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  • Kolehmainen, Pekka (Helsingin yliopisto, 2014)
    Human parechovirus (HPeV) and Ljungan virus (LV) are non-enveloped, single-stranded RNA viruses that form the genus Parechovirus in the family Picornaviridae. The interest in these viruses has notably increased over the past 15 years because of their strengthened associations to human and animal diseases. HPeV types 1 and 3 have been associated with more severe infections in young children, such as infections of the central nervous system (CNS) and sepsis-like disease. Rodent-infecting LV has been suggested to possess zoonotic potential and induce various human diseases. However, the proof for this remains lacking. This study aimed to describe the epidemiological features of HPeVs in Finland and in the Netherlands, to examine the connection between HPeV-induced infection and human diseases and to study the circulation of LV in Finland. The epidemiological analysis of stool samples, collected from 1996 to 2007, revealed that HPeVs are highly common in healthy Finnish children. HPeV was primarily detectable in children under 2 years of age. Altogether, 39% of the study participants tested positive for HPeV at least once during the study period. HPeVs circulated throughout the year, with a distinct seasonal peak in October-November. The results indicated that not only the previously described HPeV1 but also HPeV genotypes 3 and 6 circulate in Finland. Microneutralisation assays, which were set up to detect HPeV1 to 6, the most common genotypes in Europe, provided a deeper understanding of HPeV seroprevalence in the Finnish and Dutch populations. Seropositivity for HPeV1, 2 and HPeV4 to 6 was high and moderate in adults, in contrast to seropositivity for HPeV3, which was extremely low. The serological data demonstrate that HPeV types 1 to 6 might be even more prevalent than previously assumed. All six HPeV types circulate in Finland. In addition to HPeV detection in background populations, we presented the first cases of severe infection in neonates with HPeV4 and, subsequently, the first isolation of this genotype in Finland. Five hospitalised neonates with a sepsis-like disease in the fall of 2012 were positive for HPeV. Four of these children had HPeV4, indicating a potential small epidemic of this genotype, whereas one HPeV remained untyped. In addition, we detected HPeV3 in a neonate with suspected viral sepsis in October 2011 and another untyped HPeV in a child with symptoms corresponding to acute disseminated encephalomyelitis in May 2012. Following these findings, we promoted the addition of HPeV detection to routine diagnostics of young children. To extend the knowledge regarding other parechoviruses in Finland, we studied LV antibody prevalence in both humans and rodents. The seroprevalence detected for LV was 38% in humans and 18% in bank voles (Myodes glareolus). The observation of LV antibodies in humans is relatively high because LV has never been isolated from humans. These results suggest that an LV or LV-like virus, in addition to HPeVs, circulates frequently among human populations in Finland.
  • Rautiainen, Henna (Helsingin yliopisto, 2008)
    Primary biliary cirrhosis (PBC) is caused by an autoimmune inflammation of the small bile ducts. It results to destruction of bile ducts, accumulation of the bile in the liver, and cirrhosis. The prevalence and incidence of PBC is increasing in the Western world. The prevalence is highest in the USA (402 per million) and incidence in Scotland (49/million/year). Our aim was to assess the epidemiology of PBC in Finland. Patients for the epidemiological study were searched from the hospital discharge records from year 1988 to 1999.The prevalence rose from 103 to 180/million from 1988 to 1999, an annual increase of 5.1%. The incidence rose from 12 to 17 /million/year, an annual increase of 3.5%. The age at death increased markedly from 65 to 76 years. The risk of liver related deaths diminished over time. The treatment of PBC is based on Ursodeoxycholic acid (UDCA). During 20 years 50% of patients end up with cirrhosis. Our treatment option was to combine budesonide, a potent corticosteroid with a high first pass metabolism in the liver, to UDCA and evaluate the liver effects and systemic effects such as bone mass