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  • Jaakkola, Susanna (Helsingin yliopisto, 2012)
    Large differences exist between countries in the context and use of postmenopausal hormone therapies. Differences also exist in genes, diet and lifestyle, which all affect the risk for cancers. I studied the effects of different estrogen-progestagen therapies (EPT) for the risk of endometrial and cervical cancer as well as uterine sarcoma in nationwide studies on postmenopausal Finnish women. A cohort of all Finnish women (> 50 years of age) who had used EPT for at least 6 months since 1994 was collected from the national Medical Reimbursement Register and followed for uterine cancers with the aid of the Finnish Cancer Registry. The risks were compared to those of the same age background population in the three cohort studies. The follow-up for the endometrial cohort study ended in 2006 and encountered a total of 1,364 endometrial cancer cases out of a total of 224,015 women with EPT. The follow-up was continued until the end of 2008 in the other cohort studies and accumulated 243,857 women with EPT of which 192 women showed cervical precancerous lesions, 97 women cervical cancers and 76 women uterine sarcomas (45 leiomyosarcomas, 24 stromal sarcomas and 7 other sarcomas). To control some of the various confounding factors and to assess, in addition to EPT, also the impact of tibolone, another study using a case-control study model was conducted. In total 7,261 women with endometrial cancer and 19,490 controls were compared in regard to the use of EPT or tibolone in 1995-2007. Hysterectomized women were excluded from the controls based on data from the Hospital Inpatient Register of the National Institute of Health and Welfare. Results were adjusted for parity, age at first delivery and hospital district, but not for body mass index, diabetes mellitus or socioeconomic status. In the cohort study, the incidence of endometrial cancer was increased among sequential EPT users after 5 years of use (standardized incidence ratio (SIR) 1.69; 95% confidence interval (CI) 1.43-1.96) when progestagen was added monthly and the risk doubled to 3.76 (2.90-4.79) when progestagen was added at 3-month intervals. In the case-control study, sequential EPT showed increased risk only after 10 years of use (odds ratio (OR) 1.38; 1.15-1.66) but long-cycle sequential EPT associated with increased risk after 5 years of use (1.63; 1.12-2.38). The use of tibolone showed no effect on endometrial cancer risk, but the number of cases (n = 19) was small. In contrast, the use of continuous combined EPT users was accompanied with a reduced risk for endometrial cancer from 3 years onwards (SIR 0.24; 0.06-0.60). Similar risk reductions for endometrial cancer were seen also in women using continuous combined EPT or an estradiol plus levonorgestrel releasing intrauterine system in the case-control study; the odds rations were 0.57 (0.37-0.88) and 0.16 (0.37-0.68), respectively. In the cohort study, endometrial cancers of women using monthly sequential EPT tended to be diagnosed more often in a localized stage than endometrial cancers in general. The most common oral progestagens as parts of EPT in Finland (norethisterone acetate, medroxyprogesterone acetate and dydrogesterone) showed no significant differences in the endometrial effects. Transdermal and oral routes of administration showed similar risks for monthly sequential EPT regimen including estradiol and norethisterone acetate. The incidence of cervical precancerous lesions in all EPT users did not differ from that in the background population, but the risk for squamous cell carcinoma was decreased (SIR 0.41; 0.28-0.58) and that of adenocarcinoma was increased (1.31; 1.01-1.67). When the use of EPT exceeded 5 years, the risk for squamous cell carcinoma showed a trend towards a further decrease 0.34 (0.16-0.65), and the risk of adenocarcinoma showed a trend towards an increase 1.83 (1.24-2.59). The risk for uterine sarcomas was not affected by the exposure to EPT for less than 5 years. Uses of EPT for 5-10 and 10+ years associated with an increased risk for uterine sarcomas (SIR 2.02; 1.36-2.91 and 3.01; 1.30-5.93); risks were highest for leiomyosarcoma. The mode of EPT did not affect these risks significantly. In conclusion, the use of postmenopausal EPT is one determinant for the occurrence of uterine cancers. Continuous combined regimens decrease and sequential regimens increase the risk for endometrial cancer; these data support earlier findings. The following new observations were made; oral and transdermal routes of administration or various types of progestagens do not modify these effects. A consistent decrease in the incidence of squamous cervical malignancies was seen in EPT users. In contrast, the incidence of cervical adenocarcinoma was increased. The risk for uterine sarcomas is increased if EPT has been used for longer times. These data are of importance for the potential users of EPT and for physicians prescribing such regimens.
