Den talande bokens poetik : en studie med fokus på olika unga vuxnas reception av tre fiktiva texter inlästa på band

The purpose of the research project The poetics of the talking book is to contribute to the knowledge about patterns of understanding in young adults’ reception of fiction, which they listened to through audio books. The problem explored was: How do different groups of listeners receive fictive text presented as a talking book with variations regarding use of voice, engagement and sound effects? The problem formulation rendered four specific research questions: 1. What patterns can be identified in the listeners’ answers regarding story structure and cognitive content in a comparative perspective comprising different reading styles in the taped versions of the text? 2. What patterns of understanding in interpretative reading can be identified in different listeners? 3. Which thoughts do the listeners have about what the talking book should sound like? 4. What affordances for young adults with the functional disability of mild mental retardation can be made visible through guided literature conversations? The theoretical frame of reference was formed by text–reader-oriented literary theory, psychological schema theory, and research regarding voice quality and communication. The project was carried out in two steps. The first phase was to produce the audio books with two variations of reading practice of three short stories with an existential theme in each text. The second step comprised interviewing of 32 young adults (a special group with a reading handicap in form of mild mental retardation, and a reference group with no handicap). The interviews formed as literary conversation were carried out three times during one year. The phenomenological-hermeneutic approach focused on the life worlds of the participants as meaning seeking beings. The analysis was carried out using method triangulation, mainly using phenomenological meaning concentration. The double hermeneutics in use when interpreting the interpretations of the participants revealed a capacity for aesthetic reading of fiction in the special group as well as in the reference group. The aesthetic qualities were found sufficient in all variations of reading by the professional readers of the audio book they listened to. The young adults also could describe how they wanted the audio book to sound: just as if you were reading yourself. A model describing the analytical steps and concepts in use was a result that can serve as an outline of a poetics for the talking book. Unexpected research results were how important the guided literary conversation turned out to be in order to realise the affordances given by the texts regarding exploration of existential themes in the young adults’ life worlds. Thus the result of the research project can be positioned as a piece of emancipatory research stressing the importance of including this group of young adults in the society’s conversation about culture and meaning.

Cognitive Development of Very Low Birth Weight Children from Infancy to Pre-school Age

The survival of preterm born infants has increased but the prevalence of long-term morbidities has still remained high. Preterm born children are at an increased risk for various developmental impairments including both severe neurological deficits as well as deficits in cognitive development. According to the literature the developmental outcome perspective differs between countries, centers, and eras. Definitions of preterm infant vary between studies, and the follow-up has been carried out with diverse methods making the comparison less reliable. It is essential to offer parents upto-date information about the outcome of preterm infants born in the same area. A centralized follow-up of children at risk makes it possible to monitor the consequences of changes in the treatment practices of hospitals on developmental outcome. This thesis is part of a larger regional, prospective multidisciplinary follow-up project entitled “Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age” (PIeniPAinoisten RIskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään, PIPARI). The thesis consists of four original studies that present data of very low birth weight (VLBW) infants born between 2001 and 2006, who are followed up from the neonatal period until the age of five years. The main outcome measure was cognitive development and secondary outcomes were significant neurological deficits (cerebral palsy, CP, deafness, and blindness). In Study I, the early crying and fussing behavior of preterm infants was studied using parental diaries, and the relation of crying behavior and cognitive and motor development at the age of two years was assessed. In Study II, the developmental outcome (cognitive, CP, deafness, and blindness) at the age of two years was studied in relation to demographic, antenatal, neonatal, and brain imaging data. Development was studied in relationship to a full-term born control group born in the same hospital. In Study III, the stability of cognitive development was studied in VLBW and full-term groups by comparing the outcomes at the ages of two and five years. Finally, in Study IV the precursors of reading skills (phonological processing, rapid automatized naming, and letter knowledge) were assessed for VLBW and full-term children at the age of five years. Pre-reading skills were studied in relation to demographic, antenatal, neonatal, and brain imaging data. The main findings of the thesis were that VLBW infants who fussed or cried more in the infancy were not at greater risk for problems in their cognitive development. However, crying was associated with poorer motor development. The developmental outcome of the present population was better that has been reported earlier and this improvement covered also cognitive development. However, the difference to fullterm born peers was still significant. Major brain pathology and intestinal perforation were independent significant risk factors for adverse outcome, also when several individual risk factors were controlled for. Cognitive development at the age of two years was strongly related with development at the age of five years, stressing the importance of the early assessment, and the possibility for early interventions. Finally, VLBW children had poorer pre-reading skills compared with their full-term born peers, but the IQ was an important mediator even when children with mental retardation were excluded from the analysis. The findings suggest that counseling parents about the developmental perspectives of their preterm infant should be based on data covering the same birth hospital. Neonatal brain imaging data and neonatal morbidity are important predictors for developmental outcome. The findings of the present study stress the importance of both short-term (two years) and long-term (five years) follow-ups for the individual, and for improving the quality of care.

Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

Benzodiazepines and Cognitive Functioning in Older Adults. With Emphasis on Long-Term Use and Withdrawal

Benzodiazepines (BZD) and benzodiazepine related drugs (RD) are the most commonly used psychotropics among the aged. The use of other psychotropics taken concomitantly with BZD/ RD or their cognitive effects with BZD/RD have not been studied frequently. The aim of this academic thesis was to describe and analyse relationships between the use of BZD/RD alone or concomitantly with antipsychotics, antidepressants, opioids, antiepileptics, opioids and anticholinergics in the aged and their health. Especially, the relationships between long-term use of BZD/RD and cognitive decline were studied. Additionally, the effect of melatonin on BZD/RD withdrawal and the cognitive effects of BZD/RD withdrawal were studied. This study used multiple data sets: the first study (I) was based on clinical data containing aged patients (≥65 years; N=164) admitted to Pori City Hospital due to acute disease. The second data set (Studies II and III) was based on population-based data from the Lieto Study, a clinico-epidemiological longitudinal study carried out among the aged (≥65 years) in the municipality of Lieto. Follow-up data was formed by combining the cohort data collected in 1990-1991 (N=1283) and in 1998-1999 (N=1596) from those who participated in both cohorts (N=617). The third data set (Studies IV and V) was based on the Satauni Study’s data. This study was performed in the City of Pori in 2009-2010. In the RCT part of the Satauni Study, ninety-two long-term users of BZD/RD were withdrawn from their drugs using melatonin against placebo. The change of their cognitive abilities was measured during and after BZD/ RD withdrawal. BZD/RD use was related to worse cognitive and functional abilities, and their use may predict worse cognitive outcomes compared with BZD/RD non-users. Hypnotic use of BZD/RD could be withdrawn with psychosocial support in motivated participants, but melatonin did not improve the withdrawal results compared to those with placebo. Cognitive abilities in psychomotor tests did not show, or showed only modest, improvements for up to six months after BZD/RD withdrawal. This suggests that the cognitive effects of BZD/RD may be longlasting or permanent.

Henkilöstöraportointi strategisen henkilöstöjohtamisen tukena - Case Eteva kuntayhtymä

Organisaatiot kohtaavat jatkuvasti uusia ja vaativia haasteita. Organisaatiot tarvit-sevat henkilöstön asiantuntemusta ja osaamista, jotta voisivat menestyä kaiken aikaa kovenevassa kilpailutilanteessa. Henkilöstön osaaminen, tiedot ja taidot on tunnistettu organisaation tärkeimmäksi voimavaraksi. Tämän tutkimuksen tavoit-teena oli selvittää, millaista tietoa henkilöstä organisaatiossa johtamis- ja esimies-työtä tekevät tarvitsevat strategisen henkilöstöjohtamisen tueksi. Tutkimus suoritettiin tapaustutkimuksena kehitysvammapalveluja tuottavassa or-ganisaatiossa. Empiirinen aineisto kerättiin ja analysoitiin määrällisin menetelmin kyselytutkimuksena. Analysoinnissa käytettiin lisäksi sisällön analyysia. Tutki-muskysely kohdennettiin kohdeorganisaatiossa johtamis- ja esimiestyötä tekevil-le. Kohdeorganisaation johtamis- ja esimiestyötä tekevät tarvitsevat strategisen hen-kilöstöjohtamisen tueksi monipuolista laadullista ja määrällistä tietoa henkilöstös-tä ja taloudesta sekä palautetta oman esimiestyön laadusta. Tieto henkilöstön työhyvinvoinnista ja työtyytyväisyydestä koettiin tärkeäksi. Tuotetut tiedot tulisi olla saatavissa yhdestä paikasta. Esimiehet tarvitsevat myös osaamisen vahvistamista tuotetun tiedon tulkintaan ja käsittelyyn.

