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  • Kallio, Arttu (2014)
    Tärkeimpiä vierasaineita metaboloivia entsyymejä elimistössä ovat sytokromi P450 (CYP) -entsyymit. Koska useat vierasaineet metaboloituvat keskenään samojen CYP-entsyymien kautta, on niiden välilä mahdollista tapahtua metabolisia yhteisvaikutuksia. Metaboliset yhteisvaikutukset voivat olla toisen vierasaineen metabolian inhiboimista tai indusoimista. Yhteisvaikutus voi olla haitallinen esimerkiksi silloin, kun sen takia elimistöön kertyy myrkyllistä metaboliittia, tai kun sen vuoksi aktiivisen lääkeaineen metaboloituminen epäaktiiviseen muotoon estyy. Työssä oli tarkoitus kehittää kvantitatiivinen menetelmä lääkeaineiden ja ympäristökemikaalien välisten metabolisten yhteisvaikutusten tutkimiseen humaanimaksamikrosomi (HLM) -inkuboinneista. HLM-preparaatit sisältävät luontaisesti suuret pitoisuudet CYP-entsyymejä, joten yhteivaikutusten määrittämiseen voitiin käyttää CYP-mallireaktioita. Valitut mallireaktiot olivat fenasetiinin O-de-etyloituminen (CYP1A2), kumariinin 7’-hydroksyloituminen (CYP2A6), diklofenaakin 4’-hydroksyloituminen (CYP2C9), bufuralolin 1’-hydroksyloituminen (CYP2D6) ja testosteronin 6β-hydroksyloituminen. Mallireaktioille määritettiin Michaelis-Mentenin vakiot ja (Km) ja maksimientsyymiaktiivisuudet (Vmax). Mallireaktioiden toimivuutta inhibitiomäärityksissä tarkasteltiin reaktioiden spesifisillä inhibiittoreilla. Kvantitatiivinen menetelmä kehitettiin erittäin korkean suorituskyvyn nestekromatografille (UPLC) ja kvadrupolilentoaikamassaspektrometrille (QTOF). Näytteet ionisoitiin sähkösumutusionisaatiolla (ESI) käyttäen positiivi-moodia. Kaikille metaboliiteille käytettiin samoja laiteparametrejä. Kvantitatiiviselle menetelmälle tehtiin validointi ICH:n (International Conference on Harmonisation) ohjeistusta mukaillen. Kvantitatiivisella menetelmällä saavutettiin riittävä lineaarisuus (R2>0,99) ja spesifisyys. Saavutet kvantitointirajat (LOQ) olivat tarpeeksi matalat (1-120 nM) inhibitiokokeissa muodostuvien pienten metaboliittipitoisuuksien kvantitointiin. Mittauksen toistettavuus ja menetelmän toistettavuus sekä tarkkuus eivät täyttäneet hyväksymiskriteereitä kaikkien metaboliittien osalta. Tuloksia tulisi yrittää parantaa esimerkiksi kokeilemalla eri laiteparametrejä. 1’-hydroksidiklofenaakin todettiin todennäköisesti hajoavan matriisiliuoksessa hapon vaikutuksesta, mikä teki tulosten luotettavuudesta heikon kyseisen metaboliitin osalta. Kumariinin metaboloitumiselle CYP2A6 kautta saatiin huomattavasti kirjallisuudesta eroava Km-arvo, jonka saattoi aiheuttaa liian pitkä inkubointiaika. CYP1A2:n, CYP2D6:n ja CYP3A4:n mallireaktioiden Km- ja Vmax-arvot vastasivat hyvin kirjallisuutta. Myös samojen mallireaktioiden spesifisille inhibiittoreille määritetyt IC50-arvot vastasivat suhteellisen hyvin kirjallisuutta. Työssä tutkittiin neljän eri polymeerin, F68:n, F127:n, Tetronic 1307:n ja polyvinyylialkoholin (PVA) vaikutuksia entsyymiaktiivisuuksiin pitoisuudella 1 mg/ml. Tällä pitoisuudella polymeerit eivät pääsääntöisesti aiheuttaneet suuria muutoksia entsyymiaktiivisuuksissa. Kuitenkin CYP2C9:lle havaittu inhibitio saattoi olla merkittävää, joskin CYP2C9:n mallireaktion luotettavuus nykyisellään todettiin heikoksi. Kehitettyä kvantitatiivista menetelmää tulisi tulevaisuudessa edelleen validoida, ja lisäksi kumariinin mallireaktion inkubointiolosuhteet tulisi optimoida, minkä jälkeen polymeereille voitaisiin määrittä IC50-arvot, joista saataisiin luotettavampi kuva niiden mahdollisesti aiheuttamasta CYP-inhibitiosta.
  • Rintamäki, Heidi (2012)
    Maailmanlaajuinen biopolttoaineiden tuotanto on kasvanut jatkuvasti tällä vuosituhannella. Biopolttoaineet on nähty keinona ehkäistä ilmastonmuutosta, vähentää liikenteen riippuvuutta fossiilisista öljyvaroista ja edistää maaseudun kehitystä. Kannustavana tekijänä ovat toimineet viralliset edistämistoimenpiteet, jotka ovat luoneet edellytykset sekä kysynnän että tarjonnan kasvamiseen. Positiivisten odotusten vastakaiuksi on muodostunut huoli biomassojen tuotannon kestävyydestä ja vaikutuksesta ruokaturvaan. Tässä tutkimuksessa käsitellään Yhdysvaltojen, Brasilian ja Euroopan unionin biopolttoainemarkkinoiden hintavaihtelua ja hintaan vaikuttavia tekijöitä. Tarkastelun kohteena ovat pellonkäytön kannalta kansainvälisessä kaupassa liikkuvat olennaisimmat bioenergiatuotteet, eli liikennekäyttöön tarkoitetut nestebiopolttoaineet; bioetanoli ja biodiesel. Näihin kysymyksiin vastataan kirjallisuuden ja empiirisen ekonometrisen mallintamisen pohjalta. Tutkimuksen teoreettinen viitekehys perustuu hintateoriaan ja tutkimusmenetelmänä käytetään ekonometristä estimointia. Tässä tutkimuksessa estimoitiin Brasilian bioetanolin, Yhdysvaltojen bioetanolin ja biodieselin markkinahintojen kehitys. Aineistot estimoitiin klassisen pienimmän neliösumman menetelmällä. Tutkimuksessa rakennettiin yksinkertaisia ekonometrisia malleja, joilla voidaan kuvata bioetanolin ja biodieselin hintavaihteluita. Mallit rakennettiin kirjallisuuden ja hintateorian perusteella. Yhdysvaltojen bioetanolin selittäviksi tekijöiksi valittiin maissin hinta, raakaöljyn hinta, bensiinin hinta, maakaasu hinta, katetuotto ja politiikan ohjelmakausi dummy-muuttujana. Yhdysvaltojen biodieselin selittäviksi tekijöiksi valittiin soijaöljyn hinta, raakaöljyn hinta, dieselin hinta, metanolin hinta, soijaöljyn nettokustannukset ja politiikan ohjelmakausi dummy-muuttujana. Brasilian bioetanolin selittäviksi muuttujiksi valittiin sokerin hinta, raakaöljyn hinta, bensiinin hinta, nestekaasun hinta ja politiikan ohjelmakausi dummy-muuttujana. Yhdysvaltojen bioetanolin hintaa kuvaavan log-lineaarisen mallin selittävistä muuttujista kaikki muuttujat olivat tilastollisesti merkitseviä paitsi raakaöljyn hinta. Yhdysvaltojen biodieselin hintaa kuvaavan log-lineaarisen mallin selittävistä muuttujista ainoastaan raakaöljyn hinta oli tilastollisesti merkitsevä. Brasilian bioetanolin hintaa kuvaavan log-lineaarisen mallin selittavistä muuttujista sokerin hinta, bensiinin hinta ja politiikan ohjelmakausi olivat merkitseviä. Kaikissa näissä malleissa autokorrelaatiota pyrittiin vähentämään Cochrane-Orcuttin menetelmää hyödynhtämällä. Heteroskedastisuutta pyrittiin vähentämään käyttämällä apuna Whiten korjattuja keskivirhe-estimaatteja. Tutkimuksessa saadut joustokertoimet olivat pieniä, mikä kertoo markkinoilla tapahtuvien hinnan muutosten vaikuttavan suhteessa vähemmän biopolttoaineiden hintoihin. Poikkeuksen tekee Brasilian bioetanolin hintaa kuvaavan log-lineaarisen mallin bensiinin joustokerroin (2,62), mikä kertoo bioetanolin hintavaihteluiden olevan melko joustavia bensiinin hinnassa tapahtuviin muutoksiin.
