Lääketieteellinen tiedekunta: Recent submissions

Now showing items 1-20 of 2071
  • Haaramo, Anu (Helsingin yliopisto, 2019)
    Crohn´s disease (CD) is a chronic inflammatory disease that can affect any part of the digestive tract, including the mouth. The reported prevalence of oral manifestations in CD varies widely and ranges from 0.5% to 80%. Orofacial granulomatosis (OFG) is a rare chronic inflammation presenting in the oral cavity and around the mouth without intestinal involvement. Typical is labial or facial oedema and ulceration in the oral mucosa. Melkersson-Rosenthal syndrome (MRS) is considered to be one manifestation of OFG, where granulomatous inflammation and oedema is accompanied by recurrent facial palsy and fissured tongue. Oral lesions in CD, OFG, and MRS cannot be clinically or histologically distinguished. Patients with OFG may develop CD and it is debated whether OFG is an oral manifestation of CD, or a separate inflammatory disorder. In addition, it is unknown whether patients with MRS are prone to develop CD in follow-up. The aim of this thesis was to investigate and compare conditions presenting with orofacial symptoms —OFG, CD, and MRS— and study the connection between these entities. This thesis consists of studies on patients with pediatric-onset OFG, patients with pediatric-onset CD who had reached adulthood and patients with triad or oligosymptomatic MRS or its monosymptomatic form cheilitis granulomatosa (CG). Otorhinolaryngological and dental examinations, evaluation of nutrition from food records, and laboratory tests were included. Orofacial findings were photographed and recorded using a structural schema. Possible factors predicting bowel disease in orofacial patients were of special interest. In patients with CD, health-related quality of life (HRQoL) was evaluated. Blood samples were collected to investigate inflammatory markers and anti-Saccharomyces cerevisiae antibodies A (ASCAbA) and G (ASCAbG). In patients with OFG, the HLA-haplotypes (Human leucocyte antigen) were also examined to evaluate the role of HLA in the pathogenesis of OFG. Stool samples were collected to evaluate faecal calprotectin, a surrogate marker for intestinal inflammation. We found that prognosis for OFG is good. Symptoms tend to diminish during the course of the disease. Of the patients with pediatric-onset OFG, 72% developed CD. Elevated ASCAbA may serve as a factor predicting the underlying or developing CD in patients with OFG. Examination of HLA-haplotypes showed that tissue antigen HLA-B*44 might be a marker for OFG, but further studies are needed. In patients with CD the oral symptoms seem to be inactive when the gut disease is under good therapeutic control. However, patients with CD and a history of perianal abscessing disease seem to be prone to oral manifestations. Of the patients with MRS or CG, in total 11.1% had a diagnosis of inflammatory bowel disease (IBD) which suggests a link between MRS and IBD, not only CD but ulcerative colitis as well. None of the nutritional factors or dental findings correlated to oral findings in patients with OFG or pediatric-onset CD. Otorhinolaryngological findings were minor in both groups. Thus, OFG and CD do not seem to increase otorhinolaryngological comorbidity.
  • Kaltiainen, Hanna (Helsingin yliopisto, 2019)
    Mild traumatic brain injuries (mTBI) are common, and while most patients recover well, there is a minority of patients suffering from prolonged symptoms lasting over three months. Pathological processes provoke low-frequency (0.5 - 7 Hz) oscillatory brain activity, measurable with electroencephalography (EEG) and magnetoencephalography (MEG). After mTBI, low frequency activity (LFA) is hypothesized to arise from cortical neurons suffering from de-afferentation after traumatic axonal injury. The natural evolution and prognostic value of low-frequency activity (LFA) measured with MEG, however, is not yet firmly established and reliable biomarkers for cognitive complaints after mTBI are lacking. The aim of this thesis was to examine the occurrence and natural evolution of low frequency activity (LFA) after mild traumatic brain injury (mTBI), and to assess its prognostic value in predicting those with prolonged symptoms. Additionally, we wanted to examine the effect of mTBI to brain oscillatory activity during cognitive tasks and find indicators for altered processing. The existence of LFA in healthy subjects might, however, hamper its’ diagnostic value. Therefore, in Study I we created a reference database of resting-state oscillatory brain activity and observed LFA in only 1,4% of healthy subjects’ MEG recordings. The Study II assessed the occurrence and evolution of LFA in resting-state MEG recordings of mTBI patients. At a single-subject level, 7/26 patients presented aberrant 4–7 Hz (theta) band activity; 3/7 patients with abnormal theta activity were without any detectable lesions in MRI. Of the twelve patients with follow-up measurements, five showed abnormal theta activity in the first recording, but only two in the second measurement, implying the importance of early measurements in clinical settings. The presence of LFA was not, however, correlated with the prevalence of self-reported symptoms. The Study III concentrated on the modulation of oscillatory activity during cognitive tasks, Paced Auditory Serial Addition Test (PASAT) and a vigilance test. Attenuation of cortical activity at alpha band (8 – 14 Hz) during PASAT compared with rest was stronger in patients than in controls (p≤0.05, corrected). Furthermore, the patients presented significant attenuation of oscillatory activity also in the left superior frontal gyrus and right prefrontal cortices which was not detected in controls. Spectral peak amplitudes of areal mean oscillatory activity at the alpha band were negatively correlated with the patients’ neuropsychological performance (p<0.01, uncorrected). Areal alpha frequency modulation during PASAT compared with rest was altered in patients: While the alpha peak frequency increased occipitally and remained stable parietally in controls, it was stable occipitally and decreased parietally in mTBI patients (p=0.012). According to our studies, LFA, especially theta-band oscillatory activity can provide an early objective sign of brain dysfunction after mTBI, and cortical oscillatory activity during a demanding cognitive task (PASAT) is altered after mTBI. Our observations suggest that both aberrant theta-band activity and the altered alpha activity during cognitive tasks may offer clinically relevant indicators of changes in neural processing after mTBI.
