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  • Louhivuori, Lauri (Helsingin yliopisto, 2015)
    Signaling pathways linked to changes in the intracellular cytosolic concentrations of free calcium are involved in a plethora of cellular activities ranging from cell division, differentiation and migration, integration of neural circuits, as well as programmed neuronal cell death. Channels that permit the entrance of calcium into neuronal cells have gathered considerable interest due to their potential of being significant therapeutic targets not least to mention a means by which to answer key neurophysiological questions. This thesis investigates two distinct calcium influx pathways: one mediated by the transient receptor potential channel family which can be either directly activated or indirectly via second messengers and the second pathway involving voltage gated calcium channels. Using a neuronal cell line model (human neuroblastoma IMR-32) as well as the neural progenitor stem cell neurosphere assay with molecular biology techniques, immunocytochemistry, calcium imaging, electrophysiology and time-lapsed imaging the thesis culminates to provide novel insights into the interplay between these channel proteins and the differentiation and migration of neuronal cells. Furthermore it provides new information on the molecular mechanisms involved in the interaction between developing neurons and radial glial cells, whereby the migrational behavior of neuronal cells is influenced by the calcium influx pathways mediated by glutamate receptors in radial glial cells.
  • Vastamäki, Heidi Anita (Helsingin yliopisto, 2015)
    ABSTRACT Vastamäki, Heidi Anita The long-term outcome of frozen shoulder Helsinki: University of Helsinki, 2015, 77 p. Publications of the ORTON Research Institute, A:39 The purpose of the current study was to assess and report the long-term outcome of frozen shoulder. The 234 patients with 257 frozen shoulders were clinically followed up for a mean 9.7 years (range, 2-30). The study includes five peer-reviewed articles. The specific aims of this project were to study: 1) the long-term outcome of the natural course of idiopathic frozen shoulder, 2) the very long-term outcome of manipulation under anesthesia (MUA), 3) the incidence and long-term outcome of postoperative frozen shoulder, 4) any influence of timing on the outcome of MUA, and 5) the long-term outcome of diabetic frozen shoulder. In general, patients with frozen shoulder recovered spontaneously over a mean duration of 15 months. After 9 year follow-up, 94% of shoulders showed a range of motion (ROM) similar to that of the contralateral, non-affected shoulder; 51% were totally pain-free, and 43% had pain ≤3/10 on the Visual Analogue Scale (VAS). In the long-term follow-up, diabetic patients shoulder ROM remained inferior to that of non-diabetic individuals. However, diabetic individuals frozen shoulders recovered to the patients own contralateral level. The very long-term outcome of manipulation under anesthesia was slightly inferior to the outcome of spontaneous recovery i.e. the natural course. After a mean 23 years follow-up of MUA, 47% of the shoulders had no pain at all. Even though ROM deteriorated between the last two follow-ups (7 vs. 23 years after MUA) the once-manipulated shoulder did reach the ROM level of the contralateral shoulder. Timing of MUA was statistically significantly associated with the outcome after manipulation of the idiopathic frozen shoulder. Optimal timing for MUA may be between 6 and 9 months from the beginning of symptoms. However, this finding may not be clinically significant. Concerning postoperative frozen shoulder after an open rotator cuff repair (RCR), the incidence was 20%. Compared to patients with no postoperative stiffness in their shoulders, the delay to postoperative healing was 3-6 months. The external rotation resolved first. One year after the surgery, the abduction and the flexion corresponded to that of the control patients shoulders. Patient age during RCR and the condition of the biceps tendon were related to the postoperative stiffness. In conclusion, the long-term outcome of frozen shoulder is good.
  • Reijula, Jere (Helsingin yliopisto, 2015)
    Exposure to tobacco smoke significantly increases the risk of several diseases including cancer, cardiovascular and pulmonary diseases. Prohibition of smoking in workplaces effectively protects workers against occupational exposure to secondhand smoke (SHS). However, Finnish restaurant employees have still been exposed to SHS at work until recent years. In 2000, a reform in tobacco legislation was launched in Finland according to which restaurants had to reserve non-smoking areas for their clients. Smoking restrictions proceeded gradually so that in 2007 a total ban on smoking was enacted in Finnish restaurants. In this study, nationwide survey data concerning occupational exposure to ETS in restaurants was used to assess the impact of tobacco legislation. Additionally, the risk of restaurant waiting personnel to develop cancer was evaluated in five Nordic countries. AIM OF THE STUDY: The overall purpose of the present study was to assess the impact of tobacco legislation on the occupational exposure to tobacco smoke in Finnish restaurants. The aim was to compare the effects of partial restrictions and a total prohibition of smoking in reducing the exposure to SHS among restaurant workers. Another objective of the study was to evaluate the risk of restaurant workers to develop cancer compared to that of the general population. MATERIAL AND METHODS: The present thesis collects the data concerning exposure to SHS in restaurant work using national questionnaire surveys conducted in 1999, 2001, 2003, 2007, 2009 and 2010 among Finnish restaurant workers (I, II and III). Each year the surveys were sent to an average of 3000 restaurant employees belonging to the Service Union United (PAM). Study I assessed the data collected with the first four questionnaires (1999-2007). In study II, the main focus was in the results of the questionnaires conducted before and after the launch of the smoke free tobacco legislation (i.e., 2007 and 2009). Study III included data from the questionnaires conducted in 2003, 2007, 2009 and 2010, respectively. Exposure to SHS in restaurant work was assessed also by measuring indoor nicotine concentrations in restaurants in three towns (Helsinki, Jyväskylä and Lappeenranta). The measurements were done in each year when the questionnaire surveys were carried out. Altogether 730 measurements were carried out between 2004 and 2010, approximately 60 measurements in each type of restaurant each year. The measurements were done with sampling devices that were placed for 4 hours in three different types of restaurants, i.e., dining restaurants, pubs and nightclubs, and bar desks. In order to assess the risk of cancer among restaurant workers, data were collected from the database of the Nordic Occupational Cancer (NOCCA) study. It consists of those 14.9 million persons aged 30-64 years who participated in any computerized census in the five Nordic countries, in 1990 or earlier. The longest follow up times were from 1961 to 2005. Among this study population, we focused on the group of waiters, comprising 16,134 males and 81,838 females. Altogether 3,100 cancer cases among male and 16,288 cancer cases among female waiters were found in study IV. Standardized incidence ratios (SIRs) for 35 common cancer sites were then calculated as ratios of the observed number and the expected number of cancer cases assuming that the cancer incidence among male and female waiters would be the same as found in the respective national populations. The numbers of excess cancer cases for each cancer site were calculated by subtracting the expected numbers of cancer cases from the observed ones. RESULTS: The prevalence of restaurant workers who were not exposed to SHS at work increased from 34% to 54% during 1999-2007. The prevalence of those who reported more than 4 hours of exposure to tobacco smoke during