density (BMD) changes. Our aim was to find out if combination of laboratory tests would serve as a surrogate marker for PBC and help reducing the need for liver biopsy. Non-cirrhotic PBC patients were randomized to receive budesonide 6 mg/day combined to UDCA 15 mg /kg/day or UDCA alone for three years. The combination therapy with UDCA and budesonide was effective: stage improved 22%, fibrosis 25%, and inflammation 32%. In the UDCA group the changes were: 20% deterioriation in stage and 70% in fibrosis, but a 10% improvement in inflammation. BMD in femoral neck decreased by 3.6% in the combination group and by 1.9% in the UDCA group. The reductions in lumbar spine were 2.8% and 0.7%. Pharmacokinetics did not differ between the stages of PBC. HA, PIIINP, bile acids, and AST were significantly different within stages I-III and could differentiate the mild fibrosis (F0F1) from the moderate (F2F3). The combination of these individual markers (PBC-score) further improved the accuracy. The area under the ROC of the PBC score, using a cut of value 66, had a sensitivity of 81.4% and a specificity of 65.2% to classify the stage of PBC. The prevalence of PBC in Finland increases, which results from increasing incidence and improved survival. The combination of budesonide and UDCA improves liver histology compared to UDCA alone in non-cirrhotic stages of PBC. The treatment may reduce BMD. Hyaluronic acid, PIIINP, AST, and bile acids may serve as tools to monitor the treatment response in the early stages of PBC. The budesonide and UDCA combination therapy is an option for those patients who do not receive full response from UDCA and are still at the non-cirrhotic stage of PBC.
  • Palo, Riikka (Helsingin yliopisto, 2013)
    Previously reported differences in transfusion practices suggest that transfusion protocols and clinical transfusion decisions may often be inappropriate. To change and monitor practices requires a follow-up system. A healthcare-integrated data-gathering system could provide the required information about blood use. The purpose of this observational study was to create a follow-up system for blood use and to gather information about transfused patients and transfusion practices in Finland. Data came from ten Finnish hospital districts (five university and five tertiary-care hospital districts) between the years 2002 and 2005. The collection process involved combining data from pre-existing electronic medical records applied for different purposes. This information was combined from these electronic systems by use of personal identification numbers and data expressed as hospital episodes. Variation in blood-use practices still existed between hospitals. For example, the percentage of red blood cell (RBC) receivers ranged in Finnish hospitals from 12% to 57% during primary knee-arthroplasty surgery. The most typical blood-transfused patient was an over 65-year-old woman receiving 2 units of RBCs. RBC products were usually transfused in pairs (such as in two-four-six units). In over 30% of FFP transfusions, plasma was given without any guidance from coagulation tests. Among moderately anemic parturients, transfusion of 0 to 2 units of RBC had no effect on length of hospitalization. Duration of hospitalization was, however, considerably longer in these anemic patients than for average Finnish mothers (5.2 days versus 3.5 days). Most of the platelet (PLT) products were transfused to hematological patients (43%). Only 1% of surgical patients received PLTs. Severity of underlying condition in surgical patients had an effect on prevalence of blood transfusions. Variability in blood-use practices suggests inappropriate blood use. Moreover, RBC transfusion in paired units is a questionable practice. FFP transfusions, not based on coagulation tests, suggest inappropriate use of plasma as well. In parturients, mild anemia treated with 1 to 2 units of RBCs does not shorten hospitalization time. This supports the current recommended thresholds for RBC transfusion. Improvement efforts concerning PLT-use practices may be directed to users of high doses of PLTs; to hematological patients, but also to digestive tract surgery and cardiac surgery patients. Knowledge of severity of the underlying disease as affecting the transfusion requirement may facilitate optimization of blood use.
