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  • Augustin, Mona (Helsingin yliopisto, 2012)
    Myocardial infarction (MI) leading eventually to heart failure is a major cause of morbidity and mor-tality in Western countries. Current studies suggest that cell-based therapies can improve cardiac function after MI. Paracrine factors mediated by transplanted cells have been suggested to be the curative factors behind this effect. In the present work, we evaluated preconditioning methods of skeletal myoblasts (SM) and bone mar-row-derived mesenchymal stem cells (MSC) prior to transplantation in MI. We used epicardial trans-plantation of cell sheets in a rat model of MI which was induced by left anterior descending (LAD) coronary artery ligation. The preconditioning methods used were heat shock (HS) pre-treatment of SMs and gene modification of MSCs. Gene modification was performed by viral VEGF and Bcl-2 transductions. After preconditioning, cell sheets were transplanted onto MI and the therapeutic effect was evaluated. Furthermore, we studied the effect of HS pre-treatment on SM differentiation under hypoxic conditions and tested the hypothesis that HS preconditioning-treatment enhances the angio-genic properties of SM sheets. Metabolic activity of VEGF and Bcl-2 over-expressing cells was as-sessed under normal nutrient supply, serum starvation and staurosporine treatment. Our results demonstrate that HS preconditioning leads to increased expression of SM differentiation-associated troponin and to reduced caspase-3 activity from differentiation under hypoxic environment. HS-preconditioning protected SM sheets from hypoxia-associated apoptosis in vitro; however it reduced vascular endothelial growth factor (VEGF) expression of the sheet, leading to a lower therapeutic effect in heart failure. MSC sheets carrying VEGF showed enhanced efficacy of cell sheet transplantation therapy in an acute infarction model. These cell sheets attenuated left ventricular dysfunction and myocardial damage, and induced therapeutic angiogenesis. The metabolic activity of gene-over-expressing cells was significantly higher compared to wild type cells. Moreover, introducing VEGF expression in MSCs enhanced the metabolic activity of cells during serum starvation.
  • Keikkala, Elina (Helsingin yliopisto, 2014)
    Pre-eclampsia, defined as hypertension and proteinuria, causes significant maternal and perinatal complications. It affects about 2-8% of all pregnancies and there is no curative medication. If women at risk could be identified, prevention or, at least, reduction of the complications of pre-eclampsia might be possible. When serum biochemical markers and clinical characteristics have been combined, the prediction of pre-eclampsia has improved. We studied whether hyperglycosylated human chorionic gonadotropin (hCG-h) is useful for identifying women at risk of pre-eclampsia already in the first or second trimester of pregnancy. Concentrations of hCG, hCG-h, pregnancy-associated plasma protein-A (PAPP-A) and the free beta subunit of hCG (hCGβ) in the serum in the first trimester and of placental growth factor (PlGF), soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) and of the angiogenetic factors, angiopoietin-1 (Ang-1), -2 (Ang-2) and their common soluble endothelial cell-specific tyrosine kinase receptor Tie-2 (sTie-2) in the second trimester were studied as predictors of pre-eclampsia. For first trimester screening, 158 women who subsequently developed preeclampsia, 41 with gestational hypertension, 81 with small-for-gestational age (SGA) infants and 427 controls were selected among 12,615 pregnant women who attended for first trimester screening for Down's syndrome. For second trimester screening we used serum samples from 55 women who subsequently developed pre-eclampsia, 21 with gestational hypertension, 30 who were normotensive and gave birth to SGA infants, and 83 controls. For analysis of Ang-1, -2 and sTie-2 at 12-15 and 16-20 weeks of pregnancy, 49 women who subsequently developed preeclampsia, 16 with intrauterine growth restriction (IUGR) and 59 healthy controls were recruited among 3240 pregnant women attending for first trimester screening for Down's syndrome. Another 20 healthy women were recruited at term pregnancy for examination of the concentrations of these markers in maternal and fetal circulation and urine and the amniotic fluid before and after delivery. The proportion of hCG-h out of total hCG(%hCG-h) was lower in the first but not in second trimester in women who subsequently developed pre-eclampsia as compared to controls. In the first trimester, %hCG-h was predictive of pre-eclampsia, especially of early-onset pre-eclampsia (diagnosed before 34 weeks of pregnancy). The predictive power improved when PAPP-A, the mean arterial blood pressure and parity were combined with %hCG-h. When these four variables were used together, 69% of the women who were to develop early-onset pre-eclampsia were identified with a specificity of 90%. The concentrations of circulating Ang-2 during the second trimester were higher and those of PlGF were lower in women who later developed pre-eclampsia. Ang-2 was only 20% sensitive and at 90% specific for predicting pre-eclampsia, but PlGF performed well and was 53% sensitive and 90% specific for predicting early-onset pre-eclampsia. %hCG-h did not provide independent prognostic value in the second trimester. In conclusion, hCG-h is a promising first trimester marker of early-onset preeclampsia. In line with the earlier observations, PlGF is a useful second trimester predictive marker of early-onset pre-eclampsia.
