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  • 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.
  • Schultner, Eva (Helsingin yliopisto, 2014)
    In complex societies like ant colonies individuals cooperate in the aim of maximizing offspring production. But cooperation is only flawless from afar. In fact, because adults can differ in their relatedness to brood they often have contrasting inclusive fitness interests, which may lead to outbreaks of social conflict. However, although conflicts in ant colonies typically arise over offspring production, the role of offspring as actors in social conflict has received little attention. The primary aim of this thesis was to investigate the role of larvae in ant societies, with particular emphasis on selfish larval behavior in the form of egg cannibalism. This thesis demonstrates that Formica ant larvae readily engage in egg cannibalism. Egg consumption allows larvae to increase survival and positively affects the expression of key growth-related genes. Levels of cannibalism across species decrease when relatedness between larvae and eggs is high, which suggests that cannibalism is a selfish trait that can underlie social control. Cannibalism appears to be plastic in F. aquilonia, where levels increase when larvae are presented with foreign eggs compared to sibling eggs. In addition, cannibalism intensity is highly dependent on larvae sex and size across eight species. I conclude that ant larvae are far from powerless. Instead, cannibalism may allow larvae to influence important determinants of individual fitness such as caste fate or size. By consuming eggs, larvae may furthermore affect overall colony fitness. For the first time, this thesis identifies larvae as individuals with selfish interests that have the power to act in social conflict, thus adding a new dimension to our understanding of colony dynamics in social insects. In order to understand how relatedness between individuals potentially impacts conflict in ant societies on a larger scale, this thesis furthermore focuses on the genetic network of native wood ant populations. The societies of these ants consist of many interconnected nests with hundreds of reproductive queens, where individuals move freely between nests and cooperate across nest boundaries. The combination of high queen numbers and free mixing of individuals results in extremely low relatedness within these so-called supercolonies. Here, cooperative worker behavior appears maladaptive because it may aid random individuals instead of relatives. I use network analysis to test for spatial and temporal variation in genetic structure, in order to provide a comprehensive picture of genetic substructure in native wood ant populations. I find that relatedness within supercolonies is low but positive when viewed on a population level, which may be due to limited dispersal range of individuals and ecological factors such as nest site limitation and competition against conspecifics. Genetic network analysis thus provides novel evidence that ant supercolonies can exhibit fine-scale genetic substructure, which may explain the maintenance of cooperation in these low-relatedness societies. Overall, these results offer a new perspective on the stability of cooperation in ant societies, and will hopefully contribute to our understanding of the evolutionary forces governing the balance between cooperation and conflict in other complex social systems.
  • Laakkonen, Johanna (2008)
    The study explores the first appearances of Russian ballet dancers on the stages of northern Europe in 1908 1910, particularly the performances organized by a Finnish impresario, Edvard Fazer, in Helsinki, Stockholm, Copenhagen and Berlin. The company, which consisted of dancers from the Imperial Theatres of St. Petersburg, travelled under the name The Imperial Russian Ballet of St. Petersburg. The Imperial Russian Ballet gave more than seventy performances altogether during its tours of Finland, Sweden, Denmark and central Europe. The synchronic approach of the study covers the various cities as well as genres and thus stretches the rather rigid geographical and genre boundaries of dance historiography. The study also explores the role of the canon in dance history, revealing some of the diversity which underlies the standard canonical interpretation of early twentieth-century Russian ballet by bringing in source material from the archives of northern Europe. Issues like the central position of written documentation, the importance of geographical centres, the emphasis on novelty and reformers and the short and narrow scholarly tradition have affected the formation of the dance history canon in the west, often imposing limits on the historians and narrowing the scope of research. The analysis of the tours concentrates on four themes: virtuosity, character dancing, the idea of the expressive body, and the controversy over ballet and new dance. The debate concerning the old and new within ballet is also touched upon. These issues are discussed in connection with each city, but are stressed differently depending on the local art scene. In Copenhagen, the strong local canon based on August Bournonville s works influenced the Danish criticism of Russian ballet. In Helsinki, Stockholm and Berlin, the lack of a solid local canon made critics and audiences more open to new influences, and ballet was discussed in a much broader cultural context than that provided by the local ballet tradition. The contemporary interest in the more natural, expressive human body, emerging both in theatre and dance, was an international trend that also influenced the way ballet was discussed. Character dancing, now at low ebb, played a central role in the success of the Imperial Russian Ballet, not only because of its exoticism but also because it was considered to echo the kind of performing body represented by new dance forms. By exploring this genre and its dancers, the thesis brings to light artists who are less known in the current dance history canon, but who made considerable careers in their own time.
