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  • Pierides, Georgios (Helsingin yliopisto, 2015)
    Repair of Inguinal hernia ranks among the most common surgical procedures worldwide. Large patient numbers necessitate efficacy and sophistication in the procedure. A novel self-attaching composite mesh (Parietene ProGrip , Covidien, Dublin, Ireland) and a sutured light-weight mesh (Parietene Light , Covidien) were compared double-blinded in 394 randomized patients. Outcomes were collected with a symptom diary and telephone contact during immediate convalescence and by clinical assessment one year after the operation. Outcomes up to 5 years after application of either a sutureless bilayer mesh (Prolene® Hernia System, Ethicon Endo-Surgery, Somerville, MA, USA) or standard tension-free repair (Surgipro , AutoSuture, Norwalk, CT, USA) were collected with a postal questionnaire, telephone contact, and clinical assessment in 300 patients. Health-related quality of life before and after open inguinal hernia repair was measured by RAND 36-Item Health Survey 1.0 (RAND Corporation, Santa Monica, CA, USA) in altogether 159 patients aged at least 65 years and 373 patients aged under 65 years. The results were compared within and between age groups as well as with the values from the general population. A database of 932 open mesh-based hernia repairs was subjected to regression analyses for factors predicting the presence of chronic posthernioplasty pain or more intensive postoperative inguinal pain. Outcomes between the self-attaching mesh and sutured light-weight mesh were equivalent. Applying the self-fixating mesh was faster (34 min vs. 42 min, p less than 0.001). Median sick leave was 2 weeks. At one year, 4.7% of patients perceived pain while resting, 2.0% had pain interfering with every-day life, 25.4% experienced discomfort, and 9.5% had losses in sensation in the operated groin. One recurrence (0.3%) was encountered. Sensory dysfunction of groin skin was rarer 5 years after the operation with the bilayer device than after tension-free repair (5.0% vs. 13.9%, p = 0.022). Other long-term outcomes did not differ. Occurrence of chronic pain diminished from 6.8% at 2 years to 1.3% at 5 years. Cumulative recurrence rate was 1.3%. Discomfort was present in 25.2% of patients, but 92.7% of patients were satisfied with the operation. RAND-36 showed similar improvement in both the elderly and younger patients after open inguinal hernia repair. Complication rates between the age groups did not differ. Higher preoperative VAS score (p less than 0.006), mid-weight mesh (p = 0.012), complications (p = 0.002), recurrence (p = 0.005), and younger age (p = 0.027) predicted chronic pain after open inguinal hernia repair. Higher VAS scores for inguinal pain were predicted by higher preoperative VAS scores (p less than 0.001), heavyweight meshes (p = 0.046), complications (p = 0.016) and recurrence (p = 0.001).
  • Ahlqvist, Kati (Helsingin yliopisto, 2015)
    Somatic stem cell (SSC) dysfunction is a common feature of mouse models of premature ageing, most of which are created by disturbing nuclear DNA repair, damage recognition or ROS defence. The SSC dysfunction leads to decline in SSCs ability to maintain tissue homeostasis resulting in degeneration and ageing. The role of mitochondria or mitochondrial DNA (mtDNA) integrity in SSC homeostasis is unknown. Mutator mice, which harbour proof-reading deficient mitochondrial DNA polymerase gamma, accumulate mtDNA point mutations and develop a premature ageing phenotype, whereas Deletor mice, a model for adult-onset mitochondrial myopathy, accumulate mtDNA deletions and have a normal lifespan. Accumulation of mtDNA mutations and respiratory chain (RC) defect are thought to contribute to ageing process, and the Mutator mouse was the first experimental evidence supporting this theory. The aim of this thesis work was to elucidate somatic stem cell function in both Mutator and Deletor models, to investigate whether SSC dysfunction might explain the premature ageing phenotype. Our results show that the Mutator mouse accumulates mtDNA point mutations in SSC compartments, leading to changes in SSC function already during embryonal development. Deletors do not accumulate mtDNA deletions in SSCs and have normal SSC function. This suggests that premature ageing of Mutators is due to disrupted SSC homeostasis. Hematopoietic progenitors are especially sensitive to mtDNA mutagenesis, which may partly explain the high prevalence of anemia without iron deficiency seen in elderly humans. In this thesis, a novel mechanism for mitochondrial anemias is presented. MtDNA mutagenesis in hematopoietic precursors modifies signaling which causes aberrant iron loading and delayed mitochondrial clearance from maturing erythrocytes. In consequence, Mutator mice have abnormal circulating erythrocytes carrying mitochondria, which are prematurely captured and destructed by splenic macrophages, leading to iron accumulation in spleen. Enhanced destruction of newly-born erythrocytes and concurrently depleted iron stores in the bone marrow make compensatory reticulocytosis inefficient. Delayed mitochondrial clearance was also detected in a human patient with Pearson s syndrome, a rare disorder caused by a sporadic single large mtDNA deletion and causing life-threatening anemia. Treatment with N-acetyl-L-cysteine (NAC), a glutathione precursor and a ROS scavenger, was able to rescue the SSC phenotype during embryogenesis and to normalize iron loading in vitro, suggesting that mtDNA mutagenesis affects ROS signaling. However, NAC could not prevent anemia in vivo, nor rescue delayed mitochondrial clearance in vitro. This indicates that signaling in the SSC compartment is different during embryogenesis than in adulthood. This thesis shows that mtDNA integrity is essential for SSC function. Further, a new and essential role is proposed for mitochondria in regulating their own removal from maturing reticulocytes.
