Analiz obraza ženščiny na osnove jazykovogo materiala ”Krest’janka” 1985, 1995 i 2005 gg.

Tämän tutkimuksen tarkoituksena on tutkia Venäjällä ilmestyvän ”Krest’janka”-lehden välittämää naiskuvaa. Tutkimukseen on valittu lehden vuosikerrat 1985, 1995 ja 2005, koska suuret muutokset Venäjällä ajoittuvat tälle aikavälille. Haluamme selvittää, miten naiskuva on muuttunut tänä aikana ja miten se välittyy lehden sivuilta. Tutkimukseemme olemme käyttäneet A.V. Kirilinan työssään käyttämiä metodeja. Keräsimme lehdistä kaikki verbilausekkeet, joiden subjektina on naista tarkoittava sana ja jaoimme ne luokkiin merkityksen mukaan. Jaottelun jälkeen analysoimme kerättyä aineistoa ja pyrimme löytämään kullekin vuosikerralle tyypillisiä verbilausekkeita. Tämän lisäksi keräsimme lehdistä kaikki naista kuvaavat adjektiivit ja vertailimme niiden käyttöä eri vuosina. Tulosten perusteella voidaan sanoa, että vuoden 1985 lehdissä vaikuttaa vielä voimakkaasti sosialismin ihanteet. Nainen kuvataan työnsä kautta aktiivisena ja tavoitteensa ylittävänä kansalaisena. Yksityiselämään ei juuri kiinnitetä huomiota. Vuoden 1995 ja 2005 lehtien naiset ovat keskenään hyvinkin samanlaisia. Naisen elämästä puhutaan nyt jo laajemmin. Työn lisäksi yksityiselämä ja tunteet ovat keskeisiä aiheita. Kun 1985 lehdissä ei puhuttu naisesta negatiiviseen sävyyn, niin 1995 ja 2005 vuosien lehdissä naista kuvataan myös negatiivisessa valossa. Myös yhteiskunnan epäkohtiin kiinnitetään huomiota naisen näkökulmasta.

Gde moi kryl'ja? Analiz fil'ma Alekseja Balabanova »Brat»

Tutkielma on analyysi Aleksej Balabanovin ohjaamasta elokuvasta Brat (1997). Ensimmäisessä osassa tarkastellaan Brat-elokuvaa satuna jäsentämällä sen henkilöhahmoja ja rakennetta Vladimir Proppin satujen morfologisen analyysin pohjalta. Tärkeimmille henkilöhahmoille on mahdollista löytää vastineet satujen perushahmoista, mutta elokuvasta löytyy näille hahmoille myös erityisiä valheellisia variantteja, selkeimpänä esimerkkinä veljespari Danila – sankari ja Vitja – valheellinen sankari. Myös juonenkulusta on jäsennettävissä sekä varsinainen, että valheellinen juonenkulku: varsinainen juonenkulku käsittelee päähenkilön suhdetta veljeensä, sekä heidän yhteiseen viholliseensa, valheellinen juonenkulku puolestaan päähenkilön suhdetta tarinan potentiaaliseen sankarittareen. Lisäksi elokuvasta löytyy myös kolmas, vaihtoehtoinen juonenkulku, joka liittyy musiikin funktioon elokuvassa. Toisessa osassa analysoidaan päähenkilön suhdetta muihin henkilöhahmoihin sekä ympäröivään yhteiskuntaan käsitteiden horisontaali ja vertikaali avulla. Nämä käsitteet osittain limittyvät Vladimir Papernyin teoriaan Kul’tura 2. Analyysin lähtökohtana on, että elokuvan toiminta käynnistyy sankarin pyrkimyksestä löytää oma viiteryhmänsä ja sitä kautta identiteettinsä. Isän menetyksestä, niin konkreettisesti perheen kuin symbolisesti yhteiskunnan tasolla, seuraa horisontaalin ja vertikaalin oppositio; perheyhteisön ja yhteiskunnan hajoaminen. Päähenkilön kohtaamat henkilöhahmot voidaan jakaa vertikaali- ja horisontaalivariantteihin sen mukaan, mitä arvoja nämä edustavat. Tässä yhteydessä käsitellään myös sitä, miten veljeyteen ja kansallisuuten pohjautuvat identiteetinmuodostamiskeinot epäonnistuvat, sekä miten horisontaalius ja vertikaalius, auktoriteetin ja veljeyden teemat, toteutuvat elokuvan kuvakompositioissa. Kolmannessa osassa tarkastellaan elokuvan tapahtumapaikkoja ja minkälaisia oppositioita ne muodostavat. Konkreettisesti edustettujen oppositioiden maaseutu – kaupunki, sekä Pietari – Moskova lisäksi asettuvat vastakkain myös rikollisten ja tavallisten ihmisten Pietari, ulko- ja sisätilat, sekä yleinen ja yksityinen tila. Pietarin kuvaamiseen käytetyillä oppositioilla on selviä yhtymäkohtia Vladimir Toporovin esittämään pietarilaistekstien traditioon. Viimeisessä osassa käsitellään musiikin diegeettistä funktiota Bratissa. Se toimii elokuvassa vaihtoehtoisena juonenkulkuna, konkreettisena viiteryhmän etsimisen ja identiteetin muodostamisen keinona, sekä omana, erillisenä ’fantastisena’ tilanaan. Toiminta-/rikoselokuva oli vielä 1990-luvulla suhteellisen vieras genre venäläisessä elokuvassa. Tämä analyysi osoittaa, miten tiiviisti Brat kuitenkin asettuu venäläisen kulttuurin kontekstiin. Se käy dialogia niin venäläisen kansansatuperinteen, kuin 1800-luvun pietarilaistekstien kanssa, ja soveltuu tarkasteltavaksi myös kahden venäläisen kulttuurin vaihtelun teoriaa vasten. Vaikka Bratilla ei suoria elokuvallisia edeltäjiä Venäjällä olekaan, sen teemat ovat perivenäläisiä.