  • Haapanen, Markus (Helsingin yliopisto, 2019)
    The proportion of those aged 60 years and older is expected to double from 12 to 24 per cent by the year 2050. The prevalence of frailty increases rapidly with older age and is characterized by loss in biological reserve and resistance to stressors across several physiological systems. Frail people are at an increased risk of adverse health outcomes including hospitalization and premature mortality. Effective prevention of frailty requires knowledge on its risk factors across the life course. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that early life influences may be important in determining disease risk in adulthood. There is evidence of early life influences in the pathogenesis of chronic diseases including cardiovascular disease and type 2 diabetes. The aim of the present study was to investigate early life exposures and frailty from a life-course perspective. The present study uses data from the Helsinki Birth Cohort Study that includes 8,760 individuals born in Helsinki in 1934-1944. A random subset of participants (n=2,902) was invited to participate in a baseline clinical examination; of those 2,003 participated in 2001-2004. Of these, 1,094 out of the invited 1,404 participated in a follow-up clinical examination in 2011-2013. Frailty was measured at the follow-up examination using the Fried phenotype model in participants with a mean age of 71 years. Data on infant and childhood development and exposures were extracted from healthcare records and national registers. Weight, length and body mass index (BMI) at birth were inversely associated with the presence of frailty in both sexes. Men who were frail in old age had experienced accelerated BMI gain from the age of 2 to 11 years compared to non-frail men. Similarly, men who as boys experienced wartime separation from both parents were at an increased risk of frailty compared to non-frailty. No similar associations were observed in women. Those who worked in manual labor occupations as adults were at an increased risk of frailty compared to those who worked as officials. Short leukocyte telomere length at the mean age of 61 years was associated with frailty at the mean age of 71 years. Furthermore, frail individuals had shorter telomeres at the mean age of 71 years compared to non-frail individuals. No association between telomere shortening and frailty was observed. Several life-course determinants of frailty were identified. Associations between factors taking place during gestation and early life suggest that susceptibility to frailty may be programmed early in life. Moreover, the association between BMI growth and wartime separation and frailty may vary by sex. Leukocyte telomere length may be a meaningful frailty biomarker in its ability to detect processes that are associated with frailty. The prevention of chronic disease and frailty should start already at a young age e.g. through the promotion of the health of mothers in childbearing age.
  • Vanhanen, Reetta (Helsingin yliopisto, 2019)
    A diverse T cell receptor (TCR) repertoire is essential for the adaptive immune system. T cells have to recognise and react to a huge variety of potential pathogens and at the same time maintain tolerance to self-antigens. TCR repertoire is established in the thymus during T cell development. Previous estimates of TCR diversity have studied the mature repertoire in the peripheral blood, identifying 1-3 x 106 unique TCRβ and 0.5 x 106 TCRα sequences, but the human intrathymic diversity has not been previously measured. In this thesis I provide the first estimate of the total TCR diversity in the human thymus. We have used high-throughput TCR sequencing and detected up to 10.3 x 106 unique TCRβ sequences and 3.7 x 106 TCRα sequences, which sets a new lower limit for TCR diversity. Computational estimators preseq, DivE and Chao2 produced 40 to 70 x 106 unique TCRβ sequences and 60 to 100 x 106 TCRα sequences in the human thymus. Somatic recombination produces a diverse thymic TCR repertoire that includes also the thymocytes instructed to develop into natural regulatory T cells. They are characterised by stable expression of the forkhead/winged-helix transcription factor FOXP3 and demethylation of Treg-specific-demethylated region (TSDR). Regulatory T cells develop as a separate cell lineage in the thymus and commitment occurs already at the CD4+CD8+ double positive (DP) stage. TCR-mediated signalling instructs the selection to the regulatory lineage and cytokines promote Treg development. We have used high-throughput TCR sequencing and methylation analysis of TSDR to track the timing of Treg commitment. Comparing the common TCR sequences showed that regulatory DP CD25+ and CD4SP CD25+ populations were clearly closer to each other than any other population, indicating that they are part of the common clonal and developmental pathway. The methylation analysis of TSDR in the DP and CD4+ single positive (SP) regulatory populations showed no difference between them. Thus a stable Treg phenotype can already be detected at the double positive stage. In this thesis I have studied the role of common γ chain cytokines in regulatory T cell development in the human thymus. Since thymic commitment of human Tregs begins at the double positive stage I have studied the effects and mechanisms of interleukin-2, interleukin-7 and interleukin-15 at the DP phase. Previous studies in murine models have established a two-step model. According to these studies, TCR signalling upregulates interleukin-2 receptor (IL-2R) and increases the responsiveness of developing Tregs to common γ chain cytokines that induce the expression of FOXP3. IL-7 has been considered to have a minor role in Treg development since mature peripheral Tregs express low levels of interleukin-7 receptor (IL-7R). We show that during thymic development DP FOXP3+ thymocytes upregulate IL-7R and are responsive to IL-7. At the DP stage TCR-signalling dictates Treg maturation during positive selection and IL-15 enhances Treg survival. After positive selection IL-2 and IL-7 increase the expression of FOXP3 and anti-apoptotic protein BCL-2 (B cell lymphoma 2) and promote Treg phenotype. DP FOXP3+ cells are highly susceptible to apoptosis but all three cytokines enhance their survival. Suppressing apoptosis is a key mechanism in promoting Treg development at the DP and CD4SP stage in the human thymus.
  • Pohjoranta, Elina (Helsingin yliopisto, 2019)
    In Finland more than every third abortion is performed to a woman with history of previous abortion, which indicates suboptimal contraceptive use and inadequacy of postabortion contraceptive services. Previous studies have shown that long-acting reversible contraceptive (LARC) methods, especially intrauterine devices (IUD) are most efficient in preventing repeat unwanted pregnancy. IUDs can usually be inserted at the time of surgical termination of pregnancy (TOP). After medical TOP (MTOP), an IUD can be inserted when the abortion is shown to be complete, commonly 1–4 weeks afterwards, according to various recommendations. However, attendance at post-abortion contraceptive visits is poor, and thus the planned IUD insertion often fails. We have conducted a randomized trial assessing early postabortal IUD insertion provided comprehensively as a part of abortion services. Altogether 748 women undergoing a first trimester TOP were recruited and randomized into two groups. Women in the intervention group received an IUD (either a LNG-IUS or a Cu-IUD, according to the woman’s choice), at the hospital providing the TOP, either at the time of surgical TOP or at a follow-up visit 1–4 weeks after MTOP. Women in the control group were prescribed oral contraceptives and advised to contact their primary health care (PHC) unit for IUD insertion, according to the current practice and the national guideline. All study participants were provided with a questionnaire assessing anxiety, quality of life (QoL) and sexual well-being at baseline, as well as three months and one year after the TOP. The primary outcome was to assess the effects of the intervention on the incidence of subsequent TOP, when compared to the normal practice. In this thesis, the results of the first year are described. In addition, incidence of complications related to early IUD insertion, as well as compliance to post-abortion care and IUD insertion were assessed in women choosing MTOP. As secondary outcomes, mental health and sexual well-being during the first year after TOP was assessed. During the first year of follow-up after TOP, a significant difference between the two study groups was seen in the attendance at follow-up, in receiving the planned IUD, and in the incidence of repeat unwanted pregnancy. The early insertion of IUD after MTOP was safe and did not increase the risk of severe complications or IUD expulsions. In the entire study population general reduction of anxiety was seen at three month and one year, compared to baseline. Concordantly, a better quality of life was generally reported after three months. Regarding overall sexual well-being, there was no significant change during the follow-up. Better rates in the sexuality questionnaire, i.e. better sexual well-being, were associated with having a relationship, and correlated positively with frequency of intercourse, quality of life, and negatively with anxiety. Contraceptive method appeared to have little effect on overall sexual well-being. However, at three months, IUD users had better scores of sexual well-being, compared to users of other methods. This study shows that providing TOP and IUD insertion comprehensively at the same unit with minimal delay results in higher attendance at follow-up, higher uptake of IUD and a reduced need of subsequent TOP during one-year of follow-up.