  • Luostarinen, Tapio (Helsingin yliopisto, 2015)
    Cervical cancer is the 4th most common cancer in women. In its carcinogenesis human papillomavirus (HPV) 16/18 are most important. HPV6/11 cause benign lesions. A small proportion of HPV infection(s) develop into cancer. Therefore, joint effects between HPVs and putative co-factors, Chlamydia trachomatis and smoking, are of interest but largely open. The aims of this work were to understand joint effects of infections with 1) HPV types, 2) HPVs and C. trachomatis, and 3) order of these infections in the carcinogenesis. For the 1st two aims, two case-control studies were nested within cohorts of Nordic biobanks. 1st linkage to cancer registers identified 182 cases of invasive cervical cancer (ICC, 148 squamous cell carcinomas, SCC) with prediagnostic sera until 1994. 2nd linkage with a longer follow-up until 2002 comprised 604 new ICC cases. Incidence density sampled controls were individually matched for age at serum sampling, sample storage time and region. For the 3rd aim, a case-control study in a serial setting was nested within a cohort of Swedish women participating in a cervical cancer screening programme in 1969 1995, and 118 ICCs with age and sampling-time-matched controls were identified. Finally, a case-cohort study in the Finnish Maternity Cohort was based on women with two pregnancies within 5 years. The women were followed on average for 4.8 years, from the 2nd pregnancy sample until the end of 2004. During follow-up, 490 women were diagnosed with cervical high-grade precancer. A comparison subcohort of 2796 women was randomly sampled from age and calendar time strata. IgG antibodies to HPV 6/11/16/18/31/33/45 capsids, and C. trachomatis were determined by ELISA. Serum cotinine, a marker for recent smoking, was measured by immunoassays. HPV and C. trachomatis DNA in smears and biopsy specimen were examined by PCR. HPV DNA-positive specimens were typed. Rate ratios were estimated by conditional logistic or proportional hazards regression. Misclassification of HPV serology was corrected for. In the 1st study, we found no excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11. In the 2nd study, the excess risk was 2.4-fold, but the joint effect was again significantly smaller than the expected joint effects. Finally, if infection with HPV6 preceded infection with high-risk HPV31, there was no material excess risk of in situ cervical carcinoma. The smaller than expected joint effect between HPV types was probably due to a cell-mediated immune response to past, natural HPV6/11 infection, of which the serum antibodies were a surrogate. The risk of ICC was highly increased not only among women whose 1st smear was HPV DNA-positive but also among C. trachomatis DNA-positive women. The risk was even higher among HPV or C. trachomatis DNA positives both at the start and end of follow-up. The risk of in situ cervical carcinoma was highly increased among women whose HPV18/45 and C. trachomatis infections were virtually concomitant. The risk of SCC was increased related to C. trachomatis, after adjusting/stratifying for HPV. These results support early HPV vaccination in cervical cancer prevention. C. trachomatis should not be ignored in the preventive efforts against cervical cancer.
  • Lehtinen, Miia (Helsingin yliopisto, 2015)
    Background: Worldwide, the leading cause of morbidity and mortality is heart failure. It is most often caused by coronary artery disease (CAD) and myocardial infarction (MI), which causes death of myocardial tissue. Although coronary interventions such as coronary bypass graft surgery (CABG) can restore blood flow to ischemic areas, and established pharmacotherapy for heart failure exists, no treatment available in the clinics can regenerate the dead cardiomyocytes. For surgical treatment, patients with heart failure represent a challenge, as they are prone to surgical complications, and suitable preoperative imaging modalities to assess possible benefit from surgery are few. Aims: Cell therapies have recently emerged as a possible alternative for treating heart failure. We wanted to explore the capacity of autologous bone marrow mononuclear cells to regenerate myocardial tissue as an adjunct to CABG. The aim was to assess the therapy s safety and detect the cells possible effects on cardiac function and viability. In addition, we investigated whether it would be possible to predict benefit from CABG in these heart-failure patients with 3-vessel CAD with the aid of combined nuclear imaging data. For this, we used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to measure cardiac viability, and 99m-technetium-tetrofosmin single-photon emission computed tomography (99mTc-SPECT) to measure cardiac perfusion. Methods: Between 2006 and 2010, we enrolled 104 patients scheduled for CABG who suffered from CAD and ischemic heart failure. Preoperatively, pharmacotherapy was optimized, after which 39 patients still had left ventricular ejection fraction (LVEF) ≤45%. These patients received injections of bone marrow mononuclear cells (BMMCs) (N=20) or vehicle (N=19) intraoperatively into the myocardial infarction border area in a randomized and double-blind manner. During surgery and at the intensive care unit (ICU), the patients hemodynamics, arterial blood gases, systemic venous oxygen level, blood glucose, acid-base balance, lactate, hemoglobin, body temperature, and diuresis as well as medications needed were monitored and recorded every four hours throughout the first postoperative 24 hours. BMMC effects on the heart were evaluated by use of pre- and 1-year postoperative cardiac magnetic resonance imaging (MRI), FDG-PET, and 99mTc-SPECT and by measuring pro-B-type amino-terminal natriuretic peptide (proBNP) levels. As we later decided to extend the follow-up, these same variables, except for nuclear imaging data, as well as current quality of life were measured at a late follow-up visit in 2013. For this, we could contact 36 of the 39 patients recruited for the original study, of which 30 participated in the extended follow-up. Preoperatively, we also analyzed FDG-PET and 99mTc-SPECT data by using three quantitative techniques with a software tool to measure defects with hypoperfused but viable and non-viable myocardium in 15 control patients. One method used solely PET, two others combined PET and SPECT at different thresholds. As a reference, we used change in LV function and volume by MRI. Results: During the first-year follow-up, improvement was similar in both groups in LVEF, the predefined primary end-point measure (P=0.59), and similar improvement also occurred in local wall thickening (WT) (P=0.68) in the injected segments. Neither changes in viability by PET and SPECT and levels of proBNP differed between these groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% in the control group (interquartile range, IQR -3.3 to 10.8) but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (P=0.0002). During surgery and ICU stay, hemodynamics, arterial blood gases, systemic venous oxygen level, blood glucose, acid-base balance, lactate, hemoglobin, body temperature, and diuresis and levels of medications administered were similar between the study groups. For the extended follow-up, the median period was 60.7 months (IQR 45.1 to 72.6). No statistically significant difference was observable in change in proBNP values or in quality of life between groups. LVEF in both groups remained similarly improved (P=0.647), as also did WT (P=0.434). For controls, scar size in injected segments increased with a median of 2% (IQR -7 to 19); for BMMC patients it remained reduced with a median change of -17% (IQR -30 to -6) (P=0.011). When assessing the benefit-predictive capacity of the two techniques combining FDG-PET and 99mTc-SPECT with different thresholds and one technique using FDG-PET data only, no correlation appeared with preoperative PET- or PET-SPECT-derived viable or non-viable tissue, when compared with global functional outcome (change in LVEF) or local change in WT. Conclusions: In patients with 3-vessel disease and heart failure, the three techniques using SPECT perfusion and PET viability imaging data failed to predict the functional benefit received from CABG. Thus, these imaging modalities may provide no additional advantage to preoperative patient selection, which should be considered when planning treatment for this patient group in the clinics. In the treatment of chronic ischemic heart failure, during surgery and perioperatively in the ICU, both intramyocardial BMMC and placebo injections appear safe. Although failing to affect cardiac function, combining intramyocardial BMMC therapy with CABG can sustainably reduce scar size.
