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  • Rönnback, Mats (Helsingin yliopisto, 2007)
    Background: As the human body ages, the arteries gradually lose their elasticity and become stiffer. Although inevitable, this process is influenced by hereditary and environmental factors. Interestingly, many classic cardiovascular risk factors affect the arterial stiffness. During the last decade, accelerated arterial stiffening has been recognized as an important cardiovascular risk factor associated with increased mortality as well as with several chronic disorders. Objectives: This thesis examines the role of arterial stiffness in relation to variations in a physiological feature in healthy individuals. In addition, the effect on arterial stiffness of an acute transitory disease and the effect of a chronic disease are studied. Furthermore, the thesis analyzes the prognostic value of a marker of arterial stiffness in individuals with chronic disease. Finally, a potential method of reducing arterial stiffness is evaluated. Material and study design: The first study examines pulse wave reflection and pulse wave velocity in relation to muscle fibre distribution in healthy middle-aged men. In the second study, pulse wave reflection in women with current or previous preeclampsia is compared to a healthy control group. The effect of aging on the different blood pressure indices in patients with type 1 diabetes is examined in the third study, whereas the fourth paper studies the relation between these blood pressure indices and mortality in type 2 diabetes. The fifth study evaluates how intake of a fermented milk product containing bioactive peptides affects pulse wave reflection in individuals with mild hypertension. Results and conclusions: Muscle fibre type distribution is not an independent determinant of arterial stiffness in middle-aged males. Pulse wave reflection is increased in pregnant women with preeclampsia, but not in previously preeclamptic non-pregnant women. Patients with type 1 diabetes have a higher and more rapidly increasing pulse pressure, which suggests accelerated arterial stiffening. In elderly type 2 diabetic patients, very high and very low levels of pulse pressure are associated with higher mortality. Intake of milk-derived bioactive peptides reduces pulse wave reflection in hypertensive males but not in hypertensive females.
  • Aro, Katri (Helsingin yliopisto, 2012)
    According to the Finnish Cancer Registry, salivary gland cancer (SGC) is rare, with approximately 50 to 60 new cases in Finland annually. For pediatric patients, the Finnish Cancer Registry reported 15 new cases between 1990 and 2009. The wide spectrum of different subtypes makes this group of diseases difficult to diagnose, grade, and treat. Due to the rarity of these diseases, no specific risk factors are known, and long-term outcome data are difficult to obtain. In adults, 20% of parotid gland tumors, 50% of submandibular gland tumors, and 90% of sublingual gland tumors are malignant. Most tumors of the minor salivary glands are malignant. However, in the pediatric patient population, 50% of parotid gland tumors are malignant, but only 10% of submandibular gland tumors do. Mucoepidermoid carcinoma (MEC) is the most common (29 to 35%) malignant neoplasm of the major and minor salivary glands in both adults and children. According to the WHO, MEC is classified into three grades: low grade (LG), intermediate grade (IMG), and high grade (HG). These three grades have different growth potentials as well as different potentials to metastasize and to recur; consequently, they show major differences in outcome. Correct histopathological diagnosis thus remains vital. We evaluated the prevalence, treatment, and outcome of 52 Finnish patients with MEC of the major salivary glands. All LG-MECs (23/52) were localized to the primary site, and most patients with LG-MEC were treated and cured surgically. The three-year overall survival rate was 95% for LG-MEC, 67% for IMG-MEC, and 55% for HG-MEC patients. Patients with LG-MEC experienced no recurrences during the three-year follow up. IMG-MEC (7/52) more closely resembled HG-MEC (20/52) in its biological behavior, contradicting reports from other institutions. Patients with IMG-MEC had cervical nodal metastases in 43% of cases, and 67% developed locoregional or distant metastases during follow up. Radiotherapy was administered for 86% of IMG-MEC patients. In the HG-MEC group, nodal metastases were present at presentation in 50% of patients, and 80% also received radiotherapy. Our results suggest an aggressive treatment protocol for IMG-MEC, and that surgery seems adequate for LG-MEC. Claudins are integral protein components of tight junctions contributing to tight sealing between cells. Deregulation of claudins leads to loss of cell integrity, uncontrolled cell proliferation, advantageous potential for tumor growth and metastatic potential. No previous studies have explored the possible role of claudins in SGC. Immunohistochemical studies on claudins 1, 3, 4, and 7 for 39 major salivary gland MEC patients have revealed statistically significant differences in staining intensities. The high intensity for claudin-1 increased the likelihood of LG tumors with a favorable prognosis. HG- and IMG-MEC tumors more often had higher intensities for