studied charts on 164 patients who had undergone bowel resection in 2004-2012. The laparoscopic approach to bowel resection was of special interest, with emphasis on collecting information on complications. Increased innervation in endometriotic tissue may contribute to endometriosis-associated pain generation. We used immunohistochemistry to study the density of nerve fibers, and the effect of hormonal therapies on their density, in 45 samples obtained during RVE surgery. Our results showed that even though clinical recurrence developed in 35% of cases, symptom recurrence was rare. Bowel resection was protective as regards recurrence, as were all the forms of hormone and surgical therapy that resulted in amenorrhea. Laparoscopy offers a safe route for performing RVE surgery, and should be the primary approach even as regards colorectal resection in cases of RVE. We found that the rate of complications did not depend on the type of surgery (laparoscopy vs. laparotomy) but was more related to the experience of the surgeon. Excessive innervation was identified in the RVE specimens. This innervation may be one of the explanations for the severe pain that these patients experience. The density of nerve fibers was reduced among those patients who were using either combined oral contraceptives or progestins. In conclusion, bowel resection may protect women from recurrences in cases of colorectal involvement. Following operative treatment for RVE, hormonal therapies aimed at amenorrhea should be administered to all women in order to protect them from symptom recurrence. Recurrent symptomatic disease, however, is very uncommon, and most patients greatly benefit from surgical treatment of RVE.
  • Noronen, Katariina (Helsingin yliopisto, 2016)
    The obvious goals in vascular surgery are to operate patients with symptomatic carotid stenosis before stroke, to revascularise patients with diabetic foot ulcers (DFUs) before amputation is required and to operate patients with abdominal aortic aneurysms (AAAs) before aneurysm rupture. The aim of this thesis was to investigate the timing of treatment and the concurrent impact on the outcome in these three patient cohorts in Helsinki University Hospital (HUH). For symptomatic carotid stenosis the risk of ischemic stroke is the highest in the following weeks after ischemic symptoms, hence carotid surgery is recommended within two weeks. This goal was reached for only 11% of the patients in HUH during 2007-2008, which led to organisational changes in 2009. In 2010 37% of the symptomatic patients were operated on within two weeks and the median time from symptom to surgery had shortened from 47 to 19 days. Therefore, reaching the two-week target time is an achievable goal provided that in addition to the institutional changes, efforts are also made to improve the public awareness. No studies exist on the optimal timing of revascularization in patients with DFU. The whole treatment process from referral to revascularisation was analysed for patients with DFU referred to vascular surgeon in 2010-2011. Significant discovery was that in the treatment of DFUs delay more than two weeks from referral to revascularization was associated with inferior limb salvage. DFU always need prompt diagnostics of the possible underlying ischemia and rapid revascularization once detected. Also, the acceptable delay of elective AAA repair has not been determined, and conclusive evidence on the rupture risk of large aneurysms has been lacking. In HUH during the elective treatment process of AAAs in 2005 2010 21 (5.8%) emergency operations and 11 (3.0%) aneurysm ruptures occurred. In order to minimize aneurysm ruptures and emergency operations while waiting for surgery, guidelines for the timing of elective AAA treatment process are required and the fulfilment of these guidelines need to be followed up. Of the 154 patients excluded from operative treatment 33% died of an aneurysm rupture and 5 patients out of 12 undergoing emergency operation survived. Exclusion from elective aortic repair is a decision requiring careful consideration and collaboration between different specialities.
