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  • Paavola, Jere (Helsingin yliopisto, 2014)
    Heart disease is the biggest killer world-wide, causing a quarter of all deaths. During the past two decades, it has also risen above infectious diseases as the leading cause of years of life lost. Heart failure, characterized by weak pump function of the heart, and disturbances in heart rhythm (arrhythmias) are common and interrelated mechanisms underlying cardiac mortality. Intracellular calcium ions are crucial to contraction and relaxation of the heart muscle, as well as to control of its rhythm. How calcium is handled and regulated is thus essential to normal cardiac function, and disturbances in these processes can have catastrophic consequences. Understanding the mechanisms of these disturbances is important for improving disease prevention, diagnosis, and management. The studies in this thesis focus on two conditions where cardiac calcium handling is impaired. Studies I - III examine the mechanisms of a genetic arrhythmia disease named catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by stress-induced ventricular tachycardia in a structurally normal heart. Study IV investigates cardiac function in a model of another genetic disease, autosomal dominant polycystic kidney disease (ADPKD). This systemic disease mainly affects the kidneys, and the mechanisms of the concomitant decline in cardiac function have thus far remained underinvestigated. We evaluated clinical data on cardiac function of CPVT patients, including 24h electrocardiograms, intracardiac monophasic action potential recordings, and exercise stress tests. We used cell models to study the underlying disease mechanisms in detail. During conditions of stress, CPVT cells showed increased spontaneous and irregular release of calcium from within the intracellular stores through the cardiac ryanodine receptors. These receptors, which function as intracellular calcium release channels, harbor the disease-causing mutation. The spontaneous release of calcium led to changes in the membrane potential of the cells, manifested as afterdepolarizations during the resting phase of the cardiac cycle. These afterdepolarizations were reproduced in the clinical monophasic action potential recordings of CPVT patients, and were shown to trigger arrhythmias in these patients. Changes in intracellular calcium alter the membrane potential, and these changes are reflected on the electrocardiogram. Thus, irregularities that might correspond to those observed in the cell model were then investigated in 24h electrocardiograms of CPVT patients. Increased irregularity of cardiac repolarization was found in the CPVT patients. Such irregularity was greater in the electrocardiograms of CPVT patients with a history of more severe arrhythmic events. Additionally, we found slowed depolarization in response to stress in CPVT cells and patients, suggesting reduced conduction velocity might contribute to an arrhythmic substrate in these patients. Cardiac function in ADPKD caused by mutations in polycystin-2, another intracellular calcium channel, was investigated in a zebrafish model lacking expression of the polycystin-2 protein. The zebrafish lacking polycystin-2 showed signs of heart failure, including reduced cardiac output, edema, and arrhythmias. Hearts, which were then examined in more detail ex vivo, showed impaired cycling of intracellular calcium, which is likely to underlie the cardiac dysfunction observed in vivo. The association of ADPKD with idiopathic dilated cardiomyopathy (IDCM) was examined using the Mayo ADPKD Mutation Database, which contains data on genotyped ADPKD patients. Examination of the ADPKD Database showed IDCM to be very common among ADPKD patients. IDCM was most prevalent in patients with mutations in polycystin-2, suggesting impaired calcium cycling as a potential pathomechanism. Studies I-III shed new light on mechanisms of arrhythmias in CPVT and related conditions, opening the way for future studies on arrhythmia risk and therapeutic evaluation. Furthermore, the results encourage pursuing the novel stem cell models for studying pathomechanisms and therapeutics. Study IV showed an association between ADPKD and IDCM. The zebrafish model suggested impaired calcium cycling as an underlying mechanism, highlighting the usefulness of zebrafish as a model in cardiac research.