  • Helmiö, Päivi (Helsingin yliopisto, 2015)
    TOWARDS BETTER PATIENT SAFETY: The WHO Surgical Checklist in Otorhinolaryngology More than one-half of adverse events in health care are related to surgery. Surgical patient injuries account for about 80% of patient injuries in otorhinolaryngology (ORL). The World Health Organisation (WHO) has developed a Surgical Safety Checklist to prevent errors in the operating theatre. Its use has been shown to reduce complications and mortality. The aims of the present study were to identify errors that may underlie those patient injuries that occur in operative ORL, to assess the effects of the WHO checklist on working processes in the operating theatre, including compliance, and to evaluate how it would fit into the specialty. Data of the patient injuries that were sustained during treatment by the ORL specialty between the years 2001 and 2011 were obtained from a search of the Finnish Patient Insurance Centre registry. The causes of the injuries were analysed, and whether the WHO checklist could have prevented the error was evaluated. The checklist was implemented in four Finnish hospitals as a pilot in 2009. A prospective before-versus-after-intervention study was conducted with a questionnaire for OT personnel in these four hospitals to evaluate the checklist. The checklist was subsequently implemented for regular use in the operative unit of the Department of Otorhinolaryngology of Helsinki University Central Hospital. After one-year of use, compliance and user attitudes were analysed by using data obtained from the operations database and a survey of operative ORL personnel. In the 10-year study period, 188 patient injuries were associated with operative ORL. A total of 142 (75.5%) of these injuries occurred due to errors that were made in the operating theatre, and in 125 cases (66.5%) a manual error in performing the surgery was the primary cause of the injury. Six injuries (3.2%) were caused by wrong site surgery. An error had some degree correspondence with a WHO checklist item for 18 injuries (9.6%) and it was determined that 9 of these injuries (4.8%) could have been prevented had the checklist been correctly used. The implementation of the checklist enhanced the communication between the surgical team members, improved verification of the patient s identity and of the correct operation site. Checklist compliance was 62.3% during first year of use. It was considered easy to use and the Safety Attitude Scores of the personnel were found to be on a high level. All check items on the list were considered important for ORL. However, a more compact checklist for outpatient surgery was requested. Patient injuries in ORL were strongly related to surgery. The WHO Surgical Safety Checklist seems to be a beneficial tool for preventing errors ORL and is highly relevant for the specialty.
  • Kerola, Anne (Helsingin yliopisto, 2015)
    Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. The aim of this work was to evaluate the prevalence of CV comorbidities and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA. Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. The same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we retrieved data on permanent or temporary disability pensions. Causes of death were obtainable until the end of 2008. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity-related disability pensions, and CV mortality rates to those of the age- and sex-specific Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs). In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR (95% CI) being 1.10 (1.01 1.20). The SRR for levothyroxine-treated hypothyroidism at RA diagnosis was 1.51 (1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 were granted a disability pension. The 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. The SMR in the entire RA cohort was 0.57 (0.52 0.62). To conclude, the risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis, highlighting the importance of CV risk detection and management and of vigilance for hypothyroidism. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. All these findings together stress the importance of recognizing, preventing, and targeting comorbidities in RA, already in the early years of the disease.
  • Kaislasuo, Janina (Helsingin yliopisto, 2015)
    The proportion of nulligravid and nulliparous women is increasing as women delay childbirth in developed countries. Simultaneously, contraceptive failure, unintended pregnancies and abortions, especially in women below the common childbearing age, are a global problem. By promoting intrauterine devices (IUDs) and subdermal implants, referred to as long-acting reversible contraceptives (LARCs), among these women, contraceptive failure caused by non-compliance of the user can be minimized, in addition to providing easy and efficient long-term contraception. However, the risk of difficulties at IUD insertion in nulligravid/nulliparous women, as well as small uterine size, have both been considered as barriers limiting the use of intrauterine contraception (IUC) in these women. The present studies were designed to study the barriers to IUC in nulligravid and nulliparous women. To compare both types of IUC available, we used the levonorgestrel-releasing intrauterine system (LNG-IUS) and the copper-releasing NovaT (TCu380Ag), with identical frames measuring 32 x 32 mm. To exclude any effect of prior pregnancy on the uterine cavity or the cervix, only nulligravid women were included. Difficulties at insertion, menstrual diaries kept after insertion (months 1 3) and at the end of the study (months 10 12) as well as adverse events were compared against uterine cavity measurements and pre-insertion menstrual characteristics reported by the women. In addition, as uterine perforation is mainly seen as a complication related to insertion, we retrospectively analysed women treated for this rare complication between 1996 and 2009 in our hospital district area. We gave 165 nulligravid women requesting their first IUD a free choice between the two IUDs after contraceptive counselling. The majority, 113 women (68.5%), chose the LNG-IUS and 52 women (31.5%) chose the copper IUD. Insertion was easy in 89% of the women. The women were satisfied, with only 17/135 women (12.6%) available for follow-up discontinuing because of adverse events. The reported numbers of days of bleeding and pain were similar to that in earlier reports on parous women. Severe pain at insertion was reported by 56.5% of the women and severe dysmenorrhoea the only factor predicting severe pain (OR 7.9, 95% CI 2.5 24.9, p less than 0.001). Dysmenorrhoea was also related to more pain during the first months with both devices. Baseline spontaneous bleeding predicted bleeding with the LNG-IUS, but not with the copper IUD. Among women using the