their work shift decreased from 46% to 24%. Between 2007 and 2009, the prevalence of restaurant workers who were not exposed to SHS at work increased from 54% to 82%. The highest increase was among workers in pubs and nightclubs (from 7% to 69%). The prevalence of restaurant workers who were exposed to SHS more than 4 hours a day at work decreased from 24% to 4%. Between 2007 and 2009, the prevalence of work-related respiratory symptoms decreased from 18% to 4% and that of eye symptoms from 23% to 6%. The median nicotine concentration in restaurants decreased from 11.7 μg/m³ to 0.1 μg/m³ between 2004 and 2010. The highest decrease in median nicotine concentration was found in pubs, where the median nicotine concentration decreased from 16.1 μg/m³ to 0.1 μg/m³. The reported exposure to SHS (at least 1 hour per work shift) decreased from 59% to 11% during 2004-2010. The cancer incidence among male and female waiters was higher than among the general population in the Nordic countries. During the study period (1961-2005), the overall risk of cancer among male waiters was 1.46 (95% confidence interval 1.41-1.51) and among female waiters 1.09 (1.07-1.11). The highest SIRs were found in cancer sites that are related to alcohol consumption. The highest numbers of excess cases among male waiters were in lung cancer (n=282) and cancer of the pharynx (n=92). Among female waiters the highest numbers of excess cancer cases were in lung cancer (n=718) and in cancer of the cervical uterus (n=314). CONCLUSION: The reform of Finnish tobacco legislation in 2000 that only partially prohibited smoking in restaurants until 2007 decreased occupational exposure to SHS but was not fully effective in protecting restaurant workers from exposure to SHS at work, whereas the total prohibition of smoking in 2007 significantly decreased restaurant workers exposure to SHS. The total ban on smoking in restaurants also decreased the prevalence of work-related respiratory and eye symptoms among restaurant workers, which most likely was associated with the decrease of exposure to SHS at work. In the follow-up, the positive effects of the strict tobacco legislation remained intact. The risk of cancer among male and female waiters was higher than among the general population in the five Nordic countries. This may be explained by high prevalence of smoking, heavy occupational exposure to tobacco smoke and high alcohol consumption among the subjects.
  • Soininen, Leena (Helsingin yliopisto, 2015)
    THE HEALTH OF THE FINNISH SAMI IN THE LIGHT OF MORTALITY AND CANCER PATTERN The Sami are regarded as indigenous people of Scandinavia and northwest Russia. Their traditional dwelling zone consists of the most northern parts of those countries. In addition to the Arctic environmental circumstances, some radioactive and chemical pollution has been found in the environment of the Sami. In this study, the mortality and cancer incidence of the Finnish Sami groups (North-, Inari- and Skolt Sami) are studied and also compared to the Sami in Sweden and Norway. The survival of the Finnish Sami cancer patients was compared to that of the Finnish general population. A person representing at least 75 per cent of any ethnic subgroup of Sami was classified as Sami. The follow-up has been from 1979 to 2010. The disease mortality among the Northern and Inari Sami was statistically significantly lower, and that of the Skolt Sami higher than that of the general population of Finland. Standardized mortality ratio (SMR) among Northern Sami was 0.88 (95% Confidence Interval (CI) 0.78-0.99), among the Inari Sami 0.85 (0.73-0.96) and among the Skolt Sami 1.20 (1.00-1.41). The mortality from accidents and suicides was significantly increased among Sami men, SMR 1.88 (1.36-2.52) and 1.78 (1.14-2.65) correspondingly. The cancer incidences of the North- and Inari Sami were low. For the North Sami, the standardized incidence rate (SIR) was 0.68 (95% Confidence Interval 0.55-0.82) and for the Inari Sami 0.57 (0.43-0.74). The SIR of Skolt Sami was 0.96 (0.71-1.27) because of the high SIR of stomach cancer, SIR 3.40 (1.47-6.69). The common cancers among the Finnish main population, prostate-, breast- and skin cancers are especially rare among the Finnish Sami. The incidence and the mortality of cancers among the Finnish Sami are rather similar to those of the Swedish and Norwegian Sami, with the exception of the Swedish Sami women, whose incidence was the same as that of the Swedish general population. The survival of the Finnish Sami cancer patients was the same as that of the corresponding cancer patients in the general population. There were no signs of radioactive or chemical pollution in the mortality or cancer incidence results. The living habits and environment of the Sami have changed, and hence also the mortality and cancer morbidity is nowadays more like that of the majority of Finnish and other western populations. They have gone through an epidemiological transition, different subgroups in different times. The traditional Sami living has been a good example of a healthy way of living, except for the risk-taking of Sami men. When looking at the low figures of some cancers, the genetic features of the Sami as a cause for it cannot be excluded.
  • Sahlstedt, Leila (Helsingin yliopisto, 2015)
    Hematopoietic stem cell transplantation (HSCT) is an intensive treatment often complicated by organ injuries. Non-transferrin-bound iron (NTBI), as an inducer of free oxygen radicals, is a potential factor in the pathogenesis of these complications. We studied the appearance and timing of NTBI in transplant patients and the possibility to prevent the occurrence of NTBI by binding it with apotransferrin administration. We showed that NTBI appears regularly during the peritransplantation period in HSCT, both in allogeneic and autologous transplantation. We could demonstrate, for the first time, the exact timing and duration of the changes in transferrin saturation and the appearance and the length of the presence of NTBI. We could also show and confirm the 80% saturation of transferrin to be a reliable threshold for NTBI. In allogeneic HSCT fully saturated transferrin and the appearance of NTBI was observed by day -4 before HSCT (day 0). NTBI was detectable on average for 14 days. In autologous HSCT a similar steep rise was found in the transferrin saturation. The mean time for the first to the last NTBI-positive samples was 6.1 days, the intensity of the conditioning seemed to have an effect on the appearance of NTBI. The disappearance or marked reduction of the NTBI positive samples coincided with the recovery of the bone marrow function. Our studies indicate that the presence of NTBI is largely due to reduced utilization of iron by erythropoiesis and the reduction of serum transferrin levels caused by the transplantation process. As NTBI might contribute to the complications of HSCT, we assessed the possibility to bind NTBI during the peritransplant period with apotransferrin infusions. With a single apotransferrin dose given on day +3 NTBI disappeared from the sera of all the six patients, but reappeared 12-24 hours later. Twenty patients were given repeated doses of apotransferrin at three dose levels. The daily loading doses were given at the start of conditioning, followed by maintenance doses every other day given until day +7 to day +13. Five of the eight patients given the highest dose were NTBI negative through the study period. With lower doses there was a nonsignificant trend towards fewer days with demonstrable NTBI. Our in vitro study demonstrating the toxic effect of NTBI on hematopoietic progenitors and the beneficial effect of binding NTBI with apotransferrin on colony growth supports the possibility that binding of NTBI with exogenous apotransferrin may turn out to be clinically useful. Our studies showed that the appearance of NTBI could be prevented or reduced by apotransferrin. However, the clinical utility of apotransferrin administration and the effects on transplantation outcomes remain to be investigated in further studies.