Slovo lider i ego upotreblenie v sovremennoj rossijskoj presse

Venäjän kieleen on kautta historian lainautunut sanoja muista kielistä. Historian tapahtumat ovat vaikuttaneet siihen, mistä kielistä sanoja on lainautunut eri aikakausina. Viime vuosikymmeninä venäjän kieleen on tulvinut lainasanoja englannin kielestä yhteiskunnan eri alueille. Tiiviit poliittiset, taloudelliset ja kulttuurisuhteet maiden ja kansojen välillä ovat ulkoisia, ei-kielellisiä syitä sanojen lainaamiseen. Kielen osa-alueista sanasto on kaikista avoimin ulkoisille vaikutteille ja samalla se on alue, johon heijastuvat yhteiskunnassa tapahtuvat muutokset. Lainasanojen ilmaantumiselle kieleen on myös sisäisiä, kielellisiä syitä. Lainasanojen ilmaantumisessa kirjallisessa muodossa venäjän kieleen voidaan erottaa kolme tapaa: transplantaatio eli sitaattilaina, translitteraatio sekä käytännöllinen transkriptio, jossa jokainen vieraskielinen foneemi pyritään esittämään vastaavalla venäjän foneemilla, jolloin vieraskielisen sanan ääntämys säilyy mahdollisimman alkuperäisenä. Lider-sana on esimerkki käytännöllisestä transkriptiosta, jossa venäläinen kirjoitusasu vastaa englannin kielen ääntämystä. Tutkimuksen kohteena on englanninkielinen lainasana lider, joka on ilmaantunut venäjän kieleen jo 1800-luvun puolivälissä. Sana on johdettu verbistä lead, merkityksessä ’johtaa, olla johdossa’, ja siinä on muodostunut substantiivi leader, ’johtaja’. Tutkimusaineistoa varten on poimittu 100 poliittiseen kielenkäyttöön liittyvää lider-sanaa sähköisessä tietokannassa Integrumissa olevassa Izvestija-lehdestä kahtena eri ajanjaksona, vuoden 1994 alusta alkaen sekä vuoden 2004 alusta alkaen. Tutkimuksessa keskityttiin lider-sanan käyttöön poliittisessa kielenkäytössä, mutta tutkimusaineiston keräysvaiheessa kirjattiin ylös myös muilla aihealueilla esiintyneet lider-sanat niidenkin käytön tarkastelua varten. Tutkimusta varten tarkasteltiin, millaisia määrityksiä lider-sanalle löytyy erilaisista nykykielen sanakirjoista eri vuosikymmeniltä. Vanhin mukana oleva sanakirja on venäläis-suomalainen sanakirja vuodelta 1912, jossa lider-sana määritellään yhdellä sanalla, ’puolueenjohtaja’. Aineisto jaettiin myös kolmeen ryhmään maantieteellisen sijainnin mukaan: Venäjä, entiset neuvostotasavallat ja ulkomaat. Tällä haluttiin selvittää, käytetäänkö lider-sanaa enemmän ulkomaisten vai venäläisten tapahtumin yhteydessä. Tutkimuksessa ilmeni, että suurin osa lider-sanoista liittyi Venäjän tapahtumiin molempina tarkasteluajanjaksoina – v. 1994 osuus oli 54 % ja v. 2004 50 %. Tähän tulokseen vaikuttavat varmaankin v. 1993 joulukuussa pidetyt ensimmäiset parlamenttivaalit sekä vuoden 2003 joulukuussa pidetyt duuman vaalit. Tutkimuksessa lider-sana jaettiin seitsemään eri kategoriaan käyttöyhteytensä mukaan ja saatujen tulosten perusteella suuri9n osa sanoista kuului kategoriaan ”puolueen johtaja”, v. 1994 osuus oli 47 % ja v. 2004 oli 40 %. Lider-sanan käyttö on levinnyt myös monelle muulle alueelle: urheilu, liike-elämä, kulttuuri, taide, tiede ja tekniikka. Venäjän kieleen ilmaantuu koko ajan vieraskielisiä sanoja, mutta kaikki niistä eivät sopeudu eivätkä juurru kieleen. Lainasanan on täytettävä tiettyjä edellytyksiä, jotta sitä voitaisiin pitää kieleen sopeutuneena: mukautumien kielen foneettiseen järjestelmään, sopeutuminen kielen graafiseen järjestelmään, sopeutuminen kieliopilliseen ympäristöön, semanttinen vakiintuminen sekä vakiintuminen vähintään kahdelle temaattiselle alueelle. Lainasanan juurtumisesta ja sopeutumisesta ovat todisteena myös siitä johdetut sanat. Lider-sana täyttää kaikki em. ehdot, joten sitä voidaan pitää venäjän kieleen sopeutuneena ja juurtuneena.

Osobennosti nacional'noj ohoty na pisatelja : Literaturnaja bor'ba 2002 goda vokrug romana Vladimira Sorokina Goluboe salo

