Browsing by Subject "lääketiede"

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  • Paavola, Jere (Helsingin yliopisto, 2014)
    Heart disease is the biggest killer world-wide, causing a quarter of all deaths. During the past two decades, it has also risen above infectious diseases as the leading cause of years of life lost. Heart failure, characterized by weak pump function of the heart, and disturbances in heart rhythm (arrhythmias) are common and interrelated mechanisms underlying cardiac mortality. Intracellular calcium ions are crucial to contraction and relaxation of the heart muscle, as well as to control of its rhythm. How calcium is handled and regulated is thus essential to normal cardiac function, and disturbances in these processes can have catastrophic consequences. Understanding the mechanisms of these disturbances is important for improving disease prevention, diagnosis, and management. The studies in this thesis focus on two conditions where cardiac calcium handling is impaired. Studies I - III examine the mechanisms of a genetic arrhythmia disease named catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by stress-induced ventricular tachycardia in a structurally normal heart. Study IV investigates cardiac function in a model of another genetic disease, autosomal dominant polycystic kidney disease (ADPKD). This systemic disease mainly affects the kidneys, and the mechanisms of the concomitant decline in cardiac function have thus far remained underinvestigated. We evaluated clinical data on cardiac function of CPVT patients, including 24h electrocardiograms, intracardiac monophasic action potential recordings, and exercise stress tests. We used cell models to study the underlying disease mechanisms in detail. During conditions of stress, CPVT cells showed increased spontaneous and irregular release of calcium from within the intracellular stores through the cardiac ryanodine receptors. These receptors, which function as intracellular calcium release channels, harbor the disease-causing mutation. The spontaneous release of calcium led to changes in the membrane potential of the cells, manifested as afterdepolarizations during the resting phase of the cardiac cycle. These afterdepolarizations were reproduced in the clinical monophasic action potential recordings of CPVT patients, and were shown to trigger arrhythmias in these patients. Changes in intracellular calcium alter the membrane potential, and these changes are reflected on the electrocardiogram. Thus, irregularities that might correspond to those observed in the cell model were then investigated in 24h electrocardiograms of CPVT patients. Increased irregularity of cardiac repolarization was found in the CPVT patients. Such irregularity was greater in the electrocardiograms of CPVT patients with a history of more severe arrhythmic events. Additionally, we found slowed depolarization in response to stress in CPVT cells and patients, suggesting reduced conduction velocity might contribute to an arrhythmic substrate in these patients. Cardiac function in ADPKD caused by mutations in polycystin-2, another intracellular calcium channel, was investigated in a zebrafish model lacking expression of the polycystin-2 protein. The zebrafish lacking polycystin-2 showed signs of heart failure, including reduced cardiac output, edema, and arrhythmias. Hearts, which were then examined in more detail ex vivo, showed impaired cycling of intracellular calcium, which is likely to underlie the cardiac dysfunction observed in vivo. The association of ADPKD with idiopathic dilated cardiomyopathy (IDCM) was examined using the Mayo ADPKD Mutation Database, which contains data on genotyped ADPKD patients. Examination of the ADPKD Database showed IDCM to be very common among ADPKD patients. IDCM was most prevalent in patients with mutations in polycystin-2, suggesting impaired calcium cycling as a potential pathomechanism. Studies I-III shed new light on mechanisms of arrhythmias in CPVT and related conditions, opening the way for future studies on arrhythmia risk and therapeutic evaluation. Furthermore, the results encourage pursuing the novel stem cell models for studying pathomechanisms and therapeutics. Study IV showed an association between ADPKD and IDCM. The zebrafish model suggested impaired calcium cycling as an underlying mechanism, highlighting the usefulness of zebrafish as a model in cardiac research.
  • Hernesniemi, Sari (Helsingin yliopisto, 2012)
    Chronic myeloid leukemia (CML) is a hematologic malignancy that originates from pluripotent hematopoietic stem cells. The genetic abnormality underlying this disease, as well as a subtype of acute lymphoblastic leukemia (ALL), is a translocation between chromosomes 9 and 22, which leads to the formation of the Philadelphia (Ph) chromosome and the oncogenic BCR-ABL1 fusion protein. Targeted inhibition of the BCR-ABL1 protein with imatinib and other specific tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment and is currently regarded as the gold standard of targeted cancer therapy. In this doctoral thesis, different methodological approaches were used to characterize aberrant signaling activities in leukemic and normal cells with the ultimate aim of isolating novel prognostic markers for predicting TKI therapy outcome. First, the molecular mechanism of the disease was investigated in an ALL patient with a translocation between chromosomes 1 and 9. Cytogenetic characterization showed involvement of the ABL1 gene fused to an unknown gene. The RCSD1 gene was selected as a candidate and subsequent molecular dissection confirmed a RCSD1-ABL1 fusion. This novel fusion gene predicts sensitivity to TKI therapy in ALL patients. Second, several phosphoproteins related to immune cell function were analyzed both from the diagnostic phase CML patients and from patients under TKI therapy in order to reveal distinct signaling patterns. A single cell phosphoprotein method based on multiparameter flow cytometry was used to analyze phosphoprotein levels in different cell populations. The responsiveness of myeloid cells to ex vivo cytokine stimulation in diagnostic-phase patients was low, but was normalized in TKI-treated patients. In general, the blood leukocyte subsets responded normally to various cytokine stimulations, which indicated a non-immunosuppressive role for TKIs. This project also led to the development of a software assisted analysis program, which can conduct the whole range of flow cytometry data analysis, thereby diminishing the effort needed for manual cell population gating and interpretation. Lastly, biomarkers for therapy response were identified by analyzing aberrant signaling activities in leukemic cells collected at the time of diagnosis. The analysis was based on a phosphoproteomic array measuring phosphorylation of 46 different kinase targets. Several proteins had aberrant phosphorylation levels in patients with a poor therapy outcome − pSTAT5b being the most prominent. These biomarkers could be useful in guiding therapy selection at the time of diagnosis. In conclusion, the findings imply that TKI therapy responses can be linked to certain biological markers, which can possibly be utilized in clinical applications in the future.
