Hostility: A prospective study of the genetic and environmental background and associations with cardiovascular risk

Hostility is a multidimensional construct having wide effects on society. In its different forms, hostility is related to a large array of social and health problems, such as criminality, substance abuse, depression, and cardiovascular risks. Identifying and tackling early-life factors that contribute to hostility may have public health significance. Although the variance in hostility is estimated to be 18-50 percent heritable, there are significant gaps in knowledge regarding the molecular genetics of hostility. It is known that a cold and unsupportive home atmosphere in childhood predicts a child s later hostility. However, the long-term effects of care-giving quality on hostility in adulthood and the role of genes in this association are unclear. The present dissertation is part of the ongoing population-based prospective Young Finns study, which commenced in 1980 with 3596 3-18-year-old boys and girls who were followed for 27 years. The specific aims of the dissertation were first to study the antecedents of hostility by looking at 1) the genetic background, 2) the early environmental predictors, and 3) the gene environment interplay behind hostility. As a second aim, the thesis endeavored to examine 4) the association between hostility and cardiovascular risks, and 5) the moderating effect of demographic factors, such as gender and socioeconomic status, on this association. The study found potential gene polymorphisms from chromosomes 7, 14, 17, and 22 suggestively associated with hostility. Of early environmental influences, breastfeeding and early care-giving were found to predict hostility in adulthood. In addition, a serotonin receptor 2A polymorphism rs6313 moderated the effect of early care-giving on later hostile attitudes. Furthermore, hostility was shown to predict cardiovascular risks, such as metabolic syndrome and inflammation. Finally, parental socioeconomic status was found to moderate the association between anger and early atherosclerosis. The new genetic and early environmental antecedents of hostility identified in this research may help in understanding the development of hostility and its health risks, and in planning appropriate prevention. The significance of early influences on this development is stressed. Although the markers studied are individual- and family-related factors, these may be influenced at the societal level by giving accurate information to all individuals concerned and by improving the societal circumstances.

Molecular genetics of Usher syndrome -inherited deafness and blindness

Usher syndrome (USH) is an inherited blindness and deafness disorder with variable vestibular dysfunction. The syndrome is divided into three subtypes according to the progression and severity of clinical symptoms. The gene mutated in Usher syndrome type 3 (USH3), clarin 1 (CLRN1), was identified in Finland in 2001 and two mutations were identified in Finnish patients at that time. Prior to this thesis study, the two CLRN1 gene mutations were the only USH mutations identified in Finnish USH patients. To further clarify the Finnish USH mutation spectrum, all nine USH genes were studied. Seven mutations were identified: one was a previously known mutation in CLRN1, four were novel mutations in myosin VIIa (MYO7A) and two were a novel and a previously known mutation in usherin (USH2A). Another aim of this thesis research was to further study the structure and function of the CLRN1 gene, and to clarify the effects of mutations on protein function. The search for new splice variants resulted in the identification of eight novel splice variants in addition to the three splice variants that were already known prior to this study. Studies of the possible promoter regions for these splice variants showed the most active region included the 1000 bases upstream of the translation start site in the first exon of the main three exon splice variant. The 232 aa CLRN1 protein encoded by the main (three-exon) splice variant was transported to the plasma membrane when expressed in cultured cells. Western blot studies suggested that CLRN1 forms dimers and multimers. The CLRN1 mutant proteins studied were retained in the endoplasmic reticulum (ER) and some of the USH3 mutations caused CLRN1 to be unstable. During this study, two novel CLRN1 sequence alterations were identified and their pathogenicity was studied with cell culture protein expression. Previous studies with mice had shown that Clrn1 is expressed in mouse cochlear hair cells and spiral ganglion cells, but the expression profile in mouse retina remained unknown. The Clrn1 knockout mice display cochlear cell disruption/death, but do not have a retinal phenotype. The zebrafish, Danio rerio, clrn1 was found to be expressed in hair cells associated with hearing and balance. Clrn1 expression was also found in the inner nuclear layer (INL), photoreceptor layer and retinal pigment epithelium layer (RPE) of the zebrafish retina. When Clrn1 production was knocked down with injected morpholino oligonucleotides (MO) targeting Clrn1 translation or correct splicing, the zebrafish larvae showed symptoms similar to USH3 patients. These larvae had balance/hearing problems and reduced response to visual stimuli. The knowledge this thesis research has provided about the mutations in USH genes and the Finnish USH mutation spectrum are important in USH patient diagnostics. The extended information about the structure and function of CLRN1 is a step further in exploring USH3 pathogenesis caused by mutated CLRN1 as well as a step in finding a cure for the disease.

