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  • Kauppi, Juha (Helsingin yliopisto, 2015)
    Adenocarcinoma (AC) of the esophagus and esophagogastric junction (EGJ) is a disease with poor prognosis and increasing incidence in western countries. Its pathogenesis is associated with oxidative stress (OS) in the esophageal epithelium. Long-term survival is associated with successful radical surgery, early stage of the disease, and successful downstaging with neoadjuvant therapy. As surgery is accompanied with a large number of possible complications, it is essential to identify patients who might not benefit from surgery and on the other hand, could be treated with less invasive options. The aims of this study were 1) to assess the role of OS below EGJ in the pathogenesis of Barrett s esophagus (BE) and AC, 2) to assess the prognoses and causes of death in early esophageal AC, 3) to determine the value of 18F-fluorodeoxy-D-glucose positron emission tomography with computed tomography (FDG-PET-CT) in quantifying the response to neoadjuvant therapy and 4) to compare the novel mini-invasive technique (MIE) to traditional open esophagectomy (OE) in radical surgery. To quantify OS, we measured 8-isoprostane (8-IP), glutathione content (GSH), and 8-OH- deoxyglucose (8-OHdG) values from mucosa below EGJ, BE-mucosa, and AC-tumors from 43 patients with BE and/or AC and compared them to samples from corresponding sites of 15 healthy control patients. To determine the long-term prognosis of patients with early esophageal AC, we studied patient records and causes of deaths for 85 patients, treated with radical esophagectomy over a 27-year time span. To evaluate pre-treatment response to neoadjuvant therapy in locally advanced AC, we recorded FDG-PET-CT results before and after induction therapy in sixty-six consecutive patients who were to be operated on for locally advanced AC. Decrement in radioactive glucose uptake values was associated with survival and histological treatment response. We compared MIE to OE, to see, if minimal invasiveness reduces the rate of complications and if they are comparable in terms of oncologic radicality and survival. Proximal gastric GSH content was lower and 8-IP and 8-OHdG levels higher with statistical significance in the study patients (BE and AC) as compared to healthy controls. In patients with early esophageal AC, overall and long-term (>5 year) survival rates were mostly affected by diseases related to aging. During the first five years after the operations, disease recurrence was the most common cause of death. However, recurrence-free survival was 80% at five years and no new recurrences were detected after that. Microscopic eradication of locally advanced AC was optimally predicted by a 67% decrease in uptake values before and after induction chemotherapy, with a sensitivity of 79% and specificity of 75%. However, this association was not linear and complete eradication of radioactive glucose uptake, was not always associated with a complete histologic response. However, a decrease in glucose uptake was associated with improved overall and recurrence free survival. MIE and OE were equivalent in terms of 90-day mortality, pneumonia-, leak-, and overall complication rates. Also a minimally invasive technique was associated with significantly shorter overall hospital stay and significantly less blood loss during the operations. OS levels are also elevated below the EGJ, as lipid peroxidation can be detected (8-IP) and antioxidant defense (GSH) is reduced. Also the levels of 8-OHdG adducts were higher showing that DNA is being damaged by free radicals. This suggests that inflammation of the proximal gastric mucosa induced by gastroduodenal content, has a role in the pathogenesis of BE and esophageal AC. As the prognoses for patients with early esophageal AC were good, recurrence was still the most important cause of death. The risk was highest for patients with lymph node metastases and deep submucosal infiltration. Therefore radical surgery should be preferred with patients with a low risk of surgical complications and submucosal infiltration. In patients with intramucosal AC, endoscopic ablation should be considered. Evaluation of the patients responses to induction chemotherapy with FDG-PET-CT was not accurate enough to give indications better than the exclusion of metastatic disease. However, a significant decrease in radioactive glucose uptake was associated with improved survival, independently of histopathologic response. This information can be useful when balancing the risks of surgery against expected benefits. The perioperative and oncological results for MIE were comparable to those of the open approach and MIE seems to shorten hospital stay. However, the MIE technique is demanding and its mastery requires a sufficient number of cases and skilled practitioners.