Tutkielman lähtökohtana on oikeusjuttu, joka Venäjällä nostettiin kirjailija Vladimir Sorokinia vastaan kesällä 2002. Sorokinia ja hänen kustantamoaan Ad Marginemia syytettiin pornografian levittämisestä romaanissa Goluboe salo (1999), tarkemmin sanoen sivuilla 256 262, joilla kuvataan kommunistijohtajien Stalinin ja Hruščëvin homoseksuaalinen akti. Syytteen takana oli konservatiivinen, presidentti Vladimir Putinia ihannoiva nuorisoliike Iduščie vmeste ("Yhdessäkulkijat"). Oikeusjuttu ja siihen liittyneet tapahtumat - prosessia kutsuttiin venäläisissä tiedotusvälineissä yksinkertaisesti "Sorokinin jutuksi" ("delo Sorokina") - nostattivat Venäjällä laajan ja vilkkaan ns. kirjasodan kaunokirjallisuuden moraalitehtävästä ja kirjailijan vastuusta/vapaudesta. Työssä selvitellään, miksi nimenomaan kirjailija Vladimir Sorokin ja nimenomaan romaani Goluboe salo aiheuttivat skandaalin, mitä argumentteja polemiikissa esiintyi ja miten tapahtumat heijastavat Venäjän yhteiskunnallista tilannetta, etenkin kaunokirjallisuuden nykyistä asemaa. Metodologisesti tutkielma sijoittuu kirjallisuussosiologian ja reseptiotutkimuksen (vastaanottotutkimuksen) alalle. Tutkielman aineisto - 71 lehtiartikkelia - on koottu 31 venäläisestä valtakunnallisesta sanoma- ja aikakauslehdestä Integrum-tietokantaa hyväksikäyttäen. "Sorokinin juttua" analysoidaan artikkeleiden valossa kolmesta näkökulmasta: suhteessa 1) seksuaalisuuden ja 2) kaunokirjallisuuden asemaan Venäjällä sekä lyhyemmin suhteessa 3) muutamiin yleisyhteiskunnallisiin aspekteihin. Taustaksi selvitellään venäläisen postmodernismin teoriaa ja nk. kirjallisuusinstituution toimintaa. Tutkielmassa esitetään, että skandaali kertoo osaltaan niistä ongelmista, joiden kanssa Venäjä 2000-luvulla joutuu painiskelemaan. "Sorokinin juttu" laajeni pitkälti yli perinteisen pornografiakysymyksen; kirjasodassa tuli tiedotusvälineissä käsiteltyä seksuaalisuuden ja kaunokirjallisuuden aseman lisäksi mm. sananvapautta, tapauksen poliittisia konnotaatioita, "älymystön" ja "kansan" suhdetta, neuvostomenneisyyden pimeitä puolia sekä Venäjän suhdetta länteen. Jupakka myös nähtiin erinomaisena PR:nä Sorokinille. Goluboe salo näyttää joutuneen oikeusprosessin kohteeksi, koska siinä a) tuodaan venäläiseen kaunokirjallisuuteen avoin ja yksityiskohtainen seksuaalisuuden ja ruumiintoimintojen kuvaus b) herjataan häpeämättömästi venäläisen kaunokirjallisuuden kanonisoituja klassikoita sekä kritisoidaan terävästi neuvostomenneisyyttä, jota Venäjä ei ole vielä kyennyt tyhjentävästi käsittelemään. Skandaalissa asettuivat vastakkain ns. traditionalistinen ja postmodernistinen kirjallisuuskäsitys; edellisen mukaan kirjailijoiden tulisi kantaa yhteiskunnallinen vastuunsa, jälkimmäinen tahtoo nähdä kaunokirjallisuuden itsenäisempänä ilmiönä. Tutkimuksen lopputuloksena valtaenemmistö aineistosta näyttää enemmän tai vähemmän puolustavan Sorokinia - tosin ei niinkään hänen romaaninsa kirjallisten ansioiden vuoksi (joita harvat kiittivät), vaan silkasta periaatteesta: sanan- ja valinnanvapautta ei tahdota nähdä enää kahlittavan. Avainsanat: Sorokin - pornografia - kaunokirjallisuus - kirjallisuussosiologia - vastaanotto