  • Pierides, Georgios (Helsingin yliopisto, 2015)
    Repair of Inguinal hernia ranks among the most common surgical procedures worldwide. Large patient numbers necessitate efficacy and sophistication in the procedure. A novel self-attaching composite mesh (Parietene ProGrip , Covidien, Dublin, Ireland) and a sutured light-weight mesh (Parietene Light , Covidien) were compared double-blinded in 394 randomized patients. Outcomes were collected with a symptom diary and telephone contact during immediate convalescence and by clinical assessment one year after the operation. Outcomes up to 5 years after application of either a sutureless bilayer mesh (Prolene® Hernia System, Ethicon Endo-Surgery, Somerville, MA, USA) or standard tension-free repair (Surgipro , AutoSuture, Norwalk, CT, USA) were collected with a postal questionnaire, telephone contact, and clinical assessment in 300 patients. Health-related quality of life before and after open inguinal hernia repair was measured by RAND 36-Item Health Survey 1.0 (RAND Corporation, Santa Monica, CA, USA) in altogether 159 patients aged at least 65 years and 373 patients aged under 65 years. The results were compared within and between age groups as well as with the values from the general population. A database of 932 open mesh-based hernia repairs was subjected to regression analyses for factors predicting the presence of chronic posthernioplasty pain or more intensive postoperative inguinal pain. Outcomes between the self-attaching mesh and sutured light-weight mesh were equivalent. Applying the self-fixating mesh was faster (34 min vs. 42 min, p less than 0.001). Median sick leave was 2 weeks. At one year, 4.7% of patients perceived pain while resting, 2.0% had pain interfering with every-day life, 25.4% experienced discomfort, and 9.5% had losses in sensation in the operated groin. One recurrence (0.3%) was encountered. Sensory dysfunction of groin skin was rarer 5 years after the operation with the bilayer device than after tension-free repair (5.0% vs. 13.9%, p = 0.022). Other long-term outcomes did not differ. Occurrence of chronic pain diminished from 6.8% at 2 years to 1.3% at 5 years. Cumulative recurrence rate was 1.3%. Discomfort was present in 25.2% of patients, but 92.7% of patients were satisfied with the operation. RAND-36 showed similar improvement in both the elderly and younger patients after open inguinal hernia repair. Complication rates between the age groups did not differ. Higher preoperative VAS score (p less than 0.006), mid-weight mesh (p = 0.012), complications (p = 0.002), recurrence (p = 0.005), and younger age (p = 0.027) predicted chronic pain after open inguinal hernia repair. Higher VAS scores for inguinal pain were predicted by higher preoperative VAS scores (p less than 0.001), heavyweight meshes (p = 0.046), complications (p = 0.016) and recurrence (p = 0.001).
  • Moustgaard, Heta (Helsingin yliopisto, 2015)
    Depression is a leading cause of disability worldwide. At worst, it may lead to frequent hospitalisation and even premature death. The risk of suicide is particularly high among the depressed. This study assessed whether social and economic resources protect depressed patients from psychiatric hospital admission and premature mortality. The study also aimed to establish the role of alcohol and the rapidly increased antidepressant treatment of depression in these outcomes. The study used large, longitudinal register samples of the Finnish adult population, combining information from various administrative registers. Depression was assessed from psychiatric hospital care and antidepressant purchases. Treatment and depression outcomes were assessed in 1-10-year follow-ups. The results indicate that at least in a population already in contact with the healthcare system, antidepressant treatment and depression outcomes vary only modestly according to social factors. However, material aspects of socioeconomic position such as a low income, not owning a home and being unemployed increased the risk of hospital admission for depression by 20-40 per cent among those with previous depression treatment, even after controlling for baseline depression severity and psychiatric comorbidity, whereas education and occupational social class were unrelated to admission risk. Having no partner and living without co-resident children also increased the admission risk. None of the social factors studied buffered against excess mortality among the depressed. Educational differences in the prevalence of antidepressant use before and after hospital care for depression were small and mostly limited to the period after discharge. Antidepressant use immediately after discharge was slightly less common among those with a low level of education, but educational differences increased thereafter as antidepressant use decreased more rapidly among this group. Differences in daily antidepressant use that met treatment guidelines were more pronounced than those for any antidepressant use, suggesting a need for improving treatment adequacy and adherence particularly among patients with a low level of education. The study established the central role of excessive alcohol consumption as a pathway to depression mortality. Alcohol-related causes accounted for about half of the excess mortality of depressed men and around a third of depressed women. Improving the detection and management of substance use problems would thus be critical for reducing depression mortality. Increased antidepressant sales do not seem to have prevented female suicides. However, among men an increase in the proportion of antidepressant users receiving minimally adequate treatment reduced non-alcohol-related suicides. The results suggest that increased adequacy of antidepressant treatment has been more central in reducing suicide rates than the mere increase in per-capita antidepressant sales or prevalence of antidepressant use.