  • Al-Samadi, Ahmed (Helsingin yliopisto, 2015)
    Recurrent aphthous ulcer (RAU) is an ulcerative disease of the oral mucosa characterised by the appearance of ulcerations in the oral mucosa accompanied by an erythematous halo area surrounding the ulcer and showing signs of acute inflammation. While RAU affects approximately 20% of the population globally, its pathogenesis remains poorly understood. Furthermore, most studies concentrate on treatment while few address the pathogenesis of the disease. This project aimed to determine the mechanisms of oral epithelial cell death in RAU, the role of these cells in disease pathogenesis in terms of toll-like receptor (TLR) expression, and the ability of the these cells to produce chemokines, pro-inflammatory cytokines, and antimicrobial peptides. Together these may first aggravate and, then, down-regulate the inflammation and initiate the healing process. For this purpose, we collected 13 aphthae and 11 healthy control biopsies for immunohistochemical staining, immunofluorescence staining, and quantitative PCR. For functional studies, we cultured primary oral keratinocytes and oral squamous cell carcinoma cell-line SCC-25 and tested their responses to different stimuli. Our results highlight the importance of oral epithelial cells in RAU; interestingly, oral epithelial cells in RAU tested positive for apoptosis markers caspase-3, especially at the superficial and spinous layer, and TUNEL, but negative in controls. We also found that TLRs are primarily present in the basal and suprabasal layers of control epithelium, but their expression extends to the superficial layer in RAU epithelium. Additionally, we found significally higher expressions of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-17C, and beta defensin 2 (BD-2) in RAU oral epithelium compared with control epithelium. Functional studies on cultured primary oral keratinocytes and SCC-25 supported our results from RAU biopsies since these cells responded to damage-associated molecule patterns (DAMPs), such as self-DNA and pro-inflammatory cytokines including IL-17C, TNF-α, and interferon gamma (IFN-γ), through a significant increase in the expression of selected molecules including TLR2, TNF-α, and BD-2. Based on our findings, RAU may begin with a strong initiating factor activating a self-amplificatory cycle. This cycle is characterised by the induction of epithelial cells apoptosis at the superficial layer down to the basal layer, a change in the pattern of TLR distribution, the up-regulation of several chemokines and pro-inflammatory cytokines, and, finally, the secretion of antimicrobial peptides initating the healing process. As a result of the lack of adaptive immunity in RAU, the cycle recurs when the mucosa is subjected to an initiating factor of the same sequence.
  • Mäkinen, Laura K. (Helsingin yliopisto, 2015)
    Predicting the clinical course of an early-stage oral tongue squamous cell carcinoma (OTSCC) is challenging, as even small tumors can behave aggressively. OTSCC often metastasizes to the cervical lymph nodes, and the presence of lymph node metastasis at the time of diagnosis is considered the most important tumor-related prognostic factor in OTSCC. The mechanisms of this disease progression are poorly understood. Despite slight improvement in the prognosis of OTSCC in recent decades, the outcome of these patients is still modest. Therefore, a deeper understanding of the phenomena behind tumor progression would enable medical professionals to evaluate the aggressiveness of the disease and to adjust its treatment more effectively. The extracellular matrix and basement membrane must be broken down before a tumor can invade surrounding tissues and further spread into blood and lymph vessels. This is a process that involves various proteolytic enzymes, the most important of which are matrix metalloproteinases (MMPs). Over 25 structurally related, but genetically distinct, human MMPs have been identified and characterized: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Toll-like receptors (TLRs) are pattern-recognition molecules involved in innate immunity that are also expressed in many types of cancer. TLRs apparently play a pivotal role in malignant disease: they are related to tumor progression and, conversely, to cancer inhibition. Their expression pattern and role in oral cancer, however, remains unclear. In this thesis we studied the expression of MMPs 2, 7, 8, 9, 13, and 25 and TLRs 2, 4, 5, 7, and 9 in early-stage OTSCC. The study comprised 73 consecutive clinically T1N0M0 and T2N0M0 OTSCC patients treated at the Helsinki University Hospital, Helsinki, Finland in 1992-2002. We prepared tissue array blocks from primary tumors and immunostained them. We also used whole section slides from patients with metastasized or recurrent disease. We compared immunoexpression of MMPs and TLRs to tumor and