Prodrug strategies of antiviral nucleotides: Studies on enzymatically and thermally removable phosphate protecting groups

Antiviral nucleosides are compounds that are used against viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV). To act as therapeutic agent, the antiviral nucleoside needs to be phosphorylated to nucleotide in the body in three consecutive phosphorylation steps by cellular or viral enzymes. The first phosphorylation to the nucleoside monophosphate is often inefficient and leads to poor antiviral activity. The antiviral efficacy can be improved by applying a prodrug strategy and delivering the antiviral nucleoside directly as its monophosphate. In prodrug strategies of antiviral nucleotides, the negative charges on the phosphate moiety are temporarily masked with protecting groups. Once inside the cell, the protecting groups are removed by enzymatic or chemical processes. Many prodrug strategies apply biodegradable protecting groups, the removal of which is triggered by esterase enzymes. Several studies have, however, demonstrated that the removal rate of the second and subsequent esterase labile protecting groups significantly slows down after the first protecting group is removed due to the negative charge on the phosphodiester intermediate, which disturbs the catalytic site of the enzyme. In this thesis, esterase labile protecting group strategies where the issue of retardation could be avoided were studied. Prodrug candidates of antiviral nucleotides were synthesized and kinetic studies on the chemical and enzymatic stability were carried out. In the synthesized compounds, the second protecting group is cleaved from the monophosphate some other mechanism than esterase triggered activation or the structure of prodrug requires only one protecting group. In addition, esterase labile protecting group which is additionally thermally removable was studied. This protecting group was cleaved from oligomeric phosphodiesters both enzymatically and thermally and seems most attractive of the studied phosphate protecting groups. However, the rate of the thermal removal still is too slow to allow efficient protection of longer oligonucleotides and needs optimization. Key words: antiviral, nucleotide, prodrug, protecting group, biodegradable

Lignoselluloosapohjaisten väkevähappohydrolysaattien kromatografinen fraktiointi

Väkevän hapon katalysoiman hydrolyysin avulla lignoselluloosasta on mahdollista valmistaa arvokkaita sokereita. Katalyyttinä toimiva happo voidaan käyttää uudelleen hydrolyysissä, jos se saadaan erotettua sokereista ilman neutralointia. Tämän kandidaatintyön tavoitteena oli selvittää, soveltuuko happoretardaatiotekniikka väkevähappohydrolysaatin fraktiointiin. Työssä verrattiin happoretardaatiotekniikkaa elektrolyyttiekskluusiotekniikkaan. Työn kirjallisuusosassa käsiteltiin happoretardaation ja elektrolyyttiekskluusion teoriaa. Lisäksi esiteltiin elektrolyyttiekskluusioon ja happoretardaatioon liittyviä tutkimuksia. Työn kokeellisessa osassa suoritettiin panoskromatografiakokeita käyttäen syöttöliuoksena rikkihappoa, etikkahappoa, glukoosia ja ksyloosia sisältävää synteettistä liuosta. Erotusmateriaaleina käytettiin neljää eri anionin- ja yhtä kationinvaihtohartsia. Kokeiden perusteella tutkittiin anioninvaihtohartsin tyypin ja kolonnin latauksen vaikutusta happoretardaatiotekniikalla saavutettavaan erotustulokseen sekä verrattiin elektrolyyttiekskluusiota happoretardaatioon. Työn tulosten perusteella rikkihappo laimeni happoretardaatiotekniikalla jopa 20-kertaisesti kromatografiakolonniin syötettyyn liuokseen verrattuna, riippumatta kolonnin latauksesta ja anioninvaihtohartsista. Rikkihapon laimenemisen vuoksi happoretardaatio ei soveltunut lignoselluloosapohjaisten väkevähappohydrolysaattien fraktiointiin. Elektrolyyttiekskluusiotekniikalla rikkihapon laimeneminen oli merkittävästi vähäisempää, minkä vuoksi elektrolyyttiekskluusion todettiin soveltuvan happoretardaatiota paremmin lignoselluloosapohjaisten väkevähappohydrolysaattien fraktiointiin.