  • Merkkiniemi, Katja (Helsingin yliopisto, 2015)
    The presence of certain cancer-related genetic and epigenetic alterations in the tumor affect patients´ response to specific cancer therapies. The accurate screening of these predictive biomarkers in molecular diagnostics is important since it enables the tailoring of an optimal treatment based on molecular characteristics of the tumor. Depending on the type of gene alteration, a wide variety of methods could be applied in biomarker testing. Among the novel methods is next-generation sequencing (NGS) technology, enabling simultaneous detection of multiple alterations. The aim of this thesis was to analyze predictive or potentially predictive genetic and epigenetic alterations of diffuse gliomas and non-small cell lung cancer (NSCLC), and to evaluate the feasibility of pyrosequencing and targeted NGS in the detection of these alterations in formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens. In Study I, we assessed the genetic and epigenetic profile of diffuse gliomas by applying methylation-specific pyrosequencing to detect MGMT promoter hypermethylation, array comparative genomic hybridization to detect chromosomal copy number alterations, and immunohistochemistry (IHC) to detect IDH1 mutation status. MGMT hypermethylation, IDH1 mutations, and losses of chromosome arms 1p and 19q were typical changes in oligodendroglial tumors (grades II-III), whereas losses of 9p and 10q were frequently seen in glioblastomas (grade IV). Furthermore, we detected significant associations of 1) MGMT hypermethylation with IDH1 mutations and loss of 19q, 2) unmethylated MGMT with losses of 9p and 10q and gain of 7p, 3) IDH1 mutations with MGMT hypermethylation, 1p loss, and combined loss of 1p/19q, and 4) non-mutated IDH1 with losses of 10q. Pyrosequencing proved to be a feasible method for determination of MGMT methylation status in FFPE sample material. In Studies II and III, we compared targeted NGS with fluorescence in situ hybridization, IHC, and real-time reverse-transcription PCR in the detection of ALK fusion (Study II), and with real-time PCR in the detection of EGFR, KRAS, and BRAF mutations (Study III). All analyses were successfully performed on all FFPE samples. A good concordance was observed between the results obtained by different methods, and targeted NGS also proved to be advantageous in the identification of novel and rare variants with a potential predictive value. In Study IV, we determined the frequency of ALK fusion in 469 Finnish NSCLC patients, and the association of ALK fusion with clinicopathological characteristics and with the presence of mutations in 22 other driver genes. We detected ALK fusion at a frequency of 2.3%, suggesting that it is a relatively rare alteration in Finnish NSCLC patients. The presence of ALK fusion was significantly linked to younger age and never-/ex-light smoking history. Although most of the ALK-positive tumors had adenocarcinoma histology, also ALK-positive large cell carcinomas were detected. Characterization of ALK-positive cases by targeted NGS showed a coexistence of ALK fusion with mutations in MET, TP53, CTNNB1, and PIK3CA, but the value of these co-occurrences requires further examination. In conclusion, our studies indicate that certain genetic and epigenetic alterations occur together, and the simultaneous screening of multiple alterations may thus allow one to obtain a more comprehensive picture of the molecular background of the tumor, which could facilitate prediction of tumor behavior, prognosis, and treatment response. Our results show the feasibility of pyrosequencing and targeted NGS in FFPE tumor tissue material and also the advantages of targeted NGS over other commonly used methods in the detection of gene rearrangements and mutations, particularly the ability to simultaneously identify multiple alterations.
  • Harkonmäki, Karoliina (Helsingin yliopisto, 2007)
    The strong tendency of elderly employees to retire early and the simultaneous aging of the population have been major topics of policy and scientific debate. A key concern has been the financing of future pension schemes and possible labour shortage, especially in social and health services within the public sector. The aging of the population is inevitable, but efforts can be made to prevent or postpone early exit from the labour force, e.g., by identifying and intervening in the factors that contribute to the process of early retirement due to disability. The associations of intentions to retire early, poor mental health and different psychosocial factors with the process of disability retirement are still poorly understood. The purpose of this study was to investigate the associations of intentions to retire early, poor mental health, work and family related psychosocial factors and experiences of earlier life stages with the process of disability retirement. The data were derived from the Helsinki Health Study (HHS, N=8960) and the Health and Social Support Study (HeSSup, N=25 901). The Helsinki Health Study is an ongoing employee cohort study among middle-aged women and men. The Health and Social Support Study is an ongoing longitudinal study of a working-age sample representative of the Finnish population. The analyses were restricted to respondents 40 years of age or older. Age and gender adjusted prevalence and incidence rates were calculated. Associations were studied by using logistic, multinomial and Cox regression. Strong intentions to retire early were common among employees. Poor mental health, unfavourable working conditions and work-to-family conflicts were clearly associated with increased intentions to retire early. Strong intentions to retire early predicted disability retirement. Risk of disability retirement increased in a dose-response manner with increasing number of childhood adversities. Poor mental and somatic health, life dissatisfaction, heavy alcohol consumption, current smoking, obesity and low socioeconomic status were also predictors of disability retirement. The impact of poor mental health and adverse experiences from earlier life stages, work and family related psychosocial factors, e.g., work-family interface, the subjective experience of well-being and health related risk behaviours on the process of disability retirement should be recognised. Preventive measures against disability retirement should be launched before subjective experience of ill health, work disability and strong intentions to retire early emerge.