  • Poikonen, Eira (Helsingin yliopisto, 2011)
    Candida species are an important cause of nosocomial bloodstream infections in hospitalized patients worldwide, with associated high mortality, excess length of stay and costs. Main contributors to candidemias is profound immunosuppression due to serious underlying condition or intensive treatments leading to an increasing number of susceptible patients. The rank order of causative Candida species varies over time and in different geographic locations. The aim of this study was to obtain information on epidemiology of candidemia in Finland, to identify trends in incidence, causative species, and patient populations at risk. In order to reveal possible outbreaks and assess the value of one molecular typing method, restriction enzyme analysis (REA), in epidemiological study, we analyzed C. albicans bloodstream isolates in Uusimaa region in Southern Finland during eight years. The data from the National Infectious Disease Register were used to assess the incidence and epidemiological features of candidemia cases. In Helsinki University Central Hospital (HUCH) all patients with blood culture yielding any Candida spp. were identified from laboratory log-books and from Finnish Hospital Infection Program. All the patients with a stored blood culture isolate of C. albicans were identified through microbiology laboratory logbooks, and stored isolates were genotyped with REA in the National Institute for Health and Welfare (former KTL). The incidence of candidemia in Finland is globally relatively low, but increased between between 1990s and 2000s. The incidence was highest in males >65 years of age, but incidence rates for patients <1-15 years were lower during 2000s than during 1990s. In HUCH the incidence of candidemia remained low and constant during our 18 years of observation, but a significant shift in patient-populations at risk was observed, associated with patients treated in intensive care units, such as premature neonates and surgical patients. The predominating causative species in Finland and in HUCH is C. albicans, but the proportion of C. glabrata increased considerably. The crude one-month case fatality was constantly high between 28-33%. REA differentiated efficiently between C. albicans blood culture isolates and no clusters were observed in the hospitals involved, despite of abundant transfer of patients among them. Candida spp. are an important cause of nosocomial blood stream infections in Finland, and continued surveillance is necessary to determine the overall trends and patient groups at risk, and reduce the impact of these infections in the future. Molecular methods provide an efficient tool for investigation of suspected outbreak and should be available in the future in Finland, also.
  • 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.
  • Perälä, Jonna (Helsingin yliopisto, 2013)
    Abstract: Schizophrenia and other psychoses are among the most severe mental disorders. There are few general population surveys of psychotic disorders. Most epidemiological studies have focused on schizophrenia and bipolar I disorder, while data of many other specific psychotic disorders are scarce. This study investigated the lifetime prevalence and epidemiological features of different psychotic disorders in the adult Finnish general population. The data were derived from the Health 2000 Study, a comprehensive general population survey of Finnish adults aged 30 years and over (N=8028). In the Psychoses in Finland study, the Health 2000 Study sample was screened for psychotic disorders. Those selected by the screens were invited for a mental health interview. Final best-estimate DSM-IV diagnoses were based on systematic evaluation of the interview and the case note data. The lifetime prevalence 3.5% of psychotic disorders was higher than has been estimated in most recent general population studies. The most common disorder was schizophrenia with lifetime prevalence 1%. Substance-induced psychotic disorders were common among working aged men and psychotic disorder due to general medical condition among women aged 65 years or over. Psychotic disorders were generally associated with socioeconomic disadvantage like being unmarried, pensioned or unemployed; having low income or education level. The highest lifetime prevalence of psychotic disorders was found in northern and eastern parts of Finland. The region of birth was a more important determinant of the risk of psychotic disorders than the region of residence, and most marked in schizophrenia. Alcohol-induced psychotic disorders were common in middle-aged men and associated with high morbidity and mortality. Clinical features of delusional disorder were different from schizophrenia. Disorganized schizophrenia was a schizophrenia subtype associated with poor outcome. With a high lifetime prevalence exceeding 3%, psychotic disorders are a major public health concern. The high and unevenly distributed prevalence should be taken into account when resources are allocated to health care.