LNG-IUS, scanty menstrual bleeding (OR 8.2, 95% CI 1.4 48.2, p=0.02) and smoking (OR 8.2, 95% CI 1.8 38.6, p=0.007) predicted amenorrhoea at one year. Uterine measurements, particularly fundal cavity width, were small in comparison to the devices in a majority of the women. The odds of a difficult or failed insertion increased with shorter uterine length and a steeper flexion angle, but the great majority of insertions, even in small and more flexed uteri, were uneventful. Cervical tightness was the main reason for problems in cases of difficult insertion. No uterine threshold measurements predicting difficulties were found. Small uterine measurements were associated with both less bleeding and less pain among LNG-IUS users. Women with the widest fundal widths reported significantly more pain at the end of the one-year follow-up period compared with those with smaller widths. Uterine size did not affect bleeding in connection with the copper IUD, but there was a slight tendency towards more pain during long-term use among women with smaller uterine cavity measurements, although size groups were small with this device. Uterine size did not predict adverse events. We found 75 cases of surgically treated uterine perforation during the 15 year long study period. The incidence of perforation was low, 0.4/1000 insertions, and similar with both types of IUC. Postpartum insertion, earlier presented as the main risk factor of uterine perforation, was also common in this population (64%). The majority of cases, 71%, presented with complaints of abnormal bleeding or pain, but 29% were asymptomatic and diagnosed in connection with missing threads or pregnancy. Pregnancy was more common with a misplaced copper IUD, 33% vs. 7% with a misplaced LNG-IUS (p=0.009). We found no severe complications or intra-abdominal adhesions caused by the misplaced devices. Adhesions were local and more common in copper IUD users (58% vs. 20%, p=0.002). In conclusion, nulligravid women are satisfied users of modern IUC, with continuation rates and bleeding and pain profiles similar to those in parous women. Small uterine cavity measurements are not a barrier to IUC and pre-insertion ultrasonographic evaluation of uterine cavity size is unnecessary. As dysmenorrhoea predicts both severe insertion pain and pain during the first months of IUD use, analgesia and counselling for these women should be highlighted. Although rare, the risk of uterine perforation is increased during the postpartum period, probably reflecting uterine involution as the main reason for this complication. Neither symptoms nor surgical findings are severe in connection with current devices.
  • Rantanen, Ville (Helsingin yliopisto, 2015)
    Images provide invaluable information to Biomedicine. Especially, microscopy as an information source has been providing knowledge for research and clinical diagnostics. We have moved away from simply looking at the images to quantifiable computerized image analysis. Over the last decades, image analysis developers have prepared algorithms and software to address various scientific enquiries using images. These software are often created for a single purpose. Naturally, not even the most generic software can include all the algorithms ever created. From an image analysis developer point of view, the choice of software creates limitations. It limits the developer to the algorithms included and to the language it was developed in. Even if the software is modular and extendable, a specific language is required and the earlier algorithm implementations would have to be ported. This thesis presents an integration platform for image analysis: Anima. It is capable of using existing software and including them in analysis workflows. Since image analysis is very case specific, custom processing commands are frequently needed. Anima comes with a large number of data and image analysis components developed directly for the platform, as well as components that send custom commands to the integrated software. All of the components can be executed in a single analysis pipeline. Anima itself is built on top of Anduril, another software, inheriting its software architecture. Anduril gives Anima the power of parallel processing and rerun prevention mechanism, speeding up the development cycle of new algorithms. The usability of Anima for method development is shown by implementing new segmentation algorithms and visualization tools. The tools and methods are all suited to large data sets. To display the modularity, the tools are published as separate programs that are then integrated in Anima. The usefulness of the platform is shown by applying it in different biomedical research settings. The settings include different organisms: human, rat and nematode; different sample material: brain tissue, lymphatic nodes and serum; and different medical interests: cerebral ischemia, cancer and allergy. Anima is a versatile open-source image analysis platform, that encourages the use of best practices of programming habits. It makes the development of analysis workflows and individual algorithms more efficient.
  • Parviainen, Suvi (Helsingin yliopisto, 2015)
    It has been estimated that up to half of people living in industrial societies will get cancer. Almost all cancer deaths are caused by metastatic disease and only few metastatic solid tumors can be cured with available therapies. Therefore, novel therapeutic modalities are needed. Genetically engineered oncolytic viruses such as adenoviruses and vaccinia viruses are a promising therapeutic approach given their capacity to specifically replicate in and kill tumor cells as well as to reach distant metastasis. Oncolytic viruses have demonstrated good safety, tolerability and promising signs of anti-tumor efficacy in several clinical trials, but the efficacy of the therapy needs improvement to reach its full clinical potential. Adenoviruses are one of the most studied vectors in oncolytic virotherapy. Two major obstacles limiting the efficacy have been insufficient transduction of the tumor cells and the recognition of the virus by the immune system, which rapidly clears the virus from systemic circulation, hampering the overall efficacy. This study shows that novel capsid modifications can increase the transduction efficacy and oncolytic potency of the virus, and that embedding oncolytic virus in a silica implant might help to circumvent the problem of clearance by prompting only modest immune responses against the virus. Recently, arming oncolytic viruses with immunomodulatory molecules has been a major focus in virotherapy. Immunotherapy means inducing the patient´s immune system to recognize and attack the tumor and has been recently linked with oncolytic virotherapy, as the replication of the virus in the tumor can be immunogenic per se and also release cancer epitopes available for antigen-presenting cells. Host immune responses have been shown to be a key player in oncolytic virotherapy as the balance between anti-viral and anti-tumoral immunity determines the efficacy of the therapy. Oncolytic vaccinia virus possesses unique immunogenicity and mechanisms of action that are distinct from other treatment modalities, and its self-perpetuating nature provides an ideal platform for therapeutic transgenic insertion. Therefore we engineered novel oncolytic vaccinia viruses with granulocyte-macrophage colony-stimulating factor (GMCSF) or CD40-ligand and studied their ability to increase the therapeutical outcome and anti-tumor immune responses in preclinical animal models. In the final part of the thesis the life cycle of oncolytic vaccinia virus was studied in more detail as we were able to show that the life cycle was compromised in a feline squamous cell carcinoma cell line. This finding might be important for a deeper understanding of the vaccinia virus-host cell interactions.