patient characteristics as well as to patient outcomes. We also used Western immunoblot to examine TLR-2 and -4 expression in the highly invasive and aggressive HSC-3 OTSCC cell line. In addition, we studied the effect of TLR-2 and -4 antagonist GIT27 (4,5-dihydro-5-isoxasoleacetic acid) on the invasion of the HSC-3 cell line in myoma organotypic invasion assay. OTSCC tumors expressed both MMPs and TLRs. Nuclear expression of MMP-13, but not cytoplasmic expression of MMP-2, -8, and -9, associated with deeper invasion and advanced tumor size. Furthermore, high nuclear MMP-13 expression predicted poor disease-specific survival. High MMP-7 protein expression associated with the presence of occult cervical metastases, increased invasion depth, and higher tumor grade, and also predicted poor outcome. Immunostaining of MMP-25 failed to correlate with any clinical parameters. High TLR-2, -4, and -9 expression correlated with deeper tumor invasion. Cytoplasmic expression of TLR-2 and -4 also correlated significantly with higher tumor grade, whereas high TLR-5 expression associated with lower tumor grade. High expression of TLR-9 correlated with advanced tumor size. Negative or mild TLR-5 expression predicted poor disease-specific survival. OTSCC primary tumors, neck metastases and recurrent tumors expressed TLR-2, -4, and -9. TLR-2 and -4 antagonist GIT27 did not affect the invasion of the HSC-3 cell line in myoma organotypic invasion assay. Thus, TLRs may operate under a different mechanism of action depending on whether they are activated by damage-associated molecular patterns in cancer or by pathogen-associated molecular patterns in infection. Our results suggest that MMP-7 and MMP-13 in particular may have prognostic value in OTSCC. Their use as prognostic biomarkers, however, calls for further study. TLR-2, -4, and -9 seemed to predict invasive tumor growth. Primary tumors and neck metastases as well as recurrent tumors of OTSCC express these TLRs, suggesting that TLRs seem to play a role in both the development and progression of tongue carcinoma.
  • Laaksonen, Esti (Helsingin yliopisto, 2015)
    The estimated number of heavy consumers of alcohol is about 20 percent of population, of which 10 percent suffer from alcohol dependency. Many heavy consumers of alcohol also smoke. The effectiveness of treatments can be significantly improved with medical treatment. The problems are: how medical treatment can be utilized in practical treatment, and how to ensure treatment adherence. The aim of this study was to investigate the effectiveness of pharmacotherapies combined with a brief manual-based cognitive-behavioural intervention (CBT) in treating alcohol-dependent patients. In the large-scale clinical treatment study, which ran for 2.5 years, the effectiveness and patient response to the three drugs (naltrexone, acamprosate and disulfiram) were compared. The study used a survey drawn up guidebook for patients, Winning at last defeating the drinking problem. In addition, we researched how the reduced alcohol consumption affects the quality of life, mood and smoking. In the study of sweet preference we analyzed possible associations between sweet preference and efficacy of naltrexone treatment. In addition, we researched patients treatment adherence and medication adherence to targeted naltrexone, as well as reduction of problem drinking and craving. This combined treatment (medication and CBT) significantly reduced alcohol consumption resulting in improved quality of life. Noticeable is that compared to the other study medicines, especially during the continuous medication period, supervised disulfiram appeared superior. During the targeted medication period, there were no other significant differences between the groups except for that the abstinence days were significantly more frequent in the disulfiram group. The treatment was also associated with success in quitting smoking among patients using disulfiram. The study of sweet preference, it was significantly related to treatment measures in the naltrexone group when the outcome was relapses to heavy drinking. Our study offers a possible new explanation of the clinical observation that naltrexone is not effective for every patient. Adherence to the targeted use of naltrexone added treatment compliance and efficacy of the medicine. Patients who had less symptoms of alcohol dependence, suffered from high craving for alcohol, were unemployment, young or could not keep the drinking diary were less committed to treatment. Problem drinking can be changed to abstinence or moderate drinking with the combination of medical therapy, CBT and good treatment commitment. The benefits of treatments are probably long-term, because part of the positive results lasted over two years. The treatment methods used in this study were usable and they can be implemented in all levels of Finnish health care.