Rossijskaja Karelija i karely v imperskoi politike Rossii, 1905-1917

Russian Karelians were one of the small peasant nations of the Russian Empire that began to identify themselves as nations during the late imperial period. At that historical moment Russian Karelia fell between an economically undeveloped empire and the rapidly modernizing borderland of Finland. The economic and cultural lure of Finland drew Karelians into the Finnish camp. This attraction was seen as a challenge to Russia and influenced the straggle between Russia and Finland for the Karelians. This struggle was waged from 1905 to 1917. This work is focused on the beginning stage of the struggle, its various phases, and their results. The confrontation extended into different dimensions (economic, political, ideological, church and cultural politics) and occurred on two levels: central and regional. Countermeasures against local nationalisms developed much earlier both in Russia and in other empires for use were also used in the Russian Karelian case. Economic policies were deployed to try to make relations with Russia more alluring for Karelians and to improve their economic condition. However, these efforts produced only minimal results due to the economic weakness of the empire and a lack of finances. Fear of the economic integration of the Karelians and Finns, which would have stimulated the economy of the Karelia, also hindered these attempts. The further development of the Orthodox Church, the schools and the zemstvos in Karelia yielded fewer results than expected due to the economic underdevelopment of the region and the avoidance of the Finnish language. Policizing measures were the most successfull, as all activities in Russian Karelia by the Finns were entirely halted in practice. However, the aspiration of Russian Karelians to integrate their home districts with Finland remained a latent force that just waited for an opportunity to push to the surface again. Such a chance materialized with the Russian revolution. The Karelian question was also a part of Russian domestic political confrontation. At the and of the 1800s, the Russian nationalist right had grown strong and increasingly gained the favor of the autocracy. The right political forces exploited the Karelian question in its anti-Finnish ideology and in its general resistance to the national emancipation of the minority peoples of Russia. A separate ideology was developed, focusing on the closeness of Karelians to the "great Russian people." Simultaneously, this concept found a place in the ultramonarchist myth of the particularly close connection between the people and tsar that was prominent in the era of Nicholas II. This myth assigned the Karelians a place amongst the "simple people" faithful to the tsar.

