18 resultados para 312.454

em Helda - Digital Repository of University of Helsinki


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The early detection of hearing deficits is important to a child's development. However, examining small children with behavioural methods is often difficult. Research with ERPs (event-related potentials), recorded with EEG (electroencephalography), does not require attention or action from the child. Especially in children's ERP research, it is essential that the duration of a recording session is not too long. A new, faster optimum paradigm has been developed to record MMN (mismatch negativity), where ERPs to several sound features can be recorded in one recording session. This substantially shortens the time required for the experiment. So far, the new paradigm has been used in adult and school-aged children research. This study examines if MMN, LDN (late discriminative negativity) and P3a components can be recorded in two-year-olds with the new paradigm. The standard stimulus (p=0.50) was an 80 dB harmonic tone consisting of three harmonic frequencies (500 Hz, 1000 Hz and 1500 Hz) with a duration of 200 ms. The loudness deviants (p=0.067) were at a level of +6 dB or -6 dB compared to the standards. The frequency deviants (p=0.112) had a fundamental frequency of 550 or 454.4 Hz (small deviation), 625 or 400 Hz (medium deviation) or 750 or 333.3 Hz (large deviation). The duration deviants (p=0.112) had a duration of 175 ms (small deviation), 150 ms (medium deviation) or 100 ms (large deviation). The direction deviants (p=0.067) were presented from the left or right loudspeaker only. The gap deviant (p=0.067) included a 5-ms silent gap in the middle of the sound. Altogether 17 children participated in the experiment, of whom the data of 12 children was used in the analysis. ERP components were observed for all deviant types. The MMN was significant for duration and gap deviants. The LDN was significant for the large duration deviant and all other deviant types. No significant P3a was observed. These results indicate that the optimum paradigm can be used with two-year-olds. With this paradigm, data on several sound features can be recorded in a shorter time than with the previous paradigms used in ERP research.

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Due to the improved prognosis of many forms of cancer, an increasing number of cancer survivors are willing to return to work after their treatment. It is generally believed, however, that people with cancer are either unemployed, stay at home, or retire more often than people without cancer. This study investigated the problems that cancer survivors experience on the labour market, as well as the disease-related, sociodemographic and psychosocial factors at work that are associated with the employment and work ability of cancer survivors. The impact of cancer on employment was studied combining the data of Finnish Cancer Registry and census data of the years 1985, 1990, 1995 or 1997 of Statistics Finland. There were two data sets containing 46 312 and 12 542 people with cancer. The results showed that cancer survivors were slightly less often employed than their referents. Two to three years after the diagnosis the employment rate of the cancer survivors was 9% lower than that of their referents (64% vs. 73%), whereas the employment rate was the same before the diagnosis (78%). The employment rate varied greatly according to the cancer type and education. The probability of being employed was greater in the lower than in the higher educational groups. People with cancer were less often employed than people without cancer mainly because of their higher retirement rate (34% vs. 27%). As well as employment, retirement varied by cancer type. The risk of retirement was twofold for people having cancer of the nervous system or people with leukaemia compared to their referents, whereas people with skin cancer, for example, did not have an increased risk of retirement. The aim of the questionnaire study was to investigate whether the work ability of cancer survivors differs from that of people without cancer and whether cancer had impaired their work ability. There were 591 cancer survivors and 757 referents in the data. Even though current work ability of cancer survivors did not differ between the survivors and their referents, 26% of cancer survivors reported that their physical work ability, and 19% that their mental work ability had deteriorated due to cancer. The survivors who had other diseases or had had chemotherapy, most often reported impaired work ability, whereas survivors with a strong commitment to their work organization, or a good social climate at work, reported impairment less frequently. The aim of the other questionnaire study containing 640 people with the history of cancer was to examine extent of social support that cancer survivors needed, and had received from their work community. The cancer survivors had received most support from their co-workers, and they hoped for more support especially from the occupational health care personnel (39% of women and 29% of men). More support was especially needed by men who had lymphoma, had received chemotherapy or had a low education level. The results of this study show that the majority of the survivors are able to return to work. There is, however, a group of cancer survivors who leave work life early, have impaired work ability due to their illness, and suffer from lack of support from their work place and the occupational health services. Treatment-related, as well as sociodemographic factors play an important role in survivors' work-related problems, and presumably their possibilities to continue working.