claudin-3, portending a worse prognosis. This feature again emphasizes that IMG-MEC differs from LG-MEC. Claudins may, therefore, aid in grading tumors correctly and also serve as surrogate prognostic protein markers. The extent of immunostaining had less impact on grading than anticipated. The intensity of claudin-1 immunostaining classified tumors correctly in 90% of cases corresponding to conventional histopathological features. Between 1992 and 2011, 10 new pediatric SGC cases were identified. No gender predominated, and the median age was 14 years. The majority of SGC cases were parotid gland tumors (7/10); all tumors were LG and localized to the primary site. No recurrences occurred during the 7-month to 14-year follow up. MEC was the most common histological subtype (50%), which reflects results from other institutions. Because pediatric SGC is infrequent, experience with and guidelines for managing pediatric cases must be adapted from guidelines for adults with SGC. Establishing national or international cancer databases could offer help in managing these rare diseases. Between 1974 and 2009, information was retrieved on 437 sequential SGC patients treated at the Helsinki University Central Hospital. Due to the long time period and the most often elderly patients, many were deceased at the time of the study. Consequently, the study cohort consisted of 161 patients who were alive and able to reach. Of these, 88 (55%) answered a patient questionnaire to identify possible hereditary forms of SGC as well as elevated risk for other malignancies among the relatives of SGC patients. The enquiry revealed no cases of SGC in first-degree relatives. Thus, most likely no significant familial predisposition for SGC exists in Finland.
  • Kylmälä, Minna (Helsingin yliopisto, 2014)
    Myocardial infarct size is clinically relevant, affecting heart function and patient prognosis. After myocardial infarction (MI), it is important to establish whether myocardial dysfunction is due to permanent infarct damage, or if the myocardium is viable, in which case contraction may be improved by revascularization. Established methods for assessing infarct size and viability, such as cardiac magnetic resonance imaging with delayed contrast enhancement (DE-CMR) and myocardial perfusion imaging are neither readily available nor suitable in acute MI. In contrast, electrocardiography (ECG) and echocardiography are widely available diagnostic methods at the patient’s bedside at any hour. Echocardiographic strain rate imaging, based on measurement of myocardial velocities by tissue Doppler, is a sensitive and objective method for quantification of myocardial contraction. If myocardium contracts, it is viable. Body surface potential mapping (BSPM) records ECG with multiple leads covering the entire thorax, with a variety of ECG variables automatically calculated from its recordings. The aim of the studies for this thesis was to evaluate whether infarct size and myocardial viability can be assessed by strain rate imaging and BSPM. The studies included up to 57 patients with acute coronary syndrome, most with an infarction. BSPM with 123 leads and echocardiography were performed within 48 hours after onset of chest pain, and repeated during recovery of the infarction, at 1 to 4 weeks, and after healing, at 6 to 12 months. Global infarct size and segmental extent of infarct were determined by DE-CMR after healing. Strain rate imaging allowed assessment of viability and global infarct size in both acute and chronic MI. Strain mapping was validated, for the first time, as a semi-quantitative method for the assessment of systolic strain, and showed excellent correlation with quantitative strain values. In chronic MI, segments with systolic strain values less than -6% were most probably viable, having no infarct or a non-transmural infarct. Strain mapping proved as good as quantitative strain in distinguishing transmural from non-transmural infarcts. In acute MI, strain- and strain-rate variables could distinguish viable from non-viable segments, post-systolic strain having the best accuracy at predicting recovery of severe contraction abnormality (AUC 0.78). BSPM could estimate infarct size at all stages of the infarction, with Q- and R-wave variables, as well as the QRS integral having the strongest correlations with infarct size at all time-points. The repolarization variables were clearly inferior; only in chronic MI did the T-wave variables have nearly as strong correlations with infarct size as did QRS variables. In contrast, the repolarization variables proved good at predicting recovery of left ventricular (LV) function in acute MI, irrespective of MI location. The 1st QRS integral was the only depolarization variable good at predicting recovery of LV dysfunction, and the only variable able to estimate infarct size in addition to viability. In conclusion, strain rate imaging as well as computed ECG variables can predict recovery of myocardial function in acute MI and can assess infarct size in both acute and chronic MI. Strain values can be quickly and accurately estimated by the strain-mapping method, validated now for the first time in the assessment of infarct transmurality. These methods, easily performed at bedside, may help the clinician assess patient prognosis and the need for revascularization after MI.
