Browsing by Title

Sort by: Order: Results:

Now showing items 1797-1816 of 24532
  • Keskinen, Matti (2012)
    Tässä tutkelmassa esitellään algebrallisen ryhmän käsite sekä hieman tavallisesta poikkeava tapa ymmärtää permutaatioita. Työn tärkeimpinä kohtina voi pitää Caleyn lausetta, joka yhdistää permutaation ja ryhmän käsitteet, sekä p-ryhmän käsitettä. Työssä käsitellään myös pintapuolisesti suoraan tuloon liittyviä ryhmiä. Varsinaisia esitietovaatimuksia työn ymmärtämiseksi ei ole, mutta tietynlainen matemaattinen yleissivisistys on toivottavaa. Kenen tahansa kandidaattitasoisen matematiikan opiskelijan kuitenkin pit äisi pystyä ymmärtämään tämän tutkielman oleellinen sisältö. Esitelmäni perustuu Joseph J. Rotmanin kirjaan An Introduction to the Theory of Groups [2]. Tukena olen käyttänyt Tauno Metsänkylän ja Marjatta Näätäsen teosta Algebra I [1]. Permutaatioita käsittelevässä luvussa olen tukeutunut Pekka Tuomisen Todennäköisyyslaskenta I- kirjaan [3]. Permutaatioita oli tutkittu jo aikaisemminkin, mutta ryhmien teorian tutkimuksen aloitti varsinaisesti Galois (1811-1832). 1800-luvun lopussa ryhmäteoriaa tutkittiin lähinnä kahdessa päähaarassa. Nämä päähaarat olivat algebralliset ryhmät, erityisesti Lien ryhmät, sekä äärelliset ryhmät. 1900-luvulla ilmaantui kuitenkin kolmas päähaara, äärettömät ryhmät. Nykyään ryhmät esiintyvät monilla matematiikan aloilla, esimerkiksi geometriassa, topologiassa ja logiikassa.
  • Hakala, Jani (2012)
    The most important parameters describing the aerosol particle population are the size, concentration and composition of the aerosol particles. The size and water content of the aerosol particles are dependent of the relative humidity of the ambient air. Hygroscopicity is a measure to describe the water absorption ability of an aerosol particle. Volatility of an aerosol defines how the aerosol particles behave as a function of temperature. A Volatility-Hygroscopicity Tandem Differential Mobility Analyzer (VH-TDMA) is an instrument for size-selected investigation of particle number concentration, volatility, hygroscopicity and the hygroscopicity of the particle core, i.e. what is left of the particle after the volatilization. While knowing these qualities of aerosol particles, one can predict their behavior in different atmospheric conditions. Volatility and hygroscopicity can also be used for indirect analysis of chemical composition. The aim of this study was to build and characterize a VH-TDMA, and report the results of its field deployment at the California Nexus (CalNex) 2010 measurement campaign. The calibration measurements validated that with the VH-TDMA one can obtain accurate volatility and hygroscopicity measurements for particles between 20 nm and 145 nm. The CalNex 2010 results showed that the instrument is capable in field measurements at varying measurement conditions; and valuable data about hygroscopicty, volatility and the mixing state of several types of aerosols were measured. The data obtained was in line with the observations based on the data measured with other instruments.
  • Varho, Vilja (Helsingin yliopisto, 2007)
    Wind power has grown fast internationally. It can reduce the environmental impact of energy production and increase energy security. Finland has turbine industry but wind electricity production has been slow, and nationally set capacity targets have not been met. I explored social factors that have affected the slow development of wind power in Finland by studying the perceptions of Finnish national level wind power actors. By that I refer to people who affect the development of wind power sector, such as officials, politicians, and representatives of wind industries and various organisations. The material consisted of interviews, a questionnaire, and written sources. The perceptions of wind power, its future, and methods to promote it were divided. They were studied through discourse analysis, content analysis, and scenario construction. Definition struggles affect views of the significance and potential of wind power in Finland, and also affect investments in wind power and wind power policy choices. Views of the future were demonstrated through scenarios. The views included scenarios of fast growth, but in the most pessimistic views, wind power was not thought to be competitive without support measures even in 2025, and the wind power capacity was correspondingly low. In such a scenario, policy tool choices were expected to remain similar to ones in use at the time of the interviews. So far, the development in Finland has followed closely this pessimistic scenario. Despite the scepticism about wind electricity production, wind turbine industry was seen as a credible industry. For many wind power actors as well as for the Finnish wind power policy, the turbine industry is a significant motive to promote wind power. Domestic electricity production and the export turbine industry are linked in discourse through so-called home market argumentation. Finnish policy tools have included subsidies, research and development funding, and information policies. The criteria used to evaluate policy measures were both process-oriented and value-based. Feed-in tariffs and green certificates that are common elsewhere have not been taken to use in Finland. Some interviewees considered such tools unsuitable for free electricity markets and for the Finnish policy style, dictatorial, and being against western values. Other interviewees supported their use because of their effectiveness. The current Finnish policy tools are not sufficiently effective to increase wind power production significantly. Marginalisation of wind power in discourses, pessimistic views of the future, and the view that the small consumer demand for wind electricity represents the political views of citizens towards promoting wind power, make it more difficult to take stronger policy measures to use. Wind power has not yet significantly contributed to the ecological modernisation of the energy sector in Finland, but the situation may change as the need to reduce emissions from energy production continues.