  • Ahlqvist, Kati (Helsingin yliopisto, 2015)
    Somatic stem cell (SSC) dysfunction is a common feature of mouse models of premature ageing, most of which are created by disturbing nuclear DNA repair, damage recognition or ROS defence. The SSC dysfunction leads to decline in SSCs ability to maintain tissue homeostasis resulting in degeneration and ageing. The role of mitochondria or mitochondrial DNA (mtDNA) integrity in SSC homeostasis is unknown. Mutator mice, which harbour proof-reading deficient mitochondrial DNA polymerase gamma, accumulate mtDNA point mutations and develop a premature ageing phenotype, whereas Deletor mice, a model for adult-onset mitochondrial myopathy, accumulate mtDNA deletions and have a normal lifespan. Accumulation of mtDNA mutations and respiratory chain (RC) defect are thought to contribute to ageing process, and the Mutator mouse was the first experimental evidence supporting this theory. The aim of this thesis work was to elucidate somatic stem cell function in both Mutator and Deletor models, to investigate whether SSC dysfunction might explain the premature ageing phenotype. Our results show that the Mutator mouse accumulates mtDNA point mutations in SSC compartments, leading to changes in SSC function already during embryonal development. Deletors do not accumulate mtDNA deletions in SSCs and have normal SSC function. This suggests that premature ageing of Mutators is due to disrupted SSC homeostasis. Hematopoietic progenitors are especially sensitive to mtDNA mutagenesis, which may partly explain the high prevalence of anemia without iron deficiency seen in elderly humans. In this thesis, a novel mechanism for mitochondrial anemias is presented. MtDNA mutagenesis in hematopoietic precursors modifies signaling which causes aberrant iron loading and delayed mitochondrial clearance from maturing erythrocytes. In consequence, Mutator mice have abnormal circulating erythrocytes carrying mitochondria, which are prematurely captured and destructed by splenic macrophages, leading to iron accumulation in spleen. Enhanced destruction of newly-born erythrocytes and concurrently depleted iron stores in the bone marrow make compensatory reticulocytosis inefficient. Delayed mitochondrial clearance was also detected in a human patient with Pearson s syndrome, a rare disorder caused by a sporadic single large mtDNA deletion and causing life-threatening anemia. Treatment with N-acetyl-L-cysteine (NAC), a glutathione precursor and a ROS scavenger, was able to rescue the SSC phenotype during embryogenesis and to normalize iron loading in vitro, suggesting that mtDNA mutagenesis affects ROS signaling. However, NAC could not prevent anemia in vivo, nor rescue delayed mitochondrial clearance in vitro. This indicates that signaling in the SSC compartment is different during embryogenesis than in adulthood. This thesis shows that mtDNA integrity is essential for SSC function. Further, a new and essential role is proposed for mitochondria in regulating their own removal from maturing reticulocytes.
  • Lehtinen, Miia (Helsingin yliopisto, 2015)
    Background: Worldwide, the leading cause of morbidity and mortality is heart failure. It is most often caused by coronary artery disease (CAD) and myocardial infarction (MI), which causes death of myocardial tissue. Although coronary interventions such as coronary bypass graft surgery (CABG) can restore blood flow to ischemic areas, and established pharmacotherapy for heart failure exists, no treatment available in the clinics can regenerate the dead cardiomyocytes. For surgical treatment, patients with heart failure represent a challenge, as they are prone to surgical complications, and suitable preoperative imaging modalities to assess possible benefit from surgery are few. Aims: Cell therapies have recently emerged as a possible alternative for treating heart failure. We wanted to explore the capacity of autologous bone marrow mononuclear cells to regenerate myocardial tissue as an adjunct to CABG. The aim was to assess the therapy s safety and detect the cells possible effects on cardiac function and viability. In addition, we investigated whether it would be possible to predict benefit from CABG in these heart-failure patients with 3-vessel CAD with the aid of combined nuclear imaging data. For this, we used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to measure cardiac viability, and 99m-technetium-tetrofosmin single-photon emission computed tomography (99mTc-SPECT) to measure cardiac perfusion. Methods: Between 2006 and 2010, we enrolled 104 patients scheduled for CABG who suffered from CAD and ischemic heart failure. Preoperatively, pharmacotherapy was optimized, after which 39 patients still had left ventricular ejection fraction (LVEF) ≤45%. These patients received injections of bone marrow mononuclear cells (BMMCs) (N=20) or vehicle (N=19) intraoperatively into the myocardial infarction border area in a randomized and double-blind manner. During surgery and at the intensive care unit (ICU), the patients hemodynamics, arterial blood gases, systemic venous oxygen level, blood glucose, acid-base balance, lactate, hemoglobin, body temperature, and diuresis as well as medications needed were monitored and recorded every four hours throughout the first postoperative 24 hours. BMMC effects on the heart were evaluated by use of pre- and 1-year postoperative cardiac magnetic resonance imaging (MRI), FDG-PET, and 99mTc-SPECT and by measuring pro-B-type amino-terminal natriuretic peptide (proBNP) levels. As we later decided to extend the follow-up, these same variables, except for nuclear imaging data, as well as current quality of life were measured at a late follow-up visit in 2013. For this, we could contact 36 of the 39 patients recruited for the original study, of which 30 participated in the extended follow-up. Preoperatively, we also analyzed FDG-PET and 99mTc-SPECT data by using three quantitative techniques with a software tool to measure defects with hypoperfused but viable and non-viable myocardium in 15 control patients. One method used solely PET, two others combined PET and SPECT at different thresholds. As a reference, we used change in LV function and volume by MRI. Results: During the first-year follow-up, improvement was similar in both groups in LVEF, the predefined primary end-point measure (P=0.59), and similar improvement also occurred in local wall thickening (WT) (P=0.68) in the injected segments. Neither changes in viability by PET and SPECT and levels of proBNP differed between these groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% in the control group (interquartile range, IQR -3.3 to 10.8) but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (P=0.0002). During surgery and ICU stay, hemodynamics, arterial blood gases, systemic venous oxygen level, blood glucose, acid-base balance, lactate, hemoglobin, body temperature, and diuresis and levels of medications administered were similar between the study groups. For the extended follow-up, the median period was 60.7 months (IQR 45.1 to 72.6). No statistically significant difference was observable in change in proBNP values or in quality of life between groups. LVEF in both groups remained similarly improved (P=0.647), as also did WT (P=0.434). For controls, scar size in injected segments increased with a median of 2% (IQR -7 to 19); for BMMC patients it remained reduced with a median change of -17% (IQR -30 to -6) (P=0.011). When assessing the benefit-predictive capacity of the two techniques combining FDG-PET and 99mTc-SPECT with different thresholds and one technique using FDG-PET data only, no correlation appeared with preoperative PET- or PET-SPECT-derived viable or non-viable tissue, when compared with global functional outcome (change in LVEF) or local change in WT. Conclusions: In patients with 3-vessel disease and heart failure, the three techniques using SPECT perfusion and PET viability imaging data failed to predict the functional benefit received from CABG. Thus, these imaging modalities may provide no additional advantage to preoperative patient selection, which should be considered when planning treatment for this patient group in the clinics. In the treatment of chronic ischemic heart failure, during surgery and perioperatively in the ICU, both intramyocardial BMMC and placebo injections appear safe. Although failing to affect cardiac function, combining intramyocardial BMMC therapy with CABG can sustainably reduce scar size.