  • Rouhe, Hanna (Helsingin yliopisto, 2015)
    Every 10th pregnant women suffers from severe fear of childbirth. It causes anxiety and physical symptoms during pregnancy, and may interfere with mother-infant bonding. Caesarean sections on maternal request are rising worldwide. The major indication is fear of childbirth. There is no clinical guideline regarding how to help these women. This present study was designed to investigate the background factors of fear of childbirth; to assess the methods to screen fear of childbirth; analyse the effect of group psycho-education on delivery mode, delivery experience, costs and postnatal psycho-social well-being; and also to evaluate the psychiatric morbidity of women with fear of childbirth. We tested the fear of childbirth questionnaire in the Finnish population and simultaneously gathered the obstetrical background information of 1,348 pregnant women. We used the Fear of Childbirth VAS for the first time in measuring fear of childbirth. With a cut-off of Fear of Childbirth VAS over 5.0, the sensitivity is 98%, and the specificity is 67% for severe fear of childbirth. Nulliparous women have more fear of childbirth than parous women. Women who were more afraid of childbirth preferred caesarean section as delivery mode. Women who had have previously delivered by caesarean section or had vacuum-assisted delivery, were more fearful. The Fear of Childbirth VAS is a simple method for screening fear of childbirth. In a register-based study, we analysed specialised care with psychiatric diagnoses and psychotropic medication of 2,500 women with fear of childbirth and 5,000 control women. The prevalence of mental health problems was higher (54%) among women with fear of childbirth than among control women (34%). The most common mental disorders were anxiety disorders and depression. Mental health problems should be acknowledged in maternity care. In randomised study, nulliparous women were screened for fear of childbirth, and 371 women with severe fear of childbirth were included in our study. These women were randomised into an intervention group and convetional care. The intervention consisted of six times of group psycho-education with mindfulness relaxation exercises led by a psychologist during pregnancy and one session postnatal. Women in the intervention group had more often normal vaginal delivery (63% vs. 48%) than women in the control group. The childbirth experience was less frightening for women in the intervention group, regardless of the delivery mode. Group psycho-education improved maternal adjustment and reduced the risk of postnatal depressive symptoms. The costs of group psycho-education were saved in delivery costs, and thus this treatment causes no additional expenses to conventional care. By providing nulliparous women with group psycho-education, more resources can be appointed to parous women with fear of childbirth in special maternity care.