  • Schönberg-Norio, Daniela (Helsingin yliopisto, 2009)
    Campylobacter jejuni and C. coli are the leading causes of human bacterial gastroenteritis in developed countries. Most human Campylobacter infections are sporadic and a seasonal peak in the distribution of infections can be seen in the summer months in several countries, including Finland. A variety of risk factors for Campylobacter infections have been identified; handling and eating poultry, drinking unpasteurized milk, contact with domestic animals, and travelling abroad. However, the relative importance of the different risk factors in sporadic cases of Campylobacter infection remains unknown. In most cases, the infection is self-limiting and no specific treatment is required. Campylobacter enteritis can cause a wide range of complications, including reactive arthritis (ReA) that is reported in 1-5% of the cases. Seven clinical microbiology laboratories serving different geographical areas of Finland, participated in this multi-centre study, conducted during a seasonal peak in 2002. In a matched case-control study, domestically-acquired sporadic Campylobacter infections from three geographical areas were collected. The final study comprised 100 cases and 137 controls. Risk factors for sporadic domestically-acquired Campylobacter infections were identified on the basis of a questionnaire; swimming in natural waters was found to be a novel risk factor for Campylobacter infection. Other independent risk factors were tasting or eating raw or undercooked meat and drinking untreated water from a dug well. The role of bacterial strain and host characteristics are not fully understood in Campylobacter infections. Exposure factors, demographical characteristics, and the serotype of the Campylobacter isolate may affect the severity of the enteritis. This cross-sectional study comprised 114 patients with C. jejuni enteritis, diagnosed in three clinical microbiology laboratories; most of the patients had participated in the previous case-control study. Swimming was associated with age ≤ 5 years and serotype Pen 6,7 was found significantly more often among patients reporting swimming. The geographical distribution among serotypes varied; serotype Pen 4-complex appeared more often in patients from urban areas and serotype Pen 21 among patients from more rural areas. Thus, risk factors and sources of infection for C. jejuni infection may vary among individuals depending on age and geographical location. The in vitro susceptibilities of C. jejuni and C. coli strains isolated from patients infected abroad (85 strains) or domestically (393 strains) revealed that susceptibility to erythromycin is still high, even among isolates of foreign origin. However, the novel antimicrobial agent telithromycin did not offer any advantage over erythromycin; isolates with high minimal inhibitory concentrations (MICs) for erythromycin also showed reduced susceptibility to telithromycin. Reduced susceptibility to fluoroquinolones was detected almost exclusively among isolates of foreign origin and half of these isolates with high MICs for fluoroquinolones also showed elevated MICs for doxycycline. Questionnaires concerning complications associated with C. jejuni enteritis were sent to patients two months after becoming ill; 201 patients from seven different geographical areas were included in the study. Musculoskeletal complications after C. jejuni infection were commonly reported by patients (39%). The incidence of classical ReA was 4% and that of Achilles enthesopathy and/or heel pain 9%. Other C. jejuni-associated reactive joint symptoms were commonly reported, however, due to their milder nature seldom seen and diagnosed by a physician. The severity of the enteritis may predict further complications; stomach ache during enteritis was connected to the development of later joint pain. Early antimicrobial treatment, within two days from the start of symptoms, shortened the duration of diarrhoea by two days but did not prevent later musculoskeletal complications. Campylobacter is an important human enteropathogen and causes a significant burden of illness. As the incidence of Campylobacter infections is high, the importance of the infection and the occurrence of complications will increase. This stresses the importance of understanding the risk factors for acquiring Campylobacter infection and how bacterial strain and host characteristics may affect the risk for infection. The role of antimicrobial treatment for acute Campylobacter enteritis seems to be marginal and should be used restrictively.
  • Perko-Mäkelä, Päivikki (Helsingin yliopisto, 2011)
    Campylobacter, mainly Campylobacter jejuni and C. coli, are worldwide recognized as a major cause of bacterial food-borne gastroenteritis. Epidemiological studies have shown handling or eating of poultry to be significant risk factors for human infections. Campylobacter contamination can occur at all stages of a poultry meat production cycle. The aim of this thesis was to study the occurrence and diversity of Campylobacter in broiler and turkey production in Finland. In summer 1999, 2.9 % of slaughtered broiler flocks were Campylobacter-positive. From the isolated strains 94 % were C. jejuni and 6% were C. coli. During years 2005-2006 one turkey parent flock, the hatchery, six different commercial turkey farms and different stages of the slaughterhouse were monitored during one and the half year. No Campylobacter were detected in either of the samples from the turkey parent flock or from the hatchery using the culture method. Instead PCR detected DNA of Campylobacter from the turkey parent flock and samples from the hatchery. Six out of 12 commercial turkey flocks were found negative at the farm level but only two of those were negative at slaughter. Campylobacter-positive samples within the flock at slaughter were detected between 0% and 94% with evisceration and chilling water being the most critical stages for contamination. All of Campylobacter isolates were shown to be C. jejuni. Campylobacter-positive turkey flocks were colonized by a limited number of Campylobacter genotypes both at the farm and slaughter level. In conclusion, in our first study in 1999 a low prevalence of Campylobacter in Finnish broiler flocks was detected and it has remained at a low level during the study period until the present. In the turkey meat production, we found that flocks which were negative at the farm became contaminated with Campylobacter at the slaughter process. These results suggest that proper and efficient cleaning and disinfection of slaughter and processing premises are needed to avoid cross-contamination. Prevention of colonization at the farm by a high level of biosecurity control and hygiene may be one of the most efficient ways to reduce the amount of Campylobacter-positive poultry meat in Finland. With a persistent low level of Campylobacter-positive flocks, it could be speculated that the use of logistic slaughtering, according to Campylobacter status at farm, might have be advantageous in reducing Campylobacter contamination of retail poultry products. However, the significance of the domestic poultry meat for human campylobacteriosis in Finland should be evaluated.