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Virtanen, Anni (Helsingin yliopisto, 2015)
    High coverage amongst those at risk and a high attendance rate are essential in achieving a good impact in a cervical cancer screening programme. In Finland, attendance in the programme is approximately 70% with a slight decreasing trend. There is wide variation in the current invitation practice between municipalities. The introduction of human papillomavirus (HPV) testing in cervical cancer screening has brought about a new possible means of improving attendance rates, as HPV-testing can be performed on self-collected samples. This offers the opportunity to supply sampling devices directly to the homes of the women (self-sampling). The aim of this study was to investigate the effects and feasibility of using self-taken samples for HPV-testing to conduct cervical cancer screening of non-attendees to the Finnish cervical screening programme. The effect on attendance to the screening programme, on overall screening test coverage (including also testing outside the screening programme), on the yield of precancerous lesions detected by screening and on the costs of a screening programme were assessed, as were women s views on this new screening modality. The effects of self-sampling were first studied as a first reminder (i.e. among non-attendees after the primary invitation) in a randomized setting in comparison to a reminder letter, and then in a non-randomized setting as a second reminder after two invitation letters. As a first reminder to non-attendees after the primary invitation, a self-sampling test resulted in somewhat higher attendance than a reminder letter. The difference was small, and in terms of resulting costs (price per extra screened woman and price per detected CIN2+ lesion), a reminder letter with a pre-assigned appointment time is a more feasible choice than a self-sampling test. However, self-sampling can be used to increase screening attendance as a second reminder after two invitation letters. Overall attendance rates increased by 4-8%, and the combined effect of reminder letters and self-sampling showed a 12-23% increase. The yield of detected CIN2+ lesions increased by 25-33% with two reminders. As opportunistic screening is very common in Finland, the increase in overall test coverage remained smaller than the increase in the uptake to the programme. Based on a questionnaire study conducted alongside self-sampling, self-sampling at home helps to overcome both practical and emotional barriers to traditional screening. Women who took part in screening by self-sampling reported mainly positive experiences, but negative experiences were more common among women with a mother tongue other than Finnish or Swedish. The invitation protocol preceding the self-sampling option must be carefully arranged to achieve optimal attendance. A total attendance of well over 80% is achievable in the national programme if personal invitations and reminder letters to non-attendees are sent, scheduled appointments are used in both letters and self-sampling tests are sent to those women who still do not attend.
  • Tohmola, Niina (Helsingin yliopisto, 2015)
    Metabolites are low molecular weight compounds participating in different functions of cellular systems. Metabolites can be used as diagnostic biomarkers for numerous diseases. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a powerful tool in quantification of metabolites from various sample matrices. Good sensitivity and specificity are the main benefits of the technique. Mass spectrometry is commonly used in industry, drug research and clinical diagnostics. Extensive validation of newly developed analytical methods will construct the basis to a reliable assay, and it is significant especially when analysing e.g. patient samples. The aim of this study was to develop quantitative assays for metabolites from biological samples for biomedical research and clinical diagnostics. We designed and constructed an on-line high performance liquid chromatography (HPLC) equipment and validated an assay for direct quantification of extracellular metabolites from cell cultivation. Automated sampling for LC-MS/MS analysis of intracellular metabolites was connected to the on-line system. The on-line analysis improves the methodology and shortens the time of analysis. Furthermore, a frequent sampling data can provide valuable information about physiological indications in various cell cultivations. On-line HPLC is suitable for various biotechnological applications because of its ability to monitor and collect data during cell cultivation. We developed and validated LC-MS/MS assays for neuroendocrine tumor (NET) biomarkers 5-hydroxyindole acetic acid (5-HIAA) and vanillylmandelic acid (VMA) from human serum. Generally, urinary HPLC assays are used for the determination of NET markers. HPLC assays have certain limitations and 24-h urine collection is laborious. Our LC-MS/MS assays are specific, fast and well suited for diagnostics of NETs. Furthermore, guidelines for urine collection advise to refrain from serotonin-containing foods for three days before sample collection. We showed that such a diet restriction before serum 5-HIAA assay is not necessary. Instead, one day serotonin-free diet before sampling is sufficient because the half-life of 5-HIAA in circulation was found to be 1.3 hours. All assays developed during this study were sensitive and had a wide linear range. Our serum 5-HIAA LC-MS/MS assay is routinely used for the analysis of NET patient samples at the Helsinki University Central Hospital Laboratory, HUSLAB. Serum VMA LC-MS/MS assay will be in routine use in the HUSLAB in near future. Furthermore, On-line HPLC Ltd, (Helsinki, Finland) has commercialized the on-line HPLC equipment developed in this study.