  • Vuorento, Henna (2011)
    Pro gradu -tutkimukseni selvittää nettipokeriaiheisen medianäkyvyyden ja nettipokeripelaajien vuorovaikutussuhdetta. Työn ensimmäinen osa keskittyy siihen, miten tutkimukseeni valitut sanomalehdet kuvaavat artikkeleissaan nettipokeria ja esiintyykö niissä mielikuvien käyttöä. Työn toinen osa kartoittaa sitä, onko nettipokerin medianäkyvyydellä ja sanomalehtien nettipokeriuutisoinnissa mahdollisesti käytetyillä mielikuvilla vaikutusta pelaajiin. Tutkimukseni ensimmäinen vaihe oli kvalitatiivinen ja tutkimusaineistona toimivat nettipokeriaiheiset artikkelit valitsemistani lehdistä. Lehtiartikkelien analyysin tuloksena ilmeni, että valituissa lehdissä esiintyi kahdenlaista mielikuvien käyttöä sisältävää päädiskurssia liittyen nettipokeriin. Diskursseista ensimmäinen käsitteli nettipokeria ongelmakeskeisesti ja niitä oli aineistossa 35 prosenttia. Sen fokus kohdistui huolipuheeseen peliongelmien lisääntymisestä ja varoitustarinoihin nettipokerin pelaamisen liittyvistä riskeistä. Ongelmakeskeisyyden vastadiskurssina näyttäytyi nettipokeria positiivisessa valossa esittelevä tyyli, joka keskittyi voittojen ja luksuselämäntyylistä nauttivien pokerisankarien esittelyyn. Positiivisen kirjoitustyylin artikkeleita oli aineistossa 34 prosenttia. Tutkimuksen toisen vaiheen toteutin kvantitatiivisesti ja tutkimusaineistona toimi nettipokerinpelaajille suunnattu nettikysely. Kyselyyn vastanneista 88 prosenttia oli lukenut nettipokeriaiheista kirjoittelua sanomalehdistöstä ja 26 prosenttia ilmoitti medianäkyvyyden vaikuttaneen pelaamisen aloittamiseen. Mahdollisen peliriippuvuuden omaavien keskuudessa 36 prosenttia ilmoitti, että medianäkyvyys on vaikuttanut pelaamisen aloittamiseen. Lisäksi nettipokeriaiheinen sanomalehtikirjoittelu oli vaikuttanut pelaajien mielikuviin nettipokerista. Positiivisia mielikuvia oli lehdistä aiheesta lukeneiden keskuudessa 75 prosentilla. Lehdistä aiheesta lukemattomilla oli positiivisia mielikuvia 44 prosentilla, siis lähes 32 prosenttia vähemmän. Ongelmakeskeisiä mielikuvia oli lehdistä nettipokerista lukeneilla 52 prosenttia ja lukemattomilla 36 prosenttia, eron ollessa 16 prosenttia. Lehdistön vaikutus pelaajien mielikuviin oli suurempi niiden pelaajien kohdalla, joilla oli mahdollinen peliriippuvuus. Tulokset eivät vielä riitä kausaalijohtopäätösten tekemiseen, mutta antavat silti osviittaa siitä, että nettipokerin medianäkyvyys ja mielikuvia sisältämä journalismi voivat vaikuttaa yleisöönsä.