  • Leino, Timo (Helsingin yliopisto, 2001)
  • Ruotsalainen, Eeva (Helsingin yliopisto, 2006)
    Staphylococcus aureus is the second most common bloodstream isolate both in community- and hospital-acquired bacteremias. The clinical course of S. aureus bacteremia (SAB) is determined by its complications, particularly by the development of deep infections and thromboembolic events. Despite the progress of antimicrobial therapy, SAB is still associated with high mortality. However, injection drug users (IDUs) tend to have fewer complications and better prognosis than nonaddicts, especially in endocarditis. The present study was undertaken to investigate epidemiology, treatment and outcome of S. aureus bacteremia and endocarditis in Finland. In particular, differences in bacterial strains and their virulence factors, and host immune responses were compared between IDUs and nonaddicts. In Finland, 5045 SAB cases during 1995-2001 were included using the National Infectious Disease Register maintained by National Public Health Institute. The annual incidence of SAB increased, especially in elderly. While the increase in incidence may partly be explained by better reporting, it most likely reflects a growing population at risk, affected by such factors as age and/or severe comorbidity. Nosocomial infections accounted for 51% of cases, with no change in their proportion during the study period. The 28-day mortality was 17% and remained unchanged over time. A total of 381 patients with SAB were randomized to receive either standard antibiotic treatment or levofloxacin added to standard treatment. Levofloxacin combination therapy did not decrease the mortality, lower the incidence of deep infections, nor did it speed up the recovery during 3 months follow-up. However, patients with a deep infection appeared to benefit from combination therapy with rifampicin, as suggested also by experimental data. Deep infections were found in 84% of SAB patients within one week after randomization, and they appeared to be more common than previously reported. Endocarditis was observed in 74 of 430 patients (17%) with SAB, of whom 20 were IDUs and 54 nonaddicts. Right-sided involvement was diagnosed in 60% of addicts whereas 93% of nonaddicts had left-sided endocarditis. Unexpectedly, IDUs showed extracardiac deep infections, thromboembolic events and severe sepsis with the same frequency as nonaddicts. The prognosis of endocarditis was better among addicts due to their younger age and lack of underlying diseases in agreement with earlier reports. In total, all 44 IDUs with SAB were included and 20 of them had endocarditis. An equal number of nonaddicts with SAB were chosen as group matched controls. Serological tests were not helpful in identifying patients with a deep infection. No individual S. aureus strain dominated in endocarditis among addicts. Characterization of the virulence factors of bacterial strains did not reveal any significant differences in IDUs and nonaddicts.
  • Hakonen, Elina (Helsingin yliopisto, 2014)
    Pancreatic beta cells produce and secrete insulin into circulation in order to control blood glucose levels. The amount of beta cells is tightly controlled throughout life. If the number or function of beta cells is compromised, glucoregulation does not function properly, leading to dysglycemia. In the case of type 1 diabetes, beta cells are selectively targeted by an autoimmune attack, and die through apoptosis. Type 2 diabetes develops due to peripheral insulin resistance, combined with pancreatic beta cell failure. Individuals with type 2 diabetes show a reduced beta cell mass and increased beta cell apoptosis, leading to a relative lack of insulin. Treatments that replenish beta cell mass in diabetic patients could enable restoration of normal glycemic control and represent a potentially curative therapy. A better understanding of the factors that regulate or protect beta cell mass and function is important for the development of new treatments for all forms of diabetes. The major aim of the present study was to elucidate the role of epidermal growth factor receptor (EGFR) in beta cell mass regulation and protection against diabetogenic insults. Two mouse models were generated for these studies: one with downregulated EGFR signaling in beta cells through expression of a dominant-negative EGFR mutation, and the other with increased EGFR signaling through expression of constitutively active EGFR in beta cells. In the dominant-negative EGFR mouse model beta cell mass failed to expand during obesity and gestation, suggesting that EGFR signaling is crucial in beta cell mass regulation during these metabolic challenges. Subsequent mechanistic studies identified survivin as a candidate EGFR-regulated target mediating beta cell mass expansion during gestation. EGFR activation during the neonatal period led to increased beta cell proliferation and mass. In contrast, in adults EGFR activation had only a minor effect on beta cell proliferation and mass. Furthermore, EGFR activation protected beta cells against apoptosis in vivo during diabetogenic insults and in vitro when challenged with inflammatory cytokines. Mechanistic studies suggested that EGFR signaling protected isolated islets from cytokine-mediated beta cell death by repressing the proapoptotic protein Bim. In conclusion, EGFR signaling appears to be important in beta cell mass expansion during metabolic challenges. The observation that EGFR stimulation protects against experimental diabetes suggests that enhancing EGFR signaling could prevent or revert beta cell loss in diabetes.