  • Tuomikoski, Pauliina (Helsingin yliopisto, 2010)
    Vasomotor hot flushes are complained of by approximately 75% of postmenopausal women, but their frequency and severity show great individual variation. Hot flushes have been present in women attending observational studies showing cardiovascular benefit associated with hormone therapy use, whereas they have been absent or very mild in randomized hormone therapy trials showing cardiovascular harm. Therefore, if hot flushes are a factor connected with vascular health, they could perhaps be one explanation for the divergence of cardiovascular data in observational versus randomized studies. For the present study 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied in regard to cardiovascular health by way of pulse wave analysis, ambulatory blood pressure and several biochemical vascular markers. In addition, the possible impact of hot flushes on outcomes of hormone therapy was studied. This study shows that women with severe hot flushes exhibit a greater vasodilatory reactivity as assessed by pulse wave analysis than do women without vasomotor symptoms. This can be seen as a hot flush-related vascular benefit. Although severe night-time hot flushes seem to be accompanied by transient increases in blood pressure and heart rate, the diurnal blood pressure and heart rate profiles show no significant differences between women without and with mild, moderate or severe hot flushes. The levels of vascular markers, such as lipids, lipoproteins, C-reactive protein and sex hormone-binding globulin show no association with hot flush status. In the 6-month hormone therapy trial the women were classified as having either tolerable or intolerable hot flushes. These groups were treated in a randomized order with transdermal estradiol gel, oral estradiol alone or in combination with medroxyprogesterone acetate, or with placebo. In women with only tolerable hot flushes, oral estradiol leads to a reduced vasodilatory response and increases in 24-hour and daytime blood pressures as compared to women with intolerable hot flushes receiving the same therapy. No such effects were observed with the other treatment regimes or in women with intolerable hot flushes. The responses of vascular biomarkers to hormone therapy are unaffected by hot flush status. In conclusion, hot flush status contributes to cardiovascular health before and during hormone therapy. Severe hot flushes are associated with an increased vasodilatory, and thus, a beneficial vascular status. Oral estradiol leads to vasoconstrictive changes and increases in blood pressure, and thus to possible vascular harm, but only in women whose hot flushes are so mild that they would probably not lead to the initiation of hormone therapy in clinical practice. Healthy, recently postmenopausal women with moderate to severe hot flushes should be given the opportunity to use hormone therapy alleviate hot flushes, and if estrogen is prescribed for indications other than for the control of hot flushes, transdermal route of administration should be favored.
  • Keltanen, Terhi (Helsingin yliopisto, 2015)
    Postmortem (PM) biochemistry is utilized in cause of death (CoD) investigations. The challenges in PM biochemistry are caused mainly by the PM changes. Analytes may be degraded or denatured leading to methodological difficulties. In addition, the re-distribution may cause falsely elevated values when compared to clinical samples. Analytes may also be consumed or produced by microbial metabolism. The sample matrix is often different from that in clinical biochemistry and the reference levels need be obtained through research. The actual death process and agonal period can also lead to unique changes in the analyte concentrations. Despite these challenges, with a sufficient number of samples and adequate research it is possible to optimize biochemical methods for PM samples and obtain reference values for certain conditions. The biochemical results can provide supporting information in cases where the death is caused or associated with metabolic disturbances for instance in diabetes mellitus (DM) or alcohol abuse. Hyperglycemia and ketoacidosis in diabetes can be fatal if not treated. The macroscopical, histological and toxicological findings in autopsy may be scarce or even absent. Determination of vitreous humor (VH) glucose and ketone bodies are very informative in these cases. As ketoacidosis can be present also after heavy alcohol use, the determination of glycemic status prior to death is essential in distinguishing between these two conditions. Glycated hemoglobin (HbA1c) provides information on the glycemic balance in previous weeks. In our studies, we have assessed the results, methods and interpretation provided by analysis of glucose, lactate, ketone bodies, HbA1c and C-reactive protein (CRP) in PM samples. Optimization has been performed in routine casework according to our findings providing more accurate information to the medico-legal pathologists in their CoD investigation work. In addition, our results have provided some insights into the pathology of severe diabetic emergencies as well as to ketoacidosis due to alcohol. According to our results, we recommend that in DM and alcohol abuse related deaths VH glucose, total ketone bodies or beta-hydroxy butyrate and blood HbA1c should always be analyzed. Lactate levels may provide additional information, when the results are interpreted considering the PM interval (PMI). These analyses are recommended also in cases where no suspicion of metabolic disturbances exists, but the findings in autopsy are scarce. The collaboration between the medico-legal pathologists and the laboratory is very important for the development and understanding of PM biochemistry and to include novel analyses to support the CoD investigation. The CoD determination is very important not only on the individual level, but also nationally, since Finnish Statistics collects the CoD data, which can be than further utilized in recommendations concerning health and primary prevention.