  • Koivisto, Mia-Veera Pauliina (2009)
    Tutkimuksessa analysoidaan masennuksen ja nettiriippuvuuden välistä yhteyttä. Tutkimuskysymys on: Miten ja miksi masennus ja nettiriippuvuus ovat yhteydessä toisiinsa? Hypoteesi ilmiöiden välisestä yhteydestä asetettiin aikaisempien tutkimusten pohjalta. Nettiriippuvuuden ja masennuksen sekä muiden psykiatristen häiriöiden välisiä yhteyksiä on havaittu useissa tutkimuksissa (muun muassa Young & Rodgers 1998; Shapira 2000; Ybarra 2005; Wolak ym 2002 ja 2003). Suomalaista tutkimusta aiheesta ei löytynyt. Yhteyden tarkastelussa käytettiin aineisto- ja metoditriangulaatiota. Aineistot kerättiin Päihdelinkki-verkkopalvelusta. Kvantitatiivinen aineisto (N=8821) kerättiin IAT -nettiriippuvuustestillä, johon oli liitetty masennusta mittaava DEPS -seula sekä itse arvioitu ongelmallinen päihteidenkäyttö, ikä ja sukupuoli. Kvalitatiivisena aineistona oli nettiriippuvaisiksi itsensä kokeneiden ihmisten kertomukset (N=406) noin seitsemän vuoden ajalta. Analyysimenetelminä käytettiin ristiintaulukointia, logistista regressioanalyysiä sekä laadullista sisällönanalyysiä. Tulokseksi saatiin, että nettiriippuvuus ja masennus esiintyvät tutkimushenkilöillä usein samanaikaisesti. Yhteys todettiin sekä ristiintaulukoinneilla että keskiarvovertailuilla. Nettiriippuvaisia oli huomattavasti enemmän (35,7 %) masentuneiden kuin ei-masentuneiden joukossa (7,6 %). Masentuneiden nettiriippuvuustestin pistemäärän keskiarvo oli korkeampi (53.4) kuin ei-masentuneilla (21.7)(p<.001). Lisäksi tutkimuksessa haluttiin selvittää miten masennuksen ja nettiriippuvuuden välinen yhteys muuttuu kun sitä elaboroidaan muilla muuttujilla. Logistisella regressiomallilla masentuneiden riski nettiriippuvuuteen todettiin moninkertaiseksi verrattuna ei-masentuneisiin. Itse raportoitu päihdeongelma selitti osittain masennuksen ja nettiriippuvuuden välistä yhteyttä: sekä masennus että nettiriippuvuus olivat yleisempiä päihdeongelmia ilmoittaneilla. Masentuneiden riski (Odds Ratio) nettiriippuvuuteen oli iän, sukupuolen ja päihdeongelman vakiointien jälkeen 6.7 -kertainen verrattuna ei-masentuneisiin. Tutkimuksessa haluttiin selvittää myös miten itse raportoitu päihdeongelma, ikä ja sukupuoli ovat yhteydessä nettiriippuvuuteen. Ongelmalliseksi koettu päihteiden käyttö oli -masennuksen tavoin - voimakkaasti yhteydessä nettiriippuvuuden esiintymiseen. Ongelmallista päihteidenkäyttöä ilmoittaneista 34,4 prosenttia oli myös nettiriippuvaisia. Heistä, joilla ei omasta mielestään ollut ongelmallista päihteiden käyttöä vain 10,6 prosenttia oli nettiriippuvaisia. Päihdeongelmia ilmoittaneiden riski (Odds Ratio) nettiriippuvuuteen oli muiden muuttujien vakiointien jälkeen 2.9 -kertainen verrattuna ryhmään, jossa ei ilmoitettu ongelmallista päihteiden käyttöä. Nettiriippuvuus oli yleisempää kahdessa nuoremmassa ikäryhmässä, eli 9 18-vuotiailla. Tutkimuksessa käytettyjen muuttujien vakiointien jälkeen riski nettiriippuvuuteen oli miehillä 20 prosenttia suurempi kuin naisilla. Masennuksen ja nettiriippuvuuden välisen yhteydessä ei ollut tilastollisesti merkitseviä eroja ikäryhmien tai sukupuolten välillä. Kvalitatiivisesta aineistosta analysoitiin ihmisten omia nettiriippuvuudelleen antamia selityksiä ja niiden avulla pyrittiin ymmärtämään masennuksen ja nettiriippuvuuden välistä yhteyttä sisällöllisesti. Masentuneisuuden kuvauksia esiintyi kertomuksissa runsaasti. Nettiriippuvuuden yhteys masennukseen oli kertomuksista tulkittavissa kolmella tavalla: Sekä masennus että nettiriippuvuus voivat toimia pakokeinona stressaaviin elämäntilanteisiin tai reagointitapana suorituspaineisiin. Nettiriippuvuuden aiheuttamat ongelmat työhön, opintoihin ja sosiaaliseen elämään aiheuttavat tai vahvistavat masentunutta mielialaa. Netti toimii masentuneille lohtua tai helpotusta tuovana - ja myös koukuttavana - itsehoidon välineenä.
  • Rapo, Niina (2002)
    Tutkimuskohteeni on Internetin äitiyskeskustelupalstojen tiedon ja tuen vaihto sekä vaihdossa syntyvä äitien välinen asiantuntijuus. Tarkastelen äitiyskeskusteluja oma-apuryhmäkeskusteluina, joiden avulla äidit hakevat yhdessä tietoa ja tukea elämäntilanteensa ongelmiin. Pyrin tutkimuksessani tarkastelemaan minkälaiseksi tiedon ja tuen vaihto äitiyskeskustelupalstojen oma-apuryhmissä muodostuu. Pyrin myös tarkastelemaan minkälainen ”toisenlaisen” asiantuntijuuden, maallikkoasiantuntijuuden, foorumi äitiyden kokeneiden tiedon ja tuen vaihdossa syntyy. Monet ihmisten välisen toiminnan piirteet ovat Internetissä tunnistettavissa samanlaisina kuin ”reaalimaailmassa". Monet sosiaalisen toiminnan lait, kuten vaihto, vastavuoroisuus ja toisten huomioonotto säilyvät ihmisten välisissä Internet-suhteissa. Nämä toiminnan piirteet muovautuvat kuitenkin Internetin välineellisessä ympäristössä. Monien tuttujen sosiaalisten toiminnan piirteiden tarkastelu Internetin uudenlaisessa ympäristössä on tärkeää. Vaihto on tutkimuskohteeni toiminnan pääperiaate. Äitien keskustelut sekä tiedon ja tuen foorumi pysyvät yllä vaihdossa. Tarkastelen vaihtoa pääasiallisesti lahjana, joka voidaan nähdä tietynlaisena avunannon muotona. Tarkastelemassani ympäristössä lahjan vaihto on yleistynyt, vaihdettavat tieto ja tuki toimivat yleisluontoisina hyödykkeinä, joista kaikki voivat hyötyä. Äitien välinen tiedon ja tuen vaihtaminen on yhteisöllistä jakamista. Äitien välisessä vaihdossa ja jakamisessa syntyvää asiantuntijuutta tarkastelen kokemusperäisen sekä avoimen asiantuntijuuden avulla. Tutkimustani varten olen tarkastellut kahta suomalaista äitiyskeskustelupalstaa: Verkkoklinikan Vauvanhoito-palstaa sekä Kaksplus-lehden Internet-sivujen Keskustellaan!-palstaa. Tarkastelen näitä palstoja yhteisenä aineistona. Tutkimusmenetelmänä olen käyttänyt keskustelunanalyysiä. Keskustelunanalyysi nostaa esiin äitien vastavuoroisen keskustelutoiminnan. Keskustelunanalyysi nostaa esiin myös äitien välisen tiedon ja tuen vaihdon kysymys-vastaus -vieruspareissa muodostuvana yhteistyönä. Myös äitien keskustelun sisältö eli läheisasiantuntijoiden sekä virallisten asiantuntijoiden lausumien käsittely että äitien suhtautumistavat näihin asiantuntijuuksiin näkyvät keskustelunanalyysin avulla. Äitien välisessä tiedon ja tuen vaihdossa syntyvä maallikkoasiantuntijuus eroaa klassisesta tieteeseen, ammatteihin ja instituutioihin perustuvasta asiantuntijuudesta. Äitien kokemusperäinen tieto koetaan hyvin tärkeäksi asiantuntijuudeksi. Foorumin asiantuntijuutta ei tarjota ylhäältä alaspäin, vaan asiantuntijuus ja tietämys liikkuu äitien välillä. Jokainen äideistä toimii sekä asiantuntijana että neuvon vastaanottajana. Asiantuntijuus ei ole totaaleja ratkaisuja tarjoavaa, vaan perustuu mahdollisuuksien ja ehdotusten käsittelyyn. Kaikki tietovaranto käsitellään mahdollisena asiantuntijuutena. Internetin äitiyskeskusteluiden asiantuntijuus muodostuu eri asiantuntijuuksien vuorovaikutuksessa. Kokemusperäisen tiedon lisäksi keskusteluissa huomioidaan virallisten asiantuntijoiden tarjoamat ratkaisut. Keskusteluissa syntyvä asiantuntijuus on kokemusperäisen ja virallisen asiantuntijuuden sekä vertaistuen tietohybridi. Äitiyskeskustelupalstat voidaan nähdä kansalaistoimintana, virallisten asiantuntijuuksien vaihtoehtona, mutta myös virallista äitiyshuoltoa tukevana toimintana. Äidit myös muodostavat elämäntilanneyhteisöllisyyden foorumin. Samassa elämäntilanteessa olevat keskustelijat hakevat jokaisen äidin oman hyvän vanhemmuuden yksilöllistä päämäärää yhteen liittoutuneina.