  • Haapio, Mikko (Helsingin yliopisto, 2016)
    Background and aims. Patients with end-stage renal disease and on chronic renal replacement therapy are at increased risk of death compared to a population of the same age without end-stage renal disease. Despite some improvement in prognosis of end-stage renal disease patients during recent decades, the expected outcome remains dismal. Several factors are associated with impaired survival of patients with end-stage renal disease: especially high age, low serum albumin, chronic inflammation, and comorbidities such as diabetes and heart failure. However, a major portion of factors behind impaired survival have been insufficiently identified, and their prognostic weight is largely unknown. We therefore targeted for further exploration and measurement of factors potentially associated with survival of patients on chronic renal replacement therapy. Study patients and methods. In the four studies of this thesis, we investigated the survival of cohorts of adult patients in Finland after the start of chronic renal replacement therapy. These cohorts were in Study I, 1,604 patients with type 1 diabetes and 1,556 with glomerulonephritis who started chronic RRT during 1980–2005; in Study II, 319 patients during one year (1998) preceding start of chronic renal replacement therapy and thereafter; in Study III, all 4,463 patients who started chronic renal replacement therapy in 2000–2009; in Study IV, all 6,103 patients who entered chronic dialysis in 2000–2012. Data on patient cohorts came from the Finnish Registry for Kidney Diseases, a database including comprehensive information on Finnish patients on chronic renal replacement therapy since 1964. In Study III, data also came from the Finnish Kidney Transplant Registry. The statistical methods mainly employed in our survival analyses were Kaplan-Meier curves, the log rank test, and Cox proportional hazards regression and binary logistic regression for multivariable modeling. Results. In Study I, we showed that survival of patients with type 1 diabetes receiving chronic renal replacement therapy has improved significantly and consistently over the years and in all age-groups. Patients entering chronic renal replacement therapy in 2000–2005 had a 77% lower risk of death than those entering in 1980–1984. Said another way, median survival time of patients with type 1 diabetes on chronic renal replacement therapy has increased from 3.6 years to more than eight. In Study II, we detected a significantly higher age-adjusted mortality in those on chronic renal replacement therapy whose decline in estimated glomerular filtration rate during the predialysis phase had been the fastest. Their mortality risk was 73% higher in the patient tertile of fastest decliners compared to the slowest. This association, however, proved not to be causal, but instead jointly caused by many confounding factors, especially age, end-stage renal disease diagnoses type 1 diabetes and amyloidosis, and the comorbidities myocardial infarction and cancer. In Study III, results of our primary adjusted analyses (intention-to-treat) indicated no significant difference in risk of death between patients on chronic renal replacement therapy who started with peritoneal dialysis compared to those who started with hemodialysis. Without adjustment, the relative risk of death of peritoneal dialysis patients was 0.65 (95% CI 0.58-0.73, p<0.001) compared to hemodialysis patients. With adjustment for 26 potentially confounding variables, the corresponding relative risk was, however, 1.07 (95% CI 0.94-1.22, p=0.33). Results from our secondary analysis method (as-treated) and further with full adjustment, however, indicated a 17 to 33% higher relative risk of death for patients exclusively treated by peritoneal dialysis compared to those treated by hemodialysis exclusively. In Study IV, we developed one- and two-year all-cause mortality prediction models for patients starting chronic dialysis. These models were based on a less recent training cohort and validated with a more recent validation cohort. As a result, area under the curve for the one-year model (with seven variables) reached 0.77 and for the two-year model (with six variables) 0.74. Because mortality in the more recent patient cohort was significantly lower than in the less-recent cohort, both models slightly overestimated mortality risk. Conclusions. Based on studies described in this thesis, survival of Finnish patients with type 1 diabetes and end-stage renal disease has significantly improved since the beginning of the 1980s, despite their conspicuous increase in age, and has improved relatively more in patients with type 1 diabetes than in patients with glomerulonephritis, suggesting progress both in dialysis therapy and overall management of patients with end-stage renal disease and, quite evidently, also in management of diabetes. Furthermore, factors behind the rapid decline in estimated glomerular filtration rate during the year preceding the start of chronic renal replacement therapy, and effects of these factors on subsequent survival are now better characterized. Rate of decline in estimated glomerular filtration rate is not a causal factor for survival, but instead a marker of other factors associated with end-stage renal disease patients’ survival. In addition, based on this research, no overall difference appeared in survival regarding modality of dialysis. Patients starting chronic dialysis differ significantly between dialysis modalities with respect to many patient-level prognostic factors, but after comprehensive adjustment for these putative confounders, no survival advantage of one dialysis modality over another emerged. And lastly, important factors affecting one- and two-year mortality of Finnish patients starting chronic dialysis are now identified and their prognostic weight can be investigated. Based on these findings, we constructed two models for survival estimation hopefully to be implemented in individualized treatment-planning of patients approaching chronic renal replacement therapy.
  • Tikkanen, Roope (Helsingin yliopisto, 2009)
    Acts of violence lays a great burden on humankind. The negative effects of violence could be relieved by accurate prediction of violent recidivism. However, prediction of violence has been considered an inexact science hampered by scare knowledge of its causes. The study at hand examines risk factors of violent reconvictions and mortality among 242 Finnish male violent offenders exhibiting severe alcoholism and severe externalizing personality disorders. The violent offenders were recruited during a court-ordered 2-month inpatient mental status examination between 1990—1998. Controls were 1210 individuals matched by sex-, age-, and place of birth. After a 9-year non-incarcerated follow-up criminal register and mortality data were obtained from national registers. Risk analyses were applied to estimate odds and relative risk for recidivism and mortality. Risk variables that were included in the analyses were antisocial personality disorder (ASPD), borderline personality disorder (BPD), a comorbidity of ASPD and BPD, childhood adversities, alcohol consumption, age, and monoamine oxidase A (MAOA) genotype. In addition to risk analyses, temperament dimensions (Tridimensional Personality Questionnaire [TPQ]) were assessed. The prevalence of recidivistic acts of violence (32%) and mortality (16%) was high among the offenders. Severe personality disorders and childhood adversities increased the risk for recidivism and mortality both among offenders (OR 2.0–10.4) and in comparison between offenders and controls (RR 4.3–53.0). Offenders having BPD and a history of childhood maltreatment emerged as a group with a particularly poor prognosis. MAOA altered the effects of alcohol consumption and ageing. Alcohol consumption (+2.3%) and age (–7.3%) showed significant effects on the risk for violent reconvictions among the high activity MAOA (MAOA-H) offenders, but not among the low activity MAOA (MAOA-L) offenders. The offenders featured temperament dimensions of high novelty seeking, high harm avoidance, and low reward dependence matching Cloninger’s definition of explosive personality. The fact that the risk for recidivistic acts of violence and mortality accumulated into clearly defined subgroups supports future efforts to provide for evidence based violence prevention and risk assessments among violent offenders.