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Vuonna 2003 voimaan tulleen uuden uskonnonvapauslain muutosprosessin yhteydessä tehtiin muutoksia myös uskonnonopetusta määrittäviin lakeihin. Aikaisemmin uskonnonopetusta kuvannut termi ” oppilaan tunnustuksen mukainen” korvattiin käsitteellä ”oppilaan oman uskonnon opetus” (Lukiolaki 455/2003, Perusopetuslaki 454/2003). Tässä tutkimuksessa tarkasteltiin oppilaan omaa uskontoa perusopetuksen uskonnon opetussuunnitelmissa. Analyysi kohdistui kaikille uskontokuntasidonnaisille ryhmille yhteiseen opetussuunnitelman osaan sekä evanekelisluterilaisen, ortodoksisen, islamin ja Myöhempien Aikojen Jeesuksen Kristuksen kirkon uskonnon opetussuunnitelman perusteisiin. Tutkimus toteutettiin sisällön analyysin keinoin. -- Ensimmäisessä tutkimuskysymyksessä keskityttiin siihen, miten oma uskonto näyttäytyy opetussuunnitelman kaikille uskontosidonnaisille ryhmille yhteisessä osassa. Oppilaan oma uskonto ei siinä ole opetuksen päämäärää tai lähtökohtia määrittävässä asemassa. Omaan uskontoon tutustuminen määritetään yhdeksi opetuksen tavoitteista, jota ei kuitenkaan korosteta muihin tavoitteisiin nähden. Muita tavoitteita on esimerkiksi tutustuminen muihin uskontoihin ja uskonnon ymmärtäminen kulttuurisen ilmiön tasolla. Toisessa tutkimuskysymyksessä tarkasteltiin oppilaan oman uskonnon ilmenemistä uskontokohtaisissa opetussuunnitelmissa. Opetussuunnitelmia vertailtaessa huomattiin merkittäviä eroja siinä, millaisessa asemassa oma uskonto on opetussuunnitelman kokonaisuudessa. Vähemmistöuskontojen opetussuunnitelmissa oppilaan omaan uskontoon tutustuminen ilmenee opetuksen päämääränä. Evankelisluterilaisen uskonnon opetussuunnitelmassa sillä on välineellinen arvo pyrittäessä ymmärtämään uskontoa kulttuurisena ilmiönä. Oman uskonnon ilmenemistä opetussuunnitelmissa voi tutkimuksen perusteella hahmottaa juridisesta, kulttuurisesta ja identiteetin näkökulmasta. Merkittävimmät erot löytyivät identiteetin näkökulmasta hahmotetusta oppilaan omasta uskonnosta. Toisissa opetussuunnitelmissa oppilaan uskonnollinen identiteetti määritetään oppilaan juridisen oman uskonnon pohjalta. Toisissa suunnitelmissa oppilaan uskonnollista identiteettiä lähestytään individualisoituneen uskonnollisuuden näkökulmasta ja oppilaan henkilökohtainen uskonnollinen identiteetti jätetään oppilaan oman määrittämisen varaan. Kolmannessa tutkimuskysymyksessä keskityttiin siihen, minkä eri ulottuvuuksien kautta omaa uskontoa opetuksessa käsitellään. Aineistosta hahmotettiin viisi ulottuvuutta: instituution, rituaalinen, opillinen, narratiivinen ja eettinen ulottuvuus. Ulottuvuuksien painotuksiin eri uskontojen opetussuunnitelmissa voi nähdä vaikuttavan esimerkiksi uskonnon asema Suomessa ja uskonnon itseymmärrys uskonnon keskeisistä piirteistä sekä se, kuinka tiiviisti koulun uskonnonopetus on yhteydessä uskonnolliseen yhdyskuntaan. -- Tutkimus lisää tietoa uskonnon opetussuunnitelmien perusteista ja eri uskontojen suunnitelmien välisistä eroista. Tutkimuksen perusteella voidaan huomata, että eri opetussuunnitelmissa omalla uskonnolla on hyvin erilainen asema opetuksen lähtökohtia ja sisältöä määritettäessä. Toisissa opetussuunnitelmissa omaan uskontoon tutustuminen näyttäytyy opetuksen päämääränä ja lähtökohtana, mutta toisissa opetussuunnitelmissa opetuksen lähtökohdat kumpuavat uskontotieteellisestä ja individualisoituneen uskonnollisuuden viitekehyksestä. Näin ollen kouluissa annettavaa uskonnonopetusta ei voi pitää luonteeltaan yhdenmukaisena. Myös opetuksen kuvaaminen luonteeltaa ”oppilaan oman uskonnon opetuksena” näyttäytyy ristiriitaisena eri uskontojen opetussuunnitelmien valossa.