  • Partanen, Johanna (Helsingin yliopisto, 2012)
    Cancer progresses towards malignancy by gradual acquisition of genetic lesions that activate proto-oncogenes and inactivate tumor suppressor genes. Loss of cell polarity and cell-cell contacts are common in advanced solid cancers and often indicate aggressive disease and high metastatic potential of the primary tumor. However, the role of epithelial integrity, formed by the coordinated interplay between specialized cell adhesions and cell polarity, in the initiation of human cancers has been less clear. The major aim of this study was to explore the role of epithelial integrity as a tumor suppressor mechanism in human and murine mammary epithelial cells. The mammary gland is a unique organ, where most of its development occurs post-natally and is affected by cyclical hormonal activity. Consequently, the mammary gland needs to accommodate vast amounts of cell proliferation and tissue remodeling without compromising proliferation control. Using a three-dimensional cell culture model recapitulating many aspects of the mammary epithelium in vitro, we observed that formation of intact epithelial integrity could protect cells from excess proliferation induced by the c-Myc oncoprotein. Furthermore, disruption of epithelial integrity by loss of the apico-basal polarity gene and tumor suppressor Lkb1, restored the ability of c-Myc to induce cell cycle progression. Correspondingly, loss of Lkb1 from mouse mammary epithelial cells in vitro and in vivo led to widespread loss of epithelial integrity, as demonstrated by loss of apico-basal polarity, basement membrane (BM) deterioration and increased side branching. Furthermore, while loss of Lkb1 alone did not induce tumor formation in the mouse mammary gland, it synergized with c-Myc leading to dramatically increased tumorigenesis. Interestingly, the synergy between Lkb1 loss and c-Myc was observed to involve deregulation of serine-protease Hepsin, a BM degrading protease also implicated in human cancers. A second aim of this study was to study the mechanisms of c-Myc-induced sensitization to apoptosis and how it is modulated by epithelial integrity. We found that c-Myc induces apoptotic sensitivity specifically to TNF-related death inducing ligand (TRAIL) through activation of pro-apoptotic protein Bak and amplification of mitochondrial apoptotic signaling. Also, the apoptotic function of c-Myc was modulated by the epithelial integrity while mechanisms of c-Myc-induced apoptotic sensitivity was not. Finally, we also observed that shRNA-mediated downregulation of human orthologues of Drosophila epithelial integrity regulators causes disruption cell proliferation control leading to excess proliferation but interestingly, also to synthetic lethal phenotypes in combination with c-Myc activation. The findings presented in this thesis thus propose that the structural organization of epithelial cells as an intact epithelial integrity can modulate the action of single oncogenes, in this case c-Myc, and present an important barrier for tumor formation.