In vitro development of islets from human adult pancreatic tissues

Transplantation of isolated islets from cadaver pancreas is a promising possibility for the optimal treatment of type 1 diabetes. The lack of islets is a major problem. Here we have investigated the possibility of generating islets in tissue culture of human pancreatic cells. We first reproduced a previously reported method of in vitro generation of endocrine cells from human adult pancreatic tissue. By tracing the bromodeoxyuridine-labeled cells in differentiated islet buds, we found that the pancreatic progenitor cells represented a subpopulation of cytokeratin 19 (CK19)-positive ductal cells. Serum-free medium and Matrigel overlay were essential for the endocrine differentiation. We then examined the involvement of preexisting islet cells in islet neogenesis. About 6-10% of endocrine cells dedifferentiated and acquired a transitional phenotype by coexpressing CK19. Significant cell proliferation was only observed in CK19-positive cells, but not in chromogranin A-positive endocrine cells. The in vitro-derived human islets were morphologically and functionally immature when compared with normal islets. Their insulin mRNA levels were only 4-5% of that found in fresh human islets, and glucose-stimulated insulin release was 3 times lower than that of control islets. Moreover, some immature endocrine cells coexpressed insulin and glucagon. After transplantation in nude mice, the in vitro-generated islets became mature with one type of hormone per endocrine cell. In addition, we also found that also in both fresh islet transplants many cells coexpressed endocrine markers and ductal marker CK19 as a sign of ductal to endocrine cell transition. Finally, we studied the effects of clinically used immunosuppressive drugs on precursor cell proliferation and differentiation. Mycophenolate mofetil (MMF) severely hampered duct-cell proliferation, and significantly reduced the total DNA content indicating its antiproliferative effect on the precursors. Tacrolimus mainly affected differentiated beta cells by decreasing the insulin content per DNA as well as the proportion of insulin-positive cells. Sirolimus and daclizumab did not show any individual or synergistic side effects suggesting that these drugs are amenable for use in clinical islet transplantation. In summary, we confirm the capacity of endocrine differentiation from progenitors present in the adult human pancreas. The plasticity of differentiated cell types of human pancreas may be a potential mechanism of human pancreas regeneration. Ductal cell differentiation into endocrine cells in transplanted islets may be an important factor in sustaining the long-term function of islet transplants. The immunosuppressive protocol is likely to be an important determinant of long-term clinical islet graft function. Moreover, these results provide new information on the mechanisms of pancreatic islet regeneration and provide the basis for the development of new strategies for the treatment of insulin deficient diabetes mellitus.

Novel Multiple Sclerosis Predisposing Genetic Variants Outside the HLA Region

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

Eurasian Neogene large herbivorous mammals and climate

The development and changes in the distribution of herbivorous mammal communities during the Neogene is complex. The Eurasian scale environmental patterns reflect the large scale geographical and climatic patterns. The reorganization of these affect the biome distribution throughout the continent. The distribution of mammal taxa was closely associated with the distribution of biomes. In Eurasia the Neogene development of environments was twofold. The early and middle Miocene that seemed to have been advantageous for mammals was followed by drying of environments during the late Neogene. The mid-latitude drying was the main trend, and it is the combined result of the retreat of Paratethys, the uplift of Tibetan Plateau and changes in the ocean currents and temperatures. The common mammals were "driving" the evolution of mammalian communities. During the late Miocene we see the drying affecting more and more regions, and we see changes in the composition of mammalian communities.