  • Rajendran, Jayasimman (Helsingin yliopisto, 2019)
    A rare homozygous BCS1Lc.A232G (Ser78Gly, p.S78G) mutation in infants causes GRACILE syndrome, which is a severe mitochondrial respiratory chain complex III (CIII) disorder resulting in multiple organ dysfunction and early lethality. Pathogenesis mechanisms have been studied using our viable Bcs1lp.S78G knock-in mouse model. The mouse model replicates most clinical phenotypes, such as growth restriction, hepatopathy, and tubulopathy. Like patients, the survival of homozygous mice is reduced (to 35-45 days, P35-P45 in the C57BL/6JBomTac background), mainly because of severe hypoglycemia. Aiming to improve the glycemic balance we performed an intervention with a high sugar (60% dextrose) diet. This diet did not improve energy metabolism and resulted in slightly decreased survival despite apparent normalization of some plasma metabolites. For subsequent studies, we bred the Bcs1lc.A232G mutation into a C57BL/6JCrl background, in which the survival was five-fold longer (approximately 200 days). Moreover, the extended survival brought novel phenotypes, such as encephalopathy and late-onset cardiomyopathy. In this genetic background, we investigated the effect of ketogenic diet on disease progression. The ketogenic diet had a beneficial impact on liver disease, but it had adverse effects upon long-term feeding, resulting in shortened survival. In the third study, we introduced an alternative oxidase (AOX) transgene into the Bcs1lp.S78G mice to improve respiratory chain function. The ubiquitous expression of AOX, which should bypass electron transfer and relieve CIII blockade, prevented lethal cardiomyopathy and renal-tubular atrophy, and delayed focal astrogliosis in the somatosensory cortex of the brain. The beneficial effects of AOX extended the median survival of the homozygotes to median P590. The main conclusions from these studies are that the Bcs1lp.S78G mice in a C57BL/6JCrl background present with both the known early-onset manifestations of GRACILE syndrome and some later onset manifestations found in other CIII deficiencies. The dietary interventions had limited benefits, probably because of a severe course of the disease. In contrast, bypassing the blocked electron flow using AOX had a robust beneficial effect, mainly in tissues or cells with high ATP demand such as the heart and renal proximal tubular cells.
  • Vuokko, Aki (Helsingin yliopisto, 2019)
    Symptoms attributed to indoor air work environments may persist even without observed significant deficiencies in indoor air quality. This kind of symptomatology may lead to disability, which can cause severe restrictions in daily life and interfere with work participation. The aim of this thesis was to characterize indoor air-related disability and develop interventions for symptom management. This thesis consists of four individual studies. The first study recruited 55 participants with indoor air-related symptoms and work disability from consecutive patients examined at the Finnish Institute of Occupational Health for a suspected occupational disease. In the randomized controlled trial (RCT), the physician and psychologist counseling for symptom management showed no effect on self-assessed work ability and quality of life (QOL). In the second study, a thorough clinical characterization was carried out among 12 patients referred for evaluation due to responsiveness to workplace indoor air. Patients’ symptoms manifested in multiple organ systems, with no medical explanation and in spite of workplace interventions and the absence of exposure-related causes of symptomatology. Co-occurrent diseases were frequently present. Patients had concerns over the loss of health due to indoor air. Almost all the patients reported reactions triggered by indoor molds; the majority reported sensitivity to odorous chemicals and minority to electromagnetic fields. Avoidance of certain environments had led to restrictions in several life areas. In the third study, a RCT setting was created to evaluate the effect of cognitive-behavioral therapy and psychoeducation on workers’ QOL and work ability. This study recruits patients who search medical advice from occupational health services due to recurrent medically unexplained multiorgan symptoms and disability attributed to the indoor work environment. In the fourth study, 680 pregnant women evaluated in questionnaire survey their intolerance - time prior to their pregnancy - attributed to 12 environmental factors and its associations with symptoms, work ability and functioning in daily life. The manifestations of intolerance to environmental factors formed an increasing severity continuum, ranging from annoyance to severe disability. All of those who experienced significant difficulties (2.2%) reported intolerance to indoor molds, and majority also to chemicals. Chronic indoor air-related symptomatology fulfills criteria for idiopathic environmental intolerance (IEI). A similar phenomenon, symptomatology and comorbidity, is described in functional somatic syndromes (FSS). Effective treatment interventions are required for indoor air-related disability prevention. The usefulness of treatment approaches that have shown to be efficient for FSS should be evaluated in the treatment of IEI. As regards environmental intolerance with severe disability, indoor molds seem to be the most common environmental factor in Finland.
  • Wikström, Annamaria (Helsingin yliopisto, 2019)
    Psychotic disorders are severe mental disorders with delusions, hallucinations and severe behavioural abnormalities that lead to a loss of contact with reality. Schizophrenia is the most severe psychotic disorder, but psychotic symptoms are not specific to schizophrenia. In addition to psychotic symptoms, alterations in drive and volition, affective dysregulation and cognitive deficits, such as difficulties in memory, attention and executive functioning, are often found in subjects with psychotic disorders. Currently, it is thought that vulnerability to psychosis is a continuum with individual differences existing in a person’s vulnerability to developing a psychotic disorder. Vulnerability may be due to a combined effect of personal genetic background and certain environmental stressors. Familial vulnerability is a known risk factor for future psychosis. Severe, acute forms of psychotic symptoms characterize disorders such as schizophrenia and psychotic bipolar disorder, but milder, subclinical psychotic-like experiences are also present in the general population. From previous studies it is known that non-psychotic family members of schizophrenia patients have mild cognitive deficits that manifest in neuropsychological tests. Also, among young age groups, subjects with psychotic-like experiences have often been found to have cognitive deficits which together with psychotic-like experiences have been found to predict future psychosis, at least in clinical high-risk populations. The present study aimed to explore aspects of vulnerability to psychotic disorders in two middle-aged populations who presumably have a more heightened susceptibility to psychotic disorders than the general population. Samples were drawn from large population-based studies, a schizophrenia family study and The Health 2000 and 2011 studies, from The National Institute for Health and Welfare (previously National Public Health Institute). It was found that among middle-aged subjects, healthy siblings from families with schizophrenia had mild cognitive deficits, even in the absence of a current non-psychotic psychiatric disorder. Elevated physical or social anhedonia was not found in siblings, suggesting that elevated anhedonia is more related to the illness than familial liability in middle-aged (above peak risk age for conversion to psychosis) subjects with a familial risk for psychosis. Psychotic-like experiences in middle-aged subjects may be more benign regarding risk for future psychosis than in younger age groups, since neither psychotic-like nor manic-like experiences at baseline predicted psychosis during eleven-year follow-up. However, results should be replicated in larger study groups, and if possible, with a longer follow-up period.
