Perhetaustan ja sukupuolen yhteys koulunkäyntiin

Finnish education policy has aimed at providing equal educational pathways that level educational opportunities and aims at the equity of participation. Combined with the Finnish welfare state it has succeeded in sustaining social mobility. Yet the adolescents do not necessarily have equal possibilities to achieve these educational positions. Socio-economic differences in Finland are persistent and both education and poverty are still partly inherited. This thesis concentrated on prevailing socio-economic differences on school attendance and on studying the associations between family backgrounds, gender and school attendance. The key question for this thesis was formulated as: What kind of differences in school attendance there can be found among 9th graders from Helsinki according to their family background and their gender? The core data was a school-based survey carried on in Helsinki in 2004. There were two thirds of the schools of Helsinki and 2381 respondents. The questionnaire included questions on young people s school-related experiences, school attendance, school performance and their family. The analysis had three steps: after describing the respondents the associations between school attendance and family background were analyzed using MCA (Multiple Classification Analysis). Finally the associations between school attendance, family and school environment were studied using logistic regression analysis. The results showed that schooling (school attendance) was a variety of attitudes and experiences. The analysis showed also that all the family background factors had an effect on school attendance. From the family background measurements, it seems that the perceived parental support varied most with school attendance. Apart from the school environment factors, each family-related factor is statistically significantly related to two or more school attendance factors, even when adjusted with the school environment factors. There was also a gender-related difference in school attendance. Girls seem to like school attendance more than boys; they do better at school, but are also more worried about school work. Especially the expected associations with the parental educational level, but also with perceived parental support, gender and school attendance, are important results. When they are combined with the support pupils get from firm family structure and employment status it is possible to point out some factors that are relevant when discussing the ways educational achievements are moved to next generations in good and worse.

Molecular classification of familial colorectal and endometrial carcinoma

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common known clearly hereditary cause of colorectal and endometrial cancer (CRC and EC). Dominantly inherited mutations in one of the known mismatch repair (MMR) genes predispose to HNPCC. Defective MMR leads to an accumulation of mutations especially in repeat tracts, presenting microsatellite instability. HNPCC is clinically a very heterogeneous disease. The age at onset varies and the target tissue may vary. In addition, families that fulfill the diagnostic criteria for HNPCC but fail to show any predisposing mutation in MMR genes exist. Our aim was to evaluate the genetic background of familial CRC and EC. We performed comprehensive molecular and DNA copy number analyses of CRCs fulfilling the diagnostic criteria for HNPCC. We studied the role of five pathways (MMR, Wnt, p53, CIN, PI3K/AKT) and divided the tumors into two groups, one with MMR gene germline mutations and the other without. We observed that MMR proficient familial CRC consist of two molecularly distinct groups that differ from MMR deficient tumors. Group A shows paucity of common molecular and chromosomal alterations characteristic of colorectal carcinogenesis. Group B shows molecular features similar to classical microsatellite stable tumors with gross chromosomal alterations. Our finding of a unique tumor profile in group A suggests the involvement of novel predisposing genes and pathways in colorectal cancer cohorts not linked to MMR gene defects. We investigated the genetic background of familial ECs. Among 22 families with clustering of EC, two (9%) were due to MMR gene germline mutations. The remaining familial site-specific ECs are largely comparable with HNPCC associated ECs, the main difference between these groups being MMR proficiency vs. deficiency. We studied the role of PI3K/AKT pathway in familial ECs as well and observed that PIK3CA amplifications are characteristic of familial site-specific EC without MMR gene germline mutations. Most of the high-level amplifications occurred in tumors with stable microsatellites, suggesting that these tumors are more likely associated with chromosomal rather than microsatellite instability and MMR defect. The existence of site-specific endometrial carcinoma as a separate entity remains equivocal until predisposing genes are identified. It is possible that no single highly penetrant gene for this proposed syndrome exists, it may, for example be due to a combination of multiple low penetrance genes. Despite advances in deciphering the molecular genetic background of HNPCC, it is poorly understood why certain organs are more susceptible than others to cancer development. We found that important determinants of the HNPCC tumor spectrum are, in addition to different predisposing germline mutations, organ specific target genes and different instability profiles, loss of heterozygosity at MLH1 locus, and MLH1 promoter methylation. This study provided more precise molecular classification of families with CRC and EC. Our observations on familial CRC and EC are likely to have broader significance that extends to sporadic CRC and EC as well.