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As the resistance of bacteria to conventional antibiotics has become an increasing problem, new antimicrobial drugs are urgently needed. One possible source of new antibacterial agents is a group of cationic antimicrobial peptides (CAMPs) produced by practically all living organisms. These peptides are typically small, amphipathic and positively charged and contain well defined a-helical or b-sheet secondary structures. The main antibacterial action mechanism of CAMPs is considered to be disruption of the cell membrane, but other targets of CAMPs also exist. Some bacterial species have evolved defence mechanisms against the harmful effects of CAMPs. One of the most effective defence mechanisms is reduction of the net negative charge of bacterial cell surfaces. Global analysis of gene expression of two Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, was used to further study the stress responses induced by different types of CAMPs. B. subtilis cells were treated with sublethal concentrations of a-helical peptide LL-37, b-sheet peptide protegrin 1 or synthetic analogue poly-L-lysine, and the changes in gene expression were studied using DNA macroarrays. In the case of S. aureus, three different a-helical peptides were selected for the transcriptome analyses: temporin L, ovispirin-1 and dermaseptin K4-S4(1-16). Transcriptional changes caused by peptide stress were examined using oligo DNA microarrays. The transcriptome analysis revealed two main cell signalling mechanisms mediating CAMP stress responses in Gram-positive bacteria: extracytoplasmic function (ECF)sigma factors and two-component systems (TCSs). In B. subtilis, ECF sigma factors sigW and sigM as well as TCS LiaRS responded to the cell membrane disruption caused by CAMPs. In S. aureus, CAMPs caused a similar stress response to antibiotics interfering in cell wall synthesis, and TCS VraSR was strongly activated. All of these transcriptional regulators are known to respond to several compounds other than CAMPs interfering with cell envelope integrity, suggesting that they sense cell envelope stress in general. Among the most strongly induced genes were yxdLM (in B. subtilis) and vraDE (in S. aureus) encoding homologous ABC transporters. Transcription of yxdLM and vraDE operons is controlled by TCSs YxdJK and ApsRS, respectively. These TCSs seemed to be responsible for the direct recognition of CAMPs. The yxdLM operon was specifically induced by LL-37, but its role in CAMP resistance remained unclear. VraDE was proven to be a bacitracin transporter. We also showed that the net positive charge of the cell wall affects the signalrecognition of different TCSs responding to cell envelope stress. Inactivation of the Dlt system responsible for the D-alanylation of teichoic acids had a strong and differential effect on the activity of the studied TCSs, depending on their functional role in cells and the stimuli they sense.