Kirjallisen teoksen omaperäisyys

Tutkielmassa tarkastellaan kirjallisten teosten tekijänoikeussuojan edellytyksiä EU:n jäseninä olevissa Pohjoismaissa sekä Iso-Britanniassa. Tarkastelun keskiössä on käsite omaperäisyys , joka on kansainvälisesti vakiintunut termi kuvaamaan tekijänoikeus-suojan edellytyksiä. Omaperäisyys ymmärretään sisällöllisesti varsin eri tavoin. Kansainvälisissä tekijänoikeussopimuksissa asete-taan vain vähimmäisedellytykset tekijänoikeussuojalle. Näin ollen Pohjoismaissa ja Iso-Britanniassa on voitu päätyä varsin erilaisiin käsityksiin vaatimuksen sisällöstä. EU:n tasolla on toisaalta 1980-luvulta lähtien ilmennyt pyrkimys luoda yhtenäinen sisältö omaperäisyyden käsitteelle ja näin harmo-nisoida teossuojan kansallisia edellytyksiä. Syynä tähän on ennen kaikkea ollut jäsenvaltioiden erilaisten tekijänoikeussuojan edelly-tysten vaikutus sisämarkkinoihin. Harmonisointi on tähän mennessä tapahtunut sekundäärilainsäädännön keinoin tietokoneohjelmien, tietokantojen ja valokuvien osalta. Sen sijaan jäsenvaltioiden tekijänoikeutta yhdenmukaistava ja kaikkia kirjallisia teoksia koskeva Infosoc-direktiivi ei sisällä suoraan ilmaistua vaatimusta omaperäisyydestä tekijänoikeussuojan edellytyksenä. Silloinen EY-tuomioistuin on kuitenkin 16.7.2009 julkistamassaan ns. Infopaq-ratkaisussa (C-5/08) esittänyt Infosoc-direktiiviin perusteella oman tulkintansa omaperäisyyden vaatimuksen sisällöstä ja edellytyksistä. Tutkielman tarkoituksena onkin selvittää, mitä kansallisia vaikutuksia tästä EU-oikeudellisesta omaperäisyyden käsitteestä aiheutuu unioniin kuuluvien Pohjoismaiden ja Iso-Britannian kansalliselle tekijänoikeussuojalle. Tutkielmassa selvitetään, onko EU-tuomioistuin asettanut Infopaq-ratkaisussa vain vähimmäisedellytykset kirjallisten teosten tekijänoikeussuojalle, joista jäsenvaltiot voivat vapaasti poiketa, vai onko kyse tosiasialli-sesti täysin uudesta jäsenvaltioita sitovasta vaatimuksesta. Tutkielmassa tarkastellaan ensin kansainvälisen tason sääntelykehystä. Tarkoituksena on paikallistaa ne instrumentit, joiden perus-teella kansallinen teoksen käsite Pohjoismaissa ja Iso-Britanniassa määräytyy ja joista omaperäisyyden vaatimus juontuu. Kansainvä-lisistä tekijänoikeussopimuksista on tällöin Bernin yleissopimus kaikkein merkityksellisin. Sopimus asettaa vähimmäisvaatimukset tekijänoikeussuojalle. Suojaa saadakseen teoksen on oltava omaperäinen eli henkisen luomistyön tuote. Tästä jäsenvaltiot voivat vapaasti asettaa tiukempia edellytyksiä. Lisäksi tässä yhteydessä tuodaan esiin myös EU:n pyrkimys tekijänoikeussuojan harmo-nisointiin. Tarkastelu kohdistuu tällöin sekundäärinormistoon, joka edellyttää tietokoneilta, tietokannoilta ja valokuvilta omaperäi-syyttä, mikä ilmenee tekijän henkisen luomistyön tuloksena. Kaikkia teoksia koskevassa Infosoc-direktiivissä ei puolestaan tällaista vaatimusta ole kirjoitettu näkyville. Tämän jälkeen tarkastellaan Pohjoismaiden ja Iso-Britannian kansallisia kirjallisten teosten teossuojan edellytyksiä. Tarkoituksena on tuoda esiin teossuojan edellytysten kansallisen tason keskeinen sisältö ja vertailla näitä edellytyksiä keskenään. Keskeistä on tällöin havaita, että Pohjoismaissa edellytetään tekijänoikeussuojan saamiseksi enemmän luovuutta kuin Iso-Britanniassa. Iso-Britanniassa saatetaan teossuojaa antaa myös puhtaan rutiininomaisen työn sekä tähän sisältyvän ajan ja vaivan perusteella. Näin ollen kansallisen tason eroavuudet ovat paikoin merkittävät. Kansallisen tason tarkastelun jälkeen otetaan analyysin kohteeksi EU-tuomioistuimen Infopaq-ratkaisu, jossa tuomioistuin katsoi, että suojaa saadakseen uutisartikkelista irrotetun osan on oltava omaperäinen siinä mielessä, että se on tekijänsä henkisen luomistyön tulos. Näin ollen kyse olisi samanlaisesta vaatimuksesta kuin sekundäärilainsäädännön tasolla on jo asetettu tietokoneohjelmille, tietokannoille ja valokuville. Esikysymyksenä tarkastellaan tällöin tämän EU-oikeudellisen omaperäisyyden käsitteen soveltuvuutta kirjallisiin teoksiin ylipäätään. Tämän jälkeen tuodaan esiin käsitteen tarkka sisältö. Näin kyetään analysoimaan mahdollisia kansalli-seen lainsäädäntöön kohdistuvia muutosvaikutuksia. Tässä yhteydessä korostetaan myös jäsenvaltioiden ja EU:n välisen yhteistyön merkitystä. Teossuojan edellytysten yhtenäistäminen edellyttää EU-oikeuden ja EU-tuomioistuimen ratkaisujen tarkoitusperien, tavoitteiden ja tulkintaperiaatteiden selkeää esiin tuontia. Samaten unionin on tunnistettava kansalliset erot, jottei harmonisoinnista koituisi kohtuuttomia tai mahdottomia vaatimuksia jäsenvaltioille. Vasta tällöin voidaan saavuttaa EU-oikeuden tehokas harmoni-sointi. Tutkielman lopuksi esitetään yhteenveto keskeisistä johtopäätöksistä. Tarkoituksena on korostaa vallitsevan tilanteen tulkinnallista epävarmuutta. Liian pitkälle meneviä johtopäätöksiä EU-oikeudellisen omaperäisyyden käsitteen kansallisista vaikutuksista ei voida tehdä. Jotta omaperäisyys kirjallisten teosten tekijänoikeussuojan edellytyksenä voitaisiin tehokkaasti yhtenäistää unionin tasolla, tulisi vaatimus kirjoittaa esiin joko nykyiseen Infosoc-direktiiviin tai uuteen EU-oikeudelliseen lainsäädäntöinstrumenttiin. Muutoin jäsenvaltioilla säilyy mahdollisuus soveltaa vakiintunutta kansallista omaperäisyyden käsitettä suojan edellytyksenä ottamatta huo-mioon laajempaa EU-oikeudellista tavoitetta tekijänoikeussuojan yhtenäistämisestä.