  • Schrade, Anja (Helsingin yliopisto, 2016)
    The main steroidogenic organs in mammals, the adrenal glands and gonads, arise from a common pool of mesodermal progenitor cells during embryogenesis. Precise gene regulation controls cell differentiation, growth, and homeostasis in the developing embryo and the adult. Disruptions of these spatiotemporal processes are linked to a variety of diseases, including developmental disorders, malignant transformations, and infertility. This dissertation focuses on the molecular mechanisms that regulate normal and neoplastic cell development in the adrenal cortex and testis of the mouse. The initiation of gene transcription requires the binding of transcription factors to specific cis-regulatory elements within DNA. Methylation of cytosine residues affects transcription factor binding to these regulatory elements; hypermethylation results in condensed chromatin that is inaccessible to the transcriptional machinery, whereas hypomethylation is an indicator of active gene transcription. Alterations in DNA methylation have been linked to neoplasia. We used a novel method of genome-wide methylation profiling, termed Laser Capture Microdissection-Reduced Representation Bisulfite Sequencing, to characterize the changes in promoter methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. One of the genes upregulated during gonadectomy-induced adrenocortical neoplasia is Gata4, a transcription factor normally absent in the adult adrenal gland. To determine whether GATA4 directly modulates tumorigenesis we analyzed mice with germline or conditional loss-of-function mutations in this gene. GATA4 deficiency was associated with reduced tumor growth and decreased expression of sex steroidogenic markers. GATA4 is expressed in testicular Leydig cells. To gain insight into the role of GATA4 in this cell type, we performed gene silencing experiments in a mouse Leydig cell tumor line (mLTC-1) and in primary mouse Leydig cells. Comprehensive analyses, including transcriptomic and metabolomic profiling, showed that Gata4 silencing was associated with diminished sex steroid production and impaired glycolysis. Conditional deletion of Gata4 in another testicular somatic cell type, the Sertoli cell, has been reported to increase the permeability of the blood-testis barrier (BTB) and disrupt spermatogenesis in adult mice. To elucidate the molecular underpinnings of these phenotypic abnormalities, we performed Gata4 gene silencing experiments in an immortalized Sertoli cell line (TM4) and in primary mouse Sertoli cells. GATA4 depletion was associated with altered expression of genes involved in BTB maintenance, including components of tight/adherens junctions (e.g., Tjp1, Cldn12) and the extracellular matrix (e.g., Lamc1, Col4a5). Gata4 gene silencing impaired the production of lactate, a key Sertoli cell-derived nutrient that is essential for proper spermatogenesis.
  • Juusela, Pirjo (Helsingin yliopisto, 2016)
    Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomally dominantly inherited disease, mostly found in Finland, but also with worldwide distribution. Its most characteristic clinical signs are corneal lattice dystrophy, polyneuropathy, and cutis laxa, which after onset in the thirties to forties slowly progress. AGel amyloidosis is caused by a point mutation c.640G>A/T, formerly known as c.654G>A/T, in the gene coding for both cytosolic and secretory gelsolin. Cytosolic gelsolin has many roles in cellular activities. Most importantly, it modulates actin formation and participates in cell shape alterations, motility, phagocytosis, and other functions. The c.640G>A/T gene defect causes abnormal cleavage of gelsolin and eventually leads to accumulation of aberrant secretory gelsolin as amyloid fibrils. The systemic nature of this disease has been considered to result mainly from amyloid deposits accumulating in many tissues of AGel amyloidosis patients, but the pathogenesis of the disease is not yet fully understood. Patients with AGel amyloidosis reported to their physician oral problems such as sense of dry mouth and loose or cracked teeth. This information served as a starting point for this study in which we elucidated the impact of this systemic disease on oral condition, including salivary function and periodontal health. Further, oral fibroblasts and vascular smooth muscle cells were examined in vitro to clarify whether mutated cytosolic gelsolin