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Lead contamination in the environment is of particular concern, as it is a known toxin. Until recently, however, much less attention has been given to the local contamination caused by activities at shooting ranges compared to large-scale industrial contamination. In Finland, more than 500 tons of Pb is produced each year for shotgun ammunition. The contaminant threatens various organisms, ground water and the health of human populations. However, the forest at shooting ranges usually shows no visible sign of stress compared to nearby clean environments. The aboveground biota normally reflects the belowground ecosystem. Thus, the soil microbial communities appear to bear strong resistance to contamination, despite the influence of lead. The studies forming this thesis investigated a shooting range site at Hälvälä in Southern Finland, which is heavily contaminated by lead pellets. Previously it was experimentally shown that the growth of grasses and degradation of litter are retarded. Measurements of acute toxicity of the contaminated soil or soil extracts gave conflicting results, as enchytraeid worms used as toxicity reporters were strongly affected, while reporter bacteria showed no or very minor decreases in viability. Measurements using sensitive inducible luminescent reporter bacteria suggested that the bioavailability of lead in the soil is indeed low, and this notion was supported by the very low water extractability of the lead. Nevertheless, the frequency of lead-resistant cultivable bacteria was elevated based on the isolation of cultivable strains. The bacterial and fungal diversity in heavily lead contaminated shooting sectors were compared with those of pristine sections of the shooting range area. The bacterial 16S rRNA gene and fungal ITS rRNA gene were amplified, cloned and sequenced using total DNA extracted from the soil humus layer as the template. Altogether, 917 sequenced bacterial clones and 649 sequenced fungal clones revealed a high soil microbial diversity. No effect of lead contamination was found on bacterial richness or diversity, while fungal richness and diversity significantly differed between lead contaminated and clean control areas. However, even in the case of fungi, genera that were deemed sensitive were not totally absent from the contaminated area: only their relative frequency was significantly reduced. Some operational taxonomic units (OTUs) assigned to Basidiomycota were clearly affected, and were much rarer in the lead contaminated areas. The studies of this thesis surveyed EcM sporocarps, analyzed morphotyped EcM root tips by direct sequencing, and 454-pyrosequenced fungal communities in in-growth bags. A total of 32 EcM fungi that formed conspicuous sporocarps, 27 EcM fungal OTUs from 294 root tips, and 116 EcM fungal OTUs from a total of 8 194 ITS2 454 sequences were recorded. The ordination analyses by non-parametric multidimensional scaling (NMS) indicated that Pb enrichment induced a shift in the EcM community composition. This was visible as indicative trends in the sporocarp and root tip datasets, but explicitly clear in the communities observed in the in-growth bags. The compositional shift in the EcM community was mainly attributable to an increase in the frequencies of OTUs assigned to the genus Thelephora, and to a decrease in the OTUs assigned to Pseudotomentella, Suillus and Tylospora in Pb-contaminated areas when compared to the control. The enrichment of Thelephora in contaminated areas was also observed when examining the total fungal communities in soil using DNA cloning and sequencing technology. While the compositional shifts are clear, their functional consequences for the dominant trees or soil ecosystem remain undetermined. The results indicate that at the Hälvälä shooting range, lead influences the fungal communities but not the bacterial communities. The forest ecosystem shows apparent functional redundancy, since no significant effects were seen on forest trees. Recently, by means of 454 pyrosequencing , the amount of sequences in a single analysis run can be up to one million. It has been applied in microbial ecology studies to characterize microbial communities. The handling of sequence data with traditional programs is becoming difficult and exceedingly time consuming, and novel tools are needed to handle the vast amounts of data being generated. The field of microbial ecology has recently benefited from the availability of a number of tools for describing and comparing microbial communities using robust statistical methods. However, although these programs provide methods for rapid calculation, it has become necessary to make them more amenable to larger datasets and numbers of samples from pyrosequencing. As part of this thesis, a new program was developed, MuSSA (Multi-Sample Sequence Analyser), to handle sequence data from novel high-throughput sequencing approaches in microbial community analyses. The greatest advantage of the program is that large volumes of sequence data can be manipulated, and general OTU series with a frequency value can be calculated among a large number of samples.