  • Puustinen, Lauri (Helsingin yliopisto, 2019)
    Aims: This thesis includes one study (Study I) focused on epidemiological data regarding autoimmune hepatitis (AIH) and three studies (Studies II-IV) on follow-up of AIH. Patients and methods: Patients with AIH code K73.2 or K75.4 with special reimbursement in the Social Insurance Institution of Finland registry were included. Data from the Finnish cancer register were used to calculate standardized mortality ratios (Study I). All patients with AIH diagnosis in Helsinki University Hospital were included in the retrospective study of the impact of liver histology on disease progression (Study II). Twelve patients with AIH were investigated with magnetic resonance spectroscopy, liver biopsy, and transient elastography (Study III). Follow-up biopsies of all Finnish liver transplant recipients with AIH as an indication for transplantation were combined with clinical data to evaluate the prognosis and risk factors for AIH recurrence and graft loss (Study IV). Results: We showed that the median AIH incidence between 1995 and 2015 was 1.0/100,000/year (1.2/100,000/year in women and 0.38/100,000/year in men) and increased from 0.28/100,000 to 1.0/100,000 during the study period. The prevalence of AIH in 2015 was 14/100,000, 23/100,000 in women and 6.6/100,000 in men). The standardised mortality ratio was increased in all age groups and both genders. The most prevalent excessive causes of mortality when compared to the standard population were hepatocellular carcinoma, liver cirrhosis, and AIH per se (Study I). We identified the following prognostic variables for advancing fibrosis or cirrhosis in follow-up biopsies: interface or total inflammation, necrosis, cholestasis, or rosette formation in the baseline biopsy. If inflammation in the follow-up biopsies was constantly grade two or more in the Metavir scale, the hazard ratio (HR) for cirrhosis was 5.1, (95 % Confidence interval (CI) 1.6-16.2), p<.005). Fibrosis progressed in 42% of patients, remained stable in 39% and resolved in 18% (Study II). When compared to liver histology, magnetic resonance spectroscopy revealed distinctive ratios of selected hepatocyte metabolites in patients with advanced fibrosis or active inflammation in 12 consecutive AIH patients. Transient elastography was ineffective in fibrosis quantification (Study III). After liver transplantation, AIH recurred in 36% of patients; the median time until recurrence was 5 years (range 1.1-15 years). Recurrent AIH did not affect patient or graft survival. Patient and graft survival were 94% and 86% at 1 year, 86% and 91% at 5 years, and 77% and 74% at 10 years, respectively. Immunosuppression without mycophenolate mofetil or azathioprine increased the risk of AIH recurrence (Study IV). Conclusions: The incidence and prevalence of AIH is similar in Finland as reported in other countries. Female preponderance is notable. We demonstrate that, especially in women, AIH occurs at all ages and often in the elderly. Hepatocellular carcinoma is rare but statistically is the most important cause of excess death. While liver biopsies might play a role in the follow-up of AIH, there are currently no good prognostic models that encompass liver histology. Ongoing histological inflammation is a risk factor for fibrosis progression and development of cirrhosis. Magnetic resonance imaging of the liver is a promising follow-up tool and is acceptable to patients. Transient elastography was not useful in this setting. AIH recurs after liver transplantation in 36% of patients but is of primarily benign disease course.
  • Rajala, Kaisa (Helsingin yliopisto, 2019)
    Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic disease of unknown cause. IPF patients exhibit a high symptom burden that influences their health-related quality of life (HRQOL). Its variable disease trajectory is comparable to that of many malignant disorders. The primary aim of the study was to evaluate IPF patients’ symptom burden and HRQOL from the perspective of approaching death and their end-of-life (EOL) care. The secondary aim was to identify possible predictors for escalating disease trajectory and palliative care need. Patients were identified from the FinnishIPF registry. First, we focused on 59 deceased IPF patients by reviewing their medical records and death certificates. The second and third studies focused on HRQOL and symptoms using survey methodology, namely the Modified Edmonton Symptom Assessment Scale (ESAS) and the Modified Medical Research Council Dyspnea Scale (MMRC) for symptom assessment and the RAND 36-Item Health Survey for HRQOL. In April 2015, we sent HRQOL and symptom questionnaires to 300 patients in the FinnishIPF registry, and the 82% who were willing to participate were included in our study population. Follow-up questionnaires were sent every six months. The hospital was found to be the most common place of death; thus, patients received aggressive care until the end. EOL decisions were made late (42% of decisions were made <3 days before death), if at all. Patients had high symptom burden, which increased during the last months. HRQOL was extremely low already two years before death and decreased as death approached. MMRC scores ≥2 indicated higher symptom burden and decreased HRQOL. This study showed the detrimental impact of IPF on patients’ symptoms and HRQOL as early as two years before death. Our findings support the use of MMRC as a screening tool for palliative care need. EOL planning was often performed, if at all, in the last days of life. We suggest that patients’ HRQOL improves with early-integrated palliative care, thus potentially decreasing the use of unnecessary and expensive health care resources at the end of life.
  • Sarkanen, Tomi (Helsingin yliopisto, 2019)
    After the 2009-2010 pandemic H1N1 vaccination campaign the incidence of narcolepsy increased sharply in countries where the Pandemrix vaccination was used. An increased incidence was observed also in China, where vaccine coverage was very low. Moreover, epidemiological studies are prone to biases, and animal studies suggest that H1N1 virus infection per se might be able to manifest a narcolepsy-like phenotype. Therefore, some controversy exists in the association between vaccination and narcolepsy. pNC cases had severe onset and common psychiatric comorbidity, which warranted thorough analysis of the pNC phenotype. Tools to measure narcolepsy symptoms or to help in diagnostics remain scarce. Our first aim was to systematically analyze the magnitude of the risk of H1N-vaccine-associated narcolepsy (pNC) and to examine whether an increased association emerged with any other vaccine or H1N1 virus infection. In Studies II and III, we aimed to determine whether differences were present in clinical, polysomnographic (PSG), or actigraphic (ACT) characteristics between pNC and sporadic narcolepsy (sNC). In study IV we aimed to validate the Ullanlinna Narcolepsy Scale (UNS), a population screening tool for narcolepsy published in 1994, in clinical population. Based on the meta-analysis in Study I, the relative risk of narcolepsy was increased 5- to 14-fold in children and adolescents and 2- to 7-fold in adults in the countries where Pandemrix vaccine was used widely (Finland, Sweden, Norway, France, England, Ireland). The vaccine-attributable risk in children and adolescents was 1 per 18,400 vaccines. The risk seems to have increased for two years and was not associated with any other vaccine. In study II we analyzed PSG and ACT characteristics of 69 pNC and 57 sNC subjects and in study III sleep questionnaires of 26 pNC and 25 sNC subjects. We found that pNC patients had shorter diagnostic delays, were diagnosed younger, had less periodic limb movements in sleep, and had earlier sleep-wake rhythm than sNC patients. The clinical course was highly variable in a two-year follow-up. There were no significant differences between pNC and sNC questionnaire scores. In study IV we analyzed questionnaire scores of patients with narcolepsy type 1 (n = 89), narcolepsy type 2 (n = 10), sleep apnea (n = 37), restless legs syndrome or periodic limb movement disorder (n = 56), other sleep-related disorders (n = 56), or other hypersomnias (n = 24). Sensitivity and specificity of the UNS in separating NT1 from other disorders were 83.5-85.4% and 84.1-87.6%, respectively. The UNS had a strong negative correlation with hypocretin-1 levels and mean sleep latency in MSLT.