  • Lilja, Liisa (2001)
    Kampylobakteerit ovat teollisuusmaissa tavallisimpia diagnosoituja bakteeriperäisen gastroenteriitin aiheuttajia. C. jejuni aiheuttaa noin 90-95 % infektioista ja C. coli tavallisesti 5-10 %. Suomessa sairastuu vuosittain noin 3000 henkilöä kampylobakterioosiin. Infektioiden määrä on vähäinen talvella ja keväällä, jolloin suurin osa tapauksista on ulkomaista alkuperää. Kesäkuukausien aikana kampylobakteeri-infektioiden määrä kasvaa ja tapauksista jopa puolet voi olla kotimaista alkuperää. Yleensä tapaukset ovat yksittäisiä ja epidemioita esiintyy harvoin. Tartuntalähteistä tärkeimpinä pidetään saastunutta juomavettä ja broilerinlihaa. Perinteiset kampylobakteerien tunnistamismenetelmät ruokanäytteistä ovat aikaa vieviä ja hankalia. Ne sisältävät näytteen esirikastuksen, viljelyn selektiivisille alustoille sekä biokemiallisen varmistuksen. Viime vuosina kampylobakteerien tunnistamiseen tarkoitetut nopeat menetelmät, kuten nukleiinihappohybridisaatio, PCR (polymerase chain reaction) ja ELISA (enzyme-linked immuno-sorbent assay) ovat kehittyneet. Näiden pikamenetelmien kehitys avaa uusia mahdollisuuksia mm. teollisuudelle elintarvikevalvontaan. Opinnäytetyössä verrataan EiaFoss-ELISA-kampylobakteerimenetelmää, viljelymenetelmää ja PCR-analyysia C. jejunin ja C. colin toteamiseen ja tunnistamiseen broilertuotteista. EiaFoss-ELISA-menetelmä on kvalitatiivinen määritysmenetelmä C. jejunin ja C. colin tunnistamiseen elintarvikkeista (rikastus 46 h + täysin automatisoitu analyysi 2 h). ELISA-analyysi perustuu ”sandwich”-tekniikkaan, jossa kaksi erilaista polyklonaalista vasta-ainetta ovat kampylobakteeriantigeeneja vastaan. Viljelymenetelmä sisältää näytteen rikastuksen, viljelyn CCDA-maljalle (valikoiva kampylobakteerialusta ilman verta), maljojen inkuboinnin mikroaerofiilisissä olosuhteissa, tyypillisten pesäkkeiden jatkoviljelyn ja biokemiallisen varmistuksen. Valittu PCR-menetelmä sisältää rikasteliemen esikäsittelyn BDC (Buoyant Density Sentrifugation) menetelmällä, joka erottelee ominaispainoon perustuen bakteerit ja PCR-inhibittorit rikasteliemestä ja konsentroi bakteerit, sekä C. jejuni spesifisen PCR-analyysin. Tutkimuksessa analysoitiin yhteensä 105 tuotetta, joista 60 siipikarjatuotetta oli valittu juuri menetelmien vertailuun. Vaihtelut kaikkien kolmen menetelmän tuloksissa olivat vähäisiä. EiaFoss-positiivisia oli 13, PCR-positiivisia 10 ja viljely-positiivisia näytteitä 10. Varmaksi positiiviseksi tulokseksi määriteltiin sellainen näyte, joka antoi kahdella tai kaikilla kolmella menetelmällä positiivisen tuloksen. Näin ollen varmojen positiivisten määrä oli 12, joista 11 kyseessä oli C. jejuni ja yhdessä C. coli. Sekä EiaFoss- että BDC-PCR-menetelmissä väärien negatiivisten tulosten osuus oli 1,7 % näytteistä. Viljelymenetelmän väärät negatiiviset (3,3 %) johtuivat todennäköisesti valitusta pitkästä rikastusajasta, eivätkä siksi anna täysin oikeaa kuvaa kampylobakteereiden tunnistamisesta viljelemällä. EiaFoss-menetelmällä esiintyi vääriä positiivisia tuloksia (viljely- ja PCR-negatiivisia) 3,3 %. Viljely- ja BDC-PCR-menetelmissä ei esiintynyt vääriä positiivisia. Tämän perusteella sekä EiaFoss- että BDC-PCR-menetelmät osoittautuivat helpoiksi ja luotettaviksi pikamenetelmiksi tunnistaa kampylobakteerit broilernäytteistä.