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Rheumatoid arthritis (RA) and other chronic inflammatory joint diseases already begin to affect patients health-related quality of life (HRQoL) in the earliest phases of these diseases. In treatment of inflammatory joint diseases, the last two decades have seen new strategies and treatment options introduced. Treatment is started at an earlier phase; combinations of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids are used; and in refractory cases new drugs such as tumour necrosis factor (TNF) inhibitors or other biologicals can be started. In patients with new referrals to the Department of Rheumatology of the Helsinki University Central Hospital, we evaluated the 15D and the Stanford Health Assessment Questionnaire (HAQ) results at baseline and approximately 8 months after their first visit. Altogether the analysis included 295 patients with various rheumatic diseases. The mean baseline 15D score (0.822, SD 0.114) was significantly lower than for the age-matched general population (0.903, SD 0.098). Patients with osteoarthritis (OA) and spondyloarthropathies (SPA) reported the poorest HRQoL. In patients with RA and reactive arthritis (ReA) the HRQoL improved in a statistically significant manner during the 8-month follow-up. In addition, a clinically important change appeared in patients with systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. In a study of 97 RA patients treated either with etanercept or adalimumab, we assessed their HRQoL with the RAND 36-Item Health Survey 1.0 (RAND-36) questionnaire. We also analysed changes in clinical parameters and the HAQ. With etanercept and adalimumab, the values of all domains in the RAND-36 questionnaire increased during the first 3 months. The efficacy of each in improving HRQoL was statistically significant, and the drug effects were comparable. Compared to Finnish age- and sex-matched general population values, the HRQoL of the RA patients was significantly lower at baseline and, despite the improvement, remained lower also at follow-up. Our RA patients had long-standing and severe disease that can explain the low HRQoL also at follow-up. In a pharmacoeconomic study of patients treated with infliximab we evaluated medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment. Clinical and economic data for 96 patients with different arthritis diagnoses showed, in all patients, significantly improved clinical and laboratory variables. However, the medical costs increased significantly during the second period by 12 015 (95% confidence interval, 6 496 to 18 076). Only a minimal decrease in work disability costs occurred mean decrease 130 (-1 268 to 1 072). In a study involving a switch from infliximab to etanercept, we investigated the clinical outcome in 49 patients with RA. Reasons for switching were in 42% failure to respond by American College of Rheumatology (ACR) 50% criteria; in 12% adverse event; and in 46% non-medical reasons although the patients had responded to infliximab. The Disease Activity Score with 28 joints examined (DAS28) allowed us to measure patients disease activity and compare outcome between groups based on the reason for switching. In the patients in whom infliximab was switched to etanercept for nonmedical reasons, etanercept continued to suppress disease activity effectively, and 1-year drug survival for etanercept was 77% (95% CI, 62 to 97). In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. However, the 1-year drug survival of etanercept was only 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. Although the HRQoL of patients with inflammatory joint diseases is significantly lower than that of the general population, use of early and aggressive treatment strategies including TNF-inhibitors can improve patients HRQoL effectively. Further research is needed in finding new treatment strategies for those patients who fail to respond or lose their response to TNF-inhibitors.