  • Janno, Sven (Helsingin yliopisto, 2006)
    The prevalence and assessment of neuroleptic-induced movement disorders (NIMDs) in a naturalistic schizophrenia population that uses conventional neuroleptics were studied. We recruited 99 chronic schizophrenic institutionalized adult patients from a state nursing home in central Estonia. The total prevalence of NIMDs according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was 61.6%, and 22.2% had more than one NIMD. We explored the reliability and validity of different instruments for measuring these disorders. First, we compared DSM-IV with the established observer rating scales of Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) (for neuroleptic-induced parkinsonism, NIP) and Abnormal Involuntary Movement Scale (AIMS) (for tardive dyskinesia), all three of which have been used for diagnosing NIMD. We found a good overlap of cases for neuroleptic-induced akathisia (NIA) and tardive dyskinesia (TD) but somewhat poorer overlap for NIP, for which we suggest raising the commonly used threshold value of 0.3 to 0.65. Second, we compared the established observer rating scales with an objective motor measurement, namely controlled rest lower limb activity measured by actometry. Actometry supported the validity of BARS and SAS, but it could not be used alone in this naturalistic population with several co-existing NIMDs. It could not differentiate the disorders from each other. Quantitative actometry may be useful in measuring changes in NIA and NIP severity, in situations where the diagnosis has been made using another method. Third, after the relative failure of quantitative actometry to show diagnostic power in a naturalistic population, we explored descriptive ways of analysing actometric data, and demonstrated diagnostic power pooled NIA and pseudoakathisia (PsA) in our population. A subjective question concerning movement problems was able to discriminate NIA patients from all other subjects. Answers to this question were not selective for other NIMDs. Chronic schizophrenia populations are common worldwide, NIMD affected two-thirds of our study population. Prevention, diagnosis and treatment of NIMDs warrant more attention, especially in countries where typical antipsychotics are frequently used. Our study supported the validity and reliability of DSM-IV diagnostic criteria for NIMD in comparison with established rating scales and actometry. SAS can be used with minor modifications for screening purposes. Controlled rest lower limb actometry was not diagnostically specific in our naturalistic population with several co-morbid NIMDs, but it may be sensitive in measuring changes in NIMDs.