  • Vilkki, Olli (2003)
    The research was defined as a development work and its focus was a mediated ac-tion in the learning process of a network-based group. The subjects of study were the instruments that support group work. The shared space was used as a media to improve co-operation and as a promoting base of cognitive tools. The context of the study was the change in working life and in the operation model of the trade unions. The result of the development work was a network-based group-learning model in the trade unions’ shop steward training. The development process created various tools for network-based group learning and for the shop stewards. The network-based group-learning model led into a more self-directed method than originally intended. The learning task, access to materials and linking them by means of the user interface to an oriented agenda, intensified this self-learning process. Teachers felt themselves to be obsolete until they got the idea of using the learning-network as a tool to follow-up and support the group activity. The starting point for the development work was a model of modernizing the activ-ity, where work development, fairness and social responsibility unite. The main focus of the model is to develop the functionality of working places and profes-sional skills of employees. The target is to improve the usage of the employees’ capacity. The operation model presumes tools, which support co-operation, data processing, networking and that suit into a complex production to co-operative concept building. The shared space is the main concept of this study. The shared space, which was implemented with a wall table, a display unit or a virtual community, tempted the group members to an intensive knowledge building. The conscious use of the me-dia promoted a dialogue between teachers and students. The shared space can be understood as a physical, virtual, cognitive and cultural space, where a group of people co-operate. The complementary learning task proved to be the most important cognitive tool of network-based group learning. The role of the teacher changed into maintaining the dialogue and the learning process. Overloaded tasks, technical disorder and unsat-isfactory tools in user interface led to frustration among the students. The use of action media and group dynamics brought good results. Network-based activities and playful approach generated a free atmosphere. Taking turns in action learning and network-based learning caused promoted learning. According to the study the teachers favoured individual working and a light net-work-based model, the levels of which were individual working, pair work, alter-nating pairs, team-based working pairs and a network-based community. The role of the team and the researcher in the development work was to keep up the dia-logue. The use of the shared space as a tool of co-operation between the teachers promoted the planning and development work.
  • Pussinen, Kirsi (Helsingin yliopisto, 2007)
    The aim of this work was to study, whether international fashion trends show in knit designs in Finnish craft magazines and how trends are modified. Women s knitted clothes and accessories in autumn winter season 2005 2006 were analyzed. Future research, trends, fashion, designing and knitting provides theoretical basis for this study. The trend material of this study came from Carlin Women s knitwear winter 2005 2006, which is fashion forecast for Women s knitwear. In addition to the trend book, I selected two international fashion magazines to reinforce this study. Fashion magazines were L´Officiel, 1000 models, Milan New York winter 05/06, No 52, April 2005 and Collezioni Donna, Prêt-à-porter autumn-winter 2005 2006, No 107. Finnish craft magazines in this study were MODA s issues 4/2005, 5/2005, 6/2005 and Novita s issues autumn 2005, winter 2005 and Suuri Käsityölehti s issues 8/2005, 9/2005, 10/2005. For the base of the analyze I took themes from the trend book. From fashion magazines I searched knitwear designs and these designs were sorted out by themes of trend book. To this trend and fashion material I compared knit designs from craft magazines. I analyzed how fashion trends show in knit designs and how they are modified. I also studied what features of trends were shown and which did not appear in knit designs of the craft magazines. For analyzing trend pictures and knit designs in craft magazines I applied qualitative content analysis and image analysis. According to the results of this research, effects of trend can be recognized in knit designs of craft maga-zines, although the fashion trends have been applied very discreetly. Knit designs were very similar re-gardless of magazine. The craft magazine data included approximately as many designs from Novita and MODA. In Suuri Käsityölehti provided only fifth of the designs data. There were also designs in MODA and Suuri Käsityölehti, which were made of Novita s yarns. This research material includes yarns of 15 different yarn manufacturers. Although half of all knit designs were knitted from Novita s yarn. There were 10 different yarns from Novita. Nevertheless Novita s yarn called Aino was the most popular. Finnish craft magazines have not respond to popularity of knitting. Magazines do not provide any novelty designs for knitters. Knit designs in Finnish craft magazines are usually practical basic designs without any innovativeness.
  • Jansson, Linda (Helsingin yliopisto, 2013)
    The mammalian central nervous system (CNS) develops from multipotent neural stem or progenitor cells. During development the cells proliferate actively and differentiate into all the different cell types of the brain. Neurogenesis continues in the adult brain but to a much lesser extent than during development. Adult neurogenesis is influenced by many different factors, including insults to the brain and neurodegenerative disease. Neurotransmitters have been implicated as regulators of neurogenesis. The main excitatory neurotransmitter glutamate is linked to neural progenitor cell proliferation and differentiation as well as migration of newborn neurons. Glutamate is also involved in the pathogenesis of several neurological disorders and other factors linked to brain pathogenesis, such as hypoxia and acidosis, are known to influence neural progenitor cells. Elucidating the mechanisms governing stem/progenitor cell behavior during normal and pathological conditions will aid in the development of cell-based therapies for treating insult or disease within the CNS. The aim of this thesis was to study the role of glutamate receptor agonists and antagonists in differentiation and migration of neural progenitors and their progeny to increase the understanding of how this neurotransmitter influences these cells. In addition, the effects of brain-derived neurotrophic factor (BDNF) and the reactivity of the cells to conditions associated with ischemic stroke (hypoxia/acidosis) were studied. By utilizing the neurosphere model we found that differentiating neural progenitors initially mainly expressed and responded to stimuli through metabotropic glutamate receptor 5 (mGluR5) and that the expression and functional response of the receptor corresponded with the distribution of radial glial cells. Ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors were also present during early differentiation and expressed mainly by neuron-like cells. The expression of mGluR5 decreased and the expression and functional maturity of AMPA/KA receptors increased with time in culture. Pharmacological blocking studies revealed that radial glial process extension and neuronal motility are regulated through both mGluR5 and AMPA/KA receptors, but that the receptors have opposing effects on these cellular mechanisms. After prolonged differentiation a small subpopulation of neuronal cells responding to stimulation with N-methyl-D-aspartate (NMDA) and gamma amino butyric acid (GABA) appeared. This subpopulation of cells was responsive to motogenic actions mediated by BDNF. In addition, we found that radial glial and neuron-like cells exhibited differences in resting membrane potential and intracellular pH and reacted differently when exposed to hypoxic and acidic conditions. This study contributes new information regarding neural progenitor cell characteristics and behavior when differentiated in the presence of or challenged with factors influencing neurogenesis, both during normal and pathological conditions. These findings may be useful in developing treatment programs for neurological disorders.