  • Cousminer, Diana (Helsingin yliopisto, 2015)
    Puberty is a highly variable developmental stage marked by the development of secondary sex characteristics and the attainment of reproductive maturity. Variation during childhood developmental phases correlates with altered disease risk in adulthood; variation in pubertal growth and timing, in particular, correlates with adult risk for type 2 diabetes, obesity, adverse cardiovascular heath, and hormone-dependent cancers. While normal variation in age at menarche (AAM) has recently been investigated in large-scale genome-wide association (GWA) studies, the genetic regulation of male puberty remains less understood. Moreover, extreme variation in pubertal timing is a common cause for referral to pediatric specialists, while the underlying genetic factors are largely unknown. This work aimed to identify both common and rare genetic variants influencing pubertal growth and timing in both sexes. Utilizing Finnish population-based samples with frequent height measurements across puberty, we ran GWA of growth during late puberty and uncovered an association for variants near LIN28B, the most robust menarche-associated locus. Investigation of the longitudinal effects of two partly-correlated markers, one tagging a pubertal timing effect and one tagging an effect on adult stature, revealed distinct sex-specific association patterns with height growth from birth until adulthood. Thus, the LIN28B locus tags an important developmental regulator of both growth and maturational development. We then expanded to include European-wide samples within the Early Growth Genetics (EGG) Consortium. Genetic mapping of three pubertal growth traits revealed 9 novel pubertal growth variants in addition to LIN28B, 5 of which also associated with pubertal timing, and one which associated with childhood and adult body mass index (BMI). Longitudinal investigation of these variants showed diverse patterns of association with height growth, some of which contradicted epidemiological correlations between rapid prepubertal growth, advanced puberty, and reduced final adult stature. Given the complex relationships between these traits, tracking individual unique effects across multiple periods of growth may help uncover the pathways linking childhood development with adult health outcomes. Also within the EGG Consortium, GWA meta-analysis of Tanner genital and breast staging data uncovered the first robust male puberty locus on chromosome 16 near MKL2, a locus which also associates with advanced menarche, decreased pubertal growth, and shorter adult stature. Furthermore, part of the genetic architecture underlying the onset of puberty is shared between males and females, evidenced by the high correlation between menarche-advancing alleles and earlier male genital development. However, while BMI-increasing alleles strongly correlate with advanced breast development in girls, our data shows that these variants play a more complex role in male puberty. Finally, we performed targeted sequencing of the pericentromeric region of chromosome 2 previously robustly linked with constitutional delay of growth and puberty (CDGP), an extreme delay in normal pubertal timing, in multiply affected Finnish families. Analysis of shared low-frequency variation in genes and regulatory regions of the best functional candidate genes revealed 6 protein-altering variants in a single gene, DNAH6, in 10 of the families. However, follow-up sequencing in an additional 135 Finnish CDGP cases failed to provide evidence for enrichment of DNAH6 mutations compared to a large, unique set of SISu Finnish population controls. DNAH6 is potentially an appropriate candidate gene that may be involved in the regulation of steroid hormone biosynthesis by the cytoskeleton. This study highlights the difficulties of detecting susceptibility variants under a linkage signal for complex traits. Taken together, these results advance our understanding of the genetics of pubertal timing and development in both sexes. However, more work is needed to understand how each genetic locus functions in the biology of puberty and childhood growth, and further study of the genetic loci highlighted in this work may help pinpoint the mechanisms that link the timing of this important developmental stage with adult health and risk for common diseases. Keywords: puberty, development, growth, genome-wide association studies (GWAS), targeted sequencing, constitutional delay of growth and puberty (CDGP)
  • Lehto, Hanna (Helsingin yliopisto, 2015)
    Objective: Aneurysms of the vertebral artery (VA) and its branch posterior inferior cerebellar artery (PICA) are rare, comprising only about 1 to 3% of all intracranial aneurysms. The series published thus far on these lesions are small. We aim to describe the special anatomical and morphological features of these aneurysms compared to aneurysms in other locations, and to describe the variety of symptoms they cause. We describe their treatment and analyze the outcome. Additionally, we describe their anatomy imaged with computed tomography angiography. Patients and methods: We reviewed retrospectively 9 709 consecutive patients with intracranial aneurysms treated in the Department of Neurosurgery at Helsinki University Central Hospital, Finland, between 1934 and 2011. The study population included 268 patients with 284 VA or PICA aneurysms or both. Follow-up data came from the Population Registry Centre (dates of death), Statistics Finland (causes of death), from written questionnaires to patients still alive, medical records of the Department of Neurosurgery, and for those deceased, medical records from all public health services. Results: Among all the aneurysm patients, 5.1% had an aneurysm in the VA or PICA. Most aneurysms, 51%, were located at the VA PICA junction. The proportion of fusiform aneurysms was 28%. Compared to patients with ruptured aneurysms at other locations, patients with a ruptured VA or PICA aneurysm were older and had a higher Fisher grade. Ruptured distal PICA aneurysms also re-bled more regularly. Compared to other ruptured aneurysms, ruptured VA and PICA aneurysms were smaller and more often fusiform. At least one VA or PICA aneurysm was treated in 209 (78%) patients. The most common technique for aneurysm occlusion was clipping, used in 107 aneurysms. Total occlusion of the aneurysm was achieved among saccular aneurysms in 90%, and among fusiform aneurysms in 61%. Within one year of aneurysm diagnosis, 26% of the patients were dead. Among those who survived a minimum one year and in whom the VA or PICA aneurysm received active treatment; those returning to an independent or their previous stage of life amounted to 92%. Conclusion: In treatment of VA and PICA aneurysms, their special anatomical and morphological features are challenge. Despite this, and often severe hemorrhage, most patients surviving the initial stage make a good recovery.
  • Nieminen, Tarja (Helsingin yliopisto, 2015)
    Social capital has been widely discussed in research. An increasing amount of literature has linked social capital to various health outcomes and well-being. However, both health and social capital are complex phenomena, and there is still inconsistency in the research findings. The general aim of this study was to examine the associations between social capital, health behaviour and health among adult Finnish population. The conceptualization and operationalization of social capital varies according to discipline and level. In this study, social capital is measured at the individual level assuming that an individual s investment in group activity reflects social capital seen as a resource related to social networks and group membership. Individual benefits are accessed through social connections in varied groups and society. Thus the resources do not reside within the individual but rather in the structure of person s social networks. Social capital was measured on three dimensions in this study: 1) social support, 2) social networks and participation and 3) trust and reciprocity. The association between these dimensions and health were examined. Health was investigated as self-rated health, psychological well-being and mortality. This study utilised the data of the Health 2000 Survey conducted in 2000−2001. Of people aged 30 and over, 89% participated in the home interview and 80% in the general health examination. The study material presents the whole population unusually well. The National Institute for Health and Welfare (THL; formerly the National Public Health Institute, KTL) had the overall responsibility for the project. In addition, the project organization involved a wide range of research and funding agencies. This survey contains a rich armoury of questions about health and illnesses, health behaviour, capacity for work, functional capacity and use of health services. Furthermore, it includes a broad selection of questions used in measuring social capital. The results found an accumulation of social capital and general welfare for the same groups: the highest levels of social capital were found among the young, well-educated and married people. However, all socio-demographic subgroups seem to benefit from social capital. Regardless of all socio-demographic characteristics, high levels of social capital were associated with good health, associations which varied among different health-related behaviours, but social participation had a strong statistical association with all components of health and all health behaviours. Regardless of chronic diseases people with high levels of social capital felt healthier than those with low levels. The positive association between social capital and survival was statistically significant among men and suggestive among women. These findings indicate that social capital contributes to health. Health inequalities between population sub-groups are still substantial. Health could be promoted and health inequalities reduced by developing tools for increasing social participation especially in those groups lacking social capital−and who often also suffer from several health problems.