  • Takkunen, Minna (Helsingin yliopisto, 2010)
    In epithelial-mesenchymal transition (EMT), epithelial cells acquire traits typical for mesenchymal cells, dissociate their cell-cell junctions and gain the ability to migrate. EMT is essential during embryogenesis, but may also mediate cancer progression. Basement membranes are sheets of extracellular matrix that support epithelial cells. They have a major role in maintaining the epithelial phenotype and, in cancer, preventing cell migration, invasion and metastasis. Laminins are the main components of basement membranes and may actively contribute to malignancy. We first evaluated the differences between cell lines obtained from oral squamous cell carcinoma and its recurrence. As the results indicated a change from epithelial to fibroblastoid morphology, E-cadherin to N-cadherin switch, and change in expression of cytokeratins to vimentin intermediate filaments, we concluded that these cells had undergone EMT. We further induced EMT in primary tumour cells to gain knowledge of the effects of transcription factor Snail in this cell model. The E-cadherin repressors responsible for the EMT in these cells were ZEB-1, ZEB-2 and Snail, and ectopic expression of Snail was able to augment the levels of ZEB-1 and ZEB-2. We produced and characterized two monoclonal antibodies that specifically recognized Snail in cell lines and patient samples. By immunohistochemistry, Snail protein was found in mesenchymal tissues during mouse embryonal development, in fibroblastoid cells of healing skin wounds and in fibromatosis and sarcoma specimens. Furthermore, Snail localized to the stroma and borders of tumour cell islands in colon adenocarcinoma, and in laryngeal and cervical squamous cell carcinomas. Immunofluorescence labellings, immunoprecipitations and Northern and Western blots showed that EMT induced a progressive downregulation of laminin-332 and laminin-511 and, on the other hand, an induction of mesenchymal laminin-411. Chromatin immunoprecipitation revealed that Snail could directly bind upstream to the transcription start sites of both laminin α5 and α4 chain genes, thus regulating their expression. The levels of integrin α6β4, a receptor for laminin-332, as well as the hemidesmosomal complex proteins HD1/plectin and BP180 were downregulated in EMT-experienced cells. The expression of Lutheran glycoprotein, a specific receptor for laminin-511, was diminished, whereas the levels of integrins α6β1 and α1β1 and integrin-linked kinase were increased. In quantitative cell adhesion assays, the cells adhered potently to laminin-511 and fibronectin, but only marginally to laminin-411. Western blots and immunoprecipitations indicated that laminin-411 bound to fibronectin and could compromise cell adhesion to fibronectin in a dose-dependent manner. EMT induced a highly migratory and invasive tendency in oral squamous carcinoma cells. Actin-based adhesion and invasion structures, podosomes and invadopodia, were detected in the basal cell membranes of primary tumour and spontaneously transformed cancer cells, respectively. Immunofluorescence labellings showed marked differences in their morphology, as podosomes organized a ring structure with HD1/plectin, αII-spectrin, talin, focal adhesion kinase and pacsin 2 around the core filled with actin, cortactin, vinculin and filamin A. Invadopodia had no division between ring and core and failed to organize the ring proteins, but instead assembled tail-like, narrow actin cables that showed a talin-tensin switch. Time-lapse live-cell imaging indicated that both podosomes and invadopodia were long-lived entities, but the tails of invadopodia vigorously propelled in the cytoplasm and were occasionally released from the cell membrane. Invadopodia could also be externalized outside the cytoplasm, where they still retained the ability to degrade matrix. In 3D confocal imaging combined with in situ gelatin zymography, the podosomes of primary tumour cells were large, cylindrical structures that increased in time, whereas the invadopodia in EMT-driven cells were smaller, but more numerous and degraded the underlying matrix in significantly larger amounts. Fluorescence recovery after photobleaching revealed that the substructures of podosomes were replenished more rapidly with new molecules than those of invadopodia. Overall, our results indicate that EMT has a major effect on the transcription and synthesis of both intra- and extracellular proteins, including laminins and their receptors, and on the structure and dynamics of oral squamous carcinoma cells.