  • Luostarinen, Tapio (Helsingin yliopisto, 2015)
    Cervical cancer is the 4th most common cancer in women. In its carcinogenesis human papillomavirus (HPV) 16/18 are most important. HPV6/11 cause benign lesions. A small proportion of HPV infection(s) develop into cancer. Therefore, joint effects between HPVs and putative co-factors, Chlamydia trachomatis and smoking, are of interest but largely open. The aims of this work were to understand joint effects of infections with 1) HPV types, 2) HPVs and C. trachomatis, and 3) order of these infections in the carcinogenesis. For the 1st two aims, two case-control studies were nested within cohorts of Nordic biobanks. 1st linkage to cancer registers identified 182 cases of invasive cervical cancer (ICC, 148 squamous cell carcinomas, SCC) with prediagnostic sera until 1994. 2nd linkage with a longer follow-up until 2002 comprised 604 new ICC cases. Incidence density sampled controls were individually matched for age at serum sampling, sample storage time and region. For the 3rd aim, a case-control study in a serial setting was nested within a cohort of Swedish women participating in a cervical cancer screening programme in 1969-1995, and 118 ICCs with age and sampling-time-matched controls were identified. Finally, a case-cohort study in the Finnish Maternity Cohort was based on women with two pregnancies within 5 years. The women were followed on average for 4.8 years, from the 2nd pregnancy sample until the end of 2004. During follow-up, 490 women were diagnosed with cervical high-grade precancer. A comparison subcohort of 2796 women was randomly sampled from age and calendar time strata. IgG antibodies to HPV 6/11/16/18/31/33/45 capsids, and C. trachomatis were determined by ELISA. Serum cotinine, a marker for recent smoking, was measured by immunoassays. HPV and C. trachomatis DNA in smears and biopsy specimen were examined by PCR. HPV DNA-positive specimens were typed. Rate ratios were estimated by conditional logistic or proportional hazards regression. Misclassification of HPV serology was corrected for. In the 1st study, we found no excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11. In the 2nd study, there was excess risk, but the joint effect was again significantly smaller than the expected joint effects. Finally, if infection with HPV6 preceded infection with high-risk HPV31, there was no material excess risk of in situ cervical carcinoma. The smaller than expected joint effect between HPV types was probably due to a cell-mediated immune response to past, natural HPV6/11 infection, of which the serum antibodies were a surrogate. The risk of ICC was highly increased not only among women whose 1st smear was HPV DNA-positive but also among C. trachomatis DNA-positive women. The risk was even higher among HPV or C. trachomatis DNA positives both at the start and end of follow-up. The risk of in situ cervical carcinoma was highly increased among women whose HPV18/45 and C. trachomatis infections were virtually concomitant. The risk of SCC was increased related to C. trachomatis, after adjusting/stratifying for HPV. These results support early HPV vaccination in cervical cancer prevention. C. trachomatis should not be ignored in the preventive efforts against cervical cancer.
  • Helmiö, Päivi (Helsingin yliopisto, 2015)
    TOWARDS BETTER PATIENT SAFETY: The WHO Surgical Checklist in Otorhinolaryngology More than one-half of adverse events in health care are related to surgery. Surgical patient injuries account for about 80% of patient injuries in otorhinolaryngology (ORL). The World Health Organisation (WHO) has developed a Surgical Safety Checklist to prevent errors in the operating theatre. Its use has been shown to reduce complications and mortality. The aims of the present study were to identify errors that may underlie those patient injuries that occur in operative ORL, to assess the effects of the WHO checklist on working processes in the operating theatre, including compliance, and to evaluate how it would fit into the specialty. Data of the patient injuries that were sustained during treatment by the ORL specialty between the years 2001 and 2011 were obtained from a search of the Finnish Patient Insurance Centre registry. The causes of the injuries were analysed, and whether the WHO checklist could have prevented the error was evaluated. The checklist was implemented in four Finnish hospitals as a pilot in 2009. A prospective before-versus-after-intervention study was conducted with a questionnaire for OT personnel in these four hospitals to evaluate the checklist. The checklist was subsequently implemented for regular use in the operative unit of the Department of Otorhinolaryngology of Helsinki University Central Hospital. After one-year of use, compliance and user attitudes were analysed by using data obtained from the operations database and a survey of operative ORL personnel. In the 10-year study period, 188 patient injuries were associated with operative ORL. A total of 142 (75.5%) of these injuries occurred due to errors that were made in the operating theatre, and in 125 cases (66.5%) a manual error in performing the surgery was the primary cause of the injury. Six injuries (3.2%) were caused by wrong site surgery. An error had some degree correspondence with a WHO checklist item for 18 injuries (9.6%) and it was determined that 9 of these injuries (4.8%) could have been prevented had the checklist been correctly used. The implementation of the checklist enhanced the communication between the surgical team members, improved verification of the patient s identity and of the correct operation site. Checklist compliance was 62.3% during first year of use. It was considered easy to use and the Safety Attitude Scores of the personnel were found to be on a high level. All check items on the list were considered important for ORL. However, a more compact checklist for outpatient surgery was requested. Patient injuries in ORL were strongly related to surgery. The WHO Surgical Safety Checklist seems to be a beneficial tool for preventing errors ORL and is highly relevant for the specialty.
  • Kerola, Anne (Helsingin yliopisto, 2015)
    Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. The aim of this work was to evaluate the prevalence of CV comorbidities and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA. Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. The same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we retrieved data on permanent or temporary disability pensions. Causes of death were obtainable until the end of 2008. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity-related disability pensions, and CV mortality rates to those of the age- and sex-specific Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs). In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR (95% CI) being 1.10 (1.01 1.20). The SRR for levothyroxine-treated hypothyroidism at RA diagnosis was 1.51 (1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 were granted a disability pension. The 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. The SMR in the entire RA cohort was 0.57 (0.52 0.62). To conclude, the risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis, highlighting the importance of CV risk detection and management and of vigilance for hypothyroidism. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. All these findings together stress the importance of recognizing, preventing, and targeting comorbidities in RA, already in the early years of the disease.