  • Helokunnas, Siiri (Helsingin yliopisto, 2013)
    Objectives. The main function of eye blinking is to moisten and protect the cornea. Therefore it may be surprising that blink rate can convey information about the person s emotional and cognitive state, and that people with abnormal blink rates can be perceived as unfriendly or nervous. Moreover, listeners blinks have been shown to synchronize with a videotaped speaker s blinks. For these reasons, blinks are suggested to have social functions, as well. The objective of this thesis was to probe the neural correlates of blink viewing with magnetoencephalography (MEG). The research questions were: 1) Do viewed eye blinks elicit observable MEG responses? If they do, which brain regions are involved? 2) How does the response change when the blink video is slowed down? 3) Are the self-produced blinks synchronized with the viewed blinks? Methods. The participants (n = 9) were presented with a video of a neutral female face showing no other movement than a single eye blink. The video was played back with normal speed (blink duration 351 ms) and in slow motion (950 ms); a pair of normal and slow videos was repeated 102 times. Between the blink videos, five other facial expressions were shown, and the participants task was to memorize those expressions. A 306-channel neuromagnetometer recorded the brain responses with a sampling rate of 600 Hz. After averaging and filtering the responses, the mean peak latencies, return-to-baseline durations and amplitudes were compared on the channels showing the strongest peaks. The participants blinks were measured with electro-oculogram (EOG), and the proportion of blinks occurring during the viewed blink was compared with the proportions of blinks at other time points. Results and discussion. Both fast and slow viewed blinks elicited prominent MEG responses. The mean peak latencies of the responses to the slow blinks were longer than those to the normal blink (445 ms vs. 317 ms). The responses to the slow blink also returned to the baseline later (921 ms vs. 537 ms). The maximum responses were equal in amplitude between the normal and slow conditions, contrary to our expectations based on earlier results showing that when the viewed stimuli move faster, the responses are stronger. In accordance with earlier EEG results, the cortical sources, modeled as current dipoles, were located mainly in the occipito-temporal cortical regions in the right hemisphere. The subjects also tended to blink more after the blink in the video (peak around 700 ms after the onset of the viewed blink). In conclusion, eye blinks are likely to have social relevance, and this was the first study to demonstrate with MEG how the human brain reacts to viewed blinks.
  • Kerosuo, Laura (Helsingin yliopisto, 2009)
    Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease Stem cells provide the self-renewing cell pool for developing or regenerating organs. The mechanisms underlying the decisions of a stem or progenitor cell to either self-renew and maintain multipotentiality or alternatively to differentiate are incompletely understood. In this thesis work, I have approached this question by investigating the role of the proto-oncogene Myc in the regulatory functions of neural progenitor cell (NPC) self-renewal, proliferation and differentiation. By using a retroviral transduction technique to create overexpression models in embryonic NPCs cultured as neurospheres, I show that activated levels of Myc increase NPC self-renewal. Furthermore, several mechanisms that regulate the activity of Myc were identified. Myc induced self-renewal is signalled through binding to the transcription factor Miz-1 as shown by the inhibited capacity of a Myc mutant (MycV394D), deficient in binding to Miz-1, to increase self-renewal in NPCs. Furthermore, overexpression of the newly identified proto-oncogene CIP2A recapitulates the effects of Myc overexpression in NPCs. Also the expression levels and in vivo expression patterns of Myc and CIP2A were linked together. CIP2A stabilizes Myc protein levels in several cancer types by inhibiting its degradation and our results suggest the same function for CIP2A in NPCs. Our results also support the conception of self-renewal and proliferation being two separately regulated cellular functions. Finally, I suggest that Myc regulates NPC self-renewal by influencing the way stem and progenitor cells react to the environmental cues that normally dictate the cellular identity of tissues containing self-renewing cells. Neurosphere cultures were also utilised in order to characterise functional defects in a human disease. Neural stem cell cultures obtained post-mortem from foetuses of lethal congenital contracture syndrome (LCCS) were used to reveal possible cell autonomous differentiation defects of patient NPCs. However, LCCS derived NPCs were able to differentiate normally in vitro although several transcriptional differences were identified by using microarray analysis. Proliferation rate of the patient NPCs was also increased as compared to NPCs of age-matched control foetuses.
  • Stockmann-Juvala, Helene (Helsingin yliopisto, 2007)
    Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species can also be found in moisture-damaged buildings, and therefore there may also be human exposure to Fusarium mycotoxins, including FB1. FB1 affects the metabolism of sphingolipids by inhibiting the enzyme ceramide synthase. It is neuro-, hepato- and nephrotoxic, and it is classified as possibly carcinogenic to humans. This study aimed to clarify the mechanisms behind FB1-induced neuro- and immunotoxicity. Four neural and glial cell lines of human, rat and mouse origin were exposed to graded doses of FB1 and the effects on the production of reactive oxygen species, lipid peroxidation, intracellular glutathione levels, cell viability and apoptosis were investigated. Furthermore, the effects of FB1, alone or together with lipopolysaccharide (LPS), on the mRNA and protein expression levels of different cytokines and chemokines were studied in human dendritic cells (DC). FB1 induced oxidative stress and cell death in all cell lines studied. Generally, the effects were only seen after prolonged exposure at 10 and 100 µM of FB1. Signs of apoptosis were also seen in all four cell lines. The sensitivities of the cell lines used in this study towards FB1 may be classified as human U-118MG glioblastoma > mouse GT1-7 hypothalamic > rat C6 glioblastoma > human SH-SY5Y neuroblastoma cells. When comparing cell lines of human origin, it can be concluded that glial cells seem to be more sensitive towards FB1 toxicity than those of neural origin. After exposure to FB1, significantly increased levels of the cytokine interferon-γ (IFNγ) were detected in human DC. This observation was further confirmed by FB1-induced levels of the chemokine CXCL9, which is known to be regulated by IFNγ. During co-exposure of DC to both LPS and FB1, significant inhibitions of the LPS-induced levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1β, and their regulatory chemokines CCL3 and CCL5 were observed. FB1 can thus affect immune responses in DC, and therefore, it is rather likely that it also affects other types of cells participating in the immune defence system. When evaluating the toxicity potential of FB1, it is important to consider the effects on different cell types and cell-cell interactions. The results of this study represent new information, especially about the mechanisms behind FB1-induced oxidative stress, apoptosis and immunotoxicity, as well as the varying sensitivities of different cell types towards FB1.