  • 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.
  • Virkki, Liisa (Helsingin yliopisto, 2014)
    Biological antirheumatic drugs are biotechnologically produced antibodies or fusion proteins that are used if rheumatic inflammation is not sufficiently ameliorated with conventional antirheumatic drugs. Approximately 10% of Finnish rheumatoid arthritis (RA) patients use biological drugs. Biological antirheumatic drugs target inflammatory mediators and cells. Tumor necrosis factor inhibitors (TNFi) have been used since the beginning of the 2000s, and they are still the primarily used type of biological antirheumatic drug. The efficacy and safety has been assessed in clinical drug trials usually of 6 to 12 months duration with strict inclusion and exclusion criteria. In practice these drugs are used for much longer and in very diverse patient populations. In this work, the effectiveness and adverse events (AEs) of TNFi treatment in a routine care setting were assessed using the national register of biological drugs. Biological drugs are expensive, and therefore also their cost-effectiveness and the outcomes of switching a TNFi to another one were assessed. The effectiveness of the TNFi infliximab (IFX) was similar to its efficacy in clinical trials. In about 2/3 of the patients clinically significant symptom relief was achieved within 3 months, and 42% achieved remission within the first year. The need of glucocorticoid and pain medication was reduced. In addition to methotrexate assessed in clinical trials, also other conventional antirheumatic drugs were suitable concomitant drugs. The most frequent AEs of TNFi treatment were infections, eczemas, and infusion reactions. AEs were reported in 17% of patients using biologicals, serious ones in 3.1%. No unexpected AEs were reported. 76% of RA patients benefited from IFX in terms of quality-adjusted life years (QALY); their functional capacity and subjective health improved. The median price of a QALY was 51884 . The best cost-effectiveness was achieved in patients with particularly high disease activity and significant response to the treatment. The IFX dose and methotrexate use also affected the cost-effectiveness. Switching a TNFi to another one was useful in cases where initial effectiveness was lost, and in cases of AEs such as infusion reactions, eczemas, or local injection site reactions, which did not require discontinuation of TNFi treatment altogether; in these cases the switch led to a similar or even better effect. The register research indicates that TNFi treatment is effective and relatively safe in RA refractory to other treatments. It was cost-effective in a significant portion of the patients; new drug alternatives (including biosimilars) and the contemporary treatment aim of remission may further improve the cost-effectiveness.
  • Kantola, Taru (Helsingin yliopisto, 2010)
    The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal albumin dialysis device which is used in the treatment of liver failure patients. This treatment was first utilized in Finland in 2001, and since then, over 200 patients have been treated. The aim of this thesis was to evaluate the impact of the MARS treatment on patient outcome, the clinical and biochemical variables, as well as on the psychological and economic aspects of the treatment in Finland. This thesis encompasses 195 MARS-treated patients (including patients with acute liver failure (ALF), acute-on-chronic liver failure (AOCLF) and graft failure), and a historical control group of 46 ALF patients who did not undergo MARS. All patients received a similar standard medical therapy at the same intensive care unit. The baseline data (demographics, laboratory and clinical variables) and MARS treatment-related and health-related quality-of-life data were recorded before and after treatment. The direct medical costs were determined for a period of 3.5 years.Additionally, the outcome of patients (survival, native liver recovery and need for liver transplantation) and survival predicting factors were investigated. In the outcome analysis, for the MARS-treated ALF patients, their 6-month survival (75% vs. 61%, P=0.07) and their native liver recovery rate (49% vs. 17%, P<0.001) were higher, and their need for transplantations was lower (29% vs. 57%, P= 0.001) than for the historical controls. However, the etiological distribution of the ALF patients referred to our unit has changed considerably over the past decade and the percentage of patients with a more favorable prognosis has increased. The etiology of liver failure was the most important predictor of the outcome. Other survival predicting factors in ALF included hepatic encephalopathy, the coagulation factors and the liver enzyme levels prior to MARS treatment. In terms of prognosis, the MARS treatment of the cirrhotic AOCLF patient seems meaningful only when the patient is eligible for transplantation. The MARS treatment appears to halt the progression of encephalopathy and reduce the blood concentration of neuroactive amino acids, albumin-bound and water-soluble toxins. In general, the effects of the MARS treatment seem to stabilize the patients, thus allowing additional time either for the native liver to recover, or for the patients to endure the prolonged waiting for transplantation. Furthermore, for the ALF patients, the MARS treatment appeared to be less costly and more cost-efficient than the standard medical therapy alone. In conclusion, the MARS treatment appears to have a beneficial effect on the patient outcome in ALF and in those AOCLF patients who can be bridged to transplantation.