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Snow cover is very sensitive to climate change and has a large feedback effect on the climate system due to the high albedo. Snow covers almost all surfaces in Antarctica and small changes in snow properties can mean large changes in absorbed radiation. In the ongoing discussion of climatic change, the mass balance of Antarctica has received increasing focus during recent decades, since its reaction to global warming strongly influences sea-level change. The aim of the present work was to examine the spatial and temporal variations in the physical and chemical characteristics of surface snow and annual accumulation rates in western Dronning Maud Land, Antarctica. The data were collected along a 350-km-long transect from the coast to the plateau during the years 1999-2004 as a part of the Finnish Antarctic Research Programme (FINNARP). The research focused on the most recent annual accumulation in the coastal area. The results show that the distance from the sea, and the moisture source, was the most predominant factor controlling the variations in both physical (conductivity, grain size, oxygen isotope ratio and accumulation) and chemical snow properties. The sea-salt and sulphur-containing components predominated in the coastal region. The local influences of nunataks and topographic highs were also visible on snow. The variations in all measured properties were wide within single sites mostly due to redistribution by winds and sastrugi topography, which reveals the importance of the spatially representative measurements. The mean accumulations occurred on the ice shelf, in the coastal region and on the plateau: 312 ± 28, 215 ± 43 and 92 ± 25 mm w.e., respectively. Depth hoar layers were usually found under the thin ice crust and were associated with a low dielectric constant and high concentrations of nitrate. Taking into account the vast size of the Antarctic ice sheet and its geographic characteristics, it is important to extend investigation of the distribution of surface snow properties and accumulation to provide well-documented data.

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Aneuploidy is among the most obvious differences between normal and cancer cells. However, mechanisms contributing to development and maintenance of aneuploid cell growth are diverse and incompletely understood. Functional genomics analyses have shown that aneuploidy in cancer cells is correlated with diffuse gene expression signatures and that aneuploidy can arise by a variety of mechanisms, including cytokinesis failures, DNA endoreplication and possibly through polyploid intermediate states. Here, we used a novel cell spot microarray technique to identify genes with a loss-of-function effect inducing polyploidy and/or allowing maintenance of polyploid cell growth of breast cancer cells. Integrative genomics profiling of candidate genes highlighted GINS2 as a potential oncogene frequently overexpressed in clinical breast cancers as well as in several other cancer types. Multivariate analysis indicated GINS2 to be an independent prognostic factor for breast cancer outcome (p = 0.001). Suppression of GINS2 expression effectively inhibited breast cancer cell growth and induced polyploidy. In addition, protein level detection of nuclear GINS2 accurately distinguished actively proliferating cancer cells suggesting potential use as an operational biomarker.

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Adherent cells undergo remarkable changes in shape during cell division. However, the functional interplay between cell adhesion turnover and the mitotic machinery is poorly understood. The endo/exocytic trafficking of integrins is regulated by the small GTPase Rab21, which associates with several integrin alpha subunits. Here, we show that targeted trafficking of integrins to and from the cleavage furrow is required for successful cytokinesis, and that this is regulated by Rab21. Rab21 activity, integrin-Rab21 association, and integrin endocytosis are all necessary for normal cytokinesis, which becomes impaired when integrin-mediated adhesion at the cleavage furrow fails. We also describe a chromosomal deletion and loss of Rab21 gene expression in human cancer, which leads to the accumulation of multinucleate cells. Importantly, reintroduction of Rab21 rescued this phenotype. In conclusion, Rab21-regulated integrin trafficking is essential for normal cell division, and its defects may contribute to multinucleation and genomic instability, which are hallmarks of cancer.

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In Finland the organising of defence is undergoing vast restructuring. Recent legislation has redefined the central tasks of the Finnish Defence Forces. At the same time, international security cooperation, economic pressures and new administrative paradigms have steered the military towards new ways of organising. National defence is not just politics and principles; to a large extent it is also enacted in day-to-day life in organisations. The lens through which these realities of defence are analysed in this study is gender. How is the security sector – and national defence as part of it – organised in the changing security environment? What is the new division of labour between different societal actors in the face of security challenges? What happens ‘at work’ within the military and the defence sector more broadly? How does gender affect the way in which defence is organised and understood, and how do the changes in the organising of security affect gender relations? The thesis searches for answers to these questions in the context of two organisational settings in the male-dominated defence sector. The case study on a Finnish peacekeeping unit in the Balkans opens a critical view on men’s social practices and the everyday life of crisis management organisations. In the second case study, reorganising of provisioning in the Finnish Defence Forces turns out to be a complicated process where different power relations and social divisions intermingle. Tallberg’s extensive ethnographic fieldwork in the two focal organisations has produced a detailed set of data that lays the basis for critical analysis and policy development in terms of defence organising, cooperation around peace and security issues, and gender equality in organisations. Observations and results are provided for understanding social networks, militarisation, authority relations, care, public-private partnerships, personnel policies, career planning, and humour.