affects their function, thus contributing to the pathogenesis of AGel amyloidosis in general and/or in relation to periodontal health. Patients were invited to the study through their patient organization and forty patients volunteered. We found that patients frequently exhibit subjective mouth dryness, i.e. xerostomia, and also decreased saliva secretion, i.e. hyposalivation. The saliva composition was also altered. Especially, secretion rate of salivary IgA was decreased, further increasing the risk for oral diseases such as oral candidiasis and caries. Histopathological analyses in minor labial salivary gland (LSG) biopsies showed gelsolin amyloid deposits, as well as atrophy of the glands, and minor inflammation. These novel histopathological LSG findings could explain at least partly the alterations in saliva secretion and composition. In one case sicca symptoms (dry eyes and mouth, i.e. xerophthalmia and xerostomia, respectively) and LSG findings had misled to the diagnosis of Sjögren s syndrome, which was later substituted with an AGel amyloidosis diagnosis. According to this study, AGel amyloidosis, on average, does not present a generally increased risk for periodontitis. However, some patients presented a high rate of disease progression, indicating that AGel amyloidosis might in some cases be associated with periodontal problems. Because both AGel amyloidosis and periodontitis progress with age, this association appears to be more common in older patients, who had lost especially their molar teeth quite commonly. In general, however, non-specific oral microbiota and common periodontal status prevail in this disease. In vitro cell studies showed that oral fibroblasts and vascular smooth muscle cells of heterozygote AGel amyloidosis patients had similar actin cytoskeleton morphology and cytosolic gelsolin distribution, migration rate, and collagen type I metabolism as control cells. Only the reaction to staurosporine, an inhibitor of protein kinases, induced minor differences in the shape change rate between the patient and control oral fibroblasts. The altered reaction of oral fibroblasts of the patients to staurosporine should be further evaluated. These results suggest that the patient oral fibroblasts and vascular smooth muscle cells mainly function normally in vitro and may not, at least via cytosolic gelsolin-associated dysfunction, contribute to the pathogenesis of AGel amyloidosis. Thus, patients with AGel amyloidosis due to their systemic disease have greater risk for oral diseases and benefit from preventive oral hygiene procedures, such as diet advice, extra fluoride, lubricants, and regular dental check-ups.
  • Jyväkorpi, Satu (Helsingin yliopisto, 2016)
    Background: Nutrition among older people is associated with functional ability and quality of life (QoL). Malnutrition is most often observed in institutionalized older people and dependent home-careclients. Furthermore, home-dwelling older people with comorbidities, including Alzheimer’s disease (AD), are a risk group for malnutrition. However, few studies have examined the detailed nutrient intakes of older people. In many studies, low nutrient intakes and low diet quality have been observed. Prevention of deterioration in nutritional status is crucial, because poor protein and micronutrient intakes increase the risk of frailty and impaire immunity. As the number of older people increases, more information on nutrition in older populations will be needed. It is important to recognize malnutrition at its early stage and to improve nutrient intake and maintain good nutritional status of older people. The effects of nutritional counseling and education on older people’s nutritional status, nutrient intakes, diet quality, and QoL have not been rigorously studied. Objectives of the study: to determine nutritional status, nutrient intakes and associated factors in both home-dwelling and institutionalized older people at various stages of functioning, and the effectiveness of tailored nutritional counseling and nutrition education on healthy home-dwelling older people’s and AD participants’ nutritional status, nutrient intakes, number of falls, and QoL . Subjects and methods: A cross-sectional study (I, II) included institutionalized (n = 374) and home-dwelling older people with varied cognition and mobility (n = 526). Five datasets were combined: home-dwelling older people participating in nutrition education and