  • Närhi, Katja (Helsingin yliopisto, 2012)
    Although mammary glands and hair are morphologically and functionally different organs, they share similar early developmental features and arise from ectoderm like other skin appendages. Their development begins by the formation of an epithelial placode and a mesenchymal dermal condensate and crosstalk between these tissue compartments directs the subsequent developmental steps resulting in epithelial morphogenesis and the generation of specific organ shapes. Different types of hair filaments are observed in various anatomical regions and are produced by hair follicles consisting of several epithelial cell layers and a dermal papilla. The mammary gland is constructed of a nipple rising above the skin and the glandular mammary tree producing milk. Both organs continue development postnatally; new hair is produced by repeated hair cycles lasting throughout the lifetime and postpubertal mammary ductal tree is remodelled upon pregnancy and following lactation and involution. Handful of conserved signaling pathways guides both the embryonic and postnatal developmental steps of skin appendages. Hair and mammary gland development are especially known to depend on signals from the -catenin-mediated Wnt pathway. The Wnt pathway is highly complex with multiple ligands, receptors and signaling modulators, and cross-talk with other signaling pathways is apparent. Here, I have examined the role of Wnt signaling in hair and mammary gland patterning and development and its relationship to other signaling molecules within this context. The study has involved three different mouse models in which Wnt signaling is modulated either by continuous activation of -catenin, inactivation of the Wnt and Bmp pathway regulator Sostdc1, or ablation of a Wnt target gene, Fgf20. Continuous Wnt/-catenin signaling in embryonic ectoderm in Catnbex3K14/+ mice caused precocious hair development and, the formation of ectopic and mispatterned hair placodes showing disturbed morphogenesis and hair filament formation. Fgf20-null mice showed a surprisingly early hair phenotype with a loss of expression of several dermal condensate markers but presence of grossly normal morphological patterning of placodes with altered placode marker expression patterns. Loss of Sostdc1 had very mild effects on pelage hair development but interestingly, Sostdc1 appears to play a role in determing correct vibrissal hair and nipple number and the regulation of mammary bud size/form, plausibly through inhibiting Wnt signaling.
  • Launiainen, Samuli (Helsingin yliopisto, 2011)
    Interaction between forests and the atmosphere occurs by radiative and turbulent transport. The fluxes of energy and mass between surface and the atmosphere directly influence the properties of the lower atmosphere and in longer time scales the global climate. Boreal forest ecosystems are central in the global climate system, and its responses to human activities, because they are significant sources and sinks of greenhouse gases and of aerosol particles. The aim of the present work was to improve our understanding on the existing interplay between biologically active canopy, microenvironment and turbulent flow and quantify. In specific, the aim was to quantify the contribution of different canopy layers to whole forest fluxes. For this purpose, long-term micrometeorological and ecological measurements made in a Scots pine (Pinus sylvestris) forest at SMEAR II research station in Southern Finland were used. The properties of turbulent flow are strongly modified by the interaction between the canopy elements: momentum is efficiently absorbed in the upper layers of the canopy, mean wind speed and turbulence intensities decrease rapidly towards the forest floor and power spectra is modulated by spectral short-cut . In the relative open forest, diabatic stability above the canopy explained much of the changes in velocity statistics within the canopy except in strongly stable stratification. Large eddies, ranging from tens to hundred meters in size, were responsible for the major fraction of turbulent transport between a forest and the atmosphere. Because of this, the eddy-covariance (EC) method proved to be successful for measuring energy and mass exchange inside a forest canopy with