Early diagnosis of breast cancer

The greatest effect on reducing mortality in breast cancer comes from the detection and treatment of invasive cancer when it is as small as possible. Although mammography screening is known to be effective, observer errors are frequent and false-negative cancers can be found in retrospective studies of prior mammograms. In the year 2001, 67 women with 69 surgically proven cancers detected at screening in the Mammography Centre of Helsinki University Hospital had previous mammograms as well. These mammograms were analyzed by an experienced screening radiologist, who found that 36 lesions were already visible in previous screening rounds. CAD (Second Look v. 4.01) detected 23 of these missed lesions. Eight readers with different kinds of experience with mammography screening read the films of 200 women with and without CAD. These films included 35 of those missed lesions and 16 screen-detected cancers. CAD sensitivity was 70.6% and specificity 15.8%. Use of CAD lengthened the mean time spent for readings but did not significantly affect readers sensitivities or specificities. Therefore the use of applied version of CAD (Second Look v. 4.01) is questionable. Because none of those eight readers found exactly same cancers, two reading methods were compared: summarized independent reading (at least a single cancer-positive opinion within the group considered decisive) and conference consensus reading (the cancer-positive opinion of the reader majority was considered decisive). The greatest sensitivity of 74.5% was achieved when the independent readings of 4 best-performing readers were summarized. Overall the summarized independent readings were more sensitive than conference consensus readings (64.7% vs. 43.1%) while there was far less difference in mean specificities (92.4% vs. 97.7%). After detecting suspicious lesion, the radiologist has to decide what is the most accurate, fast, and cost-effective means of further work-up. The feasibility of FNAC and CNB in the diagnosis of breast lesions was compared in non-randomised, retrospective study of 580 (503 malignant) breast lesions of 572 patients. The absolute sensitivity for CNB was better than for FNAC, 96% (206/214) vs. 67% (194/289) (p < 0.0001). An additional needle biopsy or surgical biopsy was performed for 93 and 62 patients with FNAC, but for only 2 and 33 patients with CNB. The frequent need of supplement biopsies and unnecessary axillary operations due to false-positive findings made FNAC (294 ) more expensive than CNB (223 ), and because the advantage of quick analysis vanishes during the overall diagnostic and referral process, it is recommendable to use CNB as initial biopsy method.

Genetic background of bipolar disorder and related cognitive impairments

Bipolar disorder (BP) is a complex psychiatric disorder characterized by episodes of mania and depression. BP affects approximately 1% of the world’s population and shows no difference in lifetime prevalence between males and females. BP arises from complex interactions among genetic, developmental and environmental factors, and it is likely that several predisposing genes are involved in BP. The genetic background of BP is still poorly understood, although intensive and long-lasting research has identified several chromosomal regions and genes involved in susceptibility to BP. This thesis work aims to identify the genetic variants that influence bipolar disorder in the Finnish population by candidate gene and genome-wide linkage analyses in families with many BP cases. In addition to diagnosis-based phenotypes, neuropsychological traits that can be seen as potential endophenotypes or intermediate traits for BP were analyzed. In the first part of the thesis, we examined the role of the allelic variants of the TSNAX/DISC1 gene cluster to psychotic and bipolar spectrum disorders and found association of distinct allelic haplotypes with these two groups of disorders. The haplotype at the 5’ end of the Disrupted-in-Schizophrenia-1 gene (DISC1) was over-transmitted to males with psychotic disorder (p = 0.008; for an extended haplotype p = 0.0007 with both genders), whereas haplotypes at the 3’ end of DISC1 associated with bipolar spectrum disorder (p = 0.0002; for an extended haplotype p = 0.0001). The variants of these haplotypes also showed association with different cognitive traits. The haplotypes at the 5’ end associated with perseverations and auditory attention, while the variants at the 3’ end associated with several cognitive traits including verbal fluency and psychomotor processing speed. Second, in our complete set of BP families with 723 individuals we studied six functional candidate genes from three distinct signalling systems: serotonin-related genes (SLC6A4 and TPH2), BDNF -related genes (BDNF, CREB1 and NTRK2) and one gene related to the inflammation and cytokine system (P2RX7). We replicated association of the functional variant Val66Met of BDNF with BP and better performance in retention. The variants at the 5’ end of SLC6A4 also showed some evidence of association among males (p = 0.004), but the widely studied functional variants did not yield any significant results. A protective four-variant haplotype on P2RX7 showed evidence of association with BP and executive functions: semantic and phonemic fluency (p = 0.006 and p = 0.0003, respectively). Third, we analyzed 23 bipolar families originating from the North-Eastern region of Finland. A genome-wide scan was performed using the 6K single nucleotide polymorphism (SNP) array. We identified susceptibility loci at chromosomes 7q31 with a LOD score of 3.20 and at 9p13.1 with a LOD score of 4.02. We followed up both linkage findings in the complete set of 179 Finnish bipolar families. The finding on chromosome 9p13 was supported (maximum LOD score of 3.02), but the susceptibility gene itself remains unclarified. In the fourth part of the thesis, we wanted to test the role of the allelic variants that have associated with bipolar disorder in recent genome-wide association studies (GWAS). We could confirm findings for the DFNB31, SORCS2, SCL39A3, and DGKH genes. The best signal in this study comes from DFNB31, which remained significant after multiple testing corrections. Two variants of SORCS2 were allelic replications and presented the same signal as the haplotype analysis. However, no association was detected with the PALB2 gene, which was the most significantly associated region in the previous GWAS. Our results indicate that BP is heterogeneous and its genetic background may accordingly vary in different populations. In order to fully understand the allelic heterogeneity that underlies common diseases such as BP, complete genome sequencing for many individuals with and without the disease is required. Identification of the specific risk variants will help us better understand the pathophysiology underlying BP and will lead to the development of treatments with specific biochemical targets. In addition, it will further facilitate the identification of environmental factors that alter risk, which will potentially provide improved occupational, social and psychological advice for individuals with high risk of BP.