  • Usvasalo, Anu (Helsingin yliopisto, 2010)
    In recent reports, adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have had a better outcome with pediatric treatment than with adult protocols. ALL can be classified into biologic subgroups according to immunophenotype and cytogenetics, with different clinical characteristics and outcome. The proportions of the subgroups are different in children and adults. ALL subtypes in AYA patients are less well characterized. In this study, the treatment and outcome of ALL in AYA patients aged 10-25 years in Finland on pediatric and adult protocols was retrospectively analyzed. In total, 245 patients were included. The proportions of biologic subgroups in different age groups were determined. Patients with initially normal or failed karyotype were examined with oligonucleotide microarray-based comparative genomic hybridization (aCGH). Also deletions and instability of chromosome 9p were screened in ALL patients. In addition, patients with other hematologic malignancies were screened for 9p instability. aCGH data were also used to determine a gene set that classifies AYA patients at diagnosis according to their risk of relapse. Receiver operating characteristic analysis was used to assess the value of the set of genes as prognostic classifiers. The 5-year event-free survival of AYA patients treated with pediatric or adult protocols was 67% and 60% (p=0.30), respectively. White blood cell count larger than 100x109/l was associated with poor prognosis. Patients treated with pediatric protocols and assigned to an intermediate-risk group fared significantly better than those of the pediatric high-risk or adult treatment groups. Deletions of 9p were detected in 46% of AYA ALL patients. The chromosomal region 9p21.3 was always affected, and the CDKN2A gene was always deleted. In about 15% of AYA patients, the 9p21.3 deletion was smaller than 200 kb in size, and therefore, probably undetectable with conventional methods. Deletion of 9p was the most common aberration of AYA ALL patients with initially normal karyotype. Instability of 9p, defined as multiple separate areas of copy number loss or homozygous loss within a larger heterozygous area in 9p, was detected in 19% (n=27) of ALL patients. This abnormality was restricted to ALL; none of the patients with other hematologic malignancies had the aberration. The prognostic model identification procedure resulted in a model of four genes: BAK1, CDKN2B, GSTM1, and MT1F. The copy number profile combinations of these genes differentiated between AYA ALL patients at diagnosis depending on their risk of relapse. Deletions of CDKN2B and BAK1 in combination with amplification of GSTM1 and MT1F were associated with a higher probability of relapse. Unlike all previous studies, we found that the outcome of AYA patients with ALL treated using pediatric or adult therapeutic protocols was comparable. The success of adult ALL therapy emphasizes the benefit of referral of patients to academic centers and adherence to research protocols. 9p deletions and instability are common features of ALL and may act together with oncogene-activating translocations in leukemogenesis. New and more sensitive methods of molecular cytogenetics can reveal previously cryptic genetic aberrations with an important role in leukemic development and prognosis and that may be potential targets of therapy. aCGH also provides a viable approach for model design aiming at evaluation of risk of relapse in ALL.
  • Åhlström, Annika (Helsingin yliopisto, 2006)
    Acute renal failure (ARF) is a clinical syndrome characterized by rapidly decreasing glomerular filtration rate, which results in disturbances in electrolyte- and acid-base homeostasis, derangement of extracellular fluid volume, and retention of nitrogenous waste products, and is often associated with decreased urine output. ARF affects about 5-25% of patients admitted to intensive care units (ICUs), and is linked to high mortality and morbidity rates. In this thesis outcome of critically ill patients with ARF and factors related to outcome were evaluated. A total of 1662 patients from two ICUs and one acute dialysis unit in Helsinki University Hospital were included. In study I the prevalence of ARF was calculated and classified according to two ARF-specific scoring methods, the RIFLE classification and the classification created by Bellomo et al. (2001). Study II evaluated monocyte human histocompatibility leukocyte antigen-DR (HLA-DR) expression and plasma levels of one proinflammatory (interleukin (IL) 6) and two anti-inflammatory (IL-8 and IL-10) cytokines in predicting survival of critically ill ARF patients. Study III investigated serum cystatin C as a marker of renal function in ARF and its power in predicting survival of critically ill ARF patients. Study IV evaluated the effect of intermittent hemodiafiltration (HDF) on myoglobin elimination from plasma in severe rhabdomyolysis. Study V assessed long-term survival and health-related quality of life (HRQoL) in ARF patients. Neither of the ARF-specific scoring methods presented good discriminative power regarding hospital mortality. The maximum RIFLE score for the first three days in the ICU was an independent predictor of hospital mortality. As a marker of renal dysfunction, serum cystatin C failed to show benefit compared with plasma creatinine in detecting ARF or predicting patient survival. Neither cystatin C nor plasma concentrations of IL-6, IL-8, and IL-10, nor monocyte HLA-DR expression were clinically useful in predicting mortality in ARF patients. HDF may be used to clear myoglobin from plasma in rhabdomyolysis, especially if the alkalization of diuresis does not succeed. The long-term survival of patients with ARF was found to be poor. The HRQoL of those who survive is lower than that of the age- and gender-matched general population.
  • Ma, Guofeng (Helsingin yliopisto, 2009)
    Total hip replacement is the golden standard treatment for severe osteoarthritis refractory for conservative treatment. Aseptic loosening and osteolysis are the major long-term complications after total hip replacement. Foreign body giant cells and osteoclasts are locally formed around aseptically loosening implants from precursor cells by cell fusion. When the foreign body response is fully developed, it mediates inflammatory and destructive host responses, such as collagen degradation. In the present study, it was hypothesized that the wear debris and foreign body inflammation are the forces driving local osteoclast formation, peri-implant bone resorption and enhanced tissue remodeling. Therefore the object was to characterize the eventual expression and the role of fusion molecules, ADAMs (an abbreviation for A Disintegrin And Metalloproteinase, ADAM9 and ADAM12) in the fusion of progenitor cells into multinuclear giant cells. For generation of such cells, activated macrophages trying to respond to foreign debris play an important role. Matured osteoclasts together with activated macrophages mediate bone destruction by secreting protons and proteinases, including matrix metalloproteinases (MMPs) and cathepsin K. Thus this study also assessed collagen degradation and its relationship to some of the key collagenolytic proteinases in the aggressive synovial membrane-like interface tissue around aseptically loosened hip replacement implants. ADAMs were found in the interface tissues of revision total hip replacement patients. Increased expression of ADAMs at both transcriptional and translational levels was found in synovial membrane-like interface tissue of revision total hip replacement (THR) samples compared with that in primary THR samples. These studies also demonstrate that multinucleate cell formation from monocytes by stimulation with macrophage-colony stimiulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) is characterized by time dependent changes of the proportion of ADAMs positive cells. This was observed both in the interface membrane in patients and in two different in vitro models. In addition to an already established MCS-F and RANKL driven model, a new virally (parainfluenza 2) driven model (of human salivary adenocarcinoma (HSY) cells or green monkey kidney (GMK) cells) was developed to study various fusion molecules and their role in cell fusion in general. In interface membranes, collagen was highly degraded and collagen degradation significantly correlated with the number of local cells containing collagenolytic enzymes, particularly cathepsin K. As a conclusion, fusion molecules ADAM9 and ADAM12 seem to be dynamically involved in cell-cell fusion processes and multinucleate cell formation. The highly significant correlation between collagen degradation and collagenolytic enzymes, particularly cathepsin K, indicates that the local acidity of the interface membrane in the pathologic bone and soft tissue destruction. This study provides profound knowledge about cell fusion and mechanism responsible for aseptic loosening as well as increases knowledge helpful for prevention and treatment.