Cognitive deficits and the Paced Auditory Serial Addition Test performance among patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system, characterized especially by myelin and axon damage. Cognitive impairment in MS is common but difficult to detect without a neuropsychological examination. Valid and reliable methods are needed in clinical practice and research to detect deficits, follow their natural evolution, and verify treatment effects. The Paced Auditory Serial Addition Test (PASAT) is a measure of sustained and divided attention, working memory, and information processing speed, and it is widely used in MS patients neuropsychological evaluation. Additionally, the PASAT is the sole cognitive measure in an assessment tool primarly designed for MS clinical trials, the Multiple Sclerosis Functional Composite (MSFC). The aims of the present study were to determine a) the frequency, characteristics, and evolution of cognitive impairment among relapsing-remitting MS patients, and b) the validity and reliability of the PASAT in measuring cognitive performance in MS patients. The subjects were 45 relapsing-remitting MS patients from Seinäjoki Central Hospital, Department of Neurology and 48 healthy controls. Both groups underwent comprehensive neuropsychological assessments, including the PASAT, twice in a one-year follow-up, and additionally a sample of 10 patients and controls were evaluated with the PASAT in serial assessments five times in one month. The frequency of cognitive dysfunction among relapsing-remitting MS patients in the present study was 42%. Impairments were characterized especially by slowed information processing speed and memory deficits. During the one-year follow-up, the cognitive performance was relatively stable among MS patients on a group level. However, the practice effects in cognitive tests were less pronounced among MS patients than healthy controls. At an individual level the spectrum of MS patients cognitive deficits was wide in regards to their characteristics, severity, and evolution. The PASAT was moderately accurate in detecting MS-associated cognitive impairment, and 69% of patients were correctly classified as cognitively impaired or unimpaired when comprehensive neuropsychological assessment was used as a "gold standard". Self-reported nervousness and poor arithmetical skills seemed to explain misclassifications. MS-related fatigue was objectively demonstrated as fading performance towards the end of the test. Despite the observed practice effect, the reliability of the PASAT was excellent, and it was sensitive to the cognitive decline taking place during the follow-up in a subgroup of patients. The PASAT can be recommended for use in the neuropsychological assessment of MS patients. The test is fairly sensitive, but less specific; consequently, the reasons for low scores have to be carefully identified before interpreting them as clinically significant.

Boundaries in Action : An Activity-theoretical Study of Development, Learning, and Change in Health Care Organization for Patients with Multiple and Chronic Illnesses

This study examines boundaries in health care organizations. Boundaries are sometimes considered things to be avoided in everyday living. This study suggests that boundaries can be important temporally and spatially emerging locations of development, learning, and change in inter-organizational activity. Boundaries can act as mediators of cultural and social formations and practices. The data of the study was gathered in an intervention project during the years 2000-2002 in Helsinki in which the care of 26 patients with multiple and chronic illnesses was improved. The project used the Change Laboratory method that represents a research assisted method for developing work. The research questions of the study are: (1) What are the boundary dynamics of development, learning, and change in health care for patients with multiple and chronic illnesses? (2) How do individual patients experience boundaries in their health care? (3) How are the boundaries of health care constructed and reconstructed in social interaction? (4) What are the dynamics of boundary crossing in the experimentation with the new tools and new practice? The methodology of the study, the ethnography of the multi-organizational field of activity, draws on cultural-historical activity theory and anthropological methods. The ethnographic fieldwork involves multiple research techniques and a collaborative strategy for raising research data. The data of this study consists of observations, interviews, transcribed intervention sessions, and patients' health documents. According to the findings, the care of patients with multiple and chronic illnesses emerges as fragmented by divisions of a patient and professionals, specialties of medicine and levels of health care organization. These boundaries have a historical origin in the Finnish health care system. As an implication of these boundaries, patients frequently experience uncertainty and neglect in their care. However, the boundaries of a single patient were transformed in the Change Laboratory discussions among patients, professionals and researchers. In these discussions, the questioning of the prevailing boundaries was triggered by the observation of gaps in inter-organizational care. Transformation of the prevailing boundaries was achieved in implementation of the collaborative care agreement tool and the practice of negotiated care. However, the new tool and practice did not expand into general use during the project. The study identifies two complementary models for the development of health care organization in Finland. The 'care package model', which is based on productivity and process models adopted from engineering and the 'model of negotiated care', which is based on co-configuration and the public good.