Measurements of adequacy of anesthesia and level of consciousness during surgery and intensive care

The adequacy of anesthesia has been studied since the introduction of balanced general anesthesia. Commercial monitors based on electroencephalographic (EEG) signal analysis have been available for monitoring the hypnotic component of anesthesia from the beginning of the 1990s. Monitors measuring the depth of anesthesia assess the cortical function of the brain, and have gained acceptance during surgical anesthesia with most of the anesthetic agents used. However, due to frequent artifacts, they are considered unsuitable for monitoring consciousness in intensive care patients. The assessment of analgesia is one of the cornerstones of general anesthesia. Prolonged surgical stress may lead to increased morbidity and delayed postoperative recovery. However, no validated monitoring method is currently available for evaluating analgesia during general anesthesia. Awareness during anesthesia is caused by an inadequate level of hypnosis. This rare but severe complication of general anesthesia may lead to marked emotional stress and possibly posttraumatic stress disorder. In the present series of studies, the incidence of awareness and recall during outpatient anesthesia was evaluated and compared with that of in inpatient anesthesia. A total of 1500 outpatients and 2343 inpatients underwent a structured interview. Clear intraoperative recollections were rare the incidence being 0.07% in outpatients and 0.13% in inpatients. No significant differences emerged between outpatients and inpatients. However, significantly smaller doses of sevoflurane were administered to outpatients with awareness than those without recollections (p<0.05). EEG artifacts in 16 brain-dead organ donors were evaluated during organ harvest surgery in a prospective, open, nonselective study. The source of the frontotemporal biosignals in brain-dead subjects was studied, and the resistance of bispectral index (BIS) and Entropy to the signal artifacts was compared. The hypothesis was that in brain-dead subjects, most of the biosignals recorded from the forehead would consist of artifacts. The original EEG was recorded and State Entropy (SE), Response Entropy (RE), and BIS were calculated and monitored during solid organ harvest. SE differed from zero (inactive EEG) in 28%, RE in 29%, and BIS in 68% of the total recording time (p<0.0001 for all). The median values during the operation were SE 0.0, RE 0.0, and BIS 3.0. In four of the 16 organ donors, EEG was not inactive, and unphysiologically distributed, nonreactive rhythmic theta activity was present in the original EEG signal. After the results from subjects with persistent residual EEG activity were excluded, SE, RE, and BIS differed from zero in 17%, 18%, and 62% of the recorded time, respectively (p<0.0001 for all). Due to various artifacts, the highest readings in all indices were recorded without neuromuscular blockade. The main sources of artifacts were electrocauterization, electromyography (EMG), 50-Hz artifact, handling of the donor, ballistocardiography, and electrocardiography. In a prospective, randomized study of 26 patients, the ability of Surgical Stress Index (SSI) to differentiate patients with two clinically different analgesic levels during shoulder surgery was evaluated. SSI values were lower in patients with an interscalene brachial plexus block than in patients without an additional plexus block. In all patients, anesthesia was maintained with desflurane, the concentration of which was targeted to maintain SE at 50. Increased blood pressure or heart rate (HR), movement, and coughing were considered signs of intraoperative nociception and treated with alfentanil. Photoplethysmographic waveforms were collected from the contralateral arm to the operated side, and SSI was calculated offline. Two minutes