  • Priyadarshini, Madhusmita (Helsingin yliopisto, 2013)
    Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease (AD). The quest for better therapies to modify the progression of PD is still ongoing. During the last two decades, the concept of the etiological basis of PD has changed, which has been driven by genetics, the recognition of familial forms, knowledge of the effects of the environment and toxins, and genome-wide association studies. Although most cases are sporadic, approximately 5-10% of PD cases are due to genetic mutations that give rise to the familial forms. Studies using neurotoxins and also genetic mutations that underlie familial PD have implicated mitochondrial dysfunction in the pathogenesis of PD. Among the different genes associated with familial PD, PTEN-induced putative kinase1 (Pink1), responsible for the autosomal recessive type, is strongly linked to the mitochondria. To investigate in depth the underlying mechanisms of Pink1, we inhibited the function of pink1 in zebrafish using morpholino oligonucleotides (MOs). The MO was first thoroughly characterized with all necessary control experiments to avoid unspecific effects. Since the dopaminergic system is affected in PD, a marker for dopamine, tyrosine hydroxylase (TH), was used to assess damage to the system. Due to a genome duplication event that occurred early in the evolution of teleosts after the divergence from the mammals, two TH non-allelic isoforms were identified in zebrafish: th1 and th2. In the pink1 morphants, both the TH gene isoforms were altered. With in situ hybridization, the loss of th1 was found in the ventral diencephalon (dopaminergic cell groups 5, 6, 11) and th2 was reduced in the caudal hypothalamus (cell group 10b). Similar results were obtained with the cell counting method for TH1 immunoreactive cells. TH-ir indicated the loss of cells in the pretectum (group 7) and the ventral diencephalic cluster represented by cell groups 5,6,11. These pink1 morphants were exposed to subeffective doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This amalgamation of the toxin and genetic manipulation caused a locomotor deficit and also facilitated the loss of TH-ir in the same cell populations in the larval brains as was instigated by pink1 knockdown alone. To investigate the involvement of pink1 in cell damage, we used a two-color gene expression-based microarray and identified a number of genes that were potentially involved in the pathogenic mechanism of the disease. After successful data analysis, the changes in critical genes were successfully validated by quantitative real-time PCR. The gene expression changes in the morphants, identified by the microarray, were rescued by pink1 mRNA injections, suggesting the specific involvement of pink1 in the differentially expressed gene regulation. One of the significant findings was HIF signaling, an important pathway affected by pink1 knockdown. Individual factors and genes in the same pathway were validated by independent methods in the pink1 morphants to reveal whether pink1 affected hif1α or the cascade of events in the signaling pathway. Changes in the VEGF transcripts, erythropoiesis, and reactive oxygen species were observed, as were other antioxidant system genes, including cat and sod2. These pathways may provide new targets for drug development in PD. To study the mechanisms underlying the involvement of pink1 in oxidative stress-mediated PD pathology using zebrafish as a tool, we generated a transgenic line, Tg(pink1:EGFP). The Tol2 transgenic approach was used to generate Tg(pink1:EGFP) by using the zebrafish pink1 promoter. Expression of the pink1 transgene was detected in the telencephalon, midbrain, and rhombencephalon in the CNS, and in the muscle, heart, and liver among the peripheral organs. The transgenic fish line was used to study the effect of oxidative stress. When subjected to a low concentration of hydrogen peroxide (H2O2), which had no effect on the mortality or phenotype of the fish, the transgenic fish showed an increase in pink1 transgene activity in the brain of the larval zebrafish. Oxidative stress-mediated changes in TH expression are valuable for PD study. H2O2 administration did not affect the th1 transcript levels, but it significantly increased pink1 expression and reduced the th2 transcript levels. This transgenic model will be highly useful for drug development and the screening of new potential therapeutic approaches as an in vivo model.
  • Korostenskaja, Milena (Helsingin yliopisto, 2008)
    Cognitive impairments of attention, memory and executive functions are a fundamental feature of the pathophysiology of schizophrenia. The neurophysiological and neurochemical changes in the auditory cortex are shown to underlie cognitive impairmentsin schizophrenia patients. Functional state of the neural substrate of auditory information processing could be objectively and non-invasively probed with auditory event-related potentials (ERPs) and event- related fields (ERFs). In the current work, we explored the neurochemical effect on the neural origins of auditory information processing in relation to schizophrenia. By means of ERPs/ERFs we aimed to determine how neural substrates of auditory information processing are modulated by antipsychotic medication in schizophrenia spectrum patients (Studies I, II) and by neuropharmacological challenges in healthy human subjects (Studies III, IV). First, with auditory ERPs we investigated the effects of olanzapine (Study I) and risperidone (Study II) in a group of patients with schizophrenia spectrum disorders. After 2 and 4 weeks of treatment, olanzapine has no significant effects on mismatch negativity(MMN) and P300, which, as it has been suggested, respectively reflect preattentive and attention-dependent information processing. After 2 weeks of treatment, risperidone has no significant effect on P300, however risperidone reduces P200 amplitude. This latter effect of risperidone on neural resources responsible for P200 generation could be partly explained through the action of dopamine. Subsequently, we used simultaneous EEG/MEG to investigate the effects of memantine (Study III) and methylphenidate (Study IV) in healthy subjects. We found that memantine modulates MMN response without changing other ERP components. This could be interpreted as being due to the possible influence of memantine through the NMDA receptors on auditory change- detection mechanism, with processing of auditory stimuli remaining otherwise unchanged. Further, we found that methylphenidate does not modulate the MMN response. This finding could indicate no association between catecholaminergic activities and electrophysiological measures of preattentive auditory discrimination processes reflected in the MMN. However, methylphenidate decreases the P200 amplitudes. This could be interpreted as a modulation of auditory information processing reflected in P200 by dopaminergic and noradrenergic systems. Taken together, our set of studies indicates a complex pattern of neurochemical influences produced by the antipsychotic drugs in the neural substrate of auditory information processing in patients with schizophrenia spectrum disorders and by the pharmacological challenges in healthy subjects studied with ERPs and ERFs.