cooking classes (NC) (n = 54), participants from the Helsinki Businessmen Study (HBS) (n = 68), home-dwelling people with AD (n = 99) and their spousal caregivers (CGs) (n = 97), participants from the Porvoo Sarcopenia and Nutrition Trial (PSNT) (n = 208), and residents of Helsinki assisted living facilities (ALFs) (n = 374). The participants’ nutritional status was examined, using the Mini Nutritional Assessment (MNA), and nutrient intakes were retrieved from 1–3-day food records. Data on background information, comorbidities, and cognition were collected. The nutrient intakes were compared with recommended intakes. The adequacy of the nutrient intakes was determined by comparing micronutrient intakes with the average requirements. The sensitivity and specificity of the MNA in identifying older people with low energy and protein intakes were tested. In a follow-up study (III), the effect of NC classes on diet quality, nutrient intakes, and psychological well-being (PWB) was examined in independent and healthy, home-dwelling older people. The Nutrition and Alzheimer ’s disease (NuAD) trial (IV, V) was a 1-year randomized controlled trial (RCT) examining the effect of tailored nutritional counseling on home-dwelling AD participants’ nutrient intakes, QoL, and risk of falls. Couples received tailored nutritional guidance during home visits in a 1-year follow-up. The primary outcome measure was weight change and the secondary outcome measure comprised changes in protein and micronutrient intakes from 3-day food records, Health-Related Quality of Life (15D HRQoL), and rate of falls among participants with AD. Results: The groups of older people (I, II) differed in all their background characteristics. The prevalence of malnutrition (17%) and risk of malnutrition (68%) were highest among the ALF residents, followed by the PSNT group (3% and 60%, respectively). In the other groups, there were no malnourished participants. Among the home-dwelling AD participants, the risk of malnutrition was 43% and among the CGs 16%, whereas the respective figures in the HBS and NC classes were 9% and 7%. Insufficient intakes were most often encountered in the malnourished group, but poor protein and micronutrient intakes were also observed in people with normal nutritional status. Insufficient intakes of nutrients were associated with the female sex, cognitive decline, place of residence (institution), and immobility. Of all the participants, 77% had lower than recommended protein intakes. The participants suffering from mobility limitation and cognitive decline had the poorest nutritional status (p < 0.001; adjusted for age, sex, and comorbidities). However, low intakes of energy, protein, and micronutrients were observed in high proportions in all functional groups, those showing inadequate intakes of vitamins D, E, folate, and thiamine being the most common. Higher nutrient intakes were lineally associated with better nutritional status according to MNA, but the sensitivity and specificity of the MNA in identifying suboptimal energy and protein intakes was low. People who participated in NC classes improved their diet quality, PWB, vitamin-C, and fiber intakes postintervention compared with preintervention. The effect sizes varied between small to nearly medium (0.2-0.35). In the NuAD trial, 40% of participants with AD were at risk of malnutrition. There was no difference in weight change between the intervention and control groups during the 1-year study period. At 12 months, the protein intake improved in the intervention group, whereas it declined in the control group (p = 0.031, adjusted for baseline value, age, sex, Mini-Mental State Examination (MMSE), and body mass index (BMI). The participants’ HRQoL improved by 0.006 in the intervention group and declined by -0.036 in the control group (p = 0.007, adjusted for baseline value, age, sex, MMSE, and BMI). The annual rate of falls per person was 0.55 in the intervention group and 1.39 in the control group (p < 0.001 adjusted for age, sex, and MMSE). Conclusions: Poor diet quality, insufficient protein, and micronutrient intakes were commonly found in all functional groups of older people. The sensitivity and specificity of the MNA in identifying low energy and protein intakes was low. Tailored nutritional interventions improved diet quality, nutrient intakes, and HRQoL or PWB. In home-dwelling people with AD, falls decreased due to the intervention. 