  • Helve, Otto (Helsingin yliopisto, 2008)
    The aim of the present thesis was to study the role of the epithelial sodium channel (ENaC) in clearance of fetal lung fluid in the newborn infant by measurement of airway epithelial expression of ENaC, of nasal transepithelial potential difference (N-PD), and of lung compliance (LC). In addition, the effect of postnatal dexamethasone on airway epithelial ENaC expression was measured in preterm infants with bronchopulmonary dysplasia (BPD). The patient population was formed of selected term newborn infants born in the Department of Obstetrics (Studies II-IV) and selected preterm newborn infants treated in the neonatal intensive care unit of the Hospital for Children and Adolescents (Studies I and IV) of the Helsinki University Central Hospital in Finland. A small population of preterm infants suffering from BPD was included in Study I. Studies I, III, and IV included airway epithelial measurement of ENaC and in Studies II and III, measurement of N-PD and LC. In Study I, ENaC expression analyses were performed in the Research Institute of the Hospital for Sick Children in Toronto, Ontario, Canada. In the following studies, analyses were performed in the Scientific Laboratory of the Hospital for Children and Adolescents. N-PD and LC measurements were performed at bedside in these hospitals. In term newborn infants, the percentage of amiloride-sensitive N-PD, a surrogate for ENaC activity, measured during the first 4 postnatal hours correlates positively with LC measured 1 to 2 days postnatally. Preterm infants with BPD had, after a therapeutic dose of dexamethasone, higher airway epithelial ENaC expression than before treatment. These patients were subsequently weaned from mechanical ventilation, probably as a result of the clearance of extra fluid from the alveolar spaces. In addition, we found that in preterm infants ENaC expression increases with gestational age (GA). In preterm infants, ENaC expression in the airway epithelium was lower than in term newborn infants. During the early postnatal period in those born both preterm and term airway epithelial βENaC expression decreased significantly. Term newborn infants delivered vaginally had a significantly smaller airway epithelial expression of αENaC after the first postnatal day than did those delivered by cesarean section. The functional studies showed no difference in N-PD between infants delivered vaginally and by cesarean section. We therefore conclude that the low airway epithelial expression of ENaC in the preterm infant and the correlation of N-PD with LC in the term infant indicate a role for ENaC in the pathogenesis of perinatal pulmonary adaptation and neonatal respiratory distress. Because dexamethasone raised ENaC expression in preterm infants with BPD, and infants were subsequently weaned from ventilator therapy, we suggest that studies on the treatment of respiratory distress in the preterm infant should include the induction of ENaC activity.
  • Niittyvuopio, Riitta (Helsingin yliopisto, 2006)
    Essential thrombocythaemia (ET) is a myeloproliferative disease (MPD) characterized by thrombocytosis, i.e. a constant elevation of platelet count. Thrombocytosis may appear in MPDs (ET, polycythaemia vera, chronic myeloid leukaemia, myelofibrosis) and as a reactive phenomenon. The differential diagnosis of thrombocytosis is important, because the clinical course, need of therapy, and prognosis are different in patients with MPDs and in those with reactive thrombocytosis. ET patients may remain asymptomatic for years, but serious thrombohaemorrhagic and pregnancy-related complications may occur. The complications are difficult to predict. The aims of the present study were to evaluate the diagnostic findings, clinical course, and prognostic factors of ET. The present retrospective study consists of 170 ET patients. Two thirds had a platelet count < 1000 x 109/l. The diagnosis was supported by an increased number of megakaryocytes with an abnormal morphology in a bone marrow aspirate, aggregation defects in platelet function studies, and the presence of spontaneous erythroid and/or megakaryocytic colony formation in in vitro cultures of haematopoietic progenitors. About 70 % of the patients had spontaneous colony formation, while about 30 % had a normal growth pattern. Only a fifth of the patients remained asymptomatic. Half had a major thrombohaemorrhagic complication. The proportion of the patients suffering from thrombosis was as high as 45 %. About a fifth had major bleedings. Half of the patients had microvascular symptoms. Age over 60 years increased the risk of major bleedings, but the occurrence of thrombotic complications was similar in all age groups. Male gender, smoking in female patients, the presence of any spontaneous colony formation, and the presence of spontaneous megakaryocytic colony formation in younger patients were identified as risk factors for thrombosis. Pregnant ET patients had an increased risk of complications. Forty-five per cent of the pregnancies were complicated and 38 % of them ended in stillbirth. Treatment with acetylsalicylic acid alone or in combination with platelet lowering drugs improved the outcome of the pregnancy. The present findings about risk factors in ET as well as treatment outcome in the pregnancies of ET patients should be taken into account when planning treatment strategies for Finnish patients.
  • Höckerstedt, Anna Illike (Helsingin yliopisto, 2004)
  • Ståhlberg, Kaarlo (Helsingin yliopisto, 2011)
    The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity.
  • Tillonen, Jyrki (Helsingin yliopisto, 2000)