  • Honkasalo, Mikko (Helsingin yliopisto, 2015)
    Diabetes is a common chronic disease with growing prevalence in Finland like worldwide. It shortens the life expectancy and the quality of life. Despite the development in medication and devices there has been only modest improvement in the outcome, especially among type 1 diabetic patients. The aim of this study was to compare the outcome of overall diabetes care in municipalities with different primary health care models of organising the follow-up of type 1 diabetes and type 2 diabetes with special treatment problems. The study also aimed at estimating the feasibility of various indicators of the standard of diabetes care. The outcome, use and costs of health services connected with diabetes and its complications were compared in two suburban communities, Kouvola and Nurmijärvi. In Kouvola the follow-up of all patients had been based on family doctors already over 15 years whereas in Nurmijärvi the follow-up of T1D patients and the complicated T2D patients had been centralized to 1-2 doctors for the same time. The diabetic populations of these municipalities resembled each other. In the centralized system T1D became cheaper for the municipality. Differences in the quality parameters were minor. Both these results were obviously due to more consultations of the specialist level in Kouvola. However, T1D patients were significantly more satisfied with the centralized follow-up model. In conclusion, the centralized follow-up of the most demanding diabetes in PHC is cost-effective and results in high patient satisfaction. The centralized model is better in the follow-up of T1D but in T2D there were no differences between these two models.
  • Koskela-Niska, Virpi (Helsingin yliopisto, 2015)
    Both ovarian and tubal cancers are rare. Therefore only a few studies explored such postmenopausal hormone therapies (HT) as used in Finland, as a risk factor for these cancers. I compared the incidence of ovarian and tubal cancer in HT users with the incidences of these cancers in the background population in two nationwide cohort studies. To exclude a number of potential confounders I conducted two case-control studies to further elucidate HT use as a risk factor for these cancers. The cohort studies included all women aged 50 or older who had used HT-regimens for 6 months or longer in 1994-2008. These women were identified from the Finnish Medical Reimbursement Register. The ovarian cancer cohort study included 224,015 women using estradiol-progestin therapy (EPT), whereas in the primary fallopian tube carcinoma (PFTC) cohort study included altogether 365,601 women using EPT (n=247,781) or estradiol-only therapy (ET)(n=117,820). These women were followed from the first HT purchase to the diagnosis of ovarian or tubal cancer, death, emigration or to the end of the study period through the national Finnish Cancer Registry. Relative risks of these cancers in HT users were estimated by comparing the incidence of ovarian or tubal cancer in HT users to the age-matched comparable background population and calculating standardized incidence ratios (SIR) and their 95% confidence intervals (CI). In the case-control studies, all 50-year-old or older women with incident ovarian cancer (n=3,958) or PFTC (n= 360) during 1995-2007 were identified from the Cancer Registry. The Population Register provided control women, 3 per each case of ovarian cancer and 10 per each case of PFTC, and parity data. The controls had to be alive and without ovarian/primary fallopian tube cancer and they were matched for age (+/- one month) and place or residence. The controls with an oophorectomy (n=506) or a salpingectomy (n=158) were excluded leaving 11,325 and 3,442 controls, respectively. Odds ratios (OR) with 95% CIs for various HT regimens were estimated by using conditional logistic regression adjusted for parity, ages at deliveries, hysterectomy and sterilization. The use of any type of EPT for less than five years did not modify the overall risk of ovarian cancer. Instead, the use of sequential EPT for five years or longer was associated with an elevation in the overall risk of ovarian cancer (SIR 1.21, 95% CI 1.06-1.37). The risk rises were most marked for serous (1.56; 1.33-1.80) and mixed cancer (1.54; 1.22-1.91) whereas the risk for mucinous cancer was decreased (0.47; 0.22-0.86). The risk increase connected to EPT use did not depend on the progestin type, mode or route of administration of EPT. The use of ET for five years or longer was linked with an increase in the risk for serous ovarian cancer (OR 1.45, 95% CI 1.20-1.75) while the risk of mucinous cancer was decreased (0.35; 0.19-0.67). As a whole the use of ET was accompanied with borderline rise in overall ovarian cancer risk (1.15; 0.99-1.32). In the users of sequential EPT, the risk rise was similar for endometroid (1.88; 1.24-2.86) and serous (1.32; 1.01-1.71) cancers. The use of continuous EPT, tibolone or E+LNG-IUS did not modify the risk of ovarian cancer. The use of ET was not a risk factor for PFTC. However, the use of sequential EPT for five years or longer was accompanied with a risk elevation (SIR 2.15, 95% CI 1.66-2.72), which was further increased if the use of sequential EPT continued for 10 years or longer (3.36; 2.02-5.24). In contrast, the use of continuous EPT did not modify the risk for PFTC. The uses of E+LNG-IUS for five years or longer was associated with increased risks of PFTC (ORs 2.84, 95% CI 1.10-7.38 and 3.37; 2.23-5.08, respectively), but this finding was based on low number of cases and controls. Postmenopausal hormone therapy use modifies the risks of both ovarian and fallopian tube cancers. The risk of serous and endometroid ovarian cancer rises but the risk of mucinous cancer decreases. The use of sequential EPT regimen is characterized with the highest risk elevations. In absolute terms, in 10,000 women using sequential EPT for five years or longer, there would be four extra cases of ovarian cancer and two extra cases of PFTC after follow-up of five years. These data should be incorporated into modern guidelines for the optimal use of HT.