  • Sumanen, Hilla (Helsingin yliopisto, 2016)
    Work disability among young employees is a major risk for future employment and for extending working careers. Current sickness absence and disability retirement rates indicate a rising trend in reported ill health among young adults, but still they are considered a minority in health-related research and further details are lacking. Moreover, socioeconomic differences in work disability are widely recognised among older adults, but studies among younger cohorts are scarce. The aim of this study was to examine changes in sickness absence, and socioeconomic differences in sickness absence and disability retirement among young, 18-34-year-old female and male employees between 2002 and 2013. This research is register-based and is part of the Helsinki Health Study. The City of Helsinki s personnel and sickness absence registers were used to obtain socio-demographic characteristics and individual-level information on sickness absence. Information on education was obtained from Statistics Finland s register of completed education and degrees, and information on disability retirement was derived from the national register of the Finnish Centre for Pensions. Employees under the age of 35 were considered young. Those aged 35-54 comprised the reference group in two of the sub-studies. All appropriately aged members of staff permanently and temporarily employed by the City of Helsinki between 2002 and 2013 were included in the analyses. Annual sickness absence days, overall spells and spells of 1-3, 4-14 and 15+ days, as well as disability retirement events were used as outcome variables. Education was classified on four levels annually according to the highest qualification. Occupational class was assigned to one of four categories on the basis of the job title, and income quartiles were based on the monthly salary. Joinpoint regression modelling, quasi-likelihood Poisson regression, the relative index of inequality (RII) and Cox proportional hazard models were used for the statistical analyses. The results showed an initial increase and then a decrease in sickness-absence trends during the study period of 2002-2013. The turning points were predominantly between 2007 and 2010, depending on the groups under investigation and the length of the sickness absence. Young employees had more short and intermediate spells, but less long sickness absence, than older employees. Education turned out to be the strongest determinant of sickness absence among young employees, and followed a clear gradient. The occupational class differences in short sickness absence spells were not fully consistent in that routine non-manual workers had more than the lowest occupational class, in other words manual workers. Disability retirement due to any cause, and to mental and non-mental causes, followed a clear educational gradient, and mental disorders in particular led to disability retirement among young employees. These young employees had a considerable amount of sickness absence, although the bulk of it was taken in short and intermediate spells, and less in long spells: this distinguishes the younger employees from the older ones. Findings on socioeconomic differences in work disability among young employees mainly supported the previous knowledge received among older employees. The results showed that young employees should be taken into account in the design and implementation of measures for preventing work disability. Workplace and job demands should be better matched with employees work abilities. Young employees in lower socioeconomic positions are in particular need of such extra efforts. Changes in work disability among young employees should be studied and monitored more effectively, and the resulting information should be used to evaluate earlier preventive measures and to further develop efficient ways of reducing work disability.
  • Heinonen, Juho (Helsingin yliopisto, 2016)
    Drug overdoses and poisonings are global health problems resulting in several thousands deaths annually. In out-of-hospital setting, one of the most common causes of death is an overdose of tricyclic antidepressant, such as amitriptyline. In the hospital, on the other hand, local anaesthetic systemic toxicity is one of the most feared and potentially a life-threatening complication. Both tricyclic antidepressants and local anaesthetics lack specific antidotes. However, as they all are lipophilic drugs, intravenously administered lipid emulsion has been suggested as a potential treatment for both intoxications. Originally, the proposed mechanism of action of lipid emulsion was a lipid sink that entraps lipophilic drugs and prevents their action in target tissues. Nowadays, lipid emulsion is a recommended treatment for local anaesthetic systemic toxicity in, for instance, the UK and the US in spite of the fact that its actual mechanisms of action and benefit remain uncertain. In the first study of this thesis, the incidence of local anaesthetic systemic toxicity and the adoption rates of lipid emulsion treatment in Finnish anaesthesia departments were elucidated (I). The other studies of this thesis investigate the efficacy of intravenously administered lipid emulsion in both local anaesthetic toxicity and amitriptyline. The effect on lidocaine induced central nervous system toxicity were studied in human volunteers (II). The effect of lipid emulsion on levobupivacaine intoxication in a situation simulating seizures (III), on the tissue distribution of amitriptyline (IV), and on mitochondrial respiration in bupivacaine cardiac toxicity (V) were studied in pigs. In each of these studies an assessment of the degree of the entrapment of the drug by intravenous lipid emulsion was included. The incidence of local anaesthetic systemic toxicity in Finland is low, only 0.7 per 10,000 regional anaesthesias (I). Lipid emulsion treatment is adopted to less than half of the Finnish anaesthesia departments. In human volunteers, lipid emulsion does not affect the electroencephalography changes or the subjective symptoms caused by lidocaine. Lidocaine was also not entrapped into plasma, but its volume of distribution was slightly increased (II). In pigs, lipid emulsion has no effect on levobupivacaine intoxication which is exacerbated by acidosis and hypoxaemia as measured by reversing of electrocardiogram and haemodynamics from toxic changes (III). Levobupivacaine was also not entrapped into plasma. When lipid emulsion was infused in amitriptyline intoxication, amitriptyline was slightly entrapped into circulation and the brain amitriptyline concentration was reduced by 25% (IV). After higher lipid emulsion dose than recommended, recovery from bupivacaine cardiac toxicity was improved through peripheral vasoconstriction (V). Cardiac mitochondrial respiration was also slightly improved at the same time, and bupivacaine was slightly entrapped into plasma. To conclude, this is the first Finnish study to show that the incidence of local anaesthetic toxicity is very low: 0.7 per 10,000. Lipid emulsion can reduce amitriptyline brain concentration but has no effect on local anaesthetic systemic toxicity if used in clinically recommended doses. If a higher dose is administered, lipid emulsion improves recovery from local anaesthetic toxicity through peripheral vasoconstriction in pigs. The safety of the higher dose to men remains, however, unknown.