  • Kalliala, Ilkka (Helsingin yliopisto, 2010)
    Cervical cancer develops through precursor lesions, i.e. cervical intraepithelialneoplasms (CIN). These can be detected and treated before progression to invasive cancer. The major risk factor for developing cervical cancer or CIN is persistent or recurrent infection with high-risk human papilloma virus (hrHPV). Other associated risk factors include low socioeconomic status, smoking, sexually transmitted infections, and high number of sexual partners, and these risk factors can predispose to some other cancers, excess mortality, and reproductive health complications as well. The aim was to study long-term cancer incidence, mortality, and reproductive health outcomes among women treated for CIN. Based on the results, we could evaluate the efficacy and safety of CIN treatment practices and estimate the role of the risk factors of CIN patients for cancer incidence, mortality, and reproductive health. We collected a cohort of 7 599 women treated for CIN at Helsinki University Central Hospital from 1974 to 2001. Information about their cancer incidence, cause of death, birth of children and other reproductive endpoints, and socio-economic status were gathered through registerlinkages to the Finnish Cancer Registry, Finnish Population Registry, and Statistics Finland. Depending on the endpoints in question, the women treated were compared to the general population, to themselves, or to an age- and municipality-matched reference cohort. Cervical cancer incidence was increased after treatment of CIN for at least 20 years, regardless of the grade of histology at treatment. Compared to all of the colposcopically guided methods, cold knife conization (CKC) was the least effective method of treatment in terms of later CIN 3 or cervical cancer incidence. In addition to cervical cancer, incidence of other HPV-related anogenital cancers was increased among those treated, as was the incidence of lung cancer and other smoking-related cancers. Mortality from cervical cancer among the women treated was not statistically significantly elevated, and after adjustment for socio-economic status, the hazard ratio (HR) was 1.0. In fact, the excess mortality among those treated was mainly due to increased mortality from other cancers, especially from lung cancer. In terms of post-treatment fertility, the CIN treatments seem to be safe: The women had more deliveries, and their incidence of pregnancy was similar before and after treatment. Incidence of extra-uterine pregnancies and induced abortions was elevated among the treated both before and after treatment. Thus this elevation did not occur because they were treated rather to a great extent was due to the other known risk factors these women had in excess, i.e. sexually transmitted infections. The purpose of any cancer preventive activity is to reduce cancer incidence and mortality. In Finland, cervical cancer is a rare disease and death from it even rarer, mostly due to the effective screening program. Despite this, the women treated are at increased risk for cancer; not just for cervical cancer. They must be followed up carefully and for a long period of time; general health education, especially cessation of smoking, is crucial in the management process, as well as interventions towards proper use of birth control such as condoms.
  • Taskila, Taina (Helsingin yliopisto, 2007)
    Due to the improved prognosis of many forms of cancer, an increasing number of cancer survivors are willing to return to work after their treatment. It is generally believed, however, that people with cancer are either unemployed, stay at home, or retire more often than people without cancer. This study investigated the problems that cancer survivors experience on the labour market, as well as the disease-related, sociodemographic and psychosocial factors at work that are associated with the employment and work ability of cancer survivors. The impact of cancer on employment was studied combining the data of Finnish Cancer Registry and census data of the years 1985, 1990, 1995 or 1997 of Statistics Finland. There were two data sets containing 46 312 and 12 542 people with cancer. The results showed that cancer survivors were slightly less often employed than their referents. Two to three years after the diagnosis the employment rate of the cancer survivors was 9% lower than that of their referents (64% vs. 73%), whereas the employment rate was the same before the diagnosis (78%). The employment rate varied greatly according to the cancer type and education. The probability of being employed was greater in the lower than in the higher educational groups. People with cancer were less often employed than people without cancer mainly because of their higher retirement rate (34% vs. 27%). As well as employment, retirement varied by cancer type. The risk of retirement was twofold for people having cancer of the nervous system or people with leukaemia compared to their referents, whereas people with skin cancer, for example, did not have an increased risk of retirement. The aim of the questionnaire study was to investigate whether the work ability of cancer survivors differs from that of people without cancer and whether cancer had impaired their work ability. There were 591 cancer survivors and 757 referents in the data. Even though current work ability of cancer survivors did not differ between the survivors and their referents, 26% of cancer survivors reported that their physical work ability, and 19% that their mental work ability had deteriorated due to cancer. The survivors who had other diseases or had had chemotherapy, most often reported impaired work ability, whereas survivors with a strong commitment to their work organization, or a good social climate at work, reported impairment less frequently. The aim of the other questionnaire study containing 640 people with the history of cancer was to examine extent of social support that cancer survivors needed, and had received from their work community. The cancer survivors had received most support from their co-workers, and they hoped for more support especially from the occupational health care personnel (39% of women and 29% of men). More support was especially needed by men who had lymphoma, had received chemotherapy or had a low education level. The results of this study show that the majority of the survivors are able to return to work. There is, however, a group of cancer survivors who leave work life early, have impaired work ability due to their illness, and suffer from lack of support from their work place and the occupational health services. Treatment-related, as well as sociodemographic factors play an important role in survivors' work-related problems, and presumably their possibilities to continue working.
  • Nieminen, Mikko (2011)
    Yläruoansulatuskanavan syöpien tärkeimpiä riskitekijöitä ovat tupakointi, alkoholin suurkulutus ja huono suuhygienia. Näiden tekijöiden vaikutuksesta sylkeen erittyy korkeita pitoisuuksia asetaldehydiä, jonka Kansainvälinen syöväntutkimuslaitos (IARC) on luokitellut 1-ryhmän karsinogeeniksi. Suuri osa syljen asetaldehydistä on suun mikrobien tuottamaa. Tiedetään, että suun mikrobiomiin kuuluvat bakteerit ja Candida albicans -hiivat kykenevät tuottamaan mutageenisiä määriä asetaldehydiä. C. albicansin aiheuttaman kroonisen mukosiitin onkin todettu olevan karsinogeeninen. Muiden kandidalajien (non- albicans Candida, NAC) määrän on todettu kasvavan etenkin suusyöpähoitoja saavilla potilailla ja toisinaan osalle näistä potilaista kehittyy uusi primäärikarsinooma kandidamukosiitin läheisyyteen. NAC-lajien kykyä tuottaa asetaldehydiä ei kuitenkaan ole aiemmin tutkittu. Tutkimuksen tavoitteena oli selvittää pystyvätkö NAC-lajit tuottamaan karsinogeenisiä määriä asetaldehydiä etanoli- ja glukoosi-inkubaatiossa in vitro. Kaikkiaan kolmenkymmenen (n=30) kliinisen ja kantapankkiNAC-kannan kyky tuottaa asetaldehydiä etanoli- ja glukoosi-inkubaatiossa mitattiin kaasukromatografilla. Yksi C. albicans kantapankkikanta oli mukana kontrollina. Kaikki kandidahiivat tuottivat merkittäviä määriä asetaldehydiä etanoli-inkubaatiossa in vitro. C. tropicalis –kannat tuottivat eniten (252,3 µM) ja C. krusei –kannat vähiten (54,6 µM) asetaldehydiä etanolista. NAC-lajeista ainoastaan C. glabrata tuotti merkittäviä määriä asetaldehydiä glukoosia fermentoimalla. Suuontelon kolonisoituminen merkittävään asetaldehydituotantoon pystyvällä NAC-lajilla kuten C. glabratalla voi altistaa suun limakalvon paikallisesti korkeille määrille asetaldehydiä, mikä voi johtaa suusyövän kehittymiseen.