  • Moisio, Anu-Liisa (Helsingin yliopisto, 2002)
  • Wathén, Katja-Anneli (Helsingin yliopisto, 2011)
    Pre-eclampsia is a pregnancy complication that affects about 5% of all pregnancies. It is known to be associated with alterations in angiogenesis -related factors, such as vascular endothelial growth factor (VEGF). An excess of antiangiogenic substances, especially the soluble receptor-1 of VEGF (sVEGFR-1), has been observed in maternal circulation after the onset of the disease, probably reflecting their increased placental production. Smoking reduces circulating concentrations of sVEGFR-1 in non-pregnant women, and in pregnant women it reduces the risk of pre-eclampsia. Soluble VEGFR-1 acts as a natural antagonist of VEGF and placental growth factor (PlGF) in human circulation, holding a promise for potential therapeutic use. In fact, it has been used as a model to generate a fusion protein, VEGF Trap , which has been found effective in anti-angiogenic treatment of certain tumors and ocular diseases. In the present study, we evaluated the potential use of maternal serum sVEGFR-1, Angiopoietin-2 (Ang-2) and endostatin, three central anti-angiogenic markers, in early prediction of subsequent pre-eclampsia. We also studied whether smoking affects circulating sVEGFR-1 concentrations in pregnant women or their first trimester placental secretion and expression in vitro. Last, in order to allow future discussion on the potential therapy based on sVEGFR-1, we determined the biological half-life of endogenous sVEGFR-1 in human circulation, and measured the concomitant changes in free VEGF concentrations. Blood or placental samples were collected from a total of 268 pregnant women between the years 2001 2007 in Helsinki University Central Hospital for the purposes above. The biomarkers were measured using commercially available enzyme-linked immunosorbent assays (ELISA). For the analyses of sVEGFR-1, Ang-2 and endostatin, a total of 3 240 pregnant women in the Helsinki area were admitted to blood sample collection during two routine ultrasoundscreening visits at 13.7 ± 0.5 (mean ± SD) and 19.2 ± 0.6 weeks of gestation. Of them, 49 women later developing pre-eclampsia were included in the study. Their disease was further classified as mild in 29 and severe in 20 patients. Isolated early-onset intrauterine growth retardation (IUGR) was diagnosed in 16 women with otherwise normal medical histories and uncomplicated pregnancies. Fifty-nine women remaining normotensive, non-proteinuric and finally giving birth to normal-weight infants were picked to serve as the control population of the study. Maternal serum concentrations of Ang-2, endostatin and sVEGFR-1, were increased already at 16 20 weeks of pregnancy, about 13 weeks before the clinical manifestation of preeclampsia. In addition, these biomarkers could be used to identify women at risk with a moderate precision. However, larger patient series are needed to determine whether these markers could be applied for clinical use to predict preeclampsia. Intrauterine growth retardation (IUGR), especially if noted at early stages of pregnancy and not secondary to any other pregnancy complication, has been suggested to be a form of preeclampsia compromising only the placental sufficiency and the fetus, but not affecting the maternal endothelium. In fact, IUGR and preeclampsia have been proposed to share a common vascular etiology in which factors regulating early placental angiogenesis are likely to play a central role. Thus, these factors have been suggested to be involved in the pathogenesis of IUGR. However, circulating sVEGFR-1, Ang-2 and endostatin concentrations were unaffected by subsequent IUGR at early second trimester. Furthermore, smoking was not associated with alterations in maternal circulating sVEGFR-1 or its placental production. The elimination of endogenous sVEGFR-1 after pregnancy was calculated from serial samples of eight pregnant women undergoing elective Caesarean section. As typical for proteins in human compartments, the elimination of sVEGFR-1 was biphasic, containing a rapid halflife of 3.4 h and a slow one of 29 h. The decline in sVEGFR-1 concentrations after mid-trimester legal termination of pregnancy was accompanied with a simultaneous increase in the serum levels of free VEGF so that within a few days after pregnancy VEGF dominated in the maternal circulation. Our study provides novel information on the kinetics of endogenous sVEGFR-1, which serves as a potential tool in the development of new strategies against diseases associated with angiogenic imbalance and alterations in VEGF signaling.