  • Kaislasuo, Janina (Helsingin yliopisto, 2015)
    The proportion of nulligravid and nulliparous women is increasing as women delay childbirth in developed countries. Simultaneously, contraceptive failure, unintended pregnancies and abortions, especially in women below the common childbearing age, are a global problem. By promoting intrauterine devices (IUDs) and subdermal implants, referred to as long-acting reversible contraceptives (LARCs), among these women, contraceptive failure caused by non-compliance of the user can be minimized, in addition to providing easy and efficient long-term contraception. However, the risk of difficulties at IUD insertion in nulligravid/nulliparous women, as well as small uterine size, have both been considered as barriers limiting the use of intrauterine contraception (IUC) in these women. The present studies were designed to study the barriers to IUC in nulligravid and nulliparous women. To compare both types of IUC available, we used the levonorgestrel-releasing intrauterine system (LNG-IUS) and the copper-releasing NovaT (TCu380Ag), with identical frames measuring 32 x 32 mm. To exclude any effect of prior pregnancy on the uterine cavity or the cervix, only nulligravid women were included. Difficulties at insertion, menstrual diaries kept after insertion (months 1 3) and at the end of the study (months 10 12) as well as adverse events were compared against uterine cavity measurements and pre-insertion menstrual characteristics reported by the women. In addition, as uterine perforation is mainly seen as a complication related to insertion, we retrospectively analysed women treated for this rare complication between 1996 and 2009 in our hospital district area. We gave 165 nulligravid women requesting their first IUD a free choice between the two IUDs after contraceptive counselling. The majority, 113 women (68.5%), chose the LNG-IUS and 52 women (31.5%) chose the copper IUD. Insertion was easy in 89% of the women. The women were satisfied, with only 17/135 women (12.6%) available for follow-up discontinuing because of adverse events. The reported numbers of days of bleeding and pain were similar to that in earlier reports on parous women. Severe pain at insertion was reported by 56.5% of the women and severe dysmenorrhoea the only factor predicting severe pain (OR 7.9, 95% CI 2.5 24.9, p less than 0.001). Dysmenorrhoea was also related to more pain during the first months with both devices. Baseline spontaneous bleeding predicted bleeding with the LNG-IUS, but not with the copper IUD. Among women using the LNG-IUS, scanty menstrual bleeding (OR 8.2, 95% CI 1.4 48.2, p=0.02) and smoking (OR 8.2, 95% CI 1.8 38.6, p=0.007) predicted amenorrhoea at one year. Uterine measurements, particularly fundal cavity width, were small in comparison to the devices in a majority of the women. The odds of a difficult or failed insertion increased with shorter uterine length and a steeper flexion angle, but the great majority of insertions, even in small and more flexed uteri, were uneventful. Cervical tightness was the main reason for problems in cases of difficult insertion. No uterine threshold measurements predicting difficulties were found. Small uterine measurements were associated with both less bleeding and less pain among LNG-IUS users. Women with the widest fundal widths reported significantly more pain at the end of the one-year follow-up period compared with those with smaller widths. Uterine size did not affect bleeding in connection with the copper IUD, but there was a slight tendency towards more pain during long-term use among women with smaller uterine cavity measurements, although size groups were small with this device. Uterine size did not predict adverse events. We found 75 cases of surgically treated uterine perforation during the 15 year long study period. The incidence of perforation was low, 0.4/1000 insertions, and similar with both types of IUC. Postpartum insertion, earlier presented as the main risk factor of uterine perforation, was also common in this population (64%). The majority of cases, 71%, presented with complaints of abnormal bleeding or pain, but 29% were asymptomatic and diagnosed in connection with missing threads or pregnancy. Pregnancy was more common with a misplaced copper IUD, 33% vs. 7% with a misplaced LNG-IUS (p=0.009). We found no severe complications or intra-abdominal adhesions caused by the misplaced devices. Adhesions were local and more common in copper IUD users (58% vs. 20%, p=0.002). In conclusion, nulligravid women are satisfied users of modern IUC, with continuation rates and bleeding and pain profiles similar to those in parous women. Small uterine cavity measurements are not a barrier to IUC and pre-insertion ultrasonographic evaluation of uterine cavity size is unnecessary. As dysmenorrhoea predicts both severe insertion pain and pain during the first months of IUD use, analgesia and counselling for these women should be highlighted. Although rare, the risk of uterine perforation is increased during the postpartum period, probably reflecting uterine involution as the main reason for this complication. Neither symptoms nor surgical findings are severe in connection with current devices.
  • Rantanen, Ville (Helsingin yliopisto, 2015)
    Images provide invaluable information to Biomedicine. Especially, microscopy as an information source has been providing knowledge for research and clinical diagnostics. We have moved away from simply looking at the images to quantifiable computerized image analysis. Over the last decades, image analysis developers have prepared algorithms and software to address various scientific enquiries using images. These software are often created for a single purpose. Naturally, not even the most generic software can include all the algorithms ever created. From an image analysis developer point of view, the choice of software creates limitations. It limits the developer to the algorithms included and to the language it was developed in. Even if the software is modular and extendable, a specific language is required and the earlier algorithm implementations would have to be ported. This thesis presents an integration platform for image analysis: Anima. It is capable of using existing software and including them in analysis workflows. Since image analysis is very case specific, custom processing commands are frequently needed. Anima comes with a large number of data and image analysis components developed directly for the platform, as well as components that send custom commands to the integrated software. All of the components can be executed in a single analysis pipeline. Anima itself is built on top of Anduril, another software, inheriting its software architecture. Anduril gives Anima the power of parallel processing and rerun prevention mechanism, speeding up the development cycle of new algorithms. The usability of Anima for method development is shown by implementing new segmentation algorithms and visualization tools. The tools and methods are all suited to large data sets. To display the modularity, the tools are published as separate programs that are then integrated in Anima. The usefulness of the platform is shown by applying it in different biomedical research settings. The settings include different organisms: human, rat and nematode; different sample material: brain tissue, lymphatic nodes and serum; and different medical interests: cerebral ischemia, cancer and allergy. Anima is a versatile open-source image analysis platform, that encourages the use of best practices of programming habits. It makes the development of analysis workflows and individual algorithms more efficient.