  • Veistinen, Lotta (Helsingin yliopisto, 2015)
    The flat bones of the skull, the calvarial bones, develop by intramembranous ossification during which mesenchymal cells first condense and subsequently differentiate into osteoblasts. Sutures separate the calvarial bones and facilitate the synchronized growth of the underlying brain and the calvaria. Hedgehog (Hh) signalling has an indisputable role in craniofacial development as well as during endochondral ossification. Yet, little is known about its function during intramembranous ossification of the calvarial bones. GLI-Kruppel family member 3 (Gli3) is a zinc-finger transcription factor that mediates Hh signalling. In the absence of Hh ligand Gli3 is proteolytically cleaved into a repressor that inhibits transcription of Hh target genes. Mutations in GLI3 cause Greig cephalopolysyndactyly syndrome in humans, in which an infrequent, but significant feature is premature fusion of the metopic suture (interfrontal suture in mice). We have used Gli3 loss-of- function mouse (Gli3Xt-J/Xt-J) as a model to investigate the effects of aberrant Hh signalling during calvarial development. In my thesis I describe how loss of Gli3 causes craniosynostosis of the lambdoid as well as interfrontal sutures in mice. Elevated proliferation and ectopic differentiation of osteoprogenitors underlies this phenomenon. We were able to rescue craniosynostosis in these mice by two mechanisms. Firstly, by elevating fibroblast growth factor (Fgf) signalling in the suture prior to its fusion by imbedding Fgf2 soaked beads in tissue culture. This induced Twist1 expression, which inhibits function of ectopically expressed Runx2. Secondly, craniosynostosis was prevented by genetically reducing Runx2 activity by generating Gli3Xt-J/Xt-J;Runx2+/- mice, which normalized elevated levels of Bmp signalling in the affected sutures. We also put forward a model of how Hh signalling helps to maintain the integrity of bone margins during calvarial development. The repressor isoform of Gli3 inhibits Runx2 activity in the early osteoprogenitor cells. Runx2, on the other hand, activates Ihh expression in the mature osteoblasts, which then induces osteogenesis by inhibiting the function of Gli3 repressor. Our findings indicate that Gli3 and Hh signalling have an important role in mediating the location of osteoblast differentiation and the speed of bone formation in the developing calvaria. Uncovering the cellular and molecular mechanisms that underlie normal calvarial development, as well as pathological processes, is a vital step in developing treatment strategies for patients with craniosynostosis.
  • 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.
  • Kaprio, Tuomas (Helsingin yliopisto, 2015)
    Background and aims Colorectal cancer (CRC) is one of the world s three most common cancers, and its incidence is rising. Novel biomarkers are essential for diagnostic and prognostic tools and to identify patients for targeted and individualized therapy. Covering all human cells, the carbohydrate units of glycoproteins, glycolipids, and proteoglycans are glycans. Carcinoma-related glycan structures are potential cancer biomarkers, since glycosylation evolves during carcinogenesis. Suggested to play a role in carcinogenesis are glycoproteins podocalyxin (PODXL) and regenerating islet-derived gene (REG) 4. PODXL s aberrant expression or allelic variation or both associate in different cancers with poor prognosis and unfavourable clinicopathological characteristics. Up-regulated REG4 expression occurs in inflammatory bowel diseases and also in gastrointestinal cancers. Reports on the association of REG4 expression with CRC prognosis have been mixed, however. Material and Methods Comparison of the N-glycan profiles of 5 rectal adenomas and 18 rectal carcinomas of different stages was by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Tumour expression of REG4 and PODXL was evaluated by immunohistochemistry in 840 consecutive CRC patients surgically treated between 1983 and 2001. In addition we evaluated in a subgroup of 220 consecutively surgically treated CRC patients the tumour expression of MUC1, MUC2, MUC5AC, synapthophysin, chromogranin, sialyl Lewis a (sLea), and pauci-mannose. All patients were treated at Helsinki University Hospital (HUH). Results Rectal adenomas and carcinomas can be distinguished from one another based on their N-glycosylation profile. Differences in N-glycosylation existed also between carcinomas of different stages. Based on these results pauci-mannose and sLea were chosen for immunohistochemical analysis: in CRC sLea correlated with poor prognosis, and in advanced CRC, pauci-mannose expression correlated with poor prognosis. PODXL was an independent marker of poor prognosis in CRC. The two antibodies showed similar prognostic profiles, but their staining patterns differed, and they recognized different groups of patients with a poor prognosis. Combination of the two PODXL antibodies identified a group of patients with even worse prognosis. REG4 expression associated with MUC1, MUC2, and MUC5AC expression in CRC and was a marker of favourable prognosis in non-mucinous CRC. Conclusion Mass spectrometry identified several carcinoma-related glycans and a method of transforming these results into immunohistochemistry was demonstrated. PODXL was a marker of poor prognosis in CRC, whereas REG4 expression predicted a favourable prognosis in non-mucinous CRC.