  • Hernesniemi, Sari (Helsingin yliopisto, 2012)
    Chronic myeloid leukemia (CML) is a hematologic malignancy that originates from pluripotent hematopoietic stem cells. The genetic abnormality underlying this disease, as well as a subtype of acute lymphoblastic leukemia (ALL), is a translocation between chromosomes 9 and 22, which leads to the formation of the Philadelphia (Ph) chromosome and the oncogenic BCR-ABL1 fusion protein. Targeted inhibition of the BCR-ABL1 protein with imatinib and other specific tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment and is currently regarded as the gold standard of targeted cancer therapy. In this doctoral thesis, different methodological approaches were used to characterize aberrant signaling activities in leukemic and normal cells with the ultimate aim of isolating novel prognostic markers for predicting TKI therapy outcome. First, the molecular mechanism of the disease was investigated in an ALL patient with a translocation between chromosomes 1 and 9. Cytogenetic characterization showed involvement of the ABL1 gene fused to an unknown gene. The RCSD1 gene was selected as a candidate and subsequent molecular dissection confirmed a RCSD1-ABL1 fusion. This novel fusion gene predicts sensitivity to TKI therapy in ALL patients. Second, several phosphoproteins related to immune cell function were analyzed both from the diagnostic phase CML patients and from patients under TKI therapy in order to reveal distinct signaling patterns. A single cell phosphoprotein method based on multiparameter flow cytometry was used to analyze phosphoprotein levels in different cell populations. The responsiveness of myeloid cells to ex vivo cytokine stimulation in diagnostic-phase patients was low, but was normalized in TKI-treated patients. In general, the blood leukocyte subsets responded normally to various cytokine stimulations, which indicated a non-immunosuppressive role for TKIs. This project also led to the development of a software assisted analysis program, which can conduct the whole range of flow cytometry data analysis, thereby diminishing the effort needed for manual cell population gating and interpretation. Lastly, biomarkers for therapy response were identified by analyzing aberrant signaling activities in leukemic cells collected at the time of diagnosis. The analysis was based on a phosphoproteomic array measuring phosphorylation of 46 different kinase targets. Several proteins had aberrant phosphorylation levels in patients with a poor therapy outcome − pSTAT5b being the most prominent. These biomarkers could be useful in guiding therapy selection at the time of diagnosis. In conclusion, the findings imply that TKI therapy responses can be linked to certain biological markers, which can possibly be utilized in clinical applications in the future.
  • Aarnio, Marja-Liisa (1968)
  • Freihoff, Roland (1963)
  • Kemppainen, Lasse (1997)
  • Cleve, Beatrice (1993)
    Dessa fördjupade studier ingick som ett delprojekt i Veterinärmedicinska högskolans studentkårs biståndsprojekt i Etiopien sommaren 1990. Spontana aborter är ett ständigt problem bland kobesättningarna i Etiopien. I detta projekt undersöktes korpå en statlig gard, Stella farm, utanför Etiopiens huvudstad Addis Abeba. Efter uppsamling av data koncentrerades undersökningen tillanalys av fodret i avseende och vitaminer och spårämnen samtsvampgifter. Infektionssjukdomar som beaktades var brucellos,leptospiros och IBR ( Infectious Bovine Rhinotracheitis ).Samtliga laboratorieundersökningar gjordes vid SVA av författaren, förutom foderanalysen som gjordes vid Statensjordbrukskemiska anstalt. Korna var till 86,4 % positiva för IBR, fodret innehöllmykotoxiner och brist på jod och A-vitamin.Undersökningsresultaten har meddelats Etiopiensjordbruksministerium.