Impaired spermatogenesis in Finnish boars and bulls

Maintenance of breeding efficiency and high semen quality is essential for reproductive success in farm animals. Early recognition of possible inheritable factors causing infertility requires constant attention. This thesis focuses on describing different manifestations of impaired spermatogenesis, their impact on fertility and partly also their incidence in populations. The reasons for spermatogenic failure are various. An interruption of germ cell differentiation, spermatogenic arrest, can lead to infertility. The incidence of azoospermia was investigated in the 1996 2005 survey of Finnish AI and farm breeding boars. We focused on the diagnosis, testicular morphometry and the possible reasons for the condition. The incidence of azoospermia was significantly higher in Yorkshire boars than in the Landrace breed. The most common diagnosis in Yorkshire boars was germ cell arrest at the primary spermatocyte level. The second most frequent diagnosis in Yorkshire boars was segmental aplasia of the Wolffian ducts with idiopathic epididymal obstruction. Other reasons for azoospermia were infrequent. In the second study we investigated the incidence of two relatively well-defined specific sperm defects in Finnish Yorkshire and Landrace boars during the same survey, the immotile short-tail sperm (ISTS) defect and the knobbed acrosome (KA) defect. In the Finnish Yorkshire boars the inherited ISTS defect, and the probably inherited KA defect, were important causes of infertility during 1996 2005. The ISTS defect was found in 7.6% and the KA defect in 0.8% of the Yorkshire boars. No Landrace boars were diagnosed with either of these two defects. In the third study we described a new sterilizing sperm defect in an oligoasthenoterazoospermic bull. Because of its morphological characteristics this defect was termed the multinuclear-multiflagellar sperm (MNMFS) defect. The number of Sertoli cells in the seminiferous tubuli was highly increased in the MNMFS bull compared with the number in normal bulls. In the following two studies we used a combined approach of fluorescence in situ hybridization (FISH), flow cytometry and morphometric studies to provide information on the cytogenetic background of macrocephalic bull spermatozoa. We described cellular features of diploid spermatozoa and compared the failures in the first and second meiotic divisions. In the last study we describe how the transplantation of testicular cells was used to determine whether spermatogonia derived from donor animals are able to colonize and produce motile spermatozoa in immune-competent unrelated boars suffering the ISTS defect. Transplantation resulted in complete focal spermatogenesis, indicated by the appearance of motile spermatozoa and confirmed by genotyping.

Phonological Mean Length of Utterance as an indicator of typical and impaired phonological development in children acquiring Finnish