after skin incision, SSI was not increased in the brachial plexus block group and was lower (38 ± 13) than in the control group (58 ± 13, p<0.005). Among the controls, one minute prior to alfentanil administration, SSI value was higher than during periods of adequate antinociception, 59 ± 11 vs. 39 ± 12 (p<0.01). The total cumulative need for alfentanil was higher in controls (2.7 ± 1.2 mg) than in the brachial plexus block group (1.6 ± 0.5 mg, p=0.008). Tetanic stimulation to the ulnar region of the hand increased SSI significantly only among patients with a brachial plexus block not covering the site of stimulation. Prognostic value of EEG-derived indices was evaluated and compared with Transcranial Doppler Ultrasonography (TCD), serum neuron-specific enolase (NSE) and S-100B after cardiac arrest. Thirty patients resuscitated from out-of-hospital arrest and treated with induced mild hypothermia for 24 h were included. Original EEG signal was recorded, and burst suppression ratio (BSR), RE, SE, and wavelet subband entropy (WSE) were calculated. Neurological outcome during the six-month period after arrest was assessed with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Twenty patients had a CPC of 1-2, one patient had a CPC of 3, and nine patients died (CPC 5). BSR, RE, and SE differed between good (CPC 1-2) and poor (CPC 3-5) outcome groups (p=0.011, p=0.011, p=0.008, respectively) during the first 24 h after arrest. WSE was borderline higher in the good outcome group between 24 and 48 h after arrest (p=0.050). All patients with status epilepticus died, and their WSE values were lower (p=0.022). S-100B was lower in the good outcome group upon arrival at the intensive care unit (p=0.010). After hypothermia treatment, NSE and S-100B values were lower (p=0.002 for both) in the good outcome group. The pulsatile index was also lower in the good outcome group (p=0.004). In conclusion, the incidence of awareness in outpatient anesthesia did not differ from that in inpatient anesthesia. Outpatients are not at increased risk for intraoperative awareness relative to inpatients undergoing general anesthesia. SE, RE, and BIS showed non-zero values that normally indicate cortical neuronal function, but were in these subjects mostly due to artifacts after clinical brain death diagnosis. Entropy was more resistant to artifacts than BIS. During general anesthesia and surgery, SSI values were lower in patients with interscalene brachial plexus block covering the sites of nociceptive stimuli. In detecting nociceptive stimuli, SSI performed better than HR, blood pressure, or RE. BSR, RE, and SE differed between the good and poor neurological outcome groups during the first 24 h after cardiac arrest, and they may be an aid in differentiating patients with good neurological outcomes from those with poor outcomes after out-of-hospital cardiac arrest.

Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Phonetic tone signals quantity and word structure

Many languages exploit suprasegmental devices in signaling word meaning. Tone languages exploit fundamental frequency whereas quantity languages rely on segmental durations to distinguish otherwise similar words. Traditionally, duration and tone have been taken as mutually exclusive. However, some evidence suggests that, in addition to durational cues, phonological quantity is associated with and co-signaled by changes in fundamental frequency in quantity languages such as Finnish, Estonian, and Serbo-Croat. The results from the present experiment show that the structure of disyllabic word stems in Finnish are indeed signaled tonally and that the phonological length of the stressed syllable is further tonally distinguished within the disyllabic sequence. The results further indicate that the observed association of tone and duration in perception is systematically exploited in speech production in Finnish.