  • Song, Xin (Helsingin yliopisto, 2015)
    Background and aims: Obesity has become the sixth most important risk factor contributing to the overall burden of a variety of diseases worldwide. The association of anthropometric measures of obesity with mortality from various causes and incidence of cancers of various sites has been investigated, but it remains controversial. The aims of this study were to: 1) evaluate the epidemiological nature of the association of anthropometric measures of obesity with mortality from various causes, and to detect a potential threshold in this association; 2) study the epidemiological nature of the association between body mass index and incidence of cancer of different sites, and to detect a potential threshold in the association; 3) compare the strengths of different anthropometric measures of obesity in relation to cardiovascular disease (CVD) mortality; 4) assess the risk of CVD mortality in relation to obesity and sex in the general population, and also separately for those with or without diabetes at baseline. Study population and Methods: This study was based on data subsets of the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study and the National FINRISK study, including 72 947 European men and 62 798 women (I), 26 636 Finnish men and 28 089 women (II), 24 686 European men and 21 965 women (III/IV), and 23 629 European men and 21 965 women (V) aged 24 years or above at baseline. Hazard ratios (HRs) corresponding to categorical or continuous body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) or waist-to-stature ratio (WSR), a body shape index (ABSI) and waist-to-hip-to-height ratio (WHHR) were estimated by the Cox proportional hazards model adjusting for several potential confounding factors measured at baseline. The non-parametric smooth functions of several anthropometric measures of obesity were fitted to health outcomes in order to explore the potential curvilinear relationship using the spline regression model, with a threshold detected by a piecewise regression model (II/III). HR per standard deviation increment of each anthropometric measure of obesity in relation to CVD mortality was compared using the paired homogeneity test (IV). Results: BMI, WC and WHtR had a U- or J-shaped relationship with all-cause mortality (I/III), whereas WHR, ABSI and WHHR had a linear positive relationship with all-cause mortality (III). BMI had a J-shaped relationship with CVD mortality (I/III), whereas anthropometric measures of abdominal obesity (WC, WHR, WHtR and ABSI) had a linear positive relationship with CVD mortality (III). BMI had a U-shaped relationship with cancer mortality in both men and women but disappeared among non-smokers, which showed no association (I). BMI had a linear positive association with incidence of cancers of the colon, liver, kidney, bladder and all sites combined in men, and of cancers of the stomach, colon, gallbladder and ovary in women, an inverse association with incidence of cancers of the lung in men and the lung and breast in women, and a J-shaped association with incidence of all cancers combined in women (II). A one-standard-deviation increase in all obesity indicators were significantly associated with a more than 19% increase of CVD mortality risk in both men and women, and the prediction for CVD mortality was stronger with anthropometric measures of abdominal obesity than that with BMI and ABSI, and most strongly with the WHtR/WSR (IV). Men had higher CVD mortality rates and higher HRs across BMI categories, and categories of abdominal obesity than women (V). The sex difference in CVD mortality was slightly smaller in obese than in non-obese individuals; the negative interactions were statistically significant between sex and WC (p =0.02), and sex and WHtR (p =0.01). None of the interaction terms was significant when the analyses were carried out among non-diabetic or diabetic individuals separately (V). Conclusions: This study confirmed the deleterious effect of obesity on mortality from various causes and incidence of cancers of certain sites. The prediction for CVD mortality with anthropometric measures of abdominal obesity was stronger than that with BMI, which may imply a more important role of fat distribution than fat accumulation and suggest that an effective obesity prevention strategy should emphasize the importance of abdominal obesity. Men had higher CVD mortality than women across all categories of anthropometric measures of obesity, which further supports the view of higher intra-abdominal fat accumulation in men than in women, even in non-obese individuals. Obesity seems slightly to diminish the female advantage in CVD mortality, irrespective of diabetes status. This may indicate that women may gradually lose their cardiovascular advantage when they are obese, probably due to a more pronounced clustering of CVD risk factors among obese women.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.