The aim of this study was to examine the applicability of the Phonological Mean Length of Utterance (pMLU) method to the data of children acquiring Finnish, for both typically developing children and children with a Specific Language Impairment (SLI). Study I examined typically developing children at the end of the one-word stage (N=17, mean age 1;8), and Study II analysed children s (N=5) productions in a follow-up study with four assessment points (ages 2;0, 2;6, 3;0, 3;6). Study III was carried out in the form of a review article that examined recent research on the phonological development of children acquiring Finnish and compared the results with general trends and cross-linguistic findings in phonological development. Study IV included children with SLI (N=4, mean age 4;10) and age-matched peers. The analyses in Studies I, II and IV were made using the quantitative pMLU method. In the pMLU method, pMLU values are counted for both the words that the children targeted (so-called target words) and the words produced by the children. When the child s average pMLU value was divided with the average target word pMLU value, it is possible to examine that child s accuracy in producing the words with the Whole-Word Proximity (PWP) value. In addition, the number of entirely correctly produced words is counted to obtain the Whole-Word Correctness (PWC) value. Qualitative analyses were carried out in order to examine how the children s phoneme inventories and deficiencies in phonotactics would explain the observed pMLU, PWP and PWC values. The results showed that the pMLU values for children acquiring Finnish were relatively high already at the end of the one-word stage (Study I). The values were found to reflect the characteristics of the ambient language. Typological features that lead to cross-linguistic differences in pMLU values were also observed in the review article (Study III), which noted that in the course of phonological acquisition there are a large number of language-specific phenomena and processes. Study II indicated that overall the children s phonological development during the follow-up period was reflected in the pMLU, PWP and PWC values, although the method showed limitations in detecting qualitative differences between the children. Correct vowels were not scored in the pMLU counts, which led to some misleadingly high pMLU and PWP results: vowel errors were only reflected in the PWC values. Typically developing children in Study II reached the highest possible pMLU results already around age 3;6. At the same time, the differences between the children with SLI and age-matched peers in the pMLU values were very prominent (Study IV). The values for the children with SLI were similar to the ones reported for two-year-old children. Qualitative analyses revealed that the phonologies of the children with SLI largely resembled the ones of younger, typically developing children. However, unusual errors were also witnessed (e.g., vowel errors, omissions of word-initial stops, consonants added to the initial position in words beginning with a vowel). This dissertation provides an application of a new tool for quantitative phonological assessment and analysis in children acquiring Finnish. The preliminary results suggest that, with some modifications, the pMLU method can be used to assess children s phonological development and that it has some advantages compared to the earlier, segment-oriented approaches. Qualitative analyses complemented the pMLU s observations on the children s phonologies. More research is needed in order to verify the levels of the pMLU, PWP and PWC values in children acquiring Finnish.

Pelin henki. Moderni ja traditionaalinen tansanialaisessa jalkapalloilussa.

Antropologisessa ja muussa yhteiskunnallisessa tutkimuksessa magia on määritelty perinteisesti traditionaaliseksi ja menneisyyteen kuuluvaksi, kun taas urheilu on määritelty magian vastakohtana dynaamiseksi moderniksi. Tässä pro gradu -tutkielmassa tarkastellaan tansanialaista jalkapallomagiaa, jota on mahdotonta määrittää kyseisen dikotomian kumpaankaan kategoriaan. Tansaniassa tammi-syyskuussa 2010 kerätyn etnografisen aineiston perusteella tutkielmassa kuvaillaan, minkälaisia merkityksiä tansanialaiset itse antavat jalkapallomagialle ja miten nämä merkityksenannot liittyvät modernin ja traditionaalisen diskurssiin. Tutkielman pääteemana on tutkittavien tansanialaisten subjektiviteetti tai persoona, joka määritellään suhteessa muihin. Tansanialaisen jalkapallon historia juontaa juurensa siirtomaa-aikaan, jolloin siirtomaahallitsijat pyrkivät lajin avulla modernisoimaan paikallista väestöä ja opettamaan heille kurinalaisuutta ja lojaalisuutta. Tähän liittyi olettamus siitä, että kulttuurit kehittyvät teleologisesti kohti yhtä modernia. Tansaniassa jalkapallon suosio on nykyisin huikeaa, mutta suosio perustuu jo olemassa oleville kulttuurisille rakenteille. Tutkielmassa analysoidaan, kuinka Tansanian kahden vanhimman ja suurimman jalkapalloseuran historia linkittyy erityisesti traditionaalisiksi nimettyihin ngomatansseihin, joihin liittyy olennaisena elementtinä kilpailullisuus. Tutkimusaineistossa korostuvat jalkapallon ja magian ambivalentit luonteet. Tansanialaiset eivät itse määrittele jalkapallomagiaa suoraan traditionaaliseksi tai moderniksi. Heidän mielestään traditionaaliseen magiaan kuuluu, että yliluonnollisia voimia käyttääkseen henkilön täytyy vahingoittaa omaa perheenjäsentään. Traditionaalinen magia on erityisen vaarallista ja sitä käytetään pahaan. Jalkapallomagian avulla puolestaan pyritään ensisijaisesti suojelemaan omaa joukkuetta ja varmistamaan ottelun voitokas lopputulos. Toisaalta jalkapallojoukkueita myös verrataan laajennettuihin perheisiin, ja jalkapallomagian toimintamuodoissa on jatkuvuutta traditionaalisen magian mekanismeihin. Analyysin loppuosa perustuu Harri Englundin käyttämään lähestymistapaan, jossa magian avulla tuodaan esille tutkittavan yhteisön keskinäisissä sosiaalisissa suhteissa olevia jännitteitä. Englundin tutkimuksessa yhteisön jäsenen syyttäminen magian käyttämisestä on hyökkäys syytetyn henkilön moraalista laatua kohtaan. Syytetyiksi joutuvat ne, jotka eivät tee näkyviksi suhteita, joilla he ovat maallisen menestyksensä ansainneet. Tansanialaisen jalkapalloilun kontekstissa voitto tai häviö ei aiheuta syyttelyä maagisesta toiminnasta. Sen sijaan henkilön moraalista laatua arvioidaan jalkapalloyhteisössä sen perusteella, kuinka omistautuneita henkilöt ovat lajille ja joukkueelleen. Tutkielmassa tullaan johtopäätökseen, että tansanialaiset määrittävät jalkapallomagiaan sekä traditionaalisen että modernin piirteitä. He tuomitsevat oman edun tavoittelun yhteisen hyvän kustannuksella. Tämä tulee esille traditionaalisessa magiassa, jossa henkilö uhraa perheensä oman menestyksensä saavuttamiseksi. Vastaavasti jalkapallon yhteydessä henkilöitä syytetään niin sanotun jalkapalloperheen rikkomisesta ja lojaaliuden puutteesta. Tansanialaiset haluavat diskurssin tasolla moderniutta, mutta arvostavat myös traditionaalista jatkuvuutta. Modernius assosioituu eurooppalaisiin, mikä näkyy muun muassa siinä, että eurooppalaisilla ajatellaan olevan myös moderneimmat jalkapallomagian toimintatavat. Modernin ja traditionaalisen kategoriat ovat aktiivisesti kuviteltuja kategorioita, jotka kuitenkin vaikuttavat toimintaan ja toiminnan moraaliseen arvottamiseen myös konkreettisesti joskin ristiriitaisesti.