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This thesis is an exploratory case study that aims to understand the attitudes affecting adoption of mobile self-services. This study used a demo mobile self-service that could be used by consumers for making address changes. The service was branded with a large and trusted Finnish brand. The theoretical framework that was used consisted of adoption theories of technology, adoption theories of self-service and literature concerning mobile services. The reviewed adoption theories of both technology and self-service had their foundation in IDT or TRA/TPB. Based on the reviewed theories an initial framework was created. The empirical data collection was done through three computer aided group interview sessions with a total of 32 respondents. The data analysis started from the premises of the initial framework. Based on the empirical data the framework was constantly reviewed and altered and the data recoded accordingly. The result of this thesis was a list of attitudinal factors that affect the adoption of a mobile self-service either positively or negatively. The factors that were found to affect the attitudes towards adoption of mobile self-services positively were: that the service was time & place independent and saved time. Most respondents, but not all, also had a positive attitude towards adoption due to ease of use and being mentally compatible with the service. Factors that affected adoption negatively were lack of technical compatibility, perceived risk for high costs and risk for malicious software. The identified factors were triangulated in respect to existing literature and general attitudes towards mobile services.

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This study identified the molecular defects underlying three lethal fetal syndromes. Lethal Congenital Contracture Syndrome 1 (LCCS1, MIM 253310) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD, MIM 611890) are fetal motor neuron diseases. They affect the nerve cells that control voluntary muscle movement, and eventually result in severe atrophy of spinal cord motor neurons and fetal immobility. Both LCCS1 and LAAHD are caused by mutations in the GLE1 gene, which encodes for a multifunctional protein involved in posttranscriptional mRNA processing. LCCS2 and LCCS3, two syndromes that are clinically similar to LCCS1, are caused by defective proteins involved in the synthesis of inositol hexakisphosphate (IP6), an essential cofactor of GLE1. This suggests a common mechanism behind these fetal motor neuron diseases, and along with accumulating evidence from genetic studies of more late-onset motor neuron diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), implicates mRNA processing as a common mechanism in motor neuron disease pathogenesis. We also studied gle1-/- zebrafish in order to investigate whether they would be a good model for studying the pathogenesis of LCCS1 and LAAHD. Mutant zebrafish exhibit cell death in their central nervous system at two days post fertilization, and the distribution of mRNA within the cells of mutant zebrafish differs from controls, encouraging further studies. The third lethal fetal syndrome is described in this study for the first time. Cocoon syndrome (MIM 613630) was discovered in a Finnish family with two affected individuals. Its hallmarks are the encasement of the limbs under the skin, and severe craniofacial abnormalities, including the lack of skull bones. We showed that Cocoon syndrome is caused by a mutation in the gene encoding the conserved helix-loop-helix ubiquitous kinase CHUK, also known as IκB kinase α (IKKα). The mutation results in the complete lack of CHUK protein expression. CHUK is a subunit of the IκB kinase enzyme that inhibits NF-κB transcription factors, but in addition, it has an essential, independent role in controlling keratinocyte differentiation, as well as informing morphogenetic events such as limb and skeletal patterning. CHUK also acts as a tumor suppressor, and is frequently inactivated in cancer. This study has brought significant new information about the molecular background of these three lethal fetal syndromes, as well as provided knowledge about the prerequisites of normal human development.

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XVIII IUFRO World Congress, Ljubljana 1986.