  • Kauppi, Juha (Helsingin yliopisto, 2015)
    Adenocarcinoma (AC) of the esophagus and esophagogastric junction (EGJ) is a disease with poor prognosis and increasing incidence in western countries. Its pathogenesis is associated with oxidative stress (OS) in the esophageal epithelium. Long-term survival is associated with successful radical surgery, early stage of the disease, and successful downstaging with neoadjuvant therapy. As surgery is accompanied with a large number of possible complications, it is essential to identify patients who might not benefit from surgery and on the other hand, could be treated with less invasive options. The aims of this study were 1) to assess the role of OS below EGJ in the pathogenesis of Barrett s esophagus (BE) and AC, 2) to assess the prognoses and causes of death in early esophageal AC, 3) to determine the value of 18F-fluorodeoxy-D-glucose positron emission tomography with computed tomography (FDG-PET-CT) in quantifying the response to neoadjuvant therapy and 4) to compare the novel mini-invasive technique (MIE) to traditional open esophagectomy (OE) in radical surgery. To quantify OS, we measured 8-isoprostane (8-IP), glutathione content (GSH), and 8-OH- deoxyglucose (8-OHdG) values from mucosa below EGJ, BE-mucosa, and AC-tumors from 43 patients with BE and/or AC and compared them to samples from corresponding sites of 15 healthy control patients. To determine the long-term prognosis of patients with early esophageal AC, we studied patient records and causes of deaths for 85 patients, treated with radical esophagectomy over a 27-year time span. To evaluate pre-treatment response to neoadjuvant therapy in locally advanced AC, we recorded FDG-PET-CT results before and after induction therapy in sixty-six consecutive patients who were to be operated on for locally advanced AC. Decrement in radioactive glucose uptake values was associated with survival and histological treatment response. We compared MIE to OE, to see, if minimal invasiveness reduces the rate of complications and if they are comparable in terms of oncologic radicality and survival. Proximal gastric GSH content was lower and 8-IP and 8-OHdG levels higher with statistical significance in the study patients (BE and AC) as compared to healthy controls. In patients with early esophageal AC, overall and long-term (>5 year) survival rates were mostly affected by diseases related to aging. During the first five years after the operations, disease recurrence was the most common cause of death. However, recurrence-free survival was 80% at five years and no new recurrences were detected after that. Microscopic eradication of locally advanced AC was optimally predicted by a 67% decrease in uptake values before and after induction chemotherapy, with a sensitivity of 79% and specificity of 75%. However, this association was not linear and complete eradication of radioactive glucose uptake, was not always associated with a complete histologic response. However, a decrease in glucose uptake was associated with improved overall and recurrence free survival. MIE and OE were equivalent in terms of 90-day mortality, pneumonia-, leak-, and overall complication rates. Also a minimally invasive technique was associated with significantly shorter overall hospital stay and significantly less blood loss during the operations. OS levels are also elevated below the EGJ, as lipid peroxidation can be detected (8-IP) and antioxidant defense (GSH) is reduced. Also the levels of 8-OHdG adducts were higher showing that DNA is being damaged by free radicals. This suggests that inflammation of the proximal gastric mucosa induced by gastroduodenal content, has a role in the pathogenesis of BE and esophageal AC. As the prognoses for patients with early esophageal AC were good, recurrence was still the most important cause of death. The risk was highest for patients with lymph node metastases and deep submucosal infiltration. Therefore radical surgery should be preferred with patients with a low risk of surgical complications and submucosal infiltration. In patients with intramucosal AC, endoscopic ablation should be considered. Evaluation of the patients responses to induction chemotherapy with FDG-PET-CT was not accurate enough to give indications better than the exclusion of metastatic disease. However, a significant decrease in radioactive glucose uptake was associated with improved survival, independently of histopathologic response. This information can be useful when balancing the risks of surgery against expected benefits. The perioperative and oncological results for MIE were comparable to those of the open approach and MIE seems to shorten hospital stay. However, the MIE technique is demanding and its mastery requires a sufficient number of cases and skilled practitioners.
  • Afonso de Carvalho Dias, Joao Daniel (Helsingin yliopisto, 2010)
    Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.