  • Salem, Abdelhakim (Helsingin yliopisto, 2019)
    Background and objective: Oral lichen planus (OLP) is a common immune disorder of the oral mucosa, which is categorized as an oral potentially malignant disorder (OPMD) to highlight its potential progression to oral cancer. Oral cancer commonly affects the mobile tongue as oral tongue squamous cell carcinoma (OTSCC), which has dismal prognosis. Histamine signals via four G protein-coupled histamine receptors (H1R-H4R). Classical H1R and H2R medications are ineffective in treating OLP or OTSCC patients. The discovery of H4R has paved the way for novel perspectives in histamine research by modulating immune responses. We therefore hypothesized that H4R is involved in the pathogenesis of OLP and may contribute to oral carcinogenesis. Materials and methods: Tissue samples from OLP, oral epithelial dysplasia (OED) and OTSCC patients, and from healthy control participants were utilized. The in vitro experiments were performed on normal human oral keratinocytes (HOKs), two OTSCC-derived cell lines (HSC-3 and SCC-25), normal salivary gland cells, in addition to supernatants from activated human mast cells (MCs). For in vitro internalization and functional assays, two specific H4R ligands (agonist HST-10, and inverse agonist ST-1007) were used. Protein expression of histamine receptors, transporters and metabolizing enzymes, and other antigens were assessed in tissue samples and cell lines by immunohistochemistry and immunofluorescence staining. The expression levels of mRNA were quantified by qRT-PCR and the highly-sensitive droplet-digital PCR technology. Western blotting assays were performed to assess apoptotic markers following H4R stimulation, while flow cytometry was used to study Annexin-V and PI labelling of dead cells. Histamine levels were analysed using high-performance liquid chromatography. Results: Briefly, H4R is expressed in healthy oral epithelial cells on mRNA and protein levels, and they were able to fully internalize H4R-ligands in a time-dependent manner. In contrast, samples from OLP, OED and OTSCC patients exhibited lower H4R level, which was negatively correlated with MC-count and OTSCC-grade. We also reported that normal HOKs are histamine-producing cells—fully equipped with histamine synthesizing, transporting and degrading molecules. Interestingly, OLP samples exhibit high levels of the histamine synthesizing and transporting molecules, whereas histamine degrading enzyme was strongly inhibited. HOKs showed a dose-dependent Lipopolysaccharides (LPS)-driven release of histamine, while high histamine levels inhibited epithelial adhesion molecules. We next showed that toll-like receptors (TLRs) are essential players in OLP. TLRs were upregulated in OLP lesions, particularly for TLR4, which is necessary for LPS signalling. Importantly, LPS and MC-mediators regulated several oral oncogenes, while H4R-stimulated cells revealed a marked resistance to apoptosis. Furthermore, LPS and histamine influenced human beta defensin 2 (hBD-2) expression, which was highly induced in OLP. Unexpectedly, hBD-2 protein was subsided in OTSCC tissues with a marked downregulation of its transcript in cancer cells. Histamine synergistically induced TNF-α- and IFN-γ-mediated hBD-2 production in HOKs. Interestingly, targeting H4R seems to regulate TNFα- and LPS-mediated expression of hBD-2. Conclusions: Briefly, human oral epithelial cells are “non-professional” histamine producing cells—capable to synthesize, release, and degrade low levels of endogenic histamine. High levels of histamine may downregulate H4R as well as key integrity molecules in HOKs and may enhance subsequent bacterial invasion in OLP. In this regard, our findings suggest a potential role of TLRs in OLP pathogenesis, by mediating LPS signalling and enhancing further immune response and histamine production. In addition, our results indicate that histamine/H4R crosstalk signalling with LPS and MCs could in part be involved in OLP and the potential inflammation-driven tumorigenesis. This was further supported by the ability of H4R to regulate cell apoptosis and modulate antibacterial response in HOKs. Further functional and preclinical studies are therefore warranted.
  • Kaye, Sanna (Helsingin yliopisto, 2019)
    Body weight and the development of obesity-related metabolic complications have multifactorial genetic background. However, acquired factors may modify the function of the genes and contribute to the development of obesity and the outcome of metabolic derangements. In population-based studies, it is impossible to disentangle the contribution of genes from unique environmental factors. As monozygotic (MZ) co-twins carry identical genes, comparison of MZ twin pairs with discordance in obesity can help to elucidate the magnitude of acquired or environmental factors. With biomarker analyses we aimed to 1) characterise the derangements in blood coagulation and fibrinolysis in acquired obesity; 2) capture the magnitude of alterations in quality and quantity of serum lipoprotein particle profile in obesity; 3) examine the contribution of genetic and environmental factors in between the association of abdominal obesity and serum NMR metabolites; and 4) describe the differences in the activation of the complement system by analysing the plasma levels and the expression of the complement system related genes with microarray in subcutaneous (sc) fat and isolated adipocytes between obesity-discordant MZ co-twins. The obesity-discordant MZ twin pairs (n=14-26 pairs, age 23–36, within-pair difference in body mass index (BMI) > 3kg/m2) derive from two population-based twin cohorts FinnTwin12 and FinnTwin16. The control group comprised BMI-concordant (within-pair BMI- difference < 3kg/m2) MZ twin pairs. The genetic and environmental contributions to the association between metabolism and abdominal obesity were determined from a larger group comprising MZ and DZ twins (n=1368) from FinnTwin cohort. Several metabolic markers (lipid and glucose metabolism, inflammation, NMR metabolomics) were measured from plasma. The adipose tissue biopsies were obtained from sc adipose tissue. The body fat mass and fat distribution were assessed with imaging modalities. Data on the habitual physical exercise and eating habits were collected with questionnaires. While all measures of body composition and metabolism were similar within the BMI-concordant twin pairs, widespread derangements in blood coagulation and fibrinolysis, lipoprotein and lipid metabolism and innate immunity emerged in acquired obesity. These changes predispose to increased risk of thrombosis, diabetes and atherosclerotic vascular disease. The pro-atherogenic alterations in lipoprotein profile emerged only if the obesity was accompanied with the concomitant increase in liver fat. Both genetic and environmental factors contribute to the association between unhealthy NMR lipoprotein and metabolite profile and abdominal obesity. Shared genes determine the co-occurrence of these phenotypic traits. The altered expression of the complement system related genes occurred in sc adipose tissue, and plasma level of complement component 3a was elevated. In young adults, it is important to assess the metabolic risk of acquired obesity individually taking account for the body fat distribution together with biomarker analyses. The weight-management is crucial in primary prevention of the metabolic morbidity.