  • Holi, Matti (Helsingin yliopisto, 2003)
  • Siljander, Heli (Helsingin yliopisto, 2010)
    Background and aims. Type 1 diabetes (T1D), an autoimmune disease in which the insulin producing beta cells are gradually destroyed, is preceded by a prodromal phase characterized by appearance of diabetes-associated autoantibodies in circulation. Both the timing of the appearance of autoantibodies and their quality have been used in the prediction of T1D among first-degree relatives of diabetic patients (FDRs). So far, no general strategies for identifying individuals at increased disease risk in the general population have been established, although the majority of new cases originate in this population. The current work aimed at assessing the predictive role of diabetes-associated immunologic and metabolic risk factors in the general population, and comparing these factors with data obtained from studies on FDRs. Subjects and methods. Study subjects in the current work were subcohorts of participants of the Childhood Diabetes in Finland Study (DiMe; n=755), the Cardiovascular Risk in Young Finns Study (LASERI; n=3475), and the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) Study subjects (n=7410). These children were observed for signs of beta-cell autoimmunity and progression to T1D, and the results obtained were compared between the FDRs and the general population cohorts. --- Results and conclusions. By combining HLA and autoantibody screening, T1D risks similar to those reported for autoantibody-positive FDRs are observed in the pediatric general population. Progression rate to T1D is high in genetically susceptible children with persistent multipositivity. Measurement of IAA affinity failed in stratifying the risk assessment in young IAA-positive children with HLA-conferred disease susceptibility, among whom affinity of IAA did not increase during the prediabetic period. Young age at seroconversion, increased weight-for-height, decreased early insulin response, and increased IAA and IA-2A levels predict T1D in young children with genetic disease susceptibility and signs of advanced beta-cell autoimmunity. Since the incidence of T1D continues to increase, efforts aimed at preventing T1D are important, and reliable disease prediction is needed both for intervention trials and for effective and safe preventive therapies in the future. Our observations confirmed that combined HLA-based screening and regular autoantibody measurements reveal similar disease risks in pediatric general population as those seen in prediabetic FDRs, and that risk assessment can be stratified further by studying glucose metabolism of prediabetic subjects. As these screening efforts are feasible in practice, the knowledge now obtained can be exploited while designing intervention trials aimed at secondary prevention of T1D.
  • Molander, Pauliina (Helsingin yliopisto, 2014)
    In the era of TNFα-blocking therapy, MH and even DR have been suggested as new therapeutic targets in both CD and UC. Recent studies have indicated that DR may be achieved in roughly half of IBD patients on TNFα-blocking maintenance therapy, resulting in more favorable treatment outcomes. However, considering the potential side-effects and economic issues associated with long-term immunosuppressive therapy with TNFα-blocking agents, the possibility of discontinuing therapy should be evaluated at least once after achieving DR. At present, no widely accepted recommendations for discontinuing TNFα-blocking therapy are available. Based on the results of our study, only for about half of patients in DR were candidates for discontinuation of TNF-blocking medication for various reasons. Nevertheless, up to 67% of IBD patients in DR at the time of cessation of TNFα-blocking therapy remained in clinical remission during the 12-month follow-up, and moreover, the majority of these patients also remained in endoscopic remission. Therefore, withdrawal of therapy could be considered in IBD patients in DR even after one-year treatment. Reassuringly, in case of a relapse, the response to restart of TNFα-blocking therapy seems to be effective and well-tolerated. To evaluate treatment response and possible relapse during maintenance therapy or after discontinuation of TNFα-blocking therapy, FC seems to be a reliable surrogate marker to replace endoscopic assessment. A normal FC after induction with TNFα-blocking agents predicts sustained remission in the majority of patients with active luminal disease receiving scheduled treatment. However, an objective cut-off value for treatment response and relapse risk is to some extent still undefined. To predict IBD relapse and identify patients requiring a close follow-up in clinical practice, FC seems to be a useful surrogate marker, as it increases and remains elevated as early as 6 months before symptomatic relapse. FC measurements should therefore be included in monitoring IBD patient s treatment response in everyday clinical practice.
  • Geneid, Ahmed (Helsingin yliopisto, 2013)
    Over the last decades, school teachers and singers have been more or less the focus of voice research, due to their specific occupational needs. Now, other population groups as well start to draw attention. These new groups include workers exposed to organic dusts in various workplaces with possible laryngeal reactions. The second group includes children operated on for subglottic stenosis with possible effects on voice and related quality of life. The third are nursery teachers insufficiently studied through field research for possible voice problems. This thesis aims to shed light on these newly emerging vulnerable groups in terms of assessing their voices through questionnaires, perceptual and acoustic voice assessment, and videolaryngoscopic examination. The thesis includes four studies. Nine subjects with suspected occupational rhinitis or asthma participated in Studies I and II. They had single blinded exposures to organic dust and placebo substances. Subjective and perceptual voice assessment was done in addition to acoustic analysis of 180 samples using glottal inverse filtering. In Study III, children s voices were perceptually assessed as well as their health- and voice-related quality of life. In Study IV, 119 female kindergarten teachers responded to a questionnaire on voice habits, voice symptoms, and impact of various working conditions on voice. In addition, videolaryngoscopy examinations took place in these teachers workplaces. Studies I and II showed that some self-assessed voice and throat symptoms changed significantly after organic dust exposure, although perceptual assessment failed to record these changes. However, inverse filtering analysis revealed changes that represent the ones reported by the subjects. In Study III, voice-related quality of life and perceptual assessment of the study group showed lower scores than the controls . Study IV showed that 71.5% of the teachers examined reported frequent strain on the voice. Organic findings were observed in 10.9% of the subjects and did not correlate with subjective voice symptoms. The thesis added new information on these high-risk groups, identifying an occupational voice-disorder risk group related to laryngeal reactions rather than voice abuse. It also added information on the long-term effects of surgery for subglottic stenosis in early infancy. Nevertheless, field videolaryngoscopy was quite accurate in determining the percentage of organic findings among nursery teachers.