From ‘Afflicted’ to Activists: Structural Violence and Climate Change Discourse in the States of Pernambuco and Paraíba in Northeast Brazil

This study approaches the problem of poverty in the hinterlands of Northeast Brazil through the concept of structural violence, linking the environmental threats posed by climate change, especially those related to droughts, to the broader social struggles in the region. When discussions about potentials and rights are incorporated into the problematic of poverty, a deeper insight is obtained regarding the various factors behind the phenomenon. It is generally believed that climate change is affecting the already marginalized and poor more than those of higher social standing, and will increasingly do so in the future. The data for this study was collected during a three month field work in the states of Pernambuco and Paraíba in Northeast Brazil. The main methods used were semi-structured interviews and participant observation, including attending seminars concerning climate change on the field. The focus of the work is to compare both layman and expert perceptions on what climate change is about, and question the assumptions about its effects in the future, mainly that of increased numbers of ‘climate refugees’ or people forced to migrate due to changes in climate. The focus on droughts, as opposed to other manifestations of climate change, arises from the fact that droughts are not only phenomena that develop over a longer time span than floods or hurricanes, but is also due to the historical persistence of droughts in the region, and both the institutional and cultural linkages that have evolved around it. The instances of structural violence that are highlighted in this study; the drought industry, land use, and the social and power relations present in the region, including those between the civil society, the state and the private agribusiness sector, all work against a backdrop of symbolic and moral realms of value production, where relations between the different actors are being negotiated anew with the rise of the climate change discourse. The main theoretical framework of the study consists of Johan Galtung’s and Paul Farmer’s theory of structural violence, Ulrich Beck’s theory of the risk society, and James Scott’s theory of everyday peasant resistance.

Snoring and sleep apnea in children

Snoring is a primary and major clinical symptom of upper airway obstruction during sleep. Sleep-disordered breathing ranges from primary snoring to significant partial upper airway obstruction, and obstructive sleep apnea. Adult snoring and obstructive sleep apnea have been extensively studied, whereas less is known about these disorders in children. Snoring and more severe obstructive sleep apnea have been shown to have a harmful effect on the neurobehavioral development of children, but the mechanisms of this effect remains unknown. Furthermore, the correlation of this effect to objective sleep study parameters remains poor. This study evaluated the prevalence of snoring in preschool-aged children in Finland. Host and environmental risk factors, and neurobehavioral and neurocognitive symptoms of children suffering from snoring or obstructive sleep apnea were also investigated. The feasibility of acoustic rhinometry in young children was assessed. The prevalence and risk factors of snoring (I) were evaluated by a questionnaire. The random sample included 2100 children aged 1-6 years living in Helsinki. All 3- to 6-year-old children whose parents reported their child to snore always, often, or sometimes were categorized as snorers, and invited to participate to the clinical study (II-IV). Non-snoring children whose parents were willing to participate in the clinical study were invited to serve as controls. Children underwent a clinical ear-nose-throat examination. Emotional, behavioral, and cognitive performances were evaluated by Child Behavioral Checklist (CBCL), Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) and NEPSY-A Developmental Neuropsychological Assessment (NEPSY). Nasal volume was measured by acoustic rhinometry, and nasal resistance by rhinomanometry. Lateral and posteroanterior cephalometry were performed. A standard overnight ambulatory polysomnography was performed in the home environment. Twenty-six healthy children were tested in order to assess the feasibility of acoustic rhinometry in young children (V). Snoring was common in children; 6.3% of children snored always or often, whereas 81.3% snored never or occasionally. No differences were apparent between snorers and non-snorers regarding age, or gender. Pediatric snoring was associated with recurrent upper respiratory infections, otitis media, and allergic rhinitis. Exposure to parental tobacco smoke, especially maternal smoking, was more common among snorers. Rhinitis was more common among children who exposured to tobacco smoke. Overnight polysomnography (PSG) was performed on 87 children; 74% showed no signs of significant upper airway obstruction during sleep. Three children had obstructive apnea/hypopnea index (OAHI) greater than 5/h. Age, gender, or a previous adenoidectomy or tonsillectomy did not correlate with OAHI, whereas tonsillar size did correlate with OAHI. Relative body weight and obesity correlated with none of the PSG parameters. In cephalometry, no clear differences or correlations were found in PSG parameters or between snorers and non-snorers. No correlations were observed between acoustic rhinometry, rhinomanometry, and PSG parameters. Psychiatric symptoms were more frequent in the snoring group than in the nonsnoring group. In particular, anxious and depressed symptoms were more prevalent in the snoring group. Snoring children frequently scored lower in language functions. However, PSG parameters correlated poorly with neurocognitive test results in these children. This study and previous studies indicate that snoring without episodes of obstructive apnea or SpO2 desaturations may cause impairment in behavioral and neurocognitive functions. The mechanism of action remains unknown. Exposure to parental tobacco smoke is more common among snorers than non-snorers, emphasizing the importance of a smoke-free environment. Children tolerated acoustic rhinometry measurements well.