Feature integration in human vision

The earliest stages of human cortical visual processing can be conceived as extraction of local stimulus features. However, more complex visual functions, such as object recognition, require integration of multiple features. Recently, neural processes underlying feature integration in the visual system have been under intensive study. A specialized mid-level stage preceding the object recognition stage has been proposed to account for the processing of contours, surfaces and shapes as well as configuration. This thesis consists of four experimental, psychophysical studies on human visual feature integration. In two studies, classification image a recently developed psychophysical reverse correlation method was used. In this method visual noise is added to near-threshold stimuli. By investigating the relationship between random features in the noise and observer s perceptual decision in each trial, it is possible to estimate what features of the stimuli are critical for the task. The method allows visualizing the critical features that are used in a psychophysical task directly as a spatial correlation map, yielding an effective "behavioral receptive field". Visual context is known to modulate the perception of stimulus features. Some of these interactions are quite complex, and it is not known whether they reflect early or late stages of perceptual processing. The first study investigated the mechanisms of collinear facilitation, where nearby collinear Gabor flankers increase the detectability of a central Gabor. The behavioral receptive field of the mechanism mediating the detection of the central Gabor stimulus was measured by the classification image method. The results show that collinear flankers increase the extent of the behavioral receptive field for the central Gabor, in the direction of the flankers. The increased sensitivity at the ends of the receptive field suggests a low-level explanation for the facilitation. The second study investigated how visual features are integrated into percepts of surface brightness. A novel variant of the classification image method with brightness matching task was used. Many theories assume that perceived brightness is based on the analysis of luminance border features. Here, for the first time this assumption was directly tested. The classification images show that the perceived brightness of both an illusory Craik-O Brien-Cornsweet stimulus and a real uniform step stimulus depends solely on the border. Moreover, the spatial tuning of the features remains almost constant when the stimulus size is changed, suggesting that brightness perception is based on the output of a single spatial frequency channel. The third and fourth studies investigated global form integration in random-dot Glass patterns. In these patterns, a global form can be immediately perceived, if even a small proportion of random dots are paired to dipoles according to a geometrical rule. In the third study the discrimination of orientation structure in highly coherent concentric and Cartesian (straight) Glass patterns was measured. The results showed that the global form was more efficiently discriminated in concentric patterns. The fourth study investigated how form detectability depends on the global regularity of the Glass pattern. The local structure was either Cartesian or curved. It was shown that randomizing the local orientation deteriorated the performance only with the curved pattern. The results give support for the idea that curved and Cartesian patterns are processed in at least partially separate neural systems.

Microarrays in molecular profiling of cancer - focus on head and neck squamous cell carcinoma