  • Laaksonen , Matti (Helsingin yliopisto, 2010)
    The Enamel matrix derivative Emdogain® (EMD) is a commercially available tissue extract preparation of porcine enamel origin. Studies have shown EMD to be clinically useful in promoting periodontal regeneration. EMD has been widely used in periodontal therapy for over ten years, but the mechanism of its action and the exact composition are not completely clear. EMD is predominantly amelogenin (>90%). However, unlike amelogenin, EMD has a number of growth factor-like effects and it has been shown to enhance the proliferation, migration and other cellular functions of periodontal ligament fibroblasts and osteoblasts. In contrast, the effects of EMD on epithelial cell lines and in particular on oral malignant cells have not been adequately studied. In addition, EMD has effects on the production of cytokines by several oral cell lines and the product is in constant interaction with different oral enzymes. Regardless of the various unknown properties of EMD, it is said to be clinically safe in regenerative procedures, also in medically compromised patients. The aim of the study was to examine whether gingival crevicular fluid (GCF), which contains several different proteolysis enzymes, could degrade EMD and alter its biological functions. In addition, the objective was to study the effects of EMD on carcinogenesis-related factors, in particular MMPs, using in vitro and in vivo models. This study also aimed to contribute to the understanding of the composition of EMD. GCF was capable of degrading EMD, depending on the periodontal status, with markedly more degradation in all states of periodontal disease compared to healthy controls. EMD was observed to stimulate the migration of periodontal ligament fibroblasts (PLF), whereas EMD together with GCF could not stimulate this proliferation. In addition, recombinant amelogenin, the main component of EMD, decreased the migration of PLFs. A comparison of changes induced by EMD and TGF-β1 in the gene profiles of carcinoma cells showed TGF-β1 to regulate a greater number of genes than EMD. However, both of the study reagents enhanced the expression of MMP-10 and MMP-9. Furthermore, EMD was found to induce several factors closely related to carcinogenesis on gene, protein, cell and in vivo levels. EMD enhanced the production of MMP-2, MMP-9 and MMP-10 proteins by cultured carcinoma cells. In addition, EMD stimulated the migration and in vitro wound closure of carcinoma cells. EMD was also capable of promoting metastasis formation in mice. In conclusion, the diseased GCF, containing various proteases, causes degradation of EMD and decreased proliferation of PLFs. Thus, this in vitro study suggests that the regenerative effect of EMD may decrease due to proteases present in periodontal tissues during the inflammation and healing of the tissues in vivo. Furthermore, EMD was observed to enhance several carcinoma-related factors and in particular the production of MMPs by benign and malignant cell lines. These findings suggest that the clinical safety of EMD with regard to dysplastic mucosal lesions should be further investigated.