  • Kallio, Eeva-Liisa (Helsingin yliopisto, 2019)
    Dementia is an age-related, progressive and chronic syndrome, which is characterized by cognitive decline from a person’s prior performance level, neuropsychiatric symptoms, and severe inability to manage everyday activities. The most common late-life cause of dementia is Alzheimer’s disease, followed by vascular dementia, Lewy body dementia, and mixed dementia. The limited efficacy of current pharmacological treatments has directed research increasingly to various non-pharmacological therapies, such as cognitive training (CT). The findings so far are inconsistent and conflicting. The two aims of this thesis were (1) to systematically evaluate the current evidence on the effects of CT in dementia; and (2) to explore the feasibility and effectiveness of a systematic CT program for patients with established dementia in a randomized controlled trial (RCT). The effects of CT on participants’ cognition, psychological well-being, and health-related quality of life (HRQoL) were investigated in a Finnish Cognitive Intervention (FINCOG) trial among older home-dwelling patients with mild to moderate dementia who participated in regular adult day care. The systematic review focused on 35 eligible RCTs including participants with dementia, using restorative or compensatory CT programs, and concerning the effects of CT on cognition, functional abilities, psychological well-being, and quality of life of patients. Beneficial effects of CT were primarily reported on global cognition, training-specific functioning, and occasionally on mood, however, several limitations in research methodology decrease the current grade of evidence. Low methodological quality of a trial resulted predominantly from low statistical power, poorly described randomization methods, and non-robust statistical methodology. Furthermore, CT interventions were highly heterogeneous, trial drop-outs inadequately described, and intention-to-treat analysis as well as long-term follow-up infrequently used. The FINCOG participants (n = 147) were randomized in two arms: CT intervention (n = 76), and control groups (n = 71). Measures of cognition, psychological well-being, and HRQoL were assessed before the intervention, and three and nine months after baseline assessment. A systematic 12-week CT program was conducted in adult day-care centers twice a week for 45 minutes. Regular CT was found to be feasible, and subjective gain was achieved by 76 % of the feedback responders. However, CT did not improve or stabilize cognition in older adults with dementia. Moreover, the participants did not benefit from CT either in terms of their HRQoL, or psychological well-being. In conclusion, the findings of this thesis do not support the effectiveness of CT among older patients with established dementia.
  • Torvinen, Saku (Helsingin yliopisto, 2019)
    Scientific evidence based on health economic evaluations is needed to enable decisions-makers to make informed decisions on resource allocations within health care systems. Usually the economic evaluations take place within health technology assessment (HTA). The use of health economic evaluations has increased during the last two decades and will hopefully contribute towards making the best possible use of limited health care resources. Prostate cancer (PC) is the most frequently diagnosed cancer in men accounting for 29% of all the cancers diagnosed in men in Finland. There are almost 50,000 men in Finland currently living with PC. The prevalence of PC is expected to rise with aging population and improved diagnostics and treatment options. This may also increase the burden from PC on the society and, consequently, resource optimization is warranted. Health-related quality of life (HRQoL) assessments in PC is an evolving field but, based on the literature, the use of preference-based single index measures to generate health state utilities or values valid for the estimation of quality adjusted life years (QALY) gained, is scarce. This is problematic, as health state utility estimates are an integral component of cost-utility analysis, which can be considered the gold standard method in health economics today. The general aim of this thesis was to study HRQoL and costs in different states of PC. HRQoL was assessed with one cancer-specific (EORTC QLQ-C30) and two generic (EQ-5D-3L and 15D) HRQoL instruments. Data (630 patients) were collected in the Helsinki and Uusimaa Hospital District in a cross-sectional setting. In addition, costs were also collected for these patients as incremental costs compared to age, gender and place of residence standardized peers. All evaluated HRQoL instruments provided valuable insight into patients’ overall HRQoL. HRQoL remained on a relatively high level until the disease progressed. Symptoms of fatigue and pain, and the background variables of financial difficulties and age, were the most important factors associated with poor HRQoL. Direct costs related to different states of PC are significant. However, productivity losses and costs of informal care also play a major role when estimating the total economic burden of PC. Excluding such a large share of costs from cost-effectiveness considerations might have a significant impact on the decision making pro¬cess of health economic evaluations or HTA. The single-index HRQoL instruments considered here (EQ-5D-3L and 15D) should not be considered interchangeable in health economic evaluations, especially in the case where HRQoL values are low or differ significantly from those of age-standardized peers.
  • Soveri, Leena-Maija (Helsingin yliopisto, 2019)
    Colorectal cancer (CRC) is a common disease in all western countries. The CRC treatment process has been revolutionised over the past years, and the prognosis of CRC has improved, but we lack information regarding the prognostic and predictive factors that would help us to optimise the therapy for an individual patient. In addition, with improved survival rates, both acute and long-term toxicities require more attention. Hypertension (HTN) is a well-recognised adverse event that is associated with all drugs involved in anti-VEGF (vascular endothelial growth factor) inhibition. The first study discussed in this thesis investigated whether HTN could act as a surrogate marker for efficacy during bevacizumab-containing therapy. According to our results, treatment-associated HTN might predict the outcome of bevacizumab-containing chemotherapy in mCRC patients and could potentially be utilized as a biomarker for continued care. The role of the H. pylori infection as a confounding gastrointestinal comorbidity in the diagnosis of CRC is not well known, and it is not established whether H. pylori infection worsens chemotherapy-induced gastrointestinal toxicity. In the second sub-study, we studied the role of different symptoms and H. pylori for CRC diagnostics. We observed that dyspeptic symptoms and the presence of H. pylori infection at the baseline delayed the initial diagnosis of CRC, but we observed no association between H. pylori infection and gastrointestinal adverse events during 5-FU-based adjuvant chemotherapy. Therefore, the eradication of H. pylori infections before providing 5-FU-based adjuvant chemotherapy cannot be routinely recommended. The association between survival and adverse events in several types of cancer has been established, but data for CRC patients are limited. In the third sub-study, we assessed whether adverse events could predict disease-free survival (DFS) or overall survival (OS) in stage II-III CRC patients. According to our results, adverse events related to treatment with adjuvant 5-FU chemotherapy in early stage CRC patients, especially non-haematological adverse events, are strongly associated with the prediction of improved DFS and OS. Adverse events could guide the clinician in bringing about dose modifications, to maximize the treatment efficacy, while ensuring a lesser level of toxicity. The use of oxaliplatin in the adjuvant setting reduces the risk of death 20% in stage III CRC patients. The major adverse event associated with oxaliplatin-based regimens is peripheral neuropathy, but the prevalence of acute and long-term neuropathy is not well established. It is not well known whether there is a difference in the neuropathy observed with two standard regimens (CAPOX and FOLFOX), and whether long-term neuropathy influences the quality of life (QOL). In the fourth sub-study, we analysed the prevalence of oxaliplatin-induced acute and long-term neuropathy during and after treatment with CAPOX and FOLFOX and studied the effect of long-term neuropathy on QOL in a real-life patient population. According to our results, long-term neuropathy is observed after therapy in a significant proportion of patients, but it does not impair global health status. Long-term neuropathy is not preventable in all patients with a reduction in the duration of therapy, but the performance status might predict the risk of long-term neuropathy.