  • Virtanen, Anni (Helsingin yliopisto, 2015)
    High coverage amongst those at risk and a high attendance rate are essential in achieving a good impact in a cervical cancer screening programme. In Finland, attendance in the programme is approximately 70% with a slight decreasing trend. There is wide variation in the current invitation practice between municipalities. The introduction of human papillomavirus (HPV) testing in cervical cancer screening has brought about a new possible means of improving attendance rates, as HPV-testing can be performed on self-collected samples. This offers the opportunity to supply sampling devices directly to the homes of the women (self-sampling). The aim of this study was to investigate the effects and feasibility of using self-taken samples for HPV-testing to conduct cervical cancer screening of non-attendees to the Finnish cervical screening programme. The effect on attendance to the screening programme, on overall screening test coverage (including also testing outside the screening programme), on the yield of precancerous lesions detected by screening and on the costs of a screening programme were assessed, as were women s views on this new screening modality. The effects of self-sampling were first studied as a first reminder (i.e. among non-attendees after the primary invitation) in a randomized setting in comparison to a reminder letter, and then in a non-randomized setting as a second reminder after two invitation letters. As a first reminder to non-attendees after the primary invitation, a self-sampling test resulted in somewhat higher attendance than a reminder letter. The difference was small, and in terms of resulting costs (price per extra screened woman and price per detected CIN2+ lesion), a reminder letter with a pre-assigned appointment time is a more feasible choice than a self-sampling test. However, self-sampling can be used to increase screening attendance as a second reminder after two invitation letters. Overall attendance rates increased by 4-8%, and the combined effect of reminder letters and self-sampling showed a 12-23% increase. The yield of detected CIN2+ lesions increased by 25-33% with two reminders. As opportunistic screening is very common in Finland, the increase in overall test coverage remained smaller than the increase in the uptake to the programme. Based on a questionnaire study conducted alongside self-sampling, self-sampling at home helps to overcome both practical and emotional barriers to traditional screening. Women who took part in screening by self-sampling reported mainly positive experiences, but negative experiences were more common among women with a mother tongue other than Finnish or Swedish. The invitation protocol preceding the self-sampling option must be carefully arranged to achieve optimal attendance. A total attendance of well over 80% is achievable in the national programme if personal invitations and reminder letters to non-attendees are sent, scheduled appointments are used in both letters and self-sampling tests are sent to those women who still do not attend.
  • Tohmola, Niina (Helsingin yliopisto, 2015)
    Metabolites are low molecular weight compounds participating in different functions of cellular systems. Metabolites can be used as diagnostic biomarkers for numerous diseases. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a powerful tool in quantification of metabolites from various sample matrices. Good sensitivity and specificity are the main benefits of the technique. Mass spectrometry is commonly used in industry, drug research and clinical diagnostics. Extensive validation of newly developed analytical methods will construct the basis to a reliable assay, and it is significant especially when analysing e.g. patient samples. The aim of this study was to develop quantitative assays for metabolites from biological samples for biomedical research and clinical diagnostics. We designed and constructed an on-line high performance liquid chromatography (HPLC) equipment and validated an assay for direct quantification of extracellular metabolites from cell cultivation. Automated sampling for LC-MS/MS analysis of intracellular metabolites was connected to the on-line system. The on-line analysis improves the methodology and shortens the time of analysis. Furthermore, a frequent sampling data can provide valuable information about physiological indications in various cell cultivations. On-line HPLC is suitable for various biotechnological applications because of its ability to monitor and collect data during cell cultivation. We developed and validated LC-MS/MS assays for neuroendocrine tumor (NET) biomarkers 5-hydroxyindole acetic acid (5-HIAA) and vanillylmandelic acid (VMA) from human serum. Generally, urinary HPLC assays are used for the determination of NET markers. HPLC assays have certain limitations and 24-h urine collection is laborious. Our LC-MS/MS assays are specific, fast and well suited for diagnostics of NETs. Furthermore, guidelines for urine collection advise to refrain from serotonin-containing foods for three days before sample collection. We showed that such a diet restriction before serum 5-HIAA assay is not necessary. Instead, one day serotonin-free diet before sampling is sufficient because the half-life of 5-HIAA in circulation was found to be 1.3 hours. All assays developed during this study were sensitive and had a wide linear range. Our serum 5-HIAA LC-MS/MS assay is routinely used for the analysis of NET patient samples at the Helsinki University Central Hospital Laboratory, HUSLAB. Serum VMA LC-MS/MS assay will be in routine use in the HUSLAB in near future. Furthermore, On-line HPLC Ltd, (Helsinki, Finland) has commercialized the on-line HPLC equipment developed in this study.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Parviainen, Suvi (Helsingin yliopisto, 2015)
    It has been estimated that up to half of people living in industrial societies will get cancer. Almost all cancer deaths are caused by metastatic disease and only few metastatic solid tumors can be cured with available therapies. Therefore, novel therapeutic modalities are needed. Genetically engineered oncolytic viruses such as adenoviruses and vaccinia viruses are a promising therapeutic approach given their capacity to specifically replicate in and kill tumor cells as well as to reach distant metastasis. Oncolytic viruses have demonstrated good safety, tolerability and promising signs of anti-tumor efficacy in several clinical trials, but the efficacy of the therapy needs improvement to reach its full clinical potential. Adenoviruses are one of the most studied vectors in oncolytic virotherapy. Two major obstacles limiting the efficacy have been insufficient transduction of the tumor cells and the recognition of the virus by the immune system, which rapidly clears the virus from systemic circulation, hampering the overall efficacy. This study shows that novel capsid modifications can increase the transduction efficacy and oncolytic potency of the virus, and that embedding oncolytic virus in a silica implant might help to circumvent the problem of clearance by prompting only modest immune responses against the virus. Recently, arming oncolytic viruses with immunomodulatory molecules has been a major focus in virotherapy. Immunotherapy means inducing the patient´s immune system to recognize and attack the tumor and has been recently linked with oncolytic virotherapy, as the replication of the virus in the tumor can be immunogenic per se and also release cancer epitopes available for antigen-presenting cells. Host immune responses have been shown to be a key player in oncolytic virotherapy as the balance between anti-viral and anti-tumoral immunity determines the efficacy of the therapy. Oncolytic vaccinia virus possesses unique immunogenicity and mechanisms of action that are distinct from other treatment modalities, and its self-perpetuating nature provides an ideal platform for therapeutic transgenic insertion. Therefore we engineered novel oncolytic vaccinia viruses with granulocyte-macrophage colony-stimulating factor (GMCSF) or CD40-ligand and studied their ability to increase the therapeutical outcome and anti-tumor immune responses in preclinical animal models. In the final part of the thesis the life cycle of oncolytic vaccinia virus was studied in more detail as we were able to show that the life cycle was compromised in a feline squamous cell carcinoma cell line. This finding might be important for a deeper understanding of the vaccinia virus-host cell interactions.