  • Siltanen, Mirjami (Helsingin yliopisto, 2004)
  • Reponen, Elina (Helsingin yliopisto, 2016)
    Background: Preoperative risk assessment and reliable outcome reporting are vital for improving quality of care and patient safety. Studies on neurosurgical patients are surprisingly scarce, and no prospective reports on unselected elective craniotomy patients exist. The objectives of this study were to review the literature on the use of preoperative risk-assessment scores in elective cranial neurosurgery and to study preoperative risk prediction, short-term outcome reporting, and patient satisfaction in the first unselected, prospective cohort of adult elective craniotomy patients. Patients and Methods: We performed a systematic review of 25 studies on five preoperative scores [The American Society of Anesthesiologists physical status classification (ASA) score, the Karnofsky Performance Score (KPS), the modified Rankin Scale (mRS), the Sex, Karnofsky, ASA, Location, and Edema (SKALE) score, and the Charlson comorbidity score] in predicting outcome in elective cranial neurosurgery. We enrolled a prospective, unselected cohort of 418 adult elective craniotomy patients in the Department of Neurosurgery, Helsinki University Hospital. Evaluation of routinely collected preoperative data, original ASA score, Helsinki ASA score, and their combinations revealed their ability to predict in-hospital new central nervous system (CNS) deficits as well as systemic and infectious complications after elective craniotomy. We evaluated the reliability and accuracy of patient-reported outcomes, postoperative mRS scores, and mRS-score differences in reflecting short-term outcome. Overall patient satisfaction rate was determined, as were associations between high or low patient satisfaction and short-term postoperative outcome. Results: Evidence as to the applicability of preoperative risk-assessment scores in elective cranial neurosurgery is scarce, with KPS receiving the most support in the literature. None of the scores predicted all postoperative outcomes; the most applicable risk score varied with the outcome measure selected. The in-hospital mortality rate was 1.0% and the 30-day rate was 2.4%. In-hospital systemic and infectious complications occurred in 6.7% of patients, and new CNS deficits in 11.2%. Advanced age, preoperatively elevated C-reactive protein (CRP) level, and high Helsinki ASA class were independent predictors of systemic and infectious complications. A combination of these variables identified one-fourth of the patients with systemic and infectious complications (p=0.005, OR 4.8, CI 1.5-15.9, AUC 0.766) and was associated with prolonged intensive care unit (ICU) stay (p=0.018) and hospital stay (p=0.004). The rate of overall complications was 46.4%, and the rate of major complications was 18.2%. Perioperative changes in mRS scores were inconsistent: among patients with no complications, the mRS score increased for 17.1% at hospital discharge and for 23.8% at 30 days. Moreover, 28.0% of patients with major complications showed no increase in mRS scores at hospital discharge. Associations between patient-reported postoperative subjective deterioration in functional status and both major and overall morbidity were significant. Furthermore, a simple unweighted composite score of PROs was more sensitive and specific than was 30-day dependent functional status (mRS score ≥3) in detecting both major and overall morbidity. In our cohort, 93.8% rated their overall satisfaction as good or excellent. Even 9 of 10 patients with postoperative major morbidity rated their satisfaction as high. Low patient satisfaction was associated neither with major (p=0.054) nor with overall (p=0.215) morbidity. Conclusions: Strong evidence supporting the use of any preoperative risk score in elective cranial neurosurgery is lacking. The Helsinki ASA score seems more suitable than the original ASA score for elective craniotomy patients, especially in combination with other preoperative risk predictors, but only for systemic and infectious complications. The rate of major complications in our cohort was moderately low considering the average age, comorbidities and operated lesions of the patients in our unselected study cohort. The postoperative mRS score and mRS-score differences were inconsistent with recorded complications, whereas PROs seem promising tools for outcomes reporting. Overall patient satisfaction was high, even in patients with complicated outcomes, and thus patient satisfaction is a poor proxy for treatment outcome and quality of care in elective cranial neurosurgery.
  • Leinonen, Jaakko (Helsingin yliopisto, 2006)
    Visual acuities at the time of referral and on the day before surgery were compared in 124 patients operated on for cataract in Vaasa Central Hospital, Finland. Preoperative visual acuity and the occurrence of ocular and general disease were compared in samples of consecutive cataract extractions performed in 1982, 1985, 1990, 1995 and 2000 in two hospitals in the Vaasa region in Finland. The repeatability and standard deviation of random measurement error in visual acuity and refractive error determination in a clinical environment in cataractous, pseudophakic and healthy eyes were estimated by re-examining visual acuity and refractive error of patients referred to cataract surgery or consultation by ophthalmic professionals. Altogether 99 eyes of 99 persons (41 cataractous, 36 pseudophakic and 22 healthy eyes) with a visual acuity range of Snellen 0.3 to 1.3 (0.52 to -0.11 logMAR) were examined. During an average waiting time of 13 months, visual acuity in the study eye decreased from 0.68 logMAR to 0.96 logMAR (from 0.2 to 0.1 in Snellen decimal values). The average decrease in vision was 0.27 logMAR per year. In the fastest quartile, visual acuity change per year was 0.75 logMAR, and in the second fastest 0.29 logMAR, the third and fourth quartiles were virtually unaffected. From 1982 to 2000, the incidence of cataract surgery increased from 1.0 to 7.2 operations per 1000 inhabitants per year in the Vaasa region. The average preoperative visual acuity in the operated eye increased by 0.85 logMAR (in decimal values from 0.03to 0.2) and in the better eye 0.27 logMAR (in decimal values from 0.23 to 0.43) over this period. The proportion of patients profoundly visually handicapped (VA in the better eye <0.1) before the operation fell from 15% to 4%, and that of patients less profoundly visually handicapped (VA in the better eye 0.1 to <0.3) from 47% to 15%. The repeatability visual acuity measurement estimated as a coefficient of repeatability for all 99 eyes was ±0.18 logMAR, and the standard deviation of measurement error was 0.06 logMAR. Eyes with the lowest visual acuity (0.3-0.45) had the largest variability, the coefficient of repeatability values being ±0.24 logMAR and eyes with a visual acuity of 0.7 or better had the smallest, ±0.12 logMAR. The repeatability of refractive error measurement was studied in the same patient material as the repeatability of visual acuity. Differences between measurements 1 and 2 were calculated as three-dimensional vector values and spherical equivalents and expressed by coefficients of repeatability. Coefficients of repeatability for all eyes for vertical, torsional and horisontal vectors were ±0.74D, ±0.34D and ±0.93D, respectively, and for spherical equivalent for all eyes ±0.74D. Eyes with lower visual acuity (0.3-0.45) had larger variability in vector and spherical equivalent values (±1.14), but the difference between visual acuity groups was not statistically significant. The difference in the mean defocus equivalent between measurements 1 and 2 was, however, significantly greater in the lower visual acuity group. If a change of ±0.5D (measured in defocus equivalents) is accepted as a basis for change of spectacles for eyes with good vision, the basis for eyes in the visual acuity range of 0.3 - 0.65 would be ±1D. Differences in repeated visual acuity measurements are partly explained by errors in refractive error measurements.