  • Lithovius, Raija (Helsingin yliopisto, 2015)
    As health care resources are limited, it is crucial to identify potential subgroups of patients with different resource needs and the major cost drivers in order to improve understanding of the cost structure of diabetes care. About one-third of the patients with type 1 diabetes develop diabetic nephropathy (DN), which is the most burdensome diabetic complication and the leading cause of end-stage renal disease (ESRD), requiring dialysis or kidney transplantation. Pharmaceutical interventions play an important role not only in controlling glycaemia, but also in preventing and treating related co-morbidities. The aim was to evaluate the use and costs of prescription medication in a large nationwide cohort of patients with type 1 diabetes, stratified by severity stages of diabetic kidney disease, and to study to what extent target values of the American Diabetes Association (ADA) guidelines were met in normal clinical settings and how achievement of the most relevant targets predicts the prognosis of the patients. All sub-studies are part of the ongoing, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). Studies I (N=3,717), II (N=1,905), III (N=330) and V (N=3,151) have longitudinal and Study IV (N=3,678) a cross-sectional design. To obtain information on purchases of prescription medications, co-morbidities and mortality, the FinnDiane data were linked with several national registers. In patients with ESRD, the 11-year cumulative costs increased fourfold or even 15-fold, when diabetes medications were excluded compared to those without severe complications. The cost of diabetes medications remained quite stable irrespective of the presence of complications and duration of diabetes. The costs were significantly higher in patients with macroalbuminuria than in those with earlier stages of DN, and the gap continued to increase until the end of follow-up. A large gap exists between evidence-based guidelines and clinical practice since only a minority of all patients reached the targets for HbA1C, blood pressure (BP) and LDL cholesterol proposed by the ADA. Failure to reach the targets was associated with increased risk of cardiovascular disease and mortality. One of the novel findings was the high prevalence of treatment-resistant hypertension (RH) which increased in parallel with the worsening of DN in patients with type 1 diabetes. Progression to a more severe stage of DN has a substantial impact on prescription medication costs, highlighting the importance of early intervention to prevent or delay the onset of diabetic kidney disease. The treatment targets of HbA1C, BP and LDL cholesterol have not been achieved. Successful implementation of these targets would be a key for the optimal prevention of CVD and mortality.
  • Laurila, Pirkka-Pekka (Helsingin yliopisto, 2015)
    Cardiovascular disease is the leading cause of death worldwide, and is characterized by disturbances in lipid metabolism. High blood LDL cholesterol is the most important risk factors for atherosclerosis, a pathological state in which the circulating lipid molecules accumulate in the blood vessel wall. Blood levels of HDL cholesterol are inversely associated with cardiovascular risk, and low HDL-cholesterol is a significant risk factor for cardiovascular disease. In this thesis, new genes predisposing to low HDL-cholesterol level were searched using genome-wide association analysis in Finnish individuals with extremely low or high HDL-cholesterol. Several new genes predisposing to low HDL-cholesterol were discovered, of which many were known to be associated with immune system and inflammatory reaction of the body, but their role in cholesterol metabolism has not previously been characterized. Some of the subjects appeared to be genetically more prone to inflammation than others, especially in the blood and adipose tissue. The more inflammation inducing genetic variants one had, the stronger was the inflammatory state of the body, especially in blood and adipose tissue, and the lower the HDL-cholesterol level. The inflammation may block the transport of cholesterol from vessel walls to circulation leading to lower HDL-cholesterol levels in the circulation. This thesis also examined the composition of HDL particles by determining the concentration of all know lipid species in HDL particles. The quality of HDL particles appeared to vary considerably. In individuals, whose HDL-cholesterol levels were low, the quality of HDL particles was also impaired; they contained smaller amounts of plasmalogens which are fat molecules known to be antioxidant and thus protective to arteries. In individuals with high HDL-cholesterol levels in the circulation, the lipid composition of the HDL particle was more beneficial regarding heart disease risk. This thesis further demonstrates that not only the quantity but also the quality of HDL particles is genetically regulated. The genetic variants regulating the level of HDL-cholesterol also govern its quality, highlighted by inflammation-increasing genetic variants also impairing HDL quality. This thesis work provides novel insights about the molecular background of HDL cholesterol and validates the strong link between inflammation and low HDL-cholesterol levels. The studies show how genetically induced inflammation reduces blood HDL-cholesterol levels and impairs HDL particle quality, potentially predisposing to cardiovascular disease.
  • Soininen, Antti (Helsingin yliopisto, 2015)
    Hydrogen free diamond-like carbon (DLC) coatings have been the subject of investigation all around the world for the last 30 years. One of the major problems in producing of thick high-quality DLC coatings has been the inadequate adhesion of the deposited film to the substrate. This obstacle is finally overcome by depositing an intermediate adhesion layer produced with high energy (>2 keV) carbon plasma before application of a high-quality coating produced with a low energy unit. To the best of our knowledge, this can be achieved (with reasonable yield for industrial purposes) only with the filtered pulsed arc discharge (FPAD) method developed by our group. In this thesis a new combination of in situ surface oxide reduction method with FPAD is presented. Novel anti-soiling DLC polymer hybrid coatings (DLC-p-h) can be deposited using a slightly modified FPAD system. Both the coatings and their deposition method are recent innovations invented in our research group. This method makes possible to combine diamond and polymer properties in the resulting coatings. Two novel hybrid coatings have been developed: DLC polytetrafluoroethylene hybrid (DLC-PTFE-h) and DLC polydimethylsiloxane hybrid (DLC-PDMS-h). These hybrid coatings are highly hydrophobic and oleophobic (dirt repelling). Therefore these novel coatings could probably be used as antifouling and wear resistant coatings to which pathogenic bacteria would adhere less than to conventional biomaterials in biomedical applications. These DLC-p-h coatings are not produced anywhere else in the world. In this thesis bacterial adhesion to DLC was studied under dynamic conditions. Our experiments demonstrated that the bacterial adhesion to DLC was similar to the adhesion to AISI 316L surgical steel commonly used in medical applications. This suggested that DLC coating can be used on implants made from AISI 316L or other materials without increasing the risk of implant-related infections. Adhesion of bacteria and human cells (hMSC, hOB, Saos-2) to our novel DLC-p-h coatings was also studied. Bacterial adhesion tests showed a potential application of DLC-PTFE-h coating as a less biofouling surface than DLC, titanium and oxidized silicon surfaces. Cell adhesion studies showed less adhesion on DLC-PDMS-h surfaces than on DLC or titanium surfaces and some of the cells even underwent programmed cell death caused by lack or loss of adhesion. Osteogenic differentiation study on DLC-PDMS-h surface showed impaired or delayed osteogenesis. Cytocompatibility and cytotoxicity tests proved that DLC-PTFE-h and DLC-PDMS-h coatings are biocompatible. In summary, these studies suggest that DLC-PTFE-h coatings could be used in medical applications where bone integration would be preferred while DLC-PDMS-h coating in orthopedic applications where an implant or implant-facet should be protected against bone overgrowth.