  • Väisänen, Heini Elena (Helsingfors universitet, 2010)
    Suomessa tehdään vuosittain noin 10 000 aborttia. Abortinjälkeistä hedelmällisyyttä on suomalaisessa tutkimuksessa tarkasteltu melko vähän etenkin yhteiskuntatieteellisesti, vaikka abortti koskettaa tuhansia naisia vuosittain. Tutkielmani tavoitteena on selvittää, millaista on abortinjälkeinen hedelmällisyyskäyttäytyminen, eli ketkä päätyvät uuteen aborttiin, ketkä synnytykseen ja ketkä eivät tule uudelleen raskaaksi. Tulosten perusteella päätellään, onko abortoivien joukossa erotettavissa ryhmiä, joille abortti voi muodostua yhdeksi ehkäisyn muodoksi ja keille se on kertaluontoinen tapahtuma. Tulokset sidotaan aiempaan teoreettiseen ja empiiriseen hedelmällisyystutkimukseen. Aineisto koostuu raskaudenkeskeytysrekisterin tiedoista vuosilta 2000–2008 ja siihen yhdistetyistä abortoineiden naisten syntymärekisteritiedoista samoilta vuosilta. Tutkielmassa tarkasteltiin niitä 63 763 naista, jotka tekivät seuranta-aikana ensimmäisen aborttinsa. Uuteen aborttiin heistä päätyi 7 743 ja synnytykseen 11 497 abortinjälkeisessä raskaudessaan. Ensimmäisen abortin (eli indeksiabortin) aikaisten taustamuuttujien vaikutusta seuraavan raskauden lopputulokseen analysoitiin elinaikamallinnuksen menetelmin (pääosin Coxin regressio). Lisäksi tarkasteltiin indeksiabortin ja uuden raskauden välillä mahdollisesti muuttuneen parisuhdestatuksen sekä sosioekonomisen aseman vaikutusta hedelmällisyyskäyttäytymiseen logistisen regressioanalyysin avulla. Tulosten avulla oli mahdollista erottaa toisistaan eritavoin abortin jälkeen käyttäytyviä ryhmiä. Uudelleen abortoivat erityisesti nuoret, lapsia jo saaneet, alemmassa sosioekonomisessa asemassa olevat ja sellaiset, joilla ei ollut parisuhdetta. Synnyttämään päätyivät 20–34-vuotiaat, opiskelunsa päättäneet, korkeassa sosioekonomisessa asemassa olevat, lapsettomat ja parisuhteessa olevat. Lisäksi maaseudulla asuminen lisäsi hieman synnytyksen todennäköisyyttä ja mikäli indeksiabortti oli tehty sikiön sairauden perusteella, todennäköisyys synnyttää kasvoi selkeästi. Raskaaksi tulivat harvemmin uudelleen yli 30-vuotiaat, lapsia saaneet ja korkeassa sosioekonomisessa asemassa olevat. Monet heistä olivat lisäksi leskiä tai eronneita. Mikäli indeksiabortin jälkeen opiskelija meni töihin, hänen synnytystodennäköisyytensä kasvoi selkeästi. Samoin kävi, jos indeksiabortin aikaan yksin elänyt muodosti uuden parisuhteen ennen toista raskauttaan. Saatujen tulosten perusteella on erotettavissa ryhmiä, joihin tulisi erityisesti kiinnittää huomiota jo ensimmäisen abortin aikaan, sillä heidän riskinsä abortoida uudelleen on muita korkeampi. Suurin vaikutus oli lapsimäärällä ja parisuhdestatuksella. Sosioekonomisen aseman sekä asuinalueen vaikutus jäi odotettua pienemmäksi, mutta ei kuitenkaan olemattomaksi.
  • Sairanen, Samuli (2013)
    The term "botnet" has surfaced in the media in recent years, showing the complications of manipulation of massive amounts of computers. These zombie computers provide platform for many illegal or otherwise shady actions, like spam mailing and denial of service-attacks. The power of such networks is noticeable on global scale, but what is really known about these networks? Why do they exist in the first place? How are botnets being created today and how they work on a technical level? How is the emergence of mobile internet computing affecting botnet creation and what kind of possibilities does it offer? Goal of this work is to illustrate the history of botnets, understand the structure of botnets, how they are built, and how they affect the whole internet culture. Also the methods for fighting against the threat of botnets are speculated.