  • Nyman, Kristofer (Helsingin yliopisto, 2019)
    Overweight and obesity are major global health concerns affecting around 2 billion people worldwide. Abdominal obesity is particularly hazardous to health associating with metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). In MetS, ectopic fat accumulates around the viscera and into organs regularly containing only minor amount of adipose tissue. This cross-sectional study was conceived to discover effects of MetS and ectopic adiposity including myocardial steatosis on cardiac function in non-diabetic men free of known heart diseases. The gold standard non-invasive method for fat quantification, proton magnetic resonance spectroscopy, was used to measure hepatic and myocardial triglyceride (TG) content. Magnetic resonance imaging (MRI) was used to assess cardiac structure and function and to quantify epicardial, pericardial, subcutaneous, and visceral abdominal fat depots. First, we examined the components of cardiac adiposity and their relationship to intra-abdominal ectopic fat deposits and cardiometabolic risk factors. MetS was associated with an increase in all examined ectopic fat depots. Myocardial TG was twofold increased in MetS. However, visceral adipose tissue (VAT) was the best independent predictor of cardiometabolic risk factors. Secondly, we studied left ventricular (LV) diastolic function and its relationship with cardiac fat depots. MetS associated with LV diastolic dysfunction and concentric LV remodeling. However, myocardial TG content was not an independent predictor of LV diastolic dysfunction. Thirdly, we studied the effect of different ectopic fat depots on LV structure and function in subjects with NAFLD and searched the role of hepatic fat content on cardiac steatosis. Epicardial and pericardial adipose tissue as well as myocardial TG content accumulated with increasing amount of both hepatic TG content and VAT. In addition, hepatic steatosis and VAT were associated with LV diastolic dysfunction. Lastly, we studied left atrial (LA) structure and function in MetS and examined the association of different ectopic fat depots and cardiometabolic risk factors with possible LA dysfunction. MetS associated with subclinical LA dysfunction without enlargement of the LA. Moreover, LA dysfunction associated with several contributory factors of MetS including waist circumference, insulin resistance, dyslipidemia, and VAT, which was the best independent predictor of LA dysfunction. Notably, the role of myocardial TG content on LA function remained inconclusive. In conclusion, MetS associates with significant changes in the structure and function of the heart. These changes are subclinical but may be followed by late complications such as heart failure or atrial fibrillation. The value of cardiovascular MRI may be early recognition of those obese subjects at risk for developing cardiovascular disease. Instead of body mass index, VAT is the best predictor of cardiac dysfunction. This study highlights the fundamental role of visceral obesity and hepatic steatosis directing their harmful effects to risk of cardiovascular diseases. The role of myocardial TG on cardiac dysfunction remains indeterminate. Therefore, cardiac energetics and the dynamic role of intramyocytic lipids, which are the primary fuel of the heart, merit further study.
  • Haljas, Kadri (Helsingin yliopisto, 2019)
    ABSTRACT Type 2 Diabetes (T2D) is an increasingly prevalent health problem and better understanding of its etiology is vital for improved prevention and treatment. It is known that T2D has multifactorial origin and mental health problems seem to accompany this progressive disorder. Of note, there is a bidirectional association between T2D and depression. One explanation for this relationship between T2D and depression could be the presence of pleiotropic genetic variants and possibly shared biological pathways. However, the underlying mechanisms remain poorly understood. Another possible common biological mechanism underlying T2D and depression comorbidity is related to disrupted circadian rhythms. It has been well established that many common disorders have seasonal fluctuations and it has been hypothesized that the amount of daylight might play an important role in seasonal fluctuations of both mental health conditions, glucose metabolism and T2D. The amount of daylight varies substantially throughout the year in Finland, making it one of the best locations to study this phenomenon. This research explores the shared genetic basis of T2D and depression as limited information exists on shared genetic risk of these conditions. Furthermore, another possible biological mechanism associated with both T2D and depression – circadian rhythm – has received limited research attention and is thus one of the focus areas of current thesis in relation to glucose metabolism. This research aims to provide better understanding in the genetic basis of increasingly prevalent health problems of T2D depression. The indicated knowledge together with understanding environmental effects of these prevalent conditions is needed in development of intervention strategies in light of the diabetes epidemic. Thus, this thesis focuses on four objectives. The first objective of this doctoral thesis is to examine whether there is a common genetic basis of T2D, glycemic indices related to T2D, and depressive symptoms. The second objective is to examine which specific genetic variants show common variation between glycemic indices and depressive symptoms. The third aim is to study if a common diabetes risk variant rs10830963 in the Melatonin Receptor 1B (MTNR1B) gene influences the relationship between depressive symptoms and glycemic indices. The final aim of this doctoral thesis is to investigate to what extent the amount of daylight moderates the associations between MTNR1B rs10830963 and glycemic indices. The first two objectives are addressed in Study I, objective three in Study II and objective four in study III. Study I is based on the summary statistics data from previously published Genome-Wide Association Studies (GWAS) of depressive symptoms by CHARGE consortium, T2D by Diagram consortium and glycemic traits by MAGIC consortium. GWAS on depressive symptoms involved 51,258 participants, GWAS on T2D involved 34,840 cases and 114,981 controls, GWAS on glycemic traits involved up to 58,074 participants. Studies II-III are conducted within the same Prevalence, Prediction and Prevention of Diabetes, the PPP-Botnia Study cohort. This prospective study cohort comprises 5,208 individuals at baseline visit and 3,850 individuals at follow-up, on average 6.8 years later. The analytic sample of Study II involved 4,455 non-diabetic participants from the baseline visit who were genotyped for MTNR1B rs10830963, had data on glycemic indices available based on an Oral Glucose Tolerance Test (OGTT) and additionally had data on depressive symptoms measured using Mental Health Inventory (MHI). The analytic sample of Study III involved 3,422 participants who had data on glycemic indices at both time points, were genotyped for MTNR1B rs10830963 and had no diabetes at baseline. The results of Study I showed that there was very low SNP-based heritability of the traits of interest and no overall SNP-based genetic correlation between glycemic traits or T2D and depressive symptoms. Yet, pleiotropic genetic variation for depressive symptoms and T2D was found in the IGF2BP2, CDKAL1, CDKNB-AS, and PLEKHA1 genes. Pleiotropic genetic variation for depressive symptoms and fasting glucose was found in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes. The results of Study II showed that the common diabetes risk variant rs10830963 in the MTNR1B gene and depressive symptoms are independently associated with glycemic traits. The associations between glycemic traits and depressive symptoms were not influenced by the variation in diabetes risk variant rs10830963. The results of Study III showed that each addition of the risk allele G of rs10830963 was associated with an increasingly worse glycemic profile across the 6.8-year follow-up. Additionally, more daylight was associated with worse glycemic response across the follow-up. Finally, the risk genotype GG of the MTNR1B rs10830963 became more insulin resistant during the follow-up, if the amount of daylight was less at the follow-up than at the baseline. Based on these findings, there are differences in underlying genetic background of glycemic traits, T2D and depressive symptoms. Additionally, on a candidate gene level, the known diabetes risk variant rs10830963 does not contribute significantly to the comorbidity between depression and diabetes. Yet, the rs10830963 and daylight are associated with glucose metabolism and the longitudinal glycemic profiles vary according to the amount of daylight, MTNR1B rs10830963 genotype and their interaction. This study contributes to the research literature in several ways. The findings provide valuable insights into the relationship of T2D and depression by addressing the common genetic background of these conditions. Furthermore, it emphasizes the importance of the amount of daylight in glucose metabolism and consequently T2D genesis.