exception of strongly stable conditions. Vertical variations of within canopy microclimate, light attenuation in particular, affect strongly the assimilation and transpiration rates. According to model simulations, assimilation rate decreases with height more rapidly than stomatal conductance (gs) and transpiration and, consequently, the vertical source-sink distributions for carbon dioxide (CO2) and water vapor (H2O) diverge. Upscaling from a shoot scale to canopy scale was found to be sensitive to chosen stomatal control description. The upscaled canopy level CO2 fluxes can vary as much as 15 % and H2O fluxes 30 % even if the gs models are calibrated against same leaf-level dataset. A pine forest has distinct overstory and understory layers, which both contribute significantly to canopy scale fluxes. The forest floor vegetation and soil accounted between 18 and 25 % of evapotranspiration and between 10 and 20 % of sensible heat exchange. Forest floor was also an important deposition surface for aerosol particles; between 10 and 35 % of dry deposition of particles within size range 10 30 nm occurred there. Because of the northern latitudes, seasonal cycle of climatic factors strongly influence the surface fluxes. Besides the seasonal constraints, partitioning of available energy to sensible and latent heat depends, through stomatal control, on the physiological state of the vegetation. In spring, available energy is consumed mainly as sensible heat and latent heat flux peaked about two months later, in July August. On the other hand, annual evapotranspiration remains rather stable over range of environmental conditions and thus any increase of accumulated radiation affects primarily the sensible heat exchange. Finally, autumn temperature had strong effect on ecosystem respiration but its influence on photosynthetic CO2 uptake was restricted by low radiation levels. Therefore, the projected autumn warming in the coming decades will presumably reduce the positive effects of earlier spring recovery in terms of carbon uptake potential of boreal forests.
  • Valve, Heikki (2012)
    Tässä tutkielmassa tarkastellaan Cantorin joukkoa ja sen soveltamista muutamiin matemaattisiin tarkoituksiin. Cantorin joukon määrittelyssä otetaan huomioon sen monet topologiset ominaisuudet. Tarkoituksena on muotoilla Cantorin joukkoon liittyvät matemaattiset erikoisuudet mahdollisimman ymmärrettävällä tavalla matematiikkaa vain vähän opiskelleelle. Cantorin joukko on hämmentänyt matemaatikkoja sen ensimmäisestä esiintymisestä lähtien. Joukko muodostetaan vaiheittain poistamalla yksikkövälistä [0, 1] avoimia kolmanneksia. Prosessin ensimmäisessä vaiheessa välistä [0, 1] poistetaan väli (1/3, 2/3). Seuraavassa vaiheessa kahdesta välistä [0, 1/3] ja [2/3, 1] poistetaan jälleen niiden keskimmäiset kolmannekset eli välit (1/9, 2/9) ja (7/9, 8/9). Kun tätä prosessia jatketaan loputtamasti, välistä [0, 1] lopulta jäljelle jäävät pisteet muodostavat Cantorin joukon. Cantorin joukkoon kuuluvat ainakin kaikkien poistettujen välien päätepisteet. Yhtenä joukon erikoisuutena on kuitenkin se, että siihen kuuluu vielä ylinumeroituvasti ääretön määrä pisteitä, jotka eivät ole poistettujen välien päätepisteitä. Tämän seurauksena myös Cantorin joukko on siis ylinumeroituvasti ääretön. Topologiset ominaisuudet ovat Cantorin joukolla myös erikoisia. Voidaan osoittaa, että joukolla ei ole sisäpisteitä eli pisteitä, joilla olisi jokin Cantorin joukkoon kuuluva ympäristö. Lisäksi voidaan osoittaa, että jokainen Cantorin joukon piste on kasautumispiste eli piste, jonka jokaisessa ympäristössä on jokin toinen Cantorin joukon piste. Pirunporrasfunktionakin tunnetun Cantorin funktion lähtö- ja maalijoukko on yksikköväli [0, 1] eli gamma : [0, 1] -> [0, 1]. Funktion määrittely aloitetaan kuitenkin usein Cantorin joukon avulla. Nimen pirunporrasfunktio on saanut portaikkoa muistuttavasta kuvaajastaan. Vaikka gamma muistuttaa portaikkoa ja ensisilmäyksellä vaikuttaa katkonaiselta, niin se on kuitenkin jatkuva ja jopa tasaisesti jatkuva. Viimeisenä asiana tässä tutkielmassa esitetään lyhyesti Cantorin joukkoon liittyvä Lebesguen käyrä. Lebesguen käyrää sanotaan avaruuden täyttäväksi käyräksi, koska se kulkee jokaisen maalijoukkonsa, tässä tapauksessa yksikköneliön [0; 1] x [0; 1], pisteen kautta.