Microarrays have a wide range of applications in the biomedical field. From the beginning, arrays have mostly been utilized in cancer research, including classification of tumors into different subgroups and identification of clinical associations. In the microarray format, a collection of small features, such as different oligonucleotides, is attached to a solid support. The advantage of microarray technology is the ability to simultaneously measure changes in the levels of multiple biomolecules. Because many diseases, including cancer, are complex, involving an interplay between various genes and environmental factors, the detection of only a single marker molecule is usually insufficient for determining disease status. Thus, a technique that simultaneously collects information on multiple molecules allows better insights into a complex disease. Since microarrays can be custom-manufactured or obtained from a number of commercial providers, understanding data quality and comparability between different platforms is important to enable the use of the technology to areas beyond basic research. When standardized, integrated array data could ultimately help to offer a complete profile of the disease, illuminating mechanisms and genes behind disorders as well as facilitating disease diagnostics. In the first part of this work, we aimed to elucidate the comparability of gene expression measurements from different oligonucleotide and cDNA microarray platforms. We compared three different gene expression microarrays; one was a commercial oligonucleotide microarray and the others commercial and custom-made cDNA microarrays. The filtered gene expression data from the commercial platforms correlated better across experiments (r=0.78-0.86) than the expression data between the custom-made and either of the two commercial platforms (r=0.62-0.76). Although the results from different platforms correlated reasonably well, combining and comparing the measurements were not straightforward. The clone errors on the custom-made array and annotation and technical differences between the platforms introduced variability in the data. In conclusion, the different gene expression microarray platforms provided results sufficiently concordant for the research setting, but the variability represents a challenge for developing diagnostic applications for the microarrays. In the second part of the work, we performed an integrated high-resolution microarray analysis of gene copy number and expression in 38 laryngeal and oral tongue squamous cell carcinoma cell lines and primary tumors. Our aim was to pinpoint genes for which expression was impacted by changes in copy number. The data revealed that especially amplifications had a clear impact on gene expression. Across the genome, 14-32% of genes in the highly amplified regions (copy number ratio >2.5) had associated overexpression. The impact of decreased copy number on gene underexpression was less clear. Using statistical analysis across the samples, we systematically identified hundreds of genes for which an increased copy number was associated with increased expression. For example, our data implied that FADD and PPFIA1 were frequently overexpressed at the 11q13 amplicon in HNSCC. The 11q13 amplicon, including known oncogenes such as CCND1 and CTTN, is well-characterized in different type of cancers, but the roles of FADD and PPFIA1 remain obscure. Taken together, the integrated microarray analysis revealed a number of known as well as novel target genes in altered regions in HNSCC. The identified genes provide a basis for functional validation and may eventually lead to the identification of novel candidates for targeted therapy in HNSCC.

Multiple socioeconomic circumstances and health : associations and explanations among Finnish and British public sector employees

Socioeconomic health inequalities have been widely documented, with a lower social position being associated with poorer physical and general health and higher mortality. For mental health the results have been more varied. However, the mechanisms by which the various dimensions of socioeconomic circumstances are associated with different domains of health are not yet fully understood. This is related to a lack of studies tackling the interrelations and pathways between multiple dimensions of socioeconomic circumstances and domains of health. In particular, evidence from comparative studies of populations from different national contexts that consider the complexity of the causes of socioeconomic health inequalities is needed. The aim of this study was to examine the associations of multiple socioeconomic circumstances with physical and mental health, more specifically physical functioning and common mental disorders. This was done in a comparative setting of two cohorts of white-collar public sector employees, one from Finland and one from Britain. The study also sought to find explanations for the observed associations between economic difficulties and health by analysing the contribution of health behaviours, living arrangements and work-family conflicts. The survey data were derived from the Finnish Helsinki Health Study baseline surveys in 2000-2002 among the City of Helsinki employees aged 40-60 years, and from the fifth phase of the London-based Whitehall II study (1997-9) which is a prospective study of civil servants aged 35-55 years at the time of recruitment. The data collection in the two countries was harmonised to safeguard maximal comparability. Physical functioning was measured with the Short Form (SF-36) physical component summary and common mental disorders with the General Health Questionnaire (GHQ-12). Socioeconomic circumstances were parental education, childhood economic difficulties, own education, occupational class, household income, housing tenure, and current economic difficulties. Further explanatory factors were health behaviours, living arrangements and work-family conflicts. The main statistical method used was logistic regression analysis. Analyses were conducted separately for the two sexes and two cohorts. Childhood and current economic difficulties were associated with poorer physical functioning and common mental disorders generally in both cohorts and sexes. Conventional dimensions of socioeconomic circumstances i.e. education, occupational class and income were associated with physical functioning and mediated each other’s effects, but in different ways in the two cohorts: education was more important in Helsinki and occupational class in London. The associations of economic difficulties with health were partly explained by work-family conflicts and other socioeconomic circumstances in both cohorts and sexes. In conclusion, this study on two country-specific cohorts confirms that different dimensions of socioeconomic circumstances are related but not interchangeable. They are also somewhat differently associated with physical and mental domains of health. In addition to conventionally measured dimensions of past and present socioeconomic circumstances, economic difficulties should be taken into account in studies and attempts to reduce health inequalities. Further explanatory factors, particularly conflicts between work and family, should also be considered when aiming to reduce inequalities and maintain the health of employees.