  • Hovi, Petteri (Helsingin yliopisto, 2011)
    Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.
  • Jakobsson, Maija (Helsingin yliopisto, 2009)
    Cervical cancer is the second most common cancer among women globally. Most, probably all cases, arise through a precursor, cervical intraepithelial neoplasia (CIN). Effective cytological screening programmes and surgical treatments of precancerous lesions have dramatically reduced its prevalence and related mortality. Although these treatments are effective, they may have adverse effects on future fertility and pregnancy outcomes. The aim of this study was to evaluate the effects of surgical treatment of the uterine cervix on pregnancy and fertility outcomes, with the focus particularly on preterm birth. The general preterm birth rates and risk factors during 1987–2005 were studied. Long-term mortality rates of the treated women were studied. In this study, information from The Medical Birth Register (MBR), The Hospital Discharge Register (HDR), The Cause-of-Death Register (CDR), and hospital records were used. Treatments were performed during 1987–2003 and subsequent deliveries, IVF treatments and deaths were analyzed. The general preterm birth rate in Finland was relatively stable, varying from 5.1% to 5.4% during the study period (1987 to 2005), although the proportion of extremely preterm births had decreased substantially by 12%.The main risk factor as regards preterm birth was multiplicity, followed by elective delivery (induction of delivery or elective cesarean section), primiparity, in vitro fertilization treatment, maternal smoking and advanced maternal age. The risk of preterm birth and low birth weight was increased after any cervical surgical treatment; after conization the risk of preterm birth was almost two-fold (RR 1.99, 95% CI 1.81– 2.20). In the conization group the risk was the highest for very preterm birth (28–31 gestational weeks) and it was also high for extremely preterm birth (less than 28 weeks). In this group the perinatal mortality was also increased. In subgroup analysis, laser ablation was not associated with preterm birth. When comparing deliveries before and after Loop conization, we found that the risk of preterm birth was increased 1.94-fold (95% CI 1.10–3.40). Adjusting for age, parity, or both did not affect our results. Large or repeat cones increased the risk of preterm birth when compared with smaller cones, suggesting that the size of the removed cone plays a role. This was corroborated by the finding that repeat treatment increased the risk as much as five-fold when compared with the background preterm birth rate. We found that the proportion of IVF deliveries (1.6% vs. 1.5%) was not increased after treatment for CIN when adjusted for year of delivery, maternal age, or parity. Those women who received both treatment for CIN and IVF treatment were older and more often primiparous, which explained the increased risk of preterm birth. We also found that mortality rates were 17% higher among women previously treated for CIN. This excess mortality was particularly seen as regards increased general disease mortality and alcohol poisoning (by 13%), suicide (by 67%) and injury death (by 31%). The risk of cervical cancer was high, as expected (SMR 7.69, 95% CI 4.23–11.15). Women treated for CIN and having a subsequent delivery had decreased general mortality rate (by -22%), and decreased disease mortality (by -37%). However, those with preterm birth had increased general mortality (SMR 2.51, 95% CI 1.24–3.78), as a result of cardiovascular diseases, alcohol-related causes, and injuries. In conclusion, the general preterm birth rate has not increased in Finland, as in many other developed countries. The rate of extremely preterm births has even decreased. While other risk factors of preterm birth, such as multiplicity and smoking during pregnancy have decreased, surgical treatments of the uterine cervix have become more important risk factors as regards preterm birth. Cervical conization is a predisposing factor as regards preterm birth, low birth weight and even perinatal mortality. The most frequently used treatment modality, Loop conization, is also associated with the increased risk of preterm birth. Treatments should be tailored individually; low-grade lesions should not be treated at all among young women. The first treatment should be curative, because repeat treatments are especially harmful. The proportion of IVF deliveries was not increased after treatment for CIN, suggesting that current treatment modalities do not strongly impair fertility. The long-term risk of cervical cancer remains high even after many years post-treatment; therefore careful surveillance is necessary. In addition, accidental deaths and deaths from injury were common among treated women, suggesting risk-taking behavior of these women. Preterm birth seems be associated with extremely high mortality rates, due to cardiovascular, alcohol-related and injury deaths. These women could benefit from health counseling, for example encouragement in quitting smoking.