  • Pärnänen, Pirjo (Helsingin yliopisto, 2010)
    The aim of this thesis was to compare the degradation of human oral epithelial proteins by proteinases of different Candida yeast species. We focused on proteins associated with Candida invasion in the cell-to-cell junction, the basement membrane zone, the extracellular matrix, and local tissue inflammatory regulators. Another main objective was to evaluate the effect of the yeast/hyphal transition and pH on the degradative capability of Candida. The enzymatic activity of the Candida proteinases was verified by gelatin zymography. Laminins-332 (Lm-322) and -511(Lm-511) produced by human oral keratinocytes were gathered from the growth media, and E-cadherin (E-Cad) was isolated from the cell membrane of the keratinocytes by immunoprecipitation. The proteins were incubated with Candida cells and cell-free fractions, and degradation was detected by fluorography. Fibronectin degradation was visualised by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE). Matrix metalloproteinase-9 (MMP-9) activation and tissue inhibitor of metalloproteinase-1 (TIMP-1) fragmentation was detected by using the Western blot and enhanced chemoluminescence (ECL) techniques. Residual activity of TIMP-1 was evaluated by a casein degradation assay. A fluorimetric assay was used to detect and compare Candida proteinase activities with MMP-9. These studies showed that the ability of the different Candida yeast species to degrade human Lm-332, fibronectin, and E-Cad vary from strain to strain and that this degradation is pH-dependent. This indicates that local acidic pH in tissue may play a role in tissue destruction by activating Candida proteinases and aid invasion of Candida into deeper tissue. A potential correlation exists between the morphological form of the yeasts and the degradative ability; the C. albicans yeast form seems to be related to superficial infections, and hyphal forms can apparently invade deeper tissues between the epithelial cells by degradation of E-Cad. Basement membrane degradation is possible, especially in the junctional epithelium, which contains only Lm-332 as a structural component. Local tissue host inflammatory mediators, such as MMP-9, were activated, and TIMP-1 was degraded by certain Candida species, thus indicating the possibility of a weakened host tissue defence mechanism in vivo.
  • Donner, Jonas (Helsingin yliopisto, 2012)
    Anxiety disorders, such as panic disorder (PD), obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and phobias are common psychiatric disorders, characterized by exaggerated, prolonged and debilitating levels of anxiety. They are complex diseases with onset influenced by both environmental and genetic factors, but so far little progress has been made in identifying solid susceptibility genes. The aim of this study was to shed light on the genetic basis of human anxiety disorders by genetic analyses of putative susceptibility genes. Altogether, 333 single nucleotide polymorphism markers from 30 genes were tested for genetic association to anxiety disorders in a sample (N = 974) derived from the Finnish population-based Health 2000 cohort. Three other samples from Spain (N = 503), Sweden (N = 2020) and USA (N = 1128) were used for replication attempts or meta-analyses. The studied genes were 1) selected based on a mouse model of anxiety-like behavior; 2) an asthma-linked receptor (neuropeptide S receptor 1; NPSR1) and its neuropeptide ligand (neuropeptide S; NPS); and 3) selected based on previous findings in anxiety disorders or anxiety-related personality traits. We also evaluated whether any of the studied genes modulate probability for anxiety disorders in interaction with childhood adverse life events, which are strong environmental risk factors for anxiety disorders. First, with a cross-species approach, we discovered that six of the murine candidate genes associated with specific human anxiety disorders. The implicated genes link novel biological pathways to anxiety susceptibility. Second, NPSR1 and NPS associated with PD in adults, and symptoms of anxiety/depression in children. Our findings suggest that NPS-NPSR1 signaling modulates predisposition not only to asthma, but also to anxiety. Third, of the putative susceptibility genes examined based on previous studies, the strongest associations were for glutamate decarboxylase 1 (GAD1) with phobias. Our results, together with previous findings in the gene, support the role of GAD1 as a risk factor for anxiety- and mood disorders, and neuroticism. Fourth, the neuropeptide Y (NPY) gene modulated the effects of the number of experienced childhood adversities on anxiety susceptibility. NPY may therefore influence individual variation in stress resilience. In conclusion, we identified altogether ten potential susceptibility genes for anxiety disorders. They should be further evaluated in independent study samples, and studied functionally to understand how they may regulate behavior. Such future studies will be essential for evaluating their therapeutic potential in treatment of anxiety disorders. Our findings also support the notion that understanding of the interplay between environmental risk factors and genetic variants is important for understanding predisposition to psychiatric disorders.