  • Särkioja, Merja (Helsingin yliopisto, 2008)
    Adenoviral gene therapy is an experimental approach to cancer refractory to standard cancer therapies. Adenoviruses can be utilized as vectors to deliver therapeutic transgenes into cancer cells, while gene therapy with oncolytic adenoviruses exploits the lytic potential of viruses to kill tumor cells. Although adenoviruses demonstrate several advantages over other vectors - such as the unparalleled transduction efficacy and natural tropism to a wide range of tissues - the gene transfer efficacy to cancer cells has been limited, consequently restricting the therapeutic effect. There are, however, several approaches to circumvent this problem. We utilized different modified adenoviruses to obtain information on adenovirus tropism towards non-small cell lung cancer (NSCLC) cells. To enhance therapeutic outcome, oncolytic adenoviruses were evaluated. Further, to enhance gene delivery to tumors, we used mesenchymal stem cells (MSCs) as carriers. To improve adenovirus specificity, we investigated whether widely used cyclooxygenase 2 (Cox-2) promoter is induced by adenovirus infection in nontarget cells and whether selectivity can be retained by the 3 untranslated region (UTR) AU-rich elements. In addition, we investigated whether switching adenovirus fiber can retain gene delivery in the presence of neutralizing antibodies. Our results show that adenoviruses, whose capsids were modified with arginine-glycine-aspartatic acid (RGD-4C), the serotype 3 knob, or polylysins displayed enhanced gene transfer into NSCLC cell lines and fresh clinical specimens from patients. The therapeutic efficacy was further improved by using respective oncolytic adenoviruses with isogenic 24bp deletion in the E1A gene. Cox-2 promoter was also shown to be induced in normal and tumor cells following adenovirus infection, but utilization of 3 UTR elements can increase the tumor specificity of the promoter. Further, the results suggested that use of MSCs could enhance the bioavailability and delivery of adenoviruses into human tumors, although cells had no tumor tropism per se. Finally, we demonstrated that changing adenovirus fiber can allow virus to escape from existing neutralizing antibodies when delivered systemically. In conclusion, these results reveal that adenovirus gene transfer and specificity can be increased by using modified adenoviruses and MSCs as carriers, and fiber modifications simultaneously decrease the effect of neutralizing antibodies. This promising data suggest that these approaches could translate into clinical testing in patients with NSCLC refractory to current modalities.
  • Makkonen, Janne (Helsingin yliopisto, 2010)
    BACKGROUND: Obesity is closely associated with insulin resistance, which is a pathophysiologic condition contributing to the important co-morbidities of obesity, such as the metabolic syndrome and type 2 diabetes mellitus. In obese subjects, adipose tissue is characterized by inflammation (macrophage infiltration, increased expression insulin resistance genes and decreased expression of insulin sensitivity genes). Increased liver fat, without excessive alcohol consumption, is defined as non-alcoholic fatty liver disease (NAFLD) and also associated with obesity and insulin resistance. It is unknown whether and how insulin resistance is associated with altered expression of adipocytokines (adipose tissue-derived signaling molecules), and whether adipose tissue inflammation and NAFLD coexist independent of obesity. Genetic factors could explain variation in liver fat independent of obesity but the heritability of NAFLD is unknown. AIMS: To determine whether acute regulation of adipocytokine expression by insulin in adipose tissue is altered in obesity. To investigate the relationship between adipose tissue inflammation and liver fat content independent of obesity. To assess the heritability of serum alanine aminotransferase (ALT) activity, a surrogate marker of liver fat. METHODS: 55 healthy normal-weight and obese volunteers were recruited. Subcutaneous adipose tissue biopsies were obtained for measurement of gene expression before and during 6 hours of euglycemic hyperinsulinemia. Liver fat content was measured by proton magnetic resonance spectroscopy, and adipose tissue inflammation was assessed by gene expression, immunohistochemistry and lipidomics analysis. Genetic factors contributing to serum ALT activity were determined in 313 twins by statistical heritability modeling. RESULTS: During insulin infusion the expression of insulin sensitivity genes remains unchanged, while the expression of insulin resistance genes increases in obese/insulin-resistant subjects compared to insulin-sensitive subjects. Adipose tissue inflammation is associated with liver fat content independent of obesity. Adipose tissue of subjects with high liver fat content is characterized infiltrated macrophages and increased expression of inflammatory genes, as well as by increased concentrations of ceramides compared to equally obese subjects with normal liver fat. A significant heritability for serum ALT activity was verified. CONCLUSIONS: Effects of insulin infusion on adipose tissue gene expression in obese/insulin-resistant subjects are not only characterized by hyporesponse of insulin sensitivity genes but also by hyperresponse of insulin resistance and inflammatory genes. This suggests that in obesity, the impaired insulin action contributes or self-perpetuates alterations in adipocytokine expression in adipose tissue. Adipose tissue inflammation is increased in subjects with high liver fat compared to equally obese subjects with normal liver fat content. Concentrations of ceramides, the putative mediators of insulin resistance, are increased in adipose tissue in subjects with high liver fat. Genetic factors contribute significantly to variation in serum ALT activity, a surrogate marker of liver fat. These data imply that adipose tissue inflammation and increased liver fat content are closely interrelated, and determine insulin resistance even independent of obesity.
  • Uusvaara, Juho (2013)
    Aging is associated with multimorbidity and increased drug consumption. Changes in pharmacokinetics and pharmacodynamics expose older people to increased risks for adverse effects. Many commonly used drugs have anticholinergic properties predisposing older people to side effects such as cognitive decline, delirium, dizziness, constipation, urinary retention, and risk for glaucoma. The general aim was to investigate the side effects and risks related to use of drugs with anticholinergic properties (DAPs) among older people. The specific aims were: 1) to clarify the association between the epsilon 4 allele of apolipoprotein E (ApoE4), DAP use, and cognitive decline; 2) to evaluate the risk of DAP usage on hospitalization and mortality; 3) to clarify the relationship between the use of DAPs and delirium and; 4) to clarify how the use of DAPs is associated with different dimensions of cognitive function. This study consists of four substudies. Study 1, 2, and 4: 400 home-dwelling individuals from the Drugs and Evidence-Based Medicine in the Elderly study, aged 75 to 90 with a history of stable atherosclerotic disease. Study 3: 425 subjects aged 70 or older in six acute geriatric wards in two Helsinki city hospitals and in seven nursing homes in Helsinki. DAPs were defined using data from previous literature. The participants drug lists were coded accordingly. ApoE4 carrier status was determined (study 1).The cognition of the participants was assessed thoroughly using MMSE test (studies 1-4), CDR scale (studies 1 and 3), and CERAD test battery (study 4). Delirium was defined by DSM-IV criteria (study 3). Information of hospitalizations and deaths were retrieved from central registers. The relation of DAP use, cognitive status and detailed cognitive functions, risk for delirium, hospitalizations, and mortality was assessed. There was an association between DAPs and lower MMSE scores, irrespective of ApoE4 status. ApoE4 carriers as a group had a lower cognitive function than the non-carriers. The CERAD subtests referring to impairment of executive functions and semantic memory were most affected among DAP users. Aspects of CERAD test assessing episodic memory, most sensitive to detection of early Alzheimer's disease, did not show differences between users and non-users of DAPs. DAP usage was associated with an increased risk for hospitalization. There was no statistically significant difference between the users and non-users of DAPs in prevalence of delirium or mortality. Use of DAPs has small but clinically significant effect on older people s cognition, especially on executive functions and semantic memory. Although they do not have significant effect on mortality or prevalence of delirium, they may increase the risk of hospitalizations.