  • Hollmen, Maria (Helsingin yliopisto, 2016)
    Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) complicating kidney transplant outcome. Liver transplant recipients are at an increased risk for kidney injury both before and after transplantation and renal dysfunction strongly associates with morbidity and mortality. Identifying kidney injury early is crucial in achieving favorable outcome after transplantation. However, there are currently no reliable methods for predicting kidney damage in transplant patients. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel marker for acute kidney injury. The aim of the study was thus to test whether kidney donor and recipient urine and serum NGAL could predict DGF and prolonged DGF lasting >14 days, and whether plasma NGAL obtained prior to liver transplantation could predict prolonged kidney injury. The studies included 99 deceased kidney donors and their 176 adult recipients and 203 consecutive liver transplant recipients. DGF was seen in 39% of the kidney grafts and the duration of DGF was prolonged in 26 cases. Long-term graft function was significantly decreased in prolonged DGF grafts. NGAL correlated with other markers that describe kidney function such as serum creatinine and GFR. Based on the results measuring serum or urine NGAL the following morning after transplantation predicts DGF and prolonged DGF. Donor urine NGAL correlated with prolonged DGF. In the liver transplant recipients, pretransplant NGAL could not predict posttransplant kidney injury. However, it predicted irreversibility of pretransplant kidney dysfunction, which is helpful in optimizing patient care and deciding whether combined liver-kidney transplantation is needed. In conclusion, measuring blood (serum or plasma) NGAL is useful in assessing kidney function after kidney and liver transplantation.
  • Nicklen, Jenna (Helsingin yliopisto, 2016)
    Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) whereby the host immune system attacks against the myelin. MS affects predominantly young adults and leads to neurological disability. Although it has worldwide penetrance, MS has different incidence rates in different parts of the world. The incidence may also vary among different parts of the country, as seen in Finland. The final diagnosis of MS may often be delayed due to the heterogeneity and relapsing nature of the disease. Occurring symptoms depend on the location of the inflammation in the central nervous system. The most common form of the disease is relapsing-remitting multiple sclerosis (RRMS), in which patients typically recover from all of their symptoms. Infections are often seen before the disease progresses or relapses. Therefore, infectious agents, especially viruses, have been under suspicion for triggering an autoimmune reaction that leads to demyelination. Human herpesviruses are considered to be possible triggers for MS pathogenesis. Objective: Most patients who have been diagnosed with MS have oligoclonal bands (OCBs) of immunoglobulins in their cerebrospinal fluid (CSF). The OCBs are intrathecally produced antibodies mainly consisting of IgG, IgA, and IgM class antibodies. Clinically, the most important antibody group in OCB analysis is the IgG class, which was the main focus in this study. The objective was to study if the OCBs of patients contain antibodies against highly neurotropic and common childhood viruses: human herpesvirus-6 (HHV-6) and varicella-zoster virus (VZV). Another objective was to study if the patients, who have virus-reactive OCBs in their CSF, have some distinguishable features. The main aim was to study the possible role of these viruses in the pathogenesis of MS, focusing on the presence of antibodies during the early stages of the disease. Methods: OCB-positive CSF-serum sample pairs were systematically collected over the course of one year. A retrospective re-detection of OCBs by isoelectric focusing (IEF) was made, and HHV-6A, HHV-6B and VZV-reactive OCBs were localized with affinity driven immunoblotting. HHV-6 IgG antibodies were analyzed from the serum with immunofluorescence assay (IFA). The binding capacity of the IgG antibodies was analyzed and the infections (primary