  • Rahkonen, Leena (Helsingin yliopisto, 2010)
    Premature delivery is a major cause of neonatal morbidity and mortality. The incidence of premature deliveries has increased around the world. In Finland 5.3%, or about 3,000 children per year are born prematurely, before 37 weeks of gestation. The corresponding figure in the United States is about 13%. The morbidity and mortality are highest among infants delivered before 32 weeks of gestation - about 600 children each year in Finland. Approximately 70% of premature deliveries are unexplained. Preterm delivery can be caused by an asympto-matic infection between uterus and the fetal membranes, such can begin already in early pregnancy. It is difficult to predict preterm delivery, and many patients are therefore unnecessarily admitted to hospital for observation and exposed to medical treatments. On the other hand, the high risk women should be identified early for the best treatment of the mother and preterm infant. --- In the prospective study conducted at the Department of Obstetric and Gynecology, Helsinki University Central Hospital two biochemical inflammation related markers were measured in the lower genital tract fluids of asymp-tomatic women in early and mid pregnancy in an order to see whether these markers could identify women with an increased risk of preterm delivery. These biomarkers were phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and matrix metalloproteinase-8 (MMP-8). The study involved 5180 asymptomatic pregnant women, examined during the first and second ultrasound screening visits. The study samples were taken from the vagina and cervicix. In addition, 246 symptomatic women were studied (pregnancy weeks 22 – 34). The study showed that increased phIGFBP-1 concentration in cervical canal fluid in early pregnancy increased the risk for preterm delivery. The risk for very premature birth (before 32 weeks of gestation) was nearly four-fold. Low MMP-8 concentration in mid pregnancy increased the risk of subsequent premature preterm rupture of fetal membranes (PPROM). Significantly high MMP-8 concentrations in the cervical fluid increased the risk for prema-ture delivery initiated by preterm labour with intact membranes. Among women with preterm contractions the shortened cervical length measured by ultrasound and elevated cervical fluid phIGFBP-1 both predicted premature delivery. In summary, because of the relatively low sensitivity of cervical fluid phIGFBP-1 this biomarker is not suitable for routine screening, but provides an additional tool in assessing the risk of preterm delivery. Cervical fluid MMP-8 is not useful in early or mid pregnancy in predicting premature delivery because of its dual role. Further studies on the role of MMP-8 are therefore needed. Our study confirms that phIGFBP-1 testing is useful in predicting pre-term delivery.
  • Pallasaho, Paula (Helsingin yliopisto, 2006)
    Objectives: To assess the prevalence and risk factor profiles of respiratory symptoms, asthma and chronic bronchitis in Helsinki, and to compare these results with those for Sweden and Estonia. Other important aims were to evaluate the prevalence and determinants of type 1 sensitization in Helsinki. Materials and methods: This presentation is a part of a large epidemiological study in Finland, Estonia and Sweden (FinEsS). The first part of the study consisted of a postal questionnaire in 1995-1996 distributed to subjects in eight study centres. The study population in each centre was a population-based random sample designed to be representative of the general population. The original study sample in Helsinki consisted of 8000 subjects aged 20-69 years, 6062 (76%) of whom participated. Comparisons between countries were based on a narrower age group, 20-64 years, since 64 years was the upper age limit used in the original study in Estonia. Thus, altogether 58 661 subjects aged 20-64 years were invited to participate in Finland, Sweden and Estonia, and 44 483 (76%) did so. The second part of the study was a clinical study with a structured interview, lung function measurements and skin-prick tests with 15 common allergens. This thesis reports only the results of the prick tests in Helsinki. Of the 1200 subjects invited to participate in Helsinki, 643 (54%) consented. Skin-prick tests were performed on subjects ≤ 60 years of age; thus, a total of 498 tests were done. Results: In Helsinki, the prevalence of physician-diagnosed asthma was 6.6% and of physician-diagnosed chronic bronchitis 3.7% among subjects aged 20-69 years. Comparison of the results between Finland, Sweden and Estonia in subjects 20-64 years of age revealed the highest prevalence of physician-diagnosed asthma in Sweden, 7.8%, while the prevalence in Finland was 5.9% and in Estonia 2.0% (p<0.001). The prevalence of physician-diagnosed asthma among those aged 20-29 years was 7.9% in Stockholm, 6.3% in Helsinki and 2.8% in Tallinn. Asthma-related symptoms were most common in Estonia, and among those with typical asthma symptoms the diagnosis of asthma was least likely in Estonia. Physician-diagnosed chronic bronchitis was reported to be 10.7% in Estonia, 3.1% in Sweden and 2.9% in Finland among subjects aged 20-64 years (p<0.001). Among those aged 20-29 years, 7.6% in Tallinn reported physician-diagnosed chronic bronchitis, while the prevalence estimates were 1.4% in Stockholm and 1.3% in Helsinki. The prevalence of smoking was similar for women in all three countries, around 30%, but large differences in smoking habits were present among men; 60% of Estonian, 39% of Finnish and 28% of Swedish men smoked. Skin-prick tests in Helsinki revealed a high prevalence of sensitization, 46.9%. For subjects aged 26-39 years, the prevalence was highest, 56.8%, and 23.7% were sensitized to at least four allergens. The most common sensitizing allergen was the dog. Sensitization to multiple allergens was associated with a high prevalence of asthma and allergic rhinitis. Conclusions: Compared with earlier Finnish studies, a higher prevalence of asthma and a lower prevalence of chronic bronchitis were found in Helsinki. The prevalence of physician-diagnosed chronic bronchitis was low in Helsinki, with only one-fifth of subjects fulfilling the symptom criteria for chronic bronchitis reporting having a diagnosis of chronic bronchitis. The prevalences of asthma and chronic bronchitis were similar in Finland and Sweden, but in Estonia physician-diagnosed asthma was less common and physician-diagnosed chronic bronchitis more common, particularly among young subjects. Further analyses revealed that the diagnosis of asthma was favoured in Finland and Sweden, while the diagnosis of chronic bronchitis was more likely in Estonia for subjects with the same symptoms. Allergic sensitization was common in Helsinki. Our findings of multiple sensitization also speak in favour of evaluating the degree of sensitization when assessing allergies.