A maximal operator, Carleson's embedding, and tent spaces for vector-valued functions

This thesis is concerned with the area of vector-valued Harmonic Analysis, where the central theme is to determine how results from classical Harmonic Analysis generalize to functions with values in an infinite dimensional Banach space. The work consists of three articles and an introduction. The first article studies the Rademacher maximal function that was originally defined by T. Hytönen, A. McIntosh and P. Portal in 2008 in order to prove a vector-valued version of Carleson's embedding theorem. The boundedness of the corresponding maximal operator on Lebesgue-(Bochner) -spaces defines the RMF-property of the range space. It is shown that the RMF-property is equivalent to a weak type inequality, which does not depend for instance on the integrability exponent, hence providing more flexibility for the RMF-property. The second article, which is written in collaboration with T. Hytönen, studies a vector-valued Carleson's embedding theorem with respect to filtrations. An earlier proof of the dyadic version assumed that the range space satisfies a certain geometric type condition, which this article shows to be also necessary. The third article deals with a vector-valued generalizations of tent spaces, originally defined by R. R. Coifman, Y. Meyer and E. M. Stein in the 80's, and concerns especially the ones related to square functions. A natural assumption on the range space is then the UMD-property. The main result is an atomic decomposition for tent spaces with integrability exponent one. In order to suit the stochastic integrals appearing in the vector-valued formulation, the proof is based on a geometric lemma for cones and differs essentially from the classical proof. Vector-valued tent spaces have also found applications in functional calculi for bisectorial operators. In the introduction these three themes come together when studying paraproduct operators for vector-valued functions. The Rademacher maximal function and Carleson's embedding theorem were applied already by Hytönen, McIntosh and Portal in order to prove boundedness for the dyadic paraproduct operator on Lebesgue-Bochner -spaces assuming that the range space satisfies both UMD- and RMF-properties. Whether UMD implies RMF is thus an interesting question. Tent spaces, on the other hand, provide a method to study continuous time paraproduct operators, although the RMF-property is not yet understood in the framework of tent spaces.

Modelling vacuum arcs : from plasma initiation to surface interactions

A better understanding of vacuum arcs is desirable in many of today's 'big science' projects including linear colliders, fusion devices, and satellite systems. For the Compact Linear Collider (CLIC) design, radio-frequency (RF) breakdowns occurring in accelerating cavities influence efficiency optimisation and cost reduction issues. Studying vacuum arcs both theoretically as well as experimentally under well-defined and reproducible direct-current (DC) conditions is the first step towards exploring RF breakdowns. In this thesis, we have studied Cu DC vacuum arcs with a combination of experiments, a particle-in-cell (PIC) model of the arc plasma, and molecular dynamics (MD) simulations of the subsequent surface damaging mechanism. We have also developed the 2D Arc-PIC code and the physics model incorporated in it, especially for the purpose of modelling the plasma initiation in vacuum arcs. Assuming the presence of a field emitter at the cathode initially, we have identified the conditions for plasma formation and have studied the transitions from field emission stage to a fully developed arc. The 'footing' of the plasma is the cathode spot that supplies the arc continuously with particles; the high-density core of the plasma is located above this cathode spot. Our results have shown that once an arc plasma is initiated, and as long as energy is available, the arc is self-maintaining due to the plasma sheath that ensures enhanced field emission and sputtering. The plasma model can already give an estimate on how the time-to-breakdown changes with the neutral evaporation rate, which is yet to be determined by atomistic simulations. Due to the non-linearity of the problem, we have also performed a code-to-code comparison. The reproducibility of plasma behaviour and time-to-breakdown with independent codes increased confidence in the results presented here. Our MD simulations identified high-flux, high-energy ion bombardment as a possible mechanism forming the early-stage surface damage in vacuum arcs. In this mechanism, sputtering occurs mostly in clusters, as a consequence of overlapping heat spikes. Different-sized experimental and simulated craters were found to be self-similar with a crater depth-to-width ratio of about 0.23 (sim) - 0.26 (exp). Experiments, which we carried out to investigate the energy dependence of DC breakdown properties, point at an intrinsic connection between DC and RF scaling laws and suggest the possibility of accumulative effects influencing the field enhancement factor.