Fragiili X -oireyhtymän molekyyligenetiikka ja diagnostiikka. Veritäpläpohjaisen fragiili X -testauksen pystyttäminen

Fragiili X (frax) -oireyhtymä on yleisin kehitysvammaisuuden perinnöllinen syy. Oireyhtymä periytyy X-kromosomissa, ja sen aiheuttaa sytosiini-guaniini-guaniini-emäskolmikon (CGG) monistuminen X-kromosomin Fragile X mental retardation 1 (FMR1) -geenin promoottorialueella. FMR1-alleelit voidaan luokitella (CGG)n-toistojen määrän mukaan neljään ryhmään: normaali (5–44), harmaa alue (45¬¬¬–54), epästabiili esimutaatio (55–200) tai täysmutaatio (yli 200). Esimutaatiotapauksissa toistojakso voi laajentua täysmutaatioksi jo yhden sukupolven aikana. Esimutaation kantajilla on havaittu monenlaisia oireita. Esimerkiksi osalla kantajanaisista on munarauhasen toiminnanhäiriöitä ja erityisesti miehillä on riski sairastua neurologiseen rappeumasairauteen. Täysmutaatiotapauksessa FMR1-promoottorialue metyloituu epänormaalisti ja geeni inaktivoituu. Täysmutaatiota kantavilla miehillä on aina frax-oireyhtymä, kun taas naisilla toisen terveen X-kromosomin suojavaikutus yleensä lieventää oireita sekä täys- että esimutaatiotapauksissa. Oireyhtymän yleisyyden, laajan oirekirjon ja lääkekehityksen edistymisen takia kiinnostus vastasyntyneiden ja kantajien seulontaa kohtaan on kasvanut. Tutkielman kokeellisessa osassa tavoitteena oli pystyttää veritäpläpohjainen automatisoitu DNA-eristysmenetelmä, joka soveltuu frax-oireyhtymän ja sen kantajien testaukseen PerkinElmerin FragilEaseTM-PCR-määrityksen kanssa. Kokonaisuudessaan testaus koostui DNA-eristyksestä, FragilEaseTM-PCR:stä, PCR-tuotteen puhdistuksesta ja monistustuotteiden havainnoinnista kapillaarigeeli-elektroforeesilla. Jokaista vaihetta optimoitiin veritäplätestaukseen sopivaksi. Frax-testaus todistettiin toimivaksi sekä aikuisten että vastasyntyneiden veritäplillä. Halkaisijaltaan 3,2 mm veritäplistä eristettyjen DNA-näytteiden epäpuhtauksista ja alhaisista pitoisuuksista huolimatta FragilEaseTM-PCR:ssä onnistuttiin monistamaan (CGG)n-alueet pienentämällä eristysnäytteiden reaktiotilavuutta ja nostamalla PCR-syklimäärää. Pisin testattu monistusalue oli 200 toistojaksoa. Lisäksi muokkaamalla DNA-eristysvaihetta ja muuttamalla PCR-tuotteen puhdistusmenetelmää onnistuttiin nostamaan lopullista saantoa. Veritäpläpohjaisen frax-testauksen osoitettiin soveltuvan niin vastasyntyneiden kuin kantajien seulontaan.