  • Säilä, Hanna (Helsingin yliopisto, 2006)
    Genetic susceptibility to juvenile idiopathic arthritis (JIA) was studied in the genetically homogeneous Finnish population by collecting families with two or three patients affected by this disease from cases seen in the Rheumatism Foundation Hospital. The number of families ranged in different studies from 37 to 45 and the total number of patients with JIA, from among whom these cases were derived, was 2 000 to 2 300. Characteristics of the disease in affected siblings in Finland were compared with a population-based series and with a sibling series from the United States. A thorough clinical and ophthalmological examination was made of all affected patients belonging to sibpair series. Information on the occurrence of chronic rheumatic diseases in parents was collected by questionnaire and diagnoses were confirmed from hospital records. All patients, their parents and most of the healthy sibs were typed for human leukocyte antigen (HLA) alleles in loci A, C, B, DR and DQ. The HLA allele distribution of the cases was compared with corresponding data from Finnish bone marrow donors. The genetic component in JIA was found to be more significant than previously believed. A concordance rate of 25% for a disease with a population prevalence of 1 per 1000 implied a relative risk of 250 for a monozygotic (MZ) twin. An estimate for the sibling risk of an affected individual was about 15- to 20-fold. The disease was basically similar in familial and sporadic cases; the mean age at disease onset was however lower in familial cases, (4.8 years vs 7.4 years). Three sibpairs (3.4 expected) were concordant for the presence of asymptomatic uveitis. Uveitis would thus not appear to have any genetic component of its own, separate from the genetic basis of JIA. Four of the parents had JIA (0.2 cases expected), four had a type of rheumatoid factor-negative arthritis similar to that seen in juvenile patients but commencing in adulthood, and one had spondyloarthropathy (SPA). These findings provide additional support for the conception of a genetic predisposition to JIA and suggest the existence of a new disease entity, JIA of adult onset. Both the linkage analysis of the affected sibpairs and the association analysis of nuclear families provided overwhelming evidence of a major contribution of HLA to the genetic susceptibility to JIA. The association analysis in the Finnish population confirmed that the most significant associations prevailed for DRB1*0801, DQB1*0402, as expected from previous observations, and indicated the independent role of Cw*0401.
  • Karjalainen, Eeva-Maija (Helsingin yliopisto, 2008)
    The objective of these studies was to evaluate possible airway inflammation and remodeling at the bronchial level in cross-country skiers without a prior diagnosis of asthma, and relate the findings to patients with mild chronic asthma and patients with newly diagnosed asthma. We also studied the association of airway inflammatory changes and bronchial hyperresponsivess (BHR), and treatment effects in cross-country skiers and in patients with newly diagnosed asthma. Bronchial biopsies were obtained from the subjects by flexible bronchoscopy, and the inflammatory cells (eosinophils, mast cells, T-lymphocytes, macrophages, and neutrophils) were identified by immunohistochemistry. Tenascin (Tn) immunoreactivity in the bronchial basement membrane (BM) was identified by immunofluorescence staining. Lung function was measured with spirometry, and BHR was assessed by methacholine (skiers) or histamine (asthmatics) challenges. Skiers with BHR and asthma-like symptoms were recruited to a drug-intervention study. Skiers were given treatment (22 weeks) with placebo or budesonide (400 µg bid). Patients with newly diagnosed asthma were given treatment for 16 weeks with placebo, salmeterol (SLM) (50 µg bid), fluticasone propionate (FP) (250 µg bid), or disodium cromoglicate (DSCG) (5 mg qid). Bronchial biopsies were obtained at baseline and at the end of the treatment period. In the skiers a distinct airway inflammation was evident. In their bronchial biopsy specimens, T-lymphocyte, macrophage, and eosinophil counts were, respectively greater by 43-fold (P<0.001), 26-fold (P<0.001, and 2-fold (P<0.001) in skiers, and by 70-fold (p>0.001), 63-fold (P<0.001), and 8-fold (P<0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than 2-fold greater than in asthmatic subjects (P<0.05). Tn expression was higher in skiers than in controls and lower in skiers than in mild asthmatics. No significant changes were seen between skiers with or without BHR in the inflammatory cell counts or Tn expression. Treatment with inhaled budesonide did not attenuate asthma-like symptoms, the inflammatory cell infiltration, or BM Tn expression in the skiers. In newly diagnosed asthmatic patients, SLM, FP, and DSCG reduced asthma symptoms, and need for rescue medication (P<0.04). BHR was reduced by doubling doses 2.78, 5.22, and 1.35 respectively (all P<0.05). SLM and placebo had no effect on cell counts or Tn expression. FP and DSCG reduced eosinophil counts in the bronchial biopsy specimens (P<0.02 and <0.048, respectively). No significant change in tenascin expression appeared in any treatment group. Regarding to atopy, no significant differences existed in the inflammatory cell counts in the bronchial mucosa of subjects with newly diagnosed asthma or in elite cross country skiers. Tn expression in the BM was significantly higher in atopic asthma than in those with nonatopic asthma. Airway inflammation occurred in elite cross-country skiers with and without respiratory symptoms or BHR. Their inflammatory cell pattern differed from that in asthma. Infiltration with eosinophils, macrophages, and mast cells was milder, but lymphocyte counts did not differ from counts in asthmatic airways. Neutrophilic infiltration was more extensive in skiers than in asthmatics. Remodeling took place in the skiers’ airways, as reflected by increased expression of BM tenascin These inflammatory changes and Tn expression may be caused by prolonged exposure of the lower airways to inadequately humidified cold air. In skiers inflammatory changes and remodeling were not reversed with anti-inflammatory treatment. In contrast, in patients with newly diagnosed asthma, anti-inflammatory treatment did attenuate eosinophilic inflammation in the bronchial mucosa. In skiers, anti-inflammatory treatment did not attenuate BHR as it did in asthmatic patients. The BHR in skiers was attenuated spontaneously during placebo treatment, with no difference from budesonide treatment. Lower training intensity during the treatment period may explain this spontaneous decrease in BHR. The origin of BHR probably differs in skiers and in asthmatics. No significant association between BHR and inflammatory cell counts or between BHR and Tn expression was evident in cross-country skiers or asthmatic subjects. Airway remodeling differed between atopic and nonatopic asthma. As opposed to nonatopic asthma, Tn expression was higher in atopic asthma and is related to inflammatory cell densities.