  • Tschamurov, Viveka (2013)
    A model is been built where two countries compete for a multinational enterprise’s (MNE’s) foreign direct investment (FDI) provided that its arrival will increase the host country’s social welfare. Both potential host countries have unionised labour markets where monopoly labour unions determine the level of the wage setting to be either decentralised, intermediate level, or centralised. The governments may influence the unions’ decision by setting a lump-sum tax on them. Both countries have two sectors, a non-sheltered and sheltered sector. The MNE will enter in the non-sheltered sector and is assumed to be more productive than the incumbent firms there. Product market competition between the MNE and domestic incumbent firms is ruled out to isolate the effect of product market competition from the effect of pure wage compression. The game evolves in five stages: (1) the governments set taxes, (2) the monopoly unions choose the level of the wage setting, (3) the MNE chooses its investment location, (4) the monopoly unions set wages, and (5) the firms set output. The purpose of the model is to learn whether the degree of centralisation of wage setting can be used as a strategic choice to attract foreign direct investment. The main results of the paper are the following. It was found that the MNE’s (incumbent unions’) most preferred choice is always centralised (decentralised) wage setting. It was shown that the governments’ most preferred choice is either decentralised or centralised wage setting – depending on the relative sizes of the two sectors. If the social welfare in country 1 is the highest under decentralised wage setting, then the optimal policy of government 1 is to set zero income taxes. If the social welfare in country 2 is the highest under centralised wage setting, then the optimal policy of government 2 is to set positive taxes slightly over that required to make the domestic incumbent labour unions prefer centralised wage setting. Given this, the MNE will always invest in country 2. The exact expressions for the stage-contingent lump-sum taxes were derived. To my best knowledge, this is a novel contribution that cannot be found elsewhere.
  • D'Ulivo, Lucia (Helsingin yliopisto, 2010)
    This doctoral thesis describes the development of a miniaturized capillary electrochromatography (CEC) technique suitable for the study of interactions between various nanodomains of biological importance. The particular focus of the study was low-density lipoprotein (LDL) particles and their interaction with components of the extracellular matrix (ECM). LDL transports cholesterol to the tissues through the blood circulation, but when the LDL level becomes too high the particles begin to permeate and accumulate in the arteries. Through binding sites on apolipoprotein B-100 (apoB-100), LDL interacts with components of the ECM, such as proteoglycans (PGs) and collagen, in what is considered the key mechanism in the retention of lipoproteins and onset of atherosclerosis. Hydrolytic enzymes and oxidizing agents in the ECM may later successively degrade the LDL surface. Metabolic diseases such as diabetes may provoke damage of the ECM structure through the non-enzymatic reaction of glucose with collagen. In this work, fused silica capillaries of 50 micrometer i.d. were successfully coated with LDL and collagen, and steroids and apoB-100 peptide fragments were introduced as model compounds for interaction studies. The LDL coating was modified with copper sulphate or hydrolytic enzymes, and the interactions of steroids with the native and oxidized lipoproteins were studied. Lipids were also removed from the LDL particle coating leaving behind an apoB-100 surface for further studies. The development of collagen and collagen decorin coatings was helpful in the elucidation of the interactions of apoB-100 peptide fragments with the primary ECM component, collagen. Furthermore, the collagen I coating provided a good platform for glycation studies and for clarification of LDL interactions with native and modified collagen. All methods developed are inexpensive, requiring just small amounts of biomaterial. Moreover, the experimental conditions in CEC are easily modified, and the analyses can be carried out in a reasonable time frame. Other techniques were employed to support and complement the CEC studies. Scanning electron microscopy and atomic force microscopy provided crucial visual information about the native and modified coatings. Asymmetrical flow field-flow fractionation enabled size measurements of the modified lipoproteins. Finally, the CEC results were exploited to develop new sensor chips for a continuous flow quartz crystal microbalance technique, which provided complementary information about LDL ECM interactions. This thesis demonstrates the potential of CEC as a valuable and flexible technique for surface interaction studies. Further, CEC can serve as a novel microreactor for the in situ modification of LDL and collagen coatings. The coatings developed in this study provide useful platforms for a diversity of future investigations on biological nanodomains.