  • Koski, Antti (Helsingin yliopisto, 2010)
    The risk is obvious for soft tissue complications after operative treatment of the Achilles tendon, calcaneal bone or after ankle arthroplasty. Such complications after malleolar fractures are, however, seldom seen. The reason behind these complications is that the soft tissue in this region is tight and does not allow much tension to the wound area after surgery. Furthermore the area of operation may be damaged by swelling after the injury, or can be affected by peripheral vascular disease. While complications in this area are unavoidable, they can be diminished. This study attempts to highlight the possible predisposing factors leading to complications in these operations and on the other hand, to determine the solutions to solve soft tissue problems in this region. The study consists of five papers. The first article is a reprint on the soft tissue reconstruction of 25 patients after their complicated Achilles tendon surgeries were analysed. The second study reviews a series of 126 patients after having undergone an operative treatment of calcaneal bone fractures and analyses the complications and possible reasons behind them. The third part analyses a series of corrections of 35 soft tissue complications after calcaneal fracture operations. The fourth part reviews a series of 7 patients who had undergone complicated ankle arthroplasties. The last article presents a series of post operative lateral defects of the ankle treated with a less frequently used distally based peroneus brevis muscle flap and analyses the results. What can be conducted from these studies is that in general, the results after the correction of even severe soft tissue complications in the ankle region are good. For the small defects around the Achilles tendon, the local flaps are useful, but the larger defects are best treated with a free flap. We found that a long delay from trauma to surgery and a long operating time were predisposing factors that lead to soft tissue complications after operatively treated calcaneal bone fractures. The more severe the injury, the greater the risk for wound complication. Surprisingly, the long-term results after infected calcaneal osteosyntheses were acceptable and the calcaneal bone seems to tolerate chronic infections very well if the soft tissue is reconstructed successfully. Behind the complicated ankle arthroplasties, unexpectedly high number of cases experiencing arteriosclerosis of the lower extremity was found. These complications lead to ankle fusion but can be solved with a free flap if the vascularity is intact or can be reconstructed. For this reason a vascular examination of the lower extremity arteries of the patients going to ankle arthroplasty is strongly recommended. Moreover postoperative lateral malleolar wound infections which typically create lateral ankle defects can successfully be treated with a peroneus brevis muscle flap covered with a free skin graft.
  • Schramko, Alexey (Helsingin yliopisto, 2010)
    Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.
  • Mero-Matikainen, Niina (Helsingin yliopisto, 1999)
  • Melkas, Susanna (Helsingin yliopisto, 2011)
    The aim of the present study was to investigate the influence of different manifestations of cerebral SVD on poststroke survival and ischemic stroke recurrence in long-term follow-up. The core imaging features of small-vessel disease (SVD) are confluent and extensive white matter changes (WMC) and lacunar infarcts. These are associated with minor motor deficits but a major negative influence on cognition, mood, and functioning in daily life, resulting from small-vessel lesions in the fronto-subcortical brain network. These sub-studies were conducted as part of the Helsinki Stroke Aging Memory (SAM) study. The SAM cohort consisted of 486 consecutive patients aged 55 to 85 years who were admitted to Helsinki University Central Hospital with acute ischemic stroke. The study included comprehensive clinical, neuropsychological, psychiatric and radiological assessment three months poststroke. The patients were followed up up for 12 years using extensive national registers. The effect of different manifestations of cerebral SVD on poststroke survival and stroke recurrence was analyzed controlling for factors such as age, education, and cardiovascular risk factors. Poststroke dementia and cognitive impairment relate to poor long-term survival. In particular, deficits in executive functions as well as visuospatial and constructional abilities predict poor outcome. The predictive value of cognitive deficits is further underlined by the finding that depression-executive dysfunction syndrome (DES), but not depression in itself, is associated with poor poststroke survival. Delirium is not independently associated with increased risk for long-term poststroke mortality, although it is associated with poststroke dementia. Furthermore, acute index stroke attributable to SVD is associated with poorer long-term survival and a higher risk for cardiac death than other stroke subtypes. Severe WMC, a surrogate of SVD, is independently related to an increased risk of stroke recurrence at five years. In summary, cognitive poststroke outcomes reflecting changes in the executive network brain, and the presence of cerebral SVD are important determinants of poststroke mortality and ischemic stroke recurrence, regardless of whether SVD is the cause of the index stroke or a condition concurrent to some other etiology.