  • Norja, Päivi (Helsingin yliopisto, 2012)
    Parvoviruses are minute single-stranded DNA viruses that infect a wide range of mammalians and invertebrates. Human parvovirus B19 (B19V) was discovered in the 1970s and was soon found to cause several diseases, including erythema infectiosum, arthropathy, anemias, fetal hydrops, and fetal death. The B19V titer in blood is high during acute infection. After primary infection, B19V has been shown to persist in tissues of symptomatic and asymptomatic persons. Prior to the commencement of this work, two new genotypes were identified for B19V that had long been considered to be very stable regarding its DNA sequence. The newly found variants are named genotype 2 and genotype 3, and the prototypic virus is genotype 1. The new genotypes were found from the blood of a child with aplastic anemia and from human skin. The most common transmission route of B19V is the respiratory tract but transmission via plasma-derived medical products also occurs. To ensure the safety of medical blood products in the European Union, new instructions were given in 2004 for B19V levels in plasma pools. These necessitate quantitative PCR (qPCR) screening for B19V DNA. Two commercially available quantitative PCR tests (qPCR A and qPCR B) existed at the beginning of this thesis project and were examined here for their ability to amplify, quantify, and differentiate B19V genotypes. qPCR A was highly sensitive for the detection of B19V genotype 1, but failed to detect B19V genotype 2 and to differentiate genotypes. qPCR B proved to be a sensitive and suitable method for detection, quantification, and differentiation of all B19V genotypes. The prevalences of B19V genotypes were examined in a large number of blood and tissue samples. B19V genotype 1 was found in 23% of maxipools of blood donor plasma, and in 17% of single samples of serum whilst no genotype 2 or 3 DNAs were detected. Various types of tissue samples contained B19V DNA of genotype 1 or genotype 2 DNA, while B19V genotype 3 DNA was absent from all the tissues studied. When grouping tissue donors according to their age, a variety in distribution of B19V genotypes was noticed. B19V genotype 1 DNA was found in all age groups, whereas genotype 2 was confined to those subjects born before 1973. Correspondingly, sera from the past two decades contained no B19V genotype 2 DNA. The results suggest that actually the newly found B19V genotype 2 is older in occurrence than the prototypic B19V genotype 1 and it has disappeared from global circulation. Furthermore, the results disclosed that persistence of B19V DNA in human tissues is lifelong and represents a source of information from our past, termed the Bioportfolio. The evolution rates of both persistent and acute B19V genomes were determined in collaboration with a British group at University of Edinburgh. As a sequencing target, the gene for viral capsid protein VP2 was amplified from serum samples collected from subjects with B19V acute infection. In comparison, the VP2 gene was amplified from tissues of subjects with serologically confirmed past B19V infection. Notably rapid sequence changes of 4x10-4 substitutions/site/year were observed in plasma-derived B19V genomes. In contrast, the evolution rate of B19Vs found in tissues was 10 times slower. In 2005, two new human parvoviruses, human bocavirus 1 (HBoV1) and human parvovirus 4 (PARV4), were discovered by molecular screening and large-scale sequencing. HBoV1 has since been shown to cause systemic infection and respiratory illness in young children. PARV4 has mainly been restricted to those with a history of intravenous drug use with the exception of Sub-Saharan Africa. Later, in 2009 and 2010, three more human bocaviruses, probably enteric viruses, were found from feces. Whether these newly found human parvoviruses share the ability of B19V to persist in human tissues, was studied. Tonsillar, synovial, and dermal tissues were examined for DNAs of these new parvoviruses; neither HBoV2-4 nor PARV4 DNAs were detected. HBoV1 DNA was found in tonsillar tissue but not in synovia or skin. HBoV1 DNA prevalence was 9 % of samples collected from young children. None of the HBoV1 IgG seropositive adults harbored HBoV1 DNA. Rather than long term persistence, the results indicate a slow evanescence of HBoV1 genomes in tonsillar tissue of children after primary exposure. With the collaboration of a German group in Regensburg, the role of B19V DNA persistence in cardiomyopathy or myocarditis was studied. The B19V DNA prevalence was 85%. B19V genotype 1 and 2 DNAs were found in 9% and 76% of heart examined, respectively. Genotype 3 was absent from all the tissues studied. The presence of B19V DNA in human heart biopsies demonstrated no correlation with clinical symptoms. Quantitative PCR methods for B19V detection in plasma-derived medical products are crucial for ensuring the viral purity of the blood products. Today, quantitative B19V PCR alone, or together with antibody assays, is commonly used in diagnosis of B19V infections. Evolution studies of parvoviruses have given us a new and unexpected perspective to rates of evolution of single-stranded DNA viruses. The ability of B19V to persist lifelong in several types of human tissues is unique among parvoviruses; human bocaviruses are not suggested to occur in solid tissues for life. The detection of B19V DNA in human heart did not indicate the pathogenesis of persistent B19V, but neither answered the question about possiblility of B19V reactivation. With known mechanism, and in light of full-length coding potential of the persistent viral DNA genomes, the persistence of B19V could, in future, provide the desired long-term permanence for gene therapy vectors. Furthermore, the persistency provides, at the global and epidemiological level, a database for analysis the occurrence and circulation of parvoviruses and their variants.