  • Auro, Kirsi (Helsingin yliopisto, 2007)
    Cardiovascular diseases (CVD) are a major cause of death and disability in Western countries and a growing health problem in the developing world. The genetic component of both coronary heart disease (CHD) and ischemic stroke events has been established in twin studies, and the traits predisposing to CVD, such as hypertension, dyslipidemias, obesity, diabetes, and smoking behavior, are all partly hereditary. Better understanding of the pathophysiology of CVD-related traits could help to target disease prevention and clinical treatment to individuals at an especially high disease risk and provide novel pharmaceutical interventions. This thesis aimed to clarify the genetic background of CVD at a population level using large Nordic population cohorts and a candidate gene approach. The first study concentrated on the allelic diversity of the thrombomodulin (THBD) gene in two Finnish cohorts, FINRISK-92 and FINRISK-97. The results from this study implied that THBD variants do not substantially contribute to CVD risk. In the second study, three other candidate genes were added to the analyses. The study investigated the epistatic effects of coagulation factor V (F5), intercellular adhesion molecule -1 (ICAM1), protein C (PROC), and THBD in the same FINRISK cohorts. The results were encouraging; we were able to identify several single SNPs and SNP combinations associating with CVD and mortality. Interestingly, THBD variants appeared in the associating SNP combinations despite the negative results from Study I, suggesting that THBD contributes to CVD through gene-gene interactions. In the third study, upstream transcription factor -1 (USF1) was analyzed in a cohort of Swedish men. USF1 was associated with metabolic syndrome, characterized by accumulation of different CVD risk factors. A putative protective and a putative risk variant were identified. A direct association with CVD was not observed. The longitudinal nature of the study also clarified the effect of USF1 variants on CVD risk factors followed in four examinations throughout adulthood. The three studies provided valuable information on the study of complex traits, highlighting the use of large study samples, the importance of replication, and the full coverage of the major allelic variants of the target genes to assure reliable findings. Although the genetic basis of coronary heart disease and ischemic stroke remains unknown, single genetic findings may facilitate the recognition of high-risk subgroups.
  • Nieminen, Mikko (Helsingin yliopisto, 2014)
    Cancers of the upper digestive tract (oral, pharyngeal, laryngeal, oesophageal and stomach) are among the ten most common cancers worldwide and are associated with high mortality and morbidity. Despite improved treatment strategies, the prognosis of these cancers remains poor. The main aetiological factors for the upper digestive tract cancers are alcohol consumption and smoking. Dietary and genetic factors can also contribute to an increased risk. Alcohol consumption, smoking and poor oral hygiene all lead to exposure of the upper digestive tract mucosa to salivary acetaldehyde. Ethanol is not carcinogenic, but acetaldehyde, its first metabolite, is. The International Agency for Research on Cancer has classified acetaldehyde associated with alcoholic consumption as a group I carcinogen. Cigarette smoke contains acetaldehyde, as does saliva after alcohol intake. Microbially fermented food products can also contain high levels of acetaldehyde. Therefore, salivary acetaldehyde levels are a result of its direct intake as well as systemic, local and microbial ethanol metabolism. The ability of the mucosa and microbes to remove acetaldehyde has been shown to be limited. Chronic Candida mucositis is associated with oro-oesophageal carcinogenesis. Candida yeasts are common colonisers of the upper digestive tract, with an extraordinary ability to form biofilms. Candida albicans is the dominant species in health and disease. The biofilm structure protects fungal cells against hostile actions, and infections are mainly biofilm-related. This is highlighted by high resistance to antifungals by yeast biofilms. Fungal cells can become dispersed from a biofilm, making it a constant source of infection. In immunocompromised patients, this process can lead to fatal systemic infections. The similarity of fungal and human cells makes the development of antifungals difficult, and treatment is often compromised. The primary aim of the research presented in this thesis was to investigate the ability of clinically important Candida yeasts to produce carcinogenic acetaldehyde in planktonic and biofilm modes of growth in vitro. Fermented milk mursik constitutes a major part of the diet in western Kenya, an area with a high local incidence of oesophageal cancer and a low prevalence of common risk factors. The second aim was to identify the microbiota of the starter cultures used for the production of mursik. The ability of these mixed cultures of bacteria and yeast to produce acetaldehyde and ethanol was assessed in a fermentation experiment. Finally, the potential anti-biofilm and anti-inflammatory effect of a Lactobacillus metabolite, 2-hydroxyisocaproic acid (HICA), was explored in vitro and in vivo. HICA has previously shown efficacy against various planktonically grown microbes. The results of the research presented in this thesis demonstrate that C. albicans biofilms can produce mutagenic levels of acetaldehyde when incubated with ethanol and glucose at clinically relevant concentrations. In addition, planktonic C. albicans and non-albicans Candida (NAC) species produce significant levels of acetaldehyde in the presence of ethanol. C. glabrata shows a unique ability among NAC species to produce mutagenic acetaldehyde in the presence of sugars. Interestingly, the production of acetaldehyde by Candida species can be significantly reduced by the sugar alcohol xylitol. Highly mutagenic levels of acetaldehyde and ethanol can be measured during the production of mursik. Candida yeasts are associated with high acetaldehyde and ethanol production during fermentation. C. albicans biofilm formation is significantly reduced in response to HICA treatment in vitro. Interestingly, certain genes belonging to the fermentative pathway and acetaldehyde metabolism are highly up-regulated under stress and during biofilm formation. An attenuated inflammatory response was observed when a C. albicans biofilm was treated with HICA in vivo. Overall, these results underline the significant potential of clinically relevant Candida yeasts to produce carcinogenic acetaldehyde. Colonisation of the upper digestive tract with Candida spp. could expose the mucosa to mutagenic levels of acetaldehyde in the presence of alcohol and dietary sugars. This could play a role in the carcinogenesis associated with Candida infection. In addition, the consumption of fermented food products such as mursik, with a high acetaldehyde and ethanol content, could elevate the risk of cancer. HICA could provide a safe and efficient approach to treat biofilm-related Candida infections and reduce the inflammation and mutagenicity associated with C. albicans biofilms.