  • Cinar, Ayse Basak (2008)
    The present study aimed to investigate how non-biologic determinants of oral health (behavior, cognition, and affect, maternal and societal influences) are interrelated with each other and with oral health among preadolescents in two different oral health care and cultural settings, Turkey and Finland. In addition, the association of their general well-being with their oral health was assessed. The cross-sectional study of Turkish (n=611) and Finnish (n=223) school preadolescents in Istanbul and Helsinki, from the fourth, fifth, and sixth grades, aged 10 to 12, was based on self-administered and pre-tested health behavior questionnaires for them and their mothers as well as the youth’s oral health records. Both questionnaires assessed self-reported dental health and oral health behaviors along with cognitive-affective factors (self-efficacy and dental anxiety). In addition, health behavior questionnaires for preadolescents (PHBQ) included questions of self-esteem and self-reported gingival health, whereas those for mothers (MHBQ) surveyed societal factors, dietary habits and body-weight of preadolescents. PHBQ were completed in classes, whereas MHBQ were carried to and from home. Dental examinations in Turkey based on World Health Organisation (WHO) criteria (1997) were carried out in the classrooms 2 weeks after the questionnaire survey by two calibrated pediatric dentists. Finns´ oral health data came with permission from records at the Helsinki City Health Department. Among the Turks, response rate for PHBQ was 97% (n=591) and 87% for the MHBQ (n=533). The corresponding Finnish rates were 65% (n=223) and 53% (n=182). Participation in oral health examinations was 95% for the Turkish (n=584) and 65% for the Finnish (n=223). Clinically assessed dental status (DMFT) and self-reported oral health of Turkish preadolescents was significantly poorer than the Finns`. A similar association occurred for well-being measures (height and weight, self-esteem), but not for school performance. Turkish preadolescents were more dentally anxious and reported lower mean values of toothbrushing self-efficacy (TBSE) and dietary self-efficacy (DSE) than did Finns. The Turks less frequently reported recommended oral health behaviors (twice daily or more toothbrushing, sweet consumption on 2 days or less/week, decreased between-meal sweet consumption) than did the Finns. In both groups, those with high TBSE were more likely to practice the recommended toothbrushing. Similarly, all with high DSE were more likely to report recommended toothbrushing and sweet consumption. High levels of TBSE and DSE contributed to low dental anxiety in various patterns in both groups. Turkish mothers less frequently reported dental health as being above average and recommended oral health behaviors as well as regular dental visits (once within 12 months). Their mean values for dental anxiety were higher and self-efficacy on implementation of twice-daily toothbrushing were lower than for the Finnish mothers. All preadolescents were likely to imitate toothbrushing and sweet consumption behaviors of their mothers. In both groups, those who reported high TBSE were more likely to have mothers who practiced recommended toothbrushing. Among Finns, high maternal self-efficacy and low dental anxiety contributed positively to preadolescent’s recommended toothbrushing and high TBSE. Among the Turks, high maternal dental anxiety contributed to that of their children. Among Turks, the mothers of public school preadolescents reported a poorer societal profile and oral health behaviors than did mothers of private school preadolescents. Public school preadolescents were more likely to imitate non-recommended toothbrushing and sweet-consumption behaviors of their mothers, whereas their counterparts in private school followed a similar trend for recommended maternal toothbrushing behavior. Self-esteem and school performance were positively correlated with TBSE and DSE in both groups. Clustering between high self-esteem and low preadolescent- and maternal dental anxiety occurred in various patterns for Turks and Finns. Societal factors contributed to self-esteem among the Turks. Among all preadolescents, good school performance was a common predictor for recommended toothbrushing. Oral health and well-being of preadolescents were interrelated. In both groups, DMFT was negatively correlated with better school performance. Body height and the societal factors were the common explanatory variables accounting for DMFT s. TBSE and school performance contributed positively to self-reported dental health, in common, among all preadolescents. High self-esteem and less frequent maternal sweet consumption among Finns, decreased number of children in the family, and recommended preadolescent toothbrushing among Turks were the other contributors to self-reported good dental health. In the present study, non-biologic determinants of oral health were interrelated and related to well-being measures in various patterns, and these all contributed to the oral health of preadolescents. Based on these findings, a need exists for improvement in Turkish preadolescents’ and their mothers’ oral health behaviors, cognition, and affect. The paired associations separately studied in the literature; self-efficacy─behavior, child─mother health behavior, general well-being─oral health, self-esteem─school performance, were all found in a holistic theoretical framework, regardless of different cultural, socio-economic, and health-care systems in the two countries, Turkey and Finland. This may indicate that the respective associations are turning out to be part of the global health culture, and therefore a need exists for similar further research including the complex interaction pathways between these associations in countries with different developmental, cultural, and health-care characteristics. Clarifying these complex relations by psychosocial holistic approaches in different cultural settings and socio-economic contexts may provide a multidimensional understanding of preadolescents’ oral health behavior that will provide enhancement of their well-being and oral health.
  • 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.