Human herpesvirus 6 in multiple sclerosis and encephalitis

Human herpesvirus 6 (HHV-6) was identified from patients with HIV and lymphoproliferative diseases in 1986. It is a β-herpesvirus and is divided into two subgroups, variants A and B. HHV-6 variant B is the cause of exanthema subitum, while variant A has not yet definitely proven to cause any disease. HHV-6, especially variant A, is a highly neurotropic virus and has been associated with many diseases of the central nervous system (CNS) such as encephalitis and multiple sclerosis (MS). The present studies were aimed to elucidate the role of HHV-6 and its two variants in neurological infections. Special attention was given to study the possible role of HHV-6 in the pathogenesis of MS. We studied the expression of HHV-6 antigens using immunohistochemistry in brain autopsy samples from patients with MS and controls. HHV-6 antigen was identified in 70% of MS specimens whereas 30% of control specimens expressed HHV-6 antigen. Serum and cerebrospinal fluid (CSF) samples were collected from patients with MS and patients with other neurological diseases (OND) from patients visiting Helsinki University Central Hospital Neurological Outpatient Clinic during the years 2003 and 2004. In addition, we studied 53 children with suspected encephalitis. We developed an immunofluorescence IgG-avidity assay for the detection of primary HHV-6A and HHV-6B infection. For HHV-6B antibodies, no differences were observed between patients with MS and OND. For HHV-6A both seroprevalence and mean titers were significantly higher in MS compared to OND. HHV-6A low-avidity IgG antibodies, suggestive of primary infection, were found in serum of two, three and one patient with definite MS, possible MS and OND, respectively. From pediatric patients with suspected encephalitis, six serum samples (11.3%) contained low-avidity antibodies, indicating a temporal association between HHV-6A infection and onset of encephalitis. Three out of 26 patients with CDMS and four out of 19 patients with CPMS had HHV-6 antibodies in their CSF compared to none of the patients with OND (p=0.06 and p=0.01, respectively). Two patients with CDMS and three patients with CPMS appeared to have specific intrathecal synthesis of HHV-6A antibodies. In addition, oligoclonal bands (OCB) were observed in the CSF of five out of nine MS patients tested, and in two the OCBs reacted specifically with HHV-6 antigen, which is a novel finding. These results indicate HHV-6 specific antibody production in the CNS and suggest that there is a subset of MS patients with an active or chronic HHV-6A infection in the CNS that might be involved in the pathogenesis of MS. Our studies suggest that HHV-6 is an important causative or associated virus in some neurological infections, such as encephalitis and it might contribute to the development of MS, at least in some cases. In conclusion, HHV-6 is a neurotropic virus that should be taken into consideration when studying acute and chronic CNS diseases of unknown origin.

Novel Multiple Sclerosis Predisposing Genetic Variants Outside the HLA Region

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Both environmental factors and several predisposing genes are required to generate MS. Despite intensive research these risk factors are still largely unknown, the pathogenesis of MS demyelination is poorly understood, and no curative treatment exists. Both prevalence and familial occurrence of MS are exceptionally high in a Finnish population subisolate, Southern Ostrobothnia, presumably due to enrichment of predisposing genetic variants within this region. Previous linkage scan on MS pedigrees from Southern Ostrobothnia detected three main MS loci on chromosomes 5p, 6p (HLA) and 17q. Linkage studies in other populations have also provided independent evidence for the location of MS susceptibility genes in these regions. Further, these loci are syntenic to the experimental autoimmune encephalomyelitis (EAE) susceptibility loci of rodents. In this thesis work an effort was made to localize MS predisposing alleles of the linked loci outside the HLA region by studying familial MS cases from the Southern Ostrobothnia isolate. Analysis of the 5p locus revealed one region, flanking the complement component 7 (C7) gene. The identified relatively rare haplotype seems to have a fairly large effect on genetic susceptibility of MS (frequency MS 12%, controls 4%; p=0.000003, OR=2.73). Evidence for association with alleles of the region and MS was seen also in more heterogeneous populations. Convincingly, plasma C7 protein levels and complement activity correlated with the risk haplotype identified. The finding stimulated us to study other complement cascade genes in MS. No evidence for association could be observed with the complement component coding genes outside 5p. A scan of the 17q locus provided evidence for association with variants of the protein kinase C alpha (PRKCA) gene (p=0.0001). Modest evidence for association with PRKCA was observed also in Canadian MS families. Finally we used a candidate gene based approach to identify potential MS loci. Mutations of DAP12 and TREM2 cause a recessively inherited CNS white matter disease PLOSL. Interestingly, DAP12 and TREM2 are located in MS regions on 6p and 19q, and we tested them as potential candidate genes in the Finnish MS sample. No evidence for association with MS was observed. This thesis provides an example of how extended families from special populations can be utilized in fine-mapping of the linked loci. A first relatively rare MS variant was identified utilizing the strength of a Finnish population subisolate. This variant seems to have an effect on activity of the complement system, which has previously been suggested to have an important role in the pathogenesis of MS.