  • Rikula, Ulla Kaisa (Helsingin yliopisto, 2008)
    Canine distemper (CD) is one of the longest-known infectious diseases of dogs and many other carnivores. Control of CD among dogs relies heavily on vaccination, while in fur farms and zoos biosecurity measures in some cases offer the only available means for CD control. Modified live CD virus vaccines have been successfully used to control CD among farmed mink, and since no licensed vaccines for other species kept for fur exist, they have also been used for foxes and raccoon dogs in CD emergency situations. CD vaccines for dogs and mink were studied in experimental settings for their ability to induce virus-neutralising (VN) antibodies in target species. Mink vaccines were also assessed in silver foxes, blue foxes and raccoon dogs. Purpose-bred beagle dogs were vaccinated twice with one of three CD vaccines: Candur® SHP, Canlan®-3 or Dohyvac® DA2P, and the levels of VN antibodies were determined at the time of vaccination and one month after the second vaccination. Fur animals were vaccinated once with Distemink®, Distem®-R-TC or vaccine 3 and the levels of VN antibodies were determined at vaccination and 2-4 times 1-4 months afterwards. Significant differences among vaccine groups were found both in the proportion of animals with measurable levels of VN antibodies and in the mean titres of antibodies. The levels of VN antibodies were also determined from a large field sample (n = 4 627) of vaccinated dogs. In addition to the three CD vaccines in the seroconversion study above, additional two vaccines, Duramune®-4 and Nobivac® DHP, had been used in the field. Each dog with a known vaccination history, date of birth, sex and breed was sampled once. Based on the overall geometric mean titre of the dogs vaccinated with a single vaccine brand, vaccines were divided into high-take (Candur®, Nobivac® and Duramune®) and low-take (Dohyvac® and Canlan®) groups. The vaccine groups differed significantly among dogs less than two years of age both in the proportion of dogs with detectable VN antibodies and in the mean titres. Both the number of vaccinations and age were associated with the titre and vaccine usage. To control for possible confounding factors, the comparison of titres among vaccine usage groups was adjusted by classifying them according to the number of vaccinations (one to four) and the age group (less than one, one to two, or over two years old). The same division into low- and high-take vaccines was observed, irrespective of the number of vaccinations the dogs had received. The observations of this seroprevalence study regarding Candur®, Canlan® and Dohyvac® were consistent with the results of the seroconversion study. CD was reintroduced into Finland in 1990 after 16 years of absence. The disease remained at a low endemic level in 1990-1994, reached epidemic proportions in 1994-1995 and disappeared during 1995. The epidemic also involved vaccinated dogs. Among the virologically-confirmed cases the proportion of Dohyvac®-vaccinated dogs was higher than expected from the market shares on the assumption that all the vaccines had an equal take. As a result of this observation, Dohyvac® was withdrawn from and Nobivac® and Duramune® introduced to the market during 1995. A drastic redistribution of the market shares between the low-take and high-take vaccines took place, and this coincided with the decline and dying out of the outbreak. The observed occurrence pattern of CD from 1990-1996 was largely attributed to the changes in the level of HI, although the possible contribution of other factors, such as developments in the dog demographics, was also recognized. It was concluded that an HI above 75% is needed to keep CD in check, i.e., only sporadic cases of CD, at most, can occur. With the currently used vaccines an HI of 80% corresponds to a vaccine coverage of some 94%. It was concluded that the development of vaccine-induced immunity is a multifactorial process depending on the properties of the vaccine, on the individual variation, age, species and other factors influencing the immunocompetence of the host. On the individual level the prevention of clinical signs is sufficient, but on the population level, halting the circulation of the virus is crucial for the definitive control of CD. The ultimate test and criterion for a vaccine is its contribution to herd immunity.