vs. past infection) were classified with avidity testing. During the clinical evaluation, the medical records of the patients were analyzed without knowing the results of the IFA or virus-reactive OCBs. This study has been ethically approved. Results: We had 18 immunocompetent adult patients with serologically primary HHV-6A or HHV-6B infections. None of them had any typical signs of a virus infection (e.g. fever or rash). Of those 18 patients 11 were diagnosed with MS with a primary infection during the early stage of the disease. Of 79 patients, 26 had HHV-6A-, HHV-6B-, or VZV reactive OCBs in their CSF. Of those 26 patients 62% were diagnosed with MS and had these virus-reactive OCBs during the early stage of MS. Patients who had any studied virus-reactive OCBs in their CSF seemed to differ from those without, including: more OCBs (p=0.001-0.003), lower protein concentration (p=0.012), and higher IgG index (p=0.007-0.014) in the CSF. They were also younger (p=0.047). Conclusion:Virus-reactive OCBs are possibly associated with MS disease pathogenesis. HHV-6 and VZV may have some association with MS disease. The pathogenesis of multiple sclerosis may have distinguishable subgroups, including pathogenesis triggered by infections with different viruses.
  • Wikstén, Eeva Johanna (Helsingin yliopisto, 2016)
    Peritonsillar abscess (PTA) is the most common otorhinolaryngological infection that requires special health care management. Its treatment varies greatly due to a lack of common clinical guidelines. Tonsillectomy (TE) is performed on a portion of PTA patients, yet it remains controversial as to which PTA patients would benefit from TE. Traditional bacterial culture is ineffective at defining the causative bacteria for PTA. Rapid microarray methods have been tested, for example on serum and joint fluid samples, but not yet on pus. Most of the bacteria found in PTA are susceptible to penicillin, but, to avoid complications, antibiotics, with unnecessary broad spectrum, are frequently used instead. The aim of the first study in this thesis was to explore the microbiology of adults with PTA using a modern identification method and to find cofactors among patients with different pathogens. Using a modern DNA-based microarray method, we examined the microbial findings in the pus aspirated from 180 PTA patients. Fusobacterium necrophorum proved to be the most prevalent bacteria, occurring more frequently in younger patients; group A Streptococcus was the second most common. The microarray method seemed to work well for identifying bacteria directly from pus. In the second study, the aim was to compare the treatment modalities for PTA in countries closely related to Finland. We sent an electronic questionnaire regarding PTA treatment to all central and university hospitals in Finland, Sweden, Norway and Denmark. The study revealed diversity among treatment modalities between the four countries. To identify factors predicting a doctor ́s decision for TE among PTA patients, in the third study, we retrieved data on 819 PTA patients from a national database, which included information on whether a TE was performed within five years after a PTA diagnosis and why. The study showed that young age and previous tonsillar infections increased the probability of having a TE performed. In the fourth study, the aim was to investigate whether combining metronidazole with penicillin enhances the recovery from PTA and whether metronidazole helps prevent PTA recurrences. A total of 200 prospectively collected patients were randomised to receive either penicillin and placebo or penicillin and metronidazole. The patients filled in an electronic diary daily for the first two weeks and then weekly for the following six weeks. Most patients (90 in each group) healed well without recurrence of PTA. Thus, metronidazole neither enhanced the recovery nor prevented recurrences; furthermore, it caused unwanted adverse effects (diarrhoea and nausea). These four explorations into PTA provided valuable insight. These results make a difference not just for one patient, but for the whole health care system; the treatment is evidence-based and can be offered to those whom it serves best.