  • Lohela, Terhi (Helsingin yliopisto, 2019)
    Over two million newborns die at birth or during their first week of life every year. The majority of early neonatal deaths occur in low- and middle-income countries (LMICs) and could be prevented with high-quality care at birth. This thesis studied quality of care and geographic and socioeconomic inequalities in access to care at birth in LMICs. Furthermore, the aim was to elucidate whether birth in a facility improves newborn survival. Quality of emergency obstetric and newborn care, routine care and non-medical care were studied through a health facility assessment in seven districts of Brong Ahafo region in Ghana. Clinical vignettes were used to assess competence of health professionals in managing obstetric emergencies. The effects of two distal determinants (distance to a health facility and socioeconomic inequalities) on early neonatal mortality and on facility delivery were studied; Distance effects were studied using Demographic and Health Survey (DHS) data from rural Malawi and Zambia and Health Facility Census data from both countries. Socioeconomic inequalities were quantified using DHS data on 679,818 live births from 72 LMICs. Hospitals and large health centres provided the highest quality of care, managed the most patients and employed the most competent staff among the 64 delivery facilities in Brong Ahafo region. Quality of care was poor in the smallest facilities. Although coverage of facility delivery was fairly high at 68%, coverage of high-quality care was only 18%. Lack of health provider competence limited emergency care more than shortages of necessary drugs and equipment for management of these emergencies. Although distance to a health facility was a strong barrier to delivery care in rural Malawi and Zambia, proximity to a delivery facility was not associated with lower early neonatal mortality. Similarly, while socioeconomic inequalities in coverage of delivery care were found to be large in the 72 countries studied, inequalities in early neonatal mortality by wealth and education were small in most countries and compared with inequalities in facility delivery and postneonatal infant mortality. The findings of this thesis point to insufficient quality of care at birth in the seven districts of Brong Ahafo region in Ghana, in Malawi and Zambia and in many DHS countries. Early neonatal mortality remains a global health problem that has not been solved by increasing coverage with institutional deliveries. Improving quality of care should be prioritised in the future.
  • Rantalainen, Ville (Helsingin yliopisto, 2019)
    Aging is the single most important risk factor for dementia, and aging is also associated with changes in cognitive abilities even in healthy aging individuals. Cognitive ability, non-pathological cognitive aging and the risk of dementia can be influenced by the developmental environment, health and lifestyle over the lifespan as well as heritable factors. However, truly lifespan studies on cognitive aging have been scarce, and many of the associations with major risk factors are not fully understood. This thesis is based on the Helsinki Birth Cohort Study and investigates four study objectives that expand the existing research literature on risk factors for non-pathological cognitive aging and the risk of dementia. We examined whether breastfeeding infancy and its longer duration is associated with higher cognitive ability in old age and aging-related change in cognitive ability (Study I), whether cognitive ability in early adulthood is associated with risk of any-onset, early-onset and late-onset dementia and Alzheimer’s disease (Study II), whether the APOE gene ɛ2/ɛ3/ɛ4 major isoforms and rs405509 promoter and rs440446 intron-1 polymorphisms are independently associated with the risk of dementia (Study III), and whether the APOE gene ɛ4 major isoform and rs405509 promoter and rs440446 intron-1 polymorphisms are independently associated with higher cognitive ability in old age aging-related change in cognitive ability (Study IV). The Helsinki Birth Cohort Study (n = 13345) comprises 8760 men (n = 4630) and women (n = 4130) born in the Helsinki University Central Hospital in 1934-44. Data on breastfeeding in infancy were extracted from birth and child welfare clinic records, and diagnoses of organic dementia until December 31, 2013 were derived from national registers. 2785 men took the Finnish Defence Forces Basic Intellectual Ability Test as part of their compulsory military service in 1952-1972 at mean age 20.1 years (SD = 1.4, range = 17.0 - 28.1), and 931 of them also participated in an invitation-based retest using the same test battery in 2009 at mean age 67.9 years (SD = 2.5, range = 64.5 – 75.7). In 2001-2004, 2003 men and women participated in a clinical study including genotyping. We had data available on APOE gene ɛ2/ɛ3/ɛ4 major isoforms and rs405509 promoter polymorphisms for 1453 of them. Of the sample with data available on APOE gene ɛ2/ɛ3/ɛ4 major isoforms and rs405509 promoter polymorphisms, 404 men had data available on cognitive ability available at mean age 20.1 (SD = 1.5, range = 17.1 - 26.6). The methods of statistical analysis included linear and mixed model regressions and Cox proportional hazard models. The men who were breastfed in infancy compared to those who were not breastfed, and men who were breastfed for a longer duration, had higher cognitive ability scores in young adulthood and old age. Furthermore, cognitive ability verbal subtest scores decreased between young adulthood and old age in the men who were not breastfed or were breastfed for less than three months whereas they increased in the men who were breastfed for at least three months (Study I). The men who had lower cognitive ability scores in young adulthood had a higher risk of early-onset dementia, but not of late- onset dementia. Also, in the subsample who had data available on cognitive ability in old age, the men who had lower cognitive ability scores in old age, and showed greater aging-related change in cognitive ability over five decades from young adulthood to old age, had a higher risk of late-onset dementia received after the cognitive ability retest (Study II). The ɛ4 major isoform of the APOE gene was independently associated with the risk of dementia but the number of minor alleles in rs405509 or rs440446 were not (Study III). The number of minor alleles in rs405509 and rs440446, but not APOE ɛ4, were associated with lower cognitive ability scores in old age independently of APOE major isoforms, and in APOE ɛ3/3 isoform carriers the number of minor alleles in rs405509 and rs440446 was also associated with greater aging- related change in the visuospatial subtest score (Study IV). The findings from Study I are in agreement with previous studies that have found that being breastfed in infancy is associated with higher cognitive ability in adulthood and suggest that the benefits of breastfeeding may persist into old age, particularly with longer durations. The findings from Study II reinforce previous suggestions that cognitive ability in early life is a risk factor for dementia in later life, however the findings also suggest that this association may vary according to the time of dementia onset and the age of cognitive ability measurement. Our findings in Study III replicate the well- documented finding that APOE ɛ4 is an independent risk factor for dementia and suggests that in this cohort rs405509 and rs440446 are not. Our findings in Study IV suggest that in this cohort rs405509 and rs440446 are associated with cognitive ability and aging-related change in cognitive ability independent of APOE major isoforms, but APOE ɛ2 or ɛ4 are not.