  • Lallukka, Tea (Helsingin yliopisto, 2008)
    Adverse health behaviors as well as obesity are key risk factors for chronic diseases. Working conditions also contribute to health outcomes. It is possible that the effects of psychosocially strenuous working conditions and other work-related factors on health are, to some extent, explained by adverse behaviors. Previous studies about the associations between several working conditions and behavioral outcomes are, however, inconclusive. Moreover, the results are derived mostly from male populations, one national setting only, and with limited information about working conditions and behavioral risk factors. Thus, with an interest in employee health, this study was set to focus on behavioral risk factors among middle-aged employees. More specifically, the main aim was to shed light on the associations of various working conditions with health behaviors, weight gain, obesity, and symptoms of angina pectoris. In addition to national focus, international comparisons were included to test the associations across countries thereby aiming to produce a more comprehensive picture. Furthermore, a special emphasis was on gaining new evidence in these areas among women. The data derived from the Helsinki Health Study, and from collaborative partners at the Whitehall II Study, University College London, UK, and the Toyama University, Japan. In Helsinki, the postal questionnaires were mailed in 2000-2002 to employees of the City of Helsinki, aged 40 60 years (n=8960). The questionnaire data covered e.g., socio-economic indicators and working conditions such as Karasek s job demands and job control, work fatigue, working overtime, work-home interface, and social support. The outcome measures consisted of smoking, drinking, physical activity, food habits, weight gain, obesity, and symptoms of angina pectoris. The international cohorts included comparable data. Logistic regression analysis was used. The models were adjusted for potential confounders such as age, education, occupational class, and marital status subject to specific aims. The results showed that working conditions were mostly unassociated with health behaviors, albeit some associations were found. Low job strain was associated with healthy food habits and non-smoking among women in Helsinki. Work fatigue, in turn, was related to drinking among men and physical inactivity among women. Work fatigue and working overtime were associated with weight gain in Helsinki among both women and men. Finally, work fatigue, low job control, working overtime, and physically strenuous work were associated with symptoms of angina pectoris among women in Helsinki. Cross-country comparisons confirmed mostly non-existent associations. High job strain was associated with physical inactivity and smoking, and passive work with physical inactivity and less drinking. Working overtime, in turn, related to non-smoking and obesity. All these associations were, however, inconsistent between cohorts and genders. In conclusion, the associations of the studied working conditions with the behavioral risk factors lacked general patters, and were, overall, weak considering the prevalence of psychosocially strenuous work and overtime hours. Thus, based on this study, the health effects of working conditions are likely to be mediated by adverse behaviors only to a minor extent. The associations of work fatigue and working overtime with weight gain and symptoms of angina pectoris are, however, of potential importance to the subsequent health and work ability of employees.
  • Luotola, Kari (Helsingin yliopisto, 2011)
    The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.
  • Kauppi, Paula (Helsingin yliopisto, 2001)
  • Karvala, Kirsi (Helsingin yliopisto, 2012)
    Indoor dampness and mold are associated with adverse respiratory health effects, of which asthma is the most frequently diagnosed disease. Respiratory and non-specific symptoms related to building dampness are usually transient, but persistent symptoms appear to be common for some persons, even despite building repairs or a change to an alternative work environment. The study assessed methods for diagnosing occupational asthma induced by indoor dampness and mold. A retrospective analysis of a group of patients examined at the Finnish Institute of Occupational Health in 1995-2004 was conducted. All of the examined 2200 workers had respiratory symptoms related to workplace dampness. According to this study, serial PEF monitoring is an applicable method in the clinical evaluation of occupational asthma induced by indoor dampness. An individual exposure assessment can be based on descriptions of the extent and location of the moisture and mold damage in the building structures and on microbial measurements. Specific IgE-mediated sensitization to molds occurs, but in a small proportion of cases only. Mechanisms of dampness-related asthma remain largely unknown. The patients were followed-up with a questionnaire survey 3-12 years after the baseline examinations. The results suggest that, for workers with work-related asthma-like symptoms occurring in relation to indoor dampness and molds at work, continuing to work in such environments creates a risk for developing asthma. Preventive measures to avoid further exposure seem to be relevant in order to prevent the development of asthma. In practice, such measures would involve the remediation of moisture and mold damage or the relocation of workers to a non-moisture damaged environment. Follow-up at occupational health services is recommended for patients with respiratory symptoms related to workplace dampness. In addition, the long-term effects on the quality of life and work ability of these workers were evaluated. Patients diagnosed with occupational asthma had worse outcomes than did patients with non-occupational asthma or only respiratory symptoms without asthma at the baseline. A perceived poor social climate at work and poor experiences with the supervisor s cooperation at an early stage of symptoms were determinants for impaired self-assessed work ability and early withdrawal from work. In addition, multiple, persistent, indoor-air symptoms at the time of the follow-up increased the risk of poor self-assessed work ability. The results are in accordance with the widely recognized fact that the causes of disability are multifactorial and are not associated with medical conditions only. More apt measures, for example, early support and workplace management practices concerning work ability, are required.