  • Riekki, Tapani (Helsingin yliopisto, 2014)
    The present thesis consists of six studies that investigate different cognitive factors that contribute to believing and unbelieving in paranormal, superstitious, magical, and supernatural (commonly referred to as paranormal beliefs). Earlier studies have found several factors reaching from personality factors to cognitive factors to cultural factors that contribute to believing. However, the research has neglected the important factor of what sets paranormal beliefs apart from other beliefs. In addition, although we know a lot about demographical and personality features that contribute to differences in paranormal beliefs, neuro-cognitive differences are still not well known or empirically tested. One explanation that takes into account the difference between paranormal beliefs and other beliefs is that paranormal beliefs stem from core knowledge confusions about the ontological properties of mental, physical, and biological phenomena. The first study of the thesis tried to gain insight into the neural basis of core knowledge confusions in an event-related electroencephalography study. The next two studies tested the possibility that cognitive inhibition, the ability to flexibly switch between thinking modes and if needed, to inhibit unwanted or irrelevant thoughts, could contribute to believing and unbelieving. In these two studies group differences between paranormal believers and skeptics were first compared by using tests of cognitive inhibition and secondly by using brain imaging. Brain imaging was done during a task that invoked paranormal interpretations. The last three studies of the thesis examined the role of the social information processing differences between paranormal believers and skeptics. Methods included brain imagining, behavioral experiments, and self-report measurements. In the first study, we tested how conceptions about the mind are related to beliefs and core knowledge confusions. In the second and third of these studies, we tested group differences between paranormal believers and skeptics by using brain imaging and a behavioral test. We investigated if the groups differ in attribution of intentions to randomly moving objects and in tendency for illusory face perception. The results suggest that core knowledge confusions are based on intuitive world knowledge and that this intuitive world knowledge is less categorized among paranormal believers than among skeptics. Cognitive inhibition was also found to contribute to paranormal beliefs: strong cognitive inhibition downplays paranormal beliefs. Social information processing was connected to paranormal beliefs in several ways. First, understanding mind and its properties in a Cartesian dualistic way was associated with paranormal beliefs and ontological confusions preceded them. Second, believers when compared to skeptics assigned more intentions to randomly moving objects. This was associated with activation of the mentalizing system at the brain level. Finally, we found out that paranormal believers were more prone to illusory face perception than skeptics were. The results underline that if one seeks to understand believing and especially unbelieving, which both are complex phenomena, individual differences in cognitive processing must be taken into account.
  • Leminen, Alina (Helsingin yliopisto, 2012)
    The representation of morphologically complex words in the mental lexicon and their neurocognitive processing has been a vigorously debated topic in psycholinguistics and the cognitive neuroscience of language. This thesis investigates the effect of stimulus modality on morphological processing, the spatiotemporal dynamics of the neural processing of inflected (e.g., work+ed ) and derived (e.g., work+er ) words and their interaction, using the Finnish language. Overall, the results suggest that the constituent morphemes of isolated written and spoken inflected words are accessed separately, whereas spoken derived words activate both their full form and the constituent morphemes. The processing of both spoken and written inflected words elicited larger N400 responses than monomorphemic words (Study I), whereas the responses to spoken derived words did not differ from those to monomorphemic words (Study IV). Spoken inflected words elicited a larger left-lateralized negativity and greater source strengths in the left temporal cortices than derived words (Study IV). Thus, the results suggest different cortical processing for derived and inflected words. Moreover, the neural mechanisms underlying inflection and derivation seem to be not only different, but also independent as indexed by the linear summation of the responses to derived and inflected stimuli in a combined (derivation+inflection) condition (Study III). Furthermore, the processing of meaningless, spoken derived pseudowords was more difficult than for existing derived words, indexed by a larger N400-type effect for the pseudowords. However, no differences were observed between meaningful derived pseudowords and existing derived words (Study II). The results of Study II suggest that semantic compatibility between morphemes seems to have a crucial role in a successful morphological analysis. As a methodological note, time-locking the auditory event-related potentials/fields (ERP/ERF) to the suffix onset revealed the processes related to morphological analysis more precisely (Studies II and IV), which also enables comparison of the neural processes in different modalities (Study I).
  • Sarajuuri, Anne (Unigrafia Oy, 2012)
    Hypoplastic left heart syndrome (HLHS) and other forms of functionally univentricular heart (UVH) are complex congenital heart defects (CHD) that during the past few decades have gained viability with staged palliative surgery. It results in the passive return of systemic venous blood to the lungs without passing through the heart. The aim of this study was to evaluate the neurodevelopmental outcome of children with HLHS and UVH in Finland with neurological, neuropsychological, and motor assessments and brain imaging, and to detect possible risk factors associated with an adverse outcome. Parental perceptions of child behavior and parenting stress were also assessed with parental question-naires. The first study cohort of patients born between 1995 and 1999, which included most of the first HLHS survivors in Finland, showed a significantly lower cognitive outcome compared to normative data among both patients with HLHS (n = 7) and with UVH (n = 19). Cerebral palsy was present in 14% of the patients with HLHS and in 10% of those with UVH, and milder difficulties in gross and fine motor functions were also commonly found. Patients with HLHS or UVH born between 2002 and 2005 were recruited in a prospective neurodevelopmental follow-up study as newborns. The neurodevelopmental evaluations at the ages of 12 months, 30 months, and 5 years revealed a significantly lower cognitive and motor outcome among the patients with HLHS (n = 23) compared to healthy age- and gender-matched controls (n = 40). The patients with UVH (n = 14) only demonstrated a statistically significant difference to controls in motor development during the earlier assessments, and at the age of 5 years also in cognitive development. A smaller sample size may have contributed to the lack of statistically significant difference in cognitive development in the earlier assessments. Major neurodevelopmental impairment was found in 26% of the patients with HLHS, and 23% of the patients with UVH at the age of 5 years. Brain magnetic resonance imaging revealed abnormalities in 82% of the patients with HLHS and 56% of those with UVH most commonly infarcts or ischemic findings of different degrees. Other than minimal ischemic findings were significantly associated with neurodevelopmental outcome. The level of parenting stress was significantly higher among the patients with HLHS compared to controls at the age of 18 months. The parents of the patients with UVH, however, did not report more stress than those of the controls. In conclusion, neurodevelopmental deficits remain a major concern among patients with UVH, and especially among those with HLHS. Neurodevelopmental follow-up is recommended for this seriously ill patient group and psychosocial support for their parents.