Novel Insights into the Molecular Genetic Background of Colorectal Tumors

Many of the genes predisposing to highly penetrant colorectal cancer (CRC) syndromes, including hereditary non-polyposis colorectal cancer (MLH1, MSH2, MSH6, PMS2), familial adenomatous polyposis (APC), Peutz-Jeghers syndrome (LKB1), juvenile polyposis (SMAD4, BMPR1A), MYH-associated polyposis (MYH), and Cowden syndrome (PTEN) have already been discovered. Identification of these genes has allowed a more precise classification of the hereditary CRC syndromes and provided a means for predictive genetic testing and surveillance. Some of the genes are also involved in sporadic cancer forms, and therefore the investigation of the rare CRC syndromes has been a breakthrough for general cancer research. Despite the accumulating knowledge on hereditary cancer syndromes, a significant number of familial CRCs remain molecularly unexplained after genetic testing, reflecting the possibility of other predisposing genes or existence of novel syndromes. Moreover, genetic variants conferring low-penetrance risk are still largely unknown. In this study, we examined the role of some new high- and low-penetrance alleles on CRC predisposition. We identified disease causing MYH mutations in a subset (9%) of patients with APC and AXIN2 mutation negative adenomatous polyposis. Due to differences in the pattern of inheritance and clinical manifestation, screening for mutations in MYH is beneficial in view of genetic counselling and surveillance. A novel functionally deficient MYH founder mutation A459D was identified in the Finnish population, and this finding had immediate clinical implications for genetic counselling of at risk families. Many patients with hamartomatous polyposis remain without molecular diagnosis due to atypical phenotypes. We therefore sought to classify 49 patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analyses of PTEN, LKB1, BMPR1A, SMAD4, ENG, BRAF, MYH, and BHD along with revision of polyp histology. Mutations were identified in 11/49 (22%) of the patients. In 6 cases the molecular diagnosis was re-classified guiding surveillance and decisions for prophylactic surgery. Re-evaluation of polyp histology with subsequent more accurate selection of candidate gene analyses is beneficial and can be recommended for patients with unexplained polyposis. Furthermore, germline mutations in ENG underlying juvenile polyposis were described for the first time, characterizing a possible novel genetically defined form of hereditary CRC. Association analyses on two putative low-penetrance alleles, NOD2 3020insC and MDM2 SNP309 were performed in a population-based series of 1042 Finnish CRC patients and in cancer-free controls. In contrast to previous results, NOD2 3020insC did not associate with CRC or age at disease onset in the Finnish population. These data suggest that NOD2 3020insC alone might not be sufficient for CRC predisposition. MDM2 SNP309 was as common in the CRC cohort as in the healthy controls. Interesting trends, however, were observed, which after correction for multiple testing did not reach statistical significance. SNP309 was more common in female CRC patients and a trend towards an earlier age at disease onset was observed in women with SNP309. Subsequent studies have supported this observation and SNP309 could affect gender- or hormone-related tumorigenesis. Finally, a large-scale unbiased effort was designed to characterize the complete mutatome of CRC with microsatellite instability (MSI). Using an approach combining expression microarray and genome database searches, we were able to identify putative MSI target genes. Further characterization of one of the genes suggested that it might play a role also in microsatellite stable CRC and Peutz-Jeghers syndrome pathogenesis.