  • Korpinen, Tuulikki (1938)
  • Elo, Johanna (Helsingin yliopisto, 2003)
  • Siltavuori, Seppo (1932)
  • García-Matos, Marta (Helsingin yliopisto, 2005)
  • Sivonen, Janne (2001)
    Tutkielma tarkastelee Ruandan konflikteja ja erityisesti vuoden 1994 kansanmurhaa, jossa noin 800 000 tutsia ja maltillista hutua surmattiin muutamassa kuukaudessa. Tutkielman etsii syitä sille, miksi etnonationalistinen hutuvoima-liike onnistui mobilisoimaan merkittävän osan maan hutuväestöstä tutsien vastaisiin väkivaltaisuuksiin vuoden 1994 kansanmurhassa. Suuri osa Ruandan hutuista liittyi pienen eliitin suunnittelemaan tuhoamiskampanjaan etnonationalistisen propagandan lietsomina, vaikkeivät propagandan väittämät vastanneet suurimman osan sosiaalista todellisuutta. Aiheeseen pureudutaan Ruandan konfliktien historiallisen tarkastelun sekä teoreettisen analyysin avulla. Kun vuoden 1994 kansanmurhaa ja siihen johtaneita tapahtumia tarkastellaan valtakunnallisella tasolla, teoreettisena lähtökohtana on Paul Jamesin kansakunnan muodostumisen teoria. Jamesin mukaan kansakunta on abstrakti yhteisö, joka perustuu konkreettisessa elämänpiirissä koettuun sosiaaliseen integraatioon. Stanley J. Tambiahin etnisen väkivallan ritualisoitumista tarkastelevan teorian pohjalta esitetään, että Ruandassa keskeisin konkreetisen elämänpiirin abstraktia hutuyhteisöä luova tekijä on ollut väkivalta ja siihen liittyvät diskurssit. Kun kansanmurhaa analysoidaan ruohonjuuritasolla, väkivaltaan ryhtymisen motiivit osoittautuvat moninaisiksi: ihmiset liittyivät hutunationalismin nimissä tehtyihin väkivaltaisuuksiin omien lähtökohtiensa ja motiiviensa perusteella. Tambiahin ja Jamesin teorioiden soveltaminen Ruandaan osoittaa, miten monimutkaisessa vuorovaikutuksessa kansallisen tason makrokonflikti ja paikallisen tason pienemmät konfliktit voivat keskenään olla. Kun kasvokkaiskontakteihin perustuva sosiaalinen integraatio luo abstrakteja yhteisöjä, ruohonjuuritason tapahtumat voivat olla hyvinkin erilaisia, mutta abstraktin yhteisön tasolla niille annetaan samankaltainen sisältö. Toisaalta konfliktin saamat merkitykset voivat kulkea ylhäältä alaspäin: ruohonjuuritason konfliktien taustalla olevat paikalliset motiivit puetaan tällöin sanoiksi makrotason etnisen konfliktin merkityssisältöjä käyttäen. Tutkielman tärkeimpiä aineistolähteitä ovat ihmisoikeusjärjestöjen ja muiden kansainvälisten järjestöjen Ruandan kansanmurhaa käsittelevät tutkimusraportit, YK:n sotarikostuomioistuimen asiakirjat sekä Ruandasta kirjoitetut etnografiat ja historialliset analyysit.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Korhonen, Silja (The Finnish Forest Research Institute, 2006)
    The purpose of this study was to extend understanding of how large firms pursuing sustained and profitable growth manage organisational renewal. A multiple-case study was conducted in 27 North American and European wood-industry companies, of which 11 were chosen for closer study. The study combined the organisational-capabilities approach to strategic management with corporate-entrepreneurship thinking. It charted the further development of an identification and classification system for capabilities comprising three dimensions: (i) the dynamism between firm-specific and industry-significant capabilities, (ii) hierarchies of capabilities and capability portfolios, and (iii) their internal structure. Capability building was analysed in the context of the organisational design, the technological systems and the type of resource-bundling process (creating new vs. entrenching existing capabilities). The thesis describes the current capability portfolios and the organisational changes in the case companies. It also clarifies the mechanisms through which companies can influence the balance between knowledge search and the efficiency of knowledge transfer and integration in their daily business activities, and consequently the diversity of their capability portfolio and the breadth and novelty of their product/service range. The largest wood-industry companies of today must develop a seemingly dual strategic focus: they have to combine leading-edge, innovative solutions with cost-efficient, large-scale production. The use of modern technology in production was no longer a primary source of competitiveness in the case companies, but rather belonged to the portfolio of basic capabilities. Knowledge and information management had become an industry imperative, on a par with cost effectiveness. Yet, during the period of this research, the case companies were better in supporting growth in volume of the existing activity than growth through new economic activities. Customer-driven, incremental innovation was preferred over firm-driven innovation through experimentation. The three main constraints on organisational renewal were the lack of slack resources, the aim for lean, centralised designs, and the inward-bound communication climate.