  • Anders, Eriksson-Palojärvi (Helsingin yliopisto, 2013)
    Myxomatous mitral valve disease causing mitral regurgitation (MR) is a common cause of heart failure in dogs. However, many aspects of pathophysiology affecting diagnostic measurements are poorly defined. The objective of this study was to add to the knowledge of different pathophysiological processes affecting measures used. Focus was put on plasma parameters, including N-terminal pro A-type natriuretic peptide (NT-proANP) and nitric oxide (NO), and first pass radionuclide angiocardiography to evaluate heart pump function and possible right sided heart enlargement associated with pulmonary hypertension. Echocardiography and thoracic radiographs were used as reference methods. Results. In normal dogs both NT-proANP (P=0.002) and NO (P=0.01) increased with age. Plasma NT-proANP concentrations for dogs under 5.9 years of age were lower than for dogs older than 5.9 years (inter quartile range 190 270 pmol/l vs. 307 530, respectively), with no overlap between groups. This discrimination was not seen for NO. In healthy dogs heart rate normalized blood pulmonary transit time (nPTT) was 4.4±0.6, dogs with asymptomatic MR 6.3±1.6, and dogs with CHF 11.8±3.4 (P < 0.001). The size of the right heart chambers increased only late in MR. Pulmonary blood volume (PBV) was associated with nPTT (R2=0.85, P < 0.0001) but not with forward stroke volume. Increase in PBV appeared late in the phase before CHF. The hazard ratio for NT-proANP was 1.21 (per 100 pmol/l; P < 0.0002). The median time to failure was 11 months for dogs with NT-proANP concentrations >1000 pmol/l and 54 months for dogs with concentrations ≤1000 pmol/l (P < 0.0001). Dogs that developed CHF had a lower mean plasma level of NO than dogs not reaching CHF (mean 23 vs. 28 µmol/l (as nitrite), P=0.016). Increased heart rate (>130 beats/min, P < 0.001) and heart murmur (3-6/6 vs. 1-2/6, P < 0.001) increased risk. Conclusions. Specific normal values for natriuretic peptides should be established for different age groups of dogs. Heart rate, murmur and NT-proANP can be used to predict risk of and time to heart failure in dogs with MR. Heart rate normalized PTT (nPTT) is a robust measure of heart pump function in MR. Both nPTT and pulmonary blood volume increase before onset of CHF. Apparent right-sided heart enlargement on radiographs is due to them being displaced by left heart chambers as they enlarge only in severe MR.
  • Pischik, Elena (Helsingin yliopisto, 2006)
    Acute intermittent porphyria (AIP, MIM #176000) is an inherited metabolic disease due to a partial deficiency of the third enzyme, hydroxymethylbilane synthase (HMBS, EC: 4.3.1.8), in the haem biosynthesis. Neurological symptoms during an acute attack, which is the major manifestation of AIP, are variable and relatively rare, but may endanger a patient's life. In the present study, 12 Russian and two Finnish AIP patients with severe neurological manifestations during an acute attack were studied prospectively from 1995 to 2006. Autonomic neuropathy manifested as abdominal pain (88%), tachycardia (94%), hypertension (75%) and constipation (88%). The most common neurological sign was acute motor peripheral neuropathy (PNP, 81%) often associated with neuropathic sensory loss (54%) and CNS involvement (85%). Despite heterogeneity of the neurological manifestations in our patients with acute porphyria, the major pattern of PNP associated with abdominal pain, dysautonomia, CNS involvement and mild hepatopathy could be demonstrated. If more strict inclusion criteria for biochemical abnormalities (>10-fold increase in excretion of urinary PBG) are applied, neurological manifestations in an acute attack are probably more homogeneous than described previously, which suggests that some of the neurological patients described previously may not have acute porphyria but rather secondary porphyrinuria. Screening for acute porphyria using urinary PBG is useful in a selected group of neurological patients with acute PNP or encephalopathy and seizures associated with pain and dysautonomia. Clinical manifestations and the outcome of acute attacks were used as a basis for developing a 30-score scale of the severity of an acute attack. This scale can easily be used in clinical practice and to standardise the outcome of an attack. Degree of muscle weakness scored by MRC, prolonged mechanical ventilation, bulbar paralysis, impairment of consciousness and hyponatraemia were important signs of a poor prognosis. Arrhythmia was less important and autonomic dysfunction, severity of pain and mental symptoms did not affect the outcome. The delay in the diagnosis and repeated administrations of precipitating factors were the main cause of proceeding of an acute attack into pareses and severe CNS involvement and a fatal outcome in two patients. Nerve conduction studies and needle EMG were performed in eleven AIP patients during an acute attack and/or in remission. Nine patients had severe PNP and two patients had an acute encephalopathy but no clinically evident PNP. In addition to axonopathy, features suggestive of demyelination could be demonstrated in patients with severe PNP during an acute attack. PNP with a moderate muscle weakness was mainly pure axonal. Sensory involvement was common in acute PNP and could be subclinical. Decreased conduction velocities with normal amplitudes of evoked potentials during acute attacks with no clinically evident PNP indicated subclinical polyneuropathy. Reversible symmetrical lesions comparable with posterior reversible encephalopathy syndrome (PRES) were revealed in two patients' brain CT or MRI during an acute attack. In other five patients brain MRI during or soon after the symptoms was normal. The frequency of reversible brain oedema in AIP is probably under-estimated since it may be short-lasting and often indistinguishable on CT or MRI. In the present study, nine different mutations were identified in the HMBS gene in 11 unrelated Russian AIP patients from North Western Russia and their 32 relatives. AIP was diagnosed in nine symptom-free relatives. The majority of the mutations were family-specific and confirmed allelic heterogeneity also among Russian AIP patients. Three mutations, c.825+5G>C, c.825+3_825+6del and c.770T>C, were novel. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R) and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. The effects of novel mutations were studied by amplification and sequencing of the reverse-transcribed total RNA obtained from the patients' lymphoblastoid or fibroblast cell lines. The mutations c.825+5G>C and c.770T>C resulted in varyable amounts of abnormal transcripts, r.822_825del (p.C275fsX2) and [r.770u>c, r.652_771del, r.613_771del (p.L257P, p.G218_L257del, p.I205_L257del)]. All mutations demonstrated low residual activities (0.1-1.3 %) when expressed in COS-1 cells confirming the causality of the mutations and the enzymatic defect of the disease. The clinical outcome, prognosis and correlation between the HMBS genotype and phenotype were studied in 143 Finnish and Russian AIP patients with ten mutations (c.33G>T, c.97delA, InsAlu333, p.R149X, p.R167W, p.R173W, p.R173Q, p.R225G, p.R225X, c.1073delA) and more than six patients in each group. The patients were selected from the pool of 287 Finnish AIP patients presented in a Finnish Porphyria Register (1966-2003) and 23 Russian AIP patients (diagnosed 1995-2003). Patients with the p.R167W and p.R225G mutations showed lower penetrance (19% and 11%) and the recurrence rate (33% and 0%) in comparison to the patients with other mutations (range 36 to 67% and 0 to 66%, respectively), as well as milder biochemical abnormalities [urinary porphobilinogen 47±10 vs. 163±21 mol/L, p<0.001; uroporphyrin 130±40 vs. 942±183 nmol/L, p<0.001] suggesting a milder form of AIP in these patients. Erythrocyte HMBS activity did not correlate with the porphobilinogen excretion in remission or the clinical of the disease. In all AIP severity patients, normal PBG excretion predicted freedom from acute attacks. Urinary PBG excretion together with gender, age at the time of diagnosis and mutation type could predict the likelihood of acute attacks in AIP patients.
  • Nevalainen, Päivi (Helsingin yliopisto, 2010)
    Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.