  • Utge, Siddheshwar J. (Helsingin yliopisto, 2012)
    Depression is a complex psychiatric disorder that comprises a variety of symptoms. In addition to depressed mood state, depression has symptoms of disturbed sleep such as early morning awakenings and fatigue. Poor sleep has been demonstrated to be one of the modifiable risk factors in the onset of depression. However, the mechanisms remain largely unknown. In the present study, depressive patients from the Finnish population-based samples were grouped according to the presence or absence of disturbed sleep. The genetic background of depression was hypothesized to be different between the groups. The regulation of sleep, and of mood, was assumed to partly share a common genetic background. The aim of this thesis was to identify genetic variants associated with depression and disturbed sleep in order to gain a better understanding of this hypothesis in the population-based Finnish samples. First, the association between genetic markers from 14 functionally-relevant candidate genes was assessed. These genes were related to serotonergic and glutamatergic neurotransmission, to neural plasticity, and to the hypothalamic-pituitary-adrenal axis (HPA-axis) with depression, depression with early morning awakenings, and depression with fatigue in a sample from the population-based Health 2000 survey. Overall, 1654 individuals were studied (384 depressed patients and 1270 population-matched controls). The data suggested that allelic variants from a gene coding for a key regulatory protein of the serotonergic neurotransmission system, TPH2, is associated with depression accompanied by fatigue in females. An association between a numbers of genes related to glutamatergic neurotransmission and neural plasticity, such as GAD1, GRIA3, and BDNF with depression accompanied by fatigue in females. A significant association between CREB1, a neural plasticity related gene, and depression in men, was also identified. Of the genes related to the HPA-axis, an association was found between CRHR1 and depression accompanied by early morning awakenings in females. The hypothesis was then expanded to encompass 18 genes from the circadian system in the same study subjects (N=1654) from the Health 2000 cohort. In this study, a significant association of two distinctive allelic variants of TIMELESS was associated with depression accompanied by fatigue (Permutation-based corrected empirical P=0.0056), to seasonal mood fluctuation (Pointwise P=0.016) in females, and with depression accompanied by early morning awakenings (Permutation-based corrected empirical P=0.0374) in males. In an independent set of 1512 control individuals (Genmets (D-) sample) from the complete Health 2000 cohort, the same variant was also associated with seasonal mood fluctuation (Pointwise P=0.036) in females, and with early morning awakenings (Pointwise P=0.038) or fatigue (Pointwise P=0.0016) in healthy males. Finally, the shared genetic background for sleep and mood in healthy individuals (N=3147) drawn from the population-based Health 2000 and FINRISK study 2007 survey was examined. In this study, for association analyses with sleep duration, 23 variants from 12 candidate genes were selected that had shown association (P less than 0.05) with depression and disturbed sleep in studies I and II. A significant association of a GRIA3 variation with sleep duration in females (Permutation-based corrected empirical P=0.00001) was identified. The frequency of the allele which associated with depression was highest among females who slept for 8 hours or less in all age groups younger than 70 years. However, no prominent associations were found among males, suggesting a sex-specific effect for the X-chromosomal GRIA3 gene. In conclusion, these results support the involvement of genes related to serotonergic (TPH2) or glutamatergic neurotransmission (GAD1, GRIA3), to neural plasticity (CREB1), to the HPA-axis (CRHR1), and the circadian system (TIMELESS), in the genetic aetiology of depression and disturbed sleep. The results obtained in this thesis support the hypothesis that the different phenotypes of depression and disturbed sleep would also be genetically distinct. Depression is heterogeneous and its genetic background may be partly different in women and men. This study also shows that the regulation of sleep and of mood may have a common genetic background.