  • Nieminen, Tarja (Helsingin yliopisto, 2015)
    Social capital has been widely discussed in research. An increasing amount of literature has linked social capital to various health outcomes and well-being. However, both health and social capital are complex phenomena, and there is still inconsistency in the research findings. The general aim of this study was to examine the associations between social capital, health behaviour and health among adult Finnish population. The conceptualization and operationalization of social capital varies according to discipline and level. In this study, social capital is measured at the individual level assuming that an individual s investment in group activity reflects social capital seen as a resource related to social networks and group membership. Individual benefits are accessed through social connections in varied groups and society. Thus the resources do not reside within the individual but rather in the structure of person s social networks. Social capital was measured on three dimensions in this study: 1) social support, 2) social networks and participation and 3) trust and reciprocity. The association between these dimensions and health were examined. Health was investigated as self-rated health, psychological well-being and mortality. This study utilised the data of the Health 2000 Survey conducted in 2000−2001. Of people aged 30 and over, 89% participated in the home interview and 80% in the general health examination. The study material presents the whole population unusually well. The National Institute for Health and Welfare (THL; formerly the National Public Health Institute, KTL) had the overall responsibility for the project. In addition, the project organization involved a wide range of research and funding agencies. This survey contains a rich armoury of questions about health and illnesses, health behaviour, capacity for work, functional capacity and use of health services. Furthermore, it includes a broad selection of questions used in measuring social capital. The results found an accumulation of social capital and general welfare for the same groups: the highest levels of social capital were found among the young, well-educated and married people. However, all socio-demographic subgroups seem to benefit from social capital. Regardless of all socio-demographic characteristics, high levels of social capital were associated with good health, associations which varied among different health-related behaviours, but social participation had a strong statistical association with all components of health and all health behaviours. Regardless of chronic diseases people with high levels of social capital felt healthier than those with low levels. The positive association between social capital and survival was statistically significant among men and suggestive among women. These findings indicate that social capital contributes to health. Health inequalities between population sub-groups are still substantial. Health could be promoted and health inequalities reduced by developing tools for increasing social participation especially in those groups lacking social capital−and who often also suffer from several health problems.
  • Cousminer, Diana (Helsingin yliopisto, 2015)
    Puberty is a highly variable developmental stage marked by the development of secondary sex characteristics and the attainment of reproductive maturity. Variation during childhood developmental phases correlates with altered disease risk in adulthood; variation in pubertal growth and timing, in particular, correlates with adult risk for type 2 diabetes, obesity, adverse cardiovascular heath, and hormone-dependent cancers. While normal variation in age at menarche (AAM) has recently been investigated in large-scale genome-wide association (GWA) studies, the genetic regulation of male puberty remains less understood. Moreover, extreme variation in pubertal timing is a common cause for referral to pediatric specialists, while the underlying genetic factors are largely unknown. This work aimed to identify both common and rare genetic variants influencing pubertal growth and timing in both sexes. Utilizing Finnish population-based samples with frequent height measurements across puberty, we ran GWA of growth during late puberty and uncovered an association for variants near LIN28B, the most robust menarche-associated locus. Investigation of the longitudinal effects of two partly-correlated markers, one tagging a pubertal timing effect and one tagging an effect on adult stature, revealed distinct sex-specific association patterns with height growth from birth until adulthood. Thus, the LIN28B locus tags an important developmental regulator of both growth and maturational development. We then expanded to include European-wide samples within the Early Growth Genetics (EGG) Consortium. Genetic mapping of three pubertal growth traits revealed 9 novel pubertal growth variants in addition to LIN28B, 5 of which also associated with pubertal timing, and one which associated with childhood and adult body mass index (BMI). Longitudinal investigation of these variants showed diverse patterns of association with height growth, some of which contradicted epidemiological correlations between rapid prepubertal growth, advanced puberty, and reduced final adult stature. Given the complex relationships between these traits, tracking individual unique effects across multiple periods of growth may help uncover the pathways linking childhood development with adult health outcomes. Also within the EGG Consortium, GWA meta-analysis of Tanner genital and breast staging data uncovered the first robust male puberty locus on chromosome 16 near MKL2, a locus which also associates with advanced menarche, decreased pubertal growth, and shorter adult stature. Furthermore, part of the genetic architecture underlying the onset of puberty is shared between males and females, evidenced by the high correlation between menarche-advancing alleles and earlier male genital development. However, while BMI-increasing alleles strongly correlate with advanced breast development in girls, our data shows that these variants play a more complex role in male puberty. Finally, we performed targeted sequencing of the pericentromeric region of chromosome 2 previously robustly linked with constitutional delay of growth and puberty (CDGP), an extreme delay in normal pubertal timing, in multiply affected Finnish families. Analysis of shared low-frequency variation in genes and regulatory regions of the best functional candidate genes revealed 6 protein-altering variants in a single gene, DNAH6, in 10 of the families. However, follow-up sequencing in an additional 135 Finnish CDGP cases failed to provide evidence for enrichment of DNAH6 mutations compared to a large, unique set of SISu Finnish population controls. DNAH6 is potentially an appropriate candidate gene that may be involved in the regulation of steroid hormone biosynthesis by the cytoskeleton. This study highlights the difficulties of detecting susceptibility variants under a linkage signal for complex traits. Taken together, these results advance our understanding of the genetics of pubertal timing and development in both sexes. However, more work is needed to understand how each genetic locus functions in the biology of puberty and childhood growth, and further study of the genetic loci highlighted in this work may help pinpoint the mechanisms that link the timing of this important developmental stage with adult health and risk for common diseases. Keywords: puberty, development, growth, genome-wide association studies (GWAS), targeted sequencing, constitutional delay of growth and puberty (CDGP)