  • Suojalehto, Hille (Helsingin yliopisto, 2014)
    Asthma and allergic rhinitis can be seen as manifestations of one disease with a common underlying inflammatory process. The aim of this thesis was to investigate airway inflammation biomarkers in asthma and rhinitis in this context in two adult populations. In the nasal biopsies we detected only modest differences between the inflammatory cells and cytokine levels of the patients with allergic rhinitis and asthma and the controls. Three microRNAs were up-regulated in the nasal mucosa of participants with current allergic rhinitis, and one microRNA was down-regulated in the asthmatic patients without current rhinitis symptoms when compared to healthy controls. In the men with long-term asthma, altered expressions of 10 microRNAs were detected, four of which were also differentially expressed in the asthmatic patients without allergic rhinitis. Among the asthmatics, differences in the microRNAs were also detected when no significant changes in the inflammatory cells and cytokines were found. In the future, microRNAs arrays might be useful as a sensitive method for assessing airway inflammation. The level of nasal nitric oxide was slightly elevated in the participants with allergic rhinitis compared to that of the controls. A positive correlation between the nasal and exhaled nitric oxide levels and an inverse correlation between the nasal nitric oxide level and CT score of sinus ostia obstruction were detected. When we evaluated the allergic rhinitis patients without marked sinus ostial obstruction, the nasal nitric oxide level correlated positively with the nasal eosinophil count. The nasal nitric oxide level reflects eosinophilic inflammation in nasal mucosa in allergic rhinitis. However, the level is dependent on sinus ostia obstruction, reducing its feasibility for monitoring allergic inflammation. In the sputum proteome analysis, we identified 31 different proteins, which were also found in the nasal lavage fluid. An increased abundance of fatty acid binding protein 5 (FABP5) was found in the sputum and nasal lavage fluid of the asthmatics. The level of FABP5 in the nasal lavage fluid positively correlated with vascular endothelial growth factor as well as cysteinyl leukotriene levels, suggesting that FABP5 may contribute to airway inflammation and remodeling. Samples from upper airways are easy to obtain, and our findings suggest that they might be useful in investigating biomarkers of lower airway inflammation in asthma.
  • Kalliola, Satu (Helsingin yliopisto, 2015)
    Background: The diagnosis of asthma in young children is based mostly on symptoms. The need for objective methods for diagnosing asthma in this age group is therefore obvious. Lung function in preschool children can be assessed with impulse oscillometry (IOS), which involves no voluntary breathing manoeuvers. Because most children with asthma have normal baseline lung function, the use of bronchoprovocative tests may improve diagnostics. Fractional concentration of nitric oxide (FeNO) is suggested to be a good measure for airway inflammation, and the method is also available for preschoolers. Aims: To examine new methods for evaluating airway hyperresresponsiveness and inflammation in young children. Further aims were to study the effect of parental smoking on lung function and airway inflammation in wheezy children and whether children with severe exercise induced bronchoconstriction exhibit small airways dysfunction. Methods: A total of 272 children (3 to 8 years old), 231 with obstructive syndromes and 41 healthy controls, were examined. Children with various clinical characteristics were recruited: troublesome lung symptoms, a history of bronchopulmonary dysplasia (BPD), early wheezing symptoms and multiple-trigger wheezing. Airway hyperresponsiveness was evaluated with exercise test, methacholine and mannitol challenge tests using IOS. FeNO measurements with two different analyzers were examined. Parental reports and children s urinary cotinine measurements served to monitor exposure to environmental tobacco smoke. Results: Exercise test with IOS succesfully identified children with probable asthma, and the methacholine challenge test was able to differentiate children with probable asthma, BPD and early wheezing from the controls. The mannitol challenge test, however, was unable to distinguish between the study groups. Furthermore, children with severe exercise-induced bronchoconstriction (EIB) exhibited small airways dysfunction. A portable FeNO analyzer proved to be more difficult than a stationary device to use in young children. In addition, its poorer accuracy in low FeNO levels diminishes its feasibility in this age group. However, a portable analyzer differentiated children with asthma from the controls. Children with smoking mothers had poorer lung function and higher FeNO than children with non-smoking mothers. Urinary cotinine concentrations closely reflected reported smoking in the family. A father s smoking had no effect on children s FeNO or lung function. Conclusions: The exercise test with IOS succesfully identified children with probable asthma. The methacholine challenge test aids in evaluating airway hyperresponsiveness in young children, although its cut-off value for this age group requires re-evaluation. A portable FeNO analyzer can also serve as a screening tool in young children, because it differentiates asthmatics from the controls with reasonable accuracy. Children with severe exercise induced bronchoconstriction exhibited small airways dysfunction, which suggests that peripheral airways are involved even in young asthmatic children. Maternal smoking clearly deteriorates lung function and increases bronchial inflammation in young children with wheeze. This objective finding with cotinine measurements emphasizes current knowledge; young children should not be exposed to environmental tobacco smoke.