  • Lilja-Maula, Liisa (Helsingin yliopisto, 2014)
    Canine idiopathic pulmonary fibrosis (CIPF) is an incurable fibrosing lung disease occurring mainly in West Highland White Terriers (WHWTs). The clinical picture of CIPF has many similarities with human idiopathic pulmonary fibrosis (IPF). Signs include dry cough, exercise intolerance, and respiratory difficulties. Prognosis for CIPF and human IPF is poor, and only limited treatment options are available. Histopathological CIPF shares features of both human usual interstitial pneumonia (UIP), the pathological counterpart of human IPF, and other human idiopathic interstitial pneumonia, the non-specific interstitial pneumonia (NSIP). Chronic bronchitis (CB) is the main differential diagnosis for CIPF, but antemortem differentiation can be challenging, as surgical lung biopsies are seldom taken and no clinically useful biomarkers are currently available. The natural history of CIPF has not been previously studied and little is known about the molecular pathophysiology of CIPF. This thesis describes the clinical course, survival, and evaluation of exercise intolerance using the 6-minute walk test in CIPF WHWTs. Bronchoalveolar lavage fluid (BALF) protein expression was studied to find potential biomarkers for CIPF, and aspects of transforming growth factor (TGF)-β related molecular pathways in pathogenesis of CIPF were investigated. In addition, results of TGF-β signaling activity and its known extracellular matrix (ECM) regulatory proteins, latent TGF-β binding protein (LTBP)-1 and fibrillin-2, in CIPF were compared with findings in human IPF/UIP and NSIP. The follow-up study showed that CIPF has a significant negative impact on life expectancy of diseased dogs. The median CIPF-specific survival after onset of clinical signs in WHWTs was 2.7 years, but individual survival varied considerably from only a few months to over 4 years. This variance indicates that CIPF may have either a slow or a rapid disease progression, as also seen in human IPF. In addition, during the disease course acute exacerbations (AEs) occurred. The 6-minute walk distance proved to be an easy and noninvasive parameter to evaluate lung function and level of exercise intolerance in CIPF WHWTs. No significant prognostic factors were identified. The quantitative comparison of BALF proteomes obtained from CIPF WHWTs, CB dogs, and healthy dogs revealed similar changes for CIPF and CB, which suggests a common response to disease processes in these otherwise different lung diseases. Specific biomarkers for CIPF were not identified. The immunohistochemical stainings suggested that increased TGF-β signaling and its ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of CIPF, as also seen in human IPF/UIP and NSIP. We demonstrated strong expression of activin B, a member of the TGF-β superfamily, in the altered alveolar epithelium of WHWTs with CIPF. Furthermore, activin B was detected in BALF of CIPF WHWTs, most notably in samples from dogs with AE, but not in BALF of healthy WHWTs. This novel finding suggests that activin B is part of the CIPF pathophysiology and might act as a potential marker of alveolar epithelial damage. Our findings add important new knowledge about the natural history and molecular pathophysiology of CIPF in WHWTs and show similarities between CIPF and human IPF. Better understanding of the complex pathogenesis of CIPF and human IPF is crucial for developing novel diagnostic tools and treatment strategies for these yet incurable diseases.
  • Ahonen, Saija (Helsingin yliopisto, 2014)
    The availability of the genome sequence and genomic tools combined with the unique phenotypic diversity and breed structure has increased interest in dog as a large, physiologically relevant animal model for human genetic research. Dogs suffer from hundreds of hereditary conditions of which many resemble closely disorders in humans. Investigation of the genetic background of these conditions is important to understand the disease mechanisms and pathways for therapeutic options, to identify novel candidate genes for corresponding human conditions, and to inform the breeding programs. Remarkable resources have been established in the University of Helsinki for canine genetic research, including one of the largest canine DNA banks. This study has focused on degenerative eye diseases of unknown genetic cause. We combined efforts in basic and clinical veterinary research with a unique network of collaboration with dog breeders and owners to establish clinically relevant study cohorts for two types of retinal degeneration in Papillon and Phaléne, and in Swedish Vallhund, SV breeds and two different types of glaucoma in Dandie Dinmont Terriers, DDT and Norwegian Elkhounds, NE. Genome wide approaches with the latest genomic tools, including SNP arrays and exome sequencing were then utilized to identify causative loci and genes. We report breakthroughs in all projects and highlight shared molecular etiologies in canine and human vision disorders. The cause of the retinal degeneration in Papillons and Phalénes was found in the CNGB1 gene, which is important for the rod cell function and has been linked before to human retinal degenerations. A unique type of multifocal retinal degeneration was described in SV with association to the upregulation of the MERTK gene. MERTK mutations cause also retinal degeneration in humans. DDTs were found to present a primary closed angle glaucoma (PACG) with severe pectinate ligament dysplasia (PLD). The disease was mapped to a region on canine chromosome 8, which is syntenic to human chromosome 14 with multiple glaucoma loci. However, further studies are required to identify the causative mutation. Finally, we found that the primary glaucoma in NEs is caused by a missense mutation in the ADAMTS10 gene. This gene has been associated with a Weill-Marchesani syndrome (WMS) with ocular and non-ocular abnormalities in humans. This study provides new candidate genes, and mechanisms for human eye disorders, and has identified models for potential therapeutic trials. At the same time breeding programs benefit from novel gene tests to eradicate the blinding conditions from the studied breeds.
  • Lukkarinen, Vaula (2014)
    Northern white cedar (Thuja occidentalis L.) (NWC) swamps are valuable both commercially and ecologically. Unfortunately, many NWC swamps are degraded and information about them is not abundant. Especially there have been no definitive studies about mosses in northern white cedar swamps and how they react to disturbances. Mosses are sensitive to changes in their environment and thus they could be used to assess ecosystem conditions of NWC swamps. The objective of this study was to determine if mosses could be used to asses conditions in NWC swamps and if there are differences between moss communities in disturbed and undisturbed sites. Seventeen sample plots were taken from 12 disturbed and undisturbed sites around upper Michigan and northern Minnesota in the summer of 2012. All mosses occurring on the plots were identified and several associated environmental parameters were measured. The main environmental conditions affecting moss communities were identified with non-metric multidimensional scaling (NMS). Multiple response permutation procedures (MRPP) were run to ascertain if there were significant differences in community composition between disturbances. Indicator species analysis was then done to identify species that are related to different types of disturbances. A one-way ANOVA was used to check for significant differences between species richness and moss cover of undisturbed and disturbed sites. Over all sixty-two moss species were identified. The results indicate that there was no significant difference in species richness or moss cover between disturbed and undisturbed sites. However, moss community composition was affected by disturbance and strongly divided by a wetness gradient. Dicranum fuscescens was found to indicate undisturbed conditions. Calliergon cordifolium and Climacium dendroides indicated disturbed sites with wet conditions. Brotherella recurvans and Eurhynchium pulchellum indicated swamps with other disturbances.