Tietokone ikäihmisen arjessa

The aged people in the target group of my study belong to generation, which has experienced the shift from agricultural society via industrial society up to the society which has been described as information society. They have grown up concurrently with the technological development, but during the recent years the technological development has accelerated. One can say that the older the target study group has come the more information technological skills they need to possess to be equal actors in our society. However, especially in case of aged people the learning and maintaining of skills in information technology has mainly been left dependent on their personal motivation. The purpose of this report is to study the use of computers in the life of the aged people. The report studies the will and ability of the aged people to learn the skill of using computers, and the new possibilities which this brings into their lives. The study questions are the following: 1) Why the aged people start to use computers? 2) How the aged people benefit information technology in their own life? 3) How computers have extended the environment of the aged people? 4) What kind of problems the aged people have experienced in use of computers? The research material consists of group interviews and individual interviews (total of 23 people). The interview material has been collected among the participants on information technology courses of the Senior University of Helsinki University during years 2004-2005. The research method used is theme interviewing. In addition, the material of opinions about information technology of people born in decades of 1920 and 1930, gathered as part of the Ikihyvä Päijät-Häme 2002 -research has been used. On basis of this research one can say that the aged people do have motivation to study the use of computers, although many interviewees commented that they also have met problems in use of computers. The motivation has grown also because the fear that without the skills to use computers they could drift into outsiders of the society, whereas instead as skilled computer users they felt to be equal citizens compared with the younger age groups, and that they can maintain their independence and autonomy. Especially, the independent use of banking routines over the Internet and use of emails seem to give them a position as modern actors. Many interview statements also underline that computers will bring both joy and benefit to the users. Studying the use of computers is a new and interesting hobby, which can fill the hole left in the life after leaving the working life. Using skills of text processing and processing of pictures one can, for example, record the traditional knowledge of the family and ancestry to the younger generations, and write articles or even books on the professional area of ones own. Single people emphasize that computers can even act as companionship substitutes. One can use Internet for virtual traveling, which provides a new dimension in use of computers. Internet can also be used to maintain family relationships, especially between grandparents and remote grandchildren. Typical problems in use of computers appeared to be that reaching the right professional helpdesk advisers of the service providers is difficult and requires lots of time and patience. However, the interviewees were not willing to give up their computers, because they had already used to these. Keywords: digital divide, aging, Internet, usability, motivation, information technology, information society.

Noninvasive biomarkers for early smoking related lung disease

Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease characterized by airway inflammation and largely irreversible airflow limitation. One major risk factor for COPD is cigarette smoking. Since the inflammatory process starts many years prior to the onset of clinical symptoms and still continues after smoking cessation, there is an urgent need to find simple non-invasive biomarkers that can be used in the early diagnosis of COPD and which could help in predicting the disease progression. The first aim of the present study was to evaluate the involvement of different oxidative/nitrosative stress markers, matrix metalloproteinases (MMPs) and their tissue inhibitor-1 (TIMP-1) in smokers and in COPD. Elevated numbers of inducible nitric oxide synthase (iNOS), nitrotyrosine, myeloperoxidase (MPO) and 4-hydroxy-2-nonenal (4-HNE) positive cells and increased levels of 8-isoprostane and lactoferrin were found in sputum of non-symptomatic smokers compared to non-smokers, and especially in subjects with stable mild to moderate COPD, and they correlated with the severity of airway obstruction. This suggests that an increased oxidant burden exists already in the airways of smokers with normal lung function values. However, none of these markers could differentiate healthy smokers from symptomatic smokers with normal lung function values i.e. those individuals who are at risk of developing COPD. In contrast what is known about asthma exhaled nitric oxide (FENO) was lower in smokers than in non-smokers, the reduced FENO value was significantly associated with neutrophilic inflammation and the elevated oxidant burden (positive cells for iNOS, nitrotyrosine and MPO). The levels of sputum MMP-8 and plasma MMP-12 appeared to differentiate subjects who have a risk for COPD development but these finding require further investigations. The levels of all studied MMPs correlated with the numbers of neutrophils, and MMP-8 and MMP-9 with markers of neutrophil activation (MPO, lactoferrin) suggesting that especially neutrophil derived oxidants may stimulate the tissue destructive MMPs already in lungs of smokers who are not yet experiencing any airflow limitation. When investigating the role of neutrophil proteases (neutrophil elastase, MMP-8, MMP-9) during COPD exacerbation and its recovery period, we found that levels of all these proteases were increased in sputum of patients with COPD exacerbation as compared to stable COPD and controls, and decreased during the one-month recovery period, giving evidence for a role of these enzymes in COPD exacerbations. In the last study, the effects of subject`s age and smoking habits were evaluated on the plasma levels of surfactant protein A (SP-A), SP-D, MMP-9 and TIMP-1. Long-term smoking increased the levels of all of these proteins. SP-A most clearly correlated with age, pack years and lung function decline (FEV1/FVC), and based on the receiver operating characteristic curve analysis, SP-A was the best marker for discriminating subjects with COPD from controls. In conclusion, these findings support the hypothesis that especially neutrophil derived oxidants may activate MMPs and induce an active remodeling process already in the lungs of smokers with normal lung function values. The marked increase of sputum levels of neutrophil proteases in smokers, stable COPD and/or during its exacerbations suggest that these enzymes play a role in the development and progression of COPD. Based on the comparison of various biomarkers, SP-A can be proposed to serve as sensitive biomarker in COPD development.

Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

Laskimonsisäisen rasvaemulsion käyttö lääkemyrkytyksissä

Puudutemyrkytysten hoitoon suositellaan joissain maissa laskimonsisäisesti annettavaa rasvaemulsiota. Suomessa kansallista suositusta ei kuitenkaan ole, eikä kyseisen hoidon yleisyyttä ole aiemmin kotimaassa tutkittu puudute-­ tai muissakaan lääkemyrkytyksissä. Tutkimuksen tavoitteena on selvittää millaiseen näyttöön hoito perustuu käymällä läpi aiheesta julkaistu kirjallisuus sekä selvittää sähköpostikyselyn avulla kuinka yleisesti anestesiaosastoilla on laadittu omia ohjeistuksia rasvaemulsion käytöstä puudutemyrkytystapauksissa. Lisäksi selvitetään onko kyseistä hoitoa jo käytetty, hoitosuositusten perustaa, käytettyjä rasvaemulsiota ja missä niitä säilytetään. Kysely lähetettiin myös kahteen ensihoitoyksikköön muiden lääkemyrkytysten hoitoon laadittujen ohjeistusten osalta. Hieman yli puolella Suomen anestesiaosastoista on laadittuna oma ohjeistus laskimonsisäisen rasvaemulsion käytöstä puudutemyrkytyksissä, vaikka hoidon tehosta on ristiriitaisaa näyttöä eikä kontrolloituja ihmistutkimuksia ole julkaistu. Ensihoitoyksiköillä taas ei ole omia suosituksia hoidosta. Hoitoa on myös käytetty viidellä anestesiaosastolla. Hoitosuositukset eri osastoilla on kuitenkin johdettu useista eri lähteistä. Käytetyin rasvaemulsio on Intralipid® ja myrkytysten hoitoon tarkoitettuja emulsioita säilytetään pääasiassa leikkaussalissa tai sen yhteydessä.

Phytophthora in Finnish nurseries

Human-mediated movement of plants and plant products is now generally accepted to be the primary mode of introduction of plant pathogens. Species of the genus Phytophthora are commonly spread in this way and have caused severe epidemics in silviculture, horticulture as well as natural systems all over the world. The aims of the study were to gather information on the occurrence of Phytophthora spp. in Finnish nurseries, to produce information for risk assessments for these Phytophthora spp. by determining their host ranges and tolerance of cold temperatures, and to establish molecular means for their detection. Phytophthora cactorum was found to persist in natural waterbodies and results suggest that irrigation water might be a source of inoculum in nurseries. In addition to P. cactorum, isolates from ornamental nursery Rhododendron yielded three species new to Finland: P. ramorum, P. plurivora and P. pini. The only species with quarantine status, P. ramorum, was most adapted to growth in cold temperatures and able to persist in the nursery in spite of an annual sanitation protocol. Phytophthora plurivora and the closely related P. pini had more hosts among Nordic tree and plant species than P. ramorum and P. cactorum, and also had higher infectivity rates. All four species survived two weeks in -5 °C , and thus soil survival of these Phytophthoras in Finland is likely under current climatic conditions. The most common tree species in Finnish nurseries, Picea abies, was highly susceptible to P. plurivora and P. pini in pathogenicity trials. In a histological examination of P. plurivora in P. abies shoot tissues, fast necrotrophic growth was observed in nearly all tissues. The production of propagules in P. abies shoot tissue was only weakly indicated. In this study, a PCR DGGE technique was developed for simultaneous detection and identification of Phytophthora spp. It reliably detected Phytophthora in plant tissues and could discriminate most test species as well as indicate instances of multiple-species infections. It proved to be a useful detection and identification tool either applied alone or in concert with traditional isolation culture techniques. All of the introduced species of Phytophthora had properties that promote a high risk of establishment and spread in Finland. It is probable that more pathogens of this genus will be introduced and become established in Finland and other Nordic countries unless efficient phytosanitary control becomes standard practice in the international plant trade.