  • Laaksonen, Esti (Helsingin yliopisto, 2015)
    The estimated number of heavy consumers of alcohol is about 20 percent of population, of which 10 percent suffer from alcohol dependency. Many heavy consumers of alcohol also smoke. The effectiveness of treatments can be significantly improved with medical treatment. The problems are: how medical treatment can be utilized in practical treatment, and how to ensure treatment adherence. The aim of this study was to investigate the effectiveness of pharmacotherapies combined with a brief manual-based cognitive-behavioural intervention (CBT) in treating alcohol-dependent patients. In the large-scale clinical treatment study, which ran for 2.5 years, the effectiveness and patient response to the three drugs (naltrexone, acamprosate and disulfiram) were compared. The study used a survey drawn up guidebook for patients, Winning at last defeating the drinking problem. In addition, we researched how the reduced alcohol consumption affects the quality of life, mood and smoking. In the study of sweet preference we analyzed possible associations between sweet preference and efficacy of naltrexone treatment. In addition, we researched patients treatment adherence and medication adherence to targeted naltrexone, as well as reduction of problem drinking and craving. This combined treatment (medication and CBT) significantly reduced alcohol consumption resulting in improved quality of life. Noticeable is that compared to the other study medicines, especially during the continuous medication period, supervised disulfiram appeared superior. During the targeted medication period, there were no other significant differences between the groups except for that the abstinence days were significantly more frequent in the disulfiram group. The treatment was also associated with success in quitting smoking among patients using disulfiram. The study of sweet preference, it was significantly related to treatment measures in the naltrexone group when the outcome was relapses to heavy drinking. Our study offers a possible new explanation of the clinical observation that naltrexone is not effective for every patient. Adherence to the targeted use of naltrexone added treatment compliance and efficacy of the medicine. Patients who had less symptoms of alcohol dependence, suffered from high craving for alcohol, were unemployment, young or could not keep the drinking diary were less committed to treatment. Problem drinking can be changed to abstinence or moderate drinking with the combination of medical therapy, CBT and good treatment commitment. The benefits of treatments are probably long-term, because part of the positive results lasted over two years. The treatment methods used in this study were usable and they can be implemented in all levels of Finnish health care.
  • Tanskanen, Maarit (Helsingin yliopisto, 2008)
    Along with the increased life span of individuals, the burden of old age-associated diseases has inevitably increased. Alzheimer s disease (AD), probably the most well known geriatric disease, belongs to the old age-associated amyloid diseases. The purpose of this study was to investigate the frequency, genetic and health-associated risk factors, mutual association, and amyloid proteins in two old age-associated amyloid disorders senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) as part of the prospective population-based Vantaa 85+ autopsy study on a Finnish population aged 85 years or more (Studies I-III), completed with a case report on a patient with advanced AGel amyloidosis (Study IV). The numbers of patients investigated in the studies (I-III) were 256, 74, and 63, respectively. The diagnosis and grading of amyloid were based upon histological examination of tissue samples obtained post mortem and stained with Congo red. The amyloid fibril and associated proteins were characterized by immunohistochemical staining methods. The genotype frequencies of 20 polymorphisms in 9 genes and information on health-associated risk factors in subjects with and without SSA and CAA were compared. In a Finnish population ≥ 95 years of age, SSA and CAA occurred in 36% and 49% of the subjects, respectively. In total, two-thirds of these very elderly individuals had SSA, CAA, or both. However, in only 14% of the population these two conditions co-occurred. In subjects 85 years or older, the prevalence of SSA was 25%. In this population, SSA was associated with age at the time of death (p=0.002), myocardial infarctions (MIs; p=0.004), the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2-macroglobulin (α2M) gene (p=0.042) and with the H2 haplotype of the tau gene (p=0.016). In contrast, the presence of CAA was strongly associated with APOE e4 (p=0.0003), with histopathological AD (p=0.0005), and with clinical dementia (p=0.01) in both e4+ (p=0.02) and e4- (p=0.06) individuals. Apart from demonstrating the amyloid fibril proteins, complement proteins 3d (C3d) and 9 (C9) were detected in the amyloid deposits of CAA and AGel amyloidosis, and α2M protein was found in fibrous scar tissue close to SSA. In conclusion, this first population based study on SSA shows that both SSA and CAA are common in very elderly individuals. Old age, MIs, the exon 24 polymorphism of the α2M gene, and H1/H2 polymorphism of the tau gene associate with SSA while clinical dementia and APOE ε4 genotype associate with CAA. The high prevalence of CAA, combined with its association with clinical dementia independent of APOE genotype, neuropathological AD, or SSA, also highlights its clinical significance in the very aged, among which the serious end stage complications of CAA, namely multiple infarctions and hemorrhages, are rare. The report on a patient having advanced AGel amyloidosis added knowledge on the disease and showed that this generally benign condition occasionally may lead to death. Further studies are warranted to confirm the findings in other populations. Also, the role of α2M and tau in the pathogenesis of SSA and the involvement of complement in the process of amyloid beta (Aβ) protein elimination from the brain remain to be clarified. Finally, the high prevalence of SSA in the elderly raises the need for prospective clinical studies to define its clinical significance.
  • 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.