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  • Pyysiäinen, Jaana (2003)
    Tutkielmassa tarkasteltiin iäkkään vanhemman hoitamista vuorovaikutuksen näkökulmasta. Tavoitteena oli selvittää hoitojärjestelystä käytyjen neuvottelujen perusteella, millainen on iäkästä vanhempaansa hoitavan liikkumavara vanhemman hoitamisen suhteen. Neuvotteluja tarkasteltiin kahdessa kontekstissa: perheen sisällä ja kunnallisen kotihoidon kanssa Janet Finchin ja Jennifer Masonin (1993) perhevelvollisuusteorian avulla. Heidän mukaansa sitoumukset muotoutuvat ajan kuluessa eksplisiittisissä ja implisiittisissä neuvotteluissa, joissa neuvotellaan myös avun antajan ja saajan vastavuoroisista moraalisista identiteeteistä. Tutkielman pääasiallisena aineistona olivat seitsemän iäkästä vanhempaansa hoitavan tyttären puolistrukturoidut teemahaastattelut. Ennen laadullista analyysiä tarkasteltiin taustateorialle rinnasteisesti iäkästä vanhempaansa hoitavan vuorovaikutusta kunnallisen kotihoidon kanssa valmiin, kvantitatiivisen aineiston analyysin avulla. Taustaempirian analyysimenetelminä käytettiin suoria jakaumia ja ristiintaulukointeja. Kvantitatiivinen tarkastelu myös johdatteli ko. kontekstia koskeviin tutkimuskysymyksiin ja antoi mahdollisuuden valita haastateltavat. Litteroidut haastattelut luokiteltiin Finchin ja Masonin teorian avulla, jolloin huomio keskittyi käytyihin ja käymättömiin neuvotteluihin. Hoitojärjestelystä käydyn vuorovaikutuksen perusteella pyrittiin esittämään tulkinta iäkästä vanhempaansa hoitavalla olevasta liikkumavarasta hoitamisen suhteen. Hoitajaksi päätyminen koettiin luonnollisena ajautumisena. Ajautumisen taustalta löytyivät yksilölle perheen sisällä muodostunut maine ja moraalinen identiteetti. Hoitamisen sitoumuksen muodostuttua liikkumavaraa pystyttiin muovaamaan neuvotteluilla. Liikkumavaraan vaikuttivat ensisijaisesti neuvottelut hoitoa tarvitsevan vanhemman kanssa, ja millä tavoin niissä oli mahdollista käsitellä asioita. Kaikkia asioita ei voitu käsitellä suoraan, ja neuvottelujen keskeisenä periaatteena oli hienovaraisuus. Epäsuorilla neuvotteluilla pyrittiin säilyttämään vanhemmalla riittävä riippumattomuuden tunne sekä etäisyys auttajan ja autettavan välillä. Vanhemman autonomian kunnioittaminen vaikutti myös siihen, ettei kunnallisen kotihoidon ja tyttären välille muodostunut suoraa neuvotteluyhteyttä. Tässä mielessä kotihoidon mukanaolo hoitojärjestelyssä ei aina lisännyt iäkästä vanhempaansa hoitavan liikkumavaraa. Kotihoidon ja omaisen väliselle vuorovaikutukselle ei tarjoutunut luontevaa tilaa. Liikkumavaran käsite sopi hyvin kuvaamaan hoitamisen kokemusta ja yksilöllä olevaa rajallista vapautta määrittää asemansa hoitojärjestelyssä. Keskeistä taustakirjallisuutta olivat Finch, Janet & Mason, Jennifer (1993) Negotiating Family Responsibilities; Qureshi, Hazel & Walker, Alan (1989) The Caring Relationship ja Gothóni, Raili (1991) Omaiset – loppuunpalaneita ihmisiä vai käyttämätön voimavara.
  • Lievonen, Lasse Matti (2013)
    Sopimustoiminnan perustavanlaatuinen lähtökohta kiteytyy sopimusvapauden periaatteeseen. Oikeusvertailevassa kontekstissa on esitetty, että sopimusoikeuden yleinen lojaliteettiperiaate (good faith) voi rajoittaa sopimusvapauden periaatteen sisältöä neuvotteluvaiheessa. Tutkielmassa on selvitetty, miten yleinen lojaliteettivelvollisuus vaikuttaa neuvotteluvastuun arviointiin civil law ja common law -oikeuskulttuureissa. Tutkielman johtopäätelmänä on, että civil law ja common law -oikeusjärjestyksissä vallitsevat erot liittyvät lähinnä argumentaatiotapaan, mutta eivät niinkään neuvotteluvelvollisuuksien konkreettiseen sisältöön. Civil law -oikeusjärjestyksissä tunnettu sopimuksentekotuottamuksen doktriini (culpa in contrahendo) vastaa sisällöllisesti pitkälti common law -oikeusjärjestyksissä tunnettuja oikeussuojakeinoja (promissory estoppel, misrepresentation, unjust enrichment). Universaali lähtökohta on, että neuvottelukumppania suojataan tilanteissa, joissa vastapuoli on synnyttänyt oikeutetun luottamuksen sopimuksen päättämiseen. Myös neuvotteluvaiheen kvalifioituihin väärinkäytöksiin (esim. petollinen harhaanjohtaminen) voidaan puuttua kaikissa kansallisissa oikeusjärjestyksissä. Edellä kuvatun mukaisesti neuvotteluissa tapahtuneisiin väärinkäytöksiin voidaan puuttua kahdessa pääasiallisessa tilanteessa: i) luottamusta sopimuksen päättämiseen on rikottu ja ii) neuvotteluissa on toimittu kvalifioidun petollisesti. Rajat ylittävässä kaupassa joudutaan neuvotteluvastuun sisältö ratkaisemaan YK:n kauppalain ja/tai Unidroit-periaatteiden avulla. Tutkielmassa on pyritty määrittämään YK:n kauppalain tarkkarajaiset soveltamisalueen ulkorajat ja määrittämään, milloin neuvotteluissa tulisi tukeutua YK:n kauppalain normistoon. Tutkielman johtopäätelmänä on esitetty, että YK:n kauppalain avulla pystytään tyhjentävästi ratkaisemaan tilanteet, jotka koskevat luottamusta sopimuksen päättämiseen (etenkin CISG 8(3) ja CISG 16 (2)(b) artiklat). Tällöin ei tulisi myöskään turvautua kansallisen oikeuden doktriineihin, koska YK:n kauppalakia tulisi tulkita sen omista lähtökohdista käsin. Neuvotteluissa tapahtuneet kvalifioidut väärinkäytökset eivät sen sijaan kuulu YK:n kauppalain soveltamisalaan ja näin ollen ne tulisi ratkaista yleisesti hyväksyttyjen kansainvälisten oikeusperiaatteiden avulla. Tutkielmassa on esitetty, että tuomioistuimet voisivat turvautua Unidroit-periaatteisiin, mikäli tavoitteena olisi määritellä kansainvälisessä kaupassa yleisesti hyväksytyt oikeusperiaatteet. Unidroit-periaatteet ovat laajalti hyväksytty oikeudellinen lähde kansainvälisessä kaupassa, ja niissä on myös kielletty neuvotteluvaiheen kvalifioidut väärinkäytökset. Unidroit-periaatteet eivät kuitenkaan tarjoa laintasoista oikeudellista suojaa ja tämän takia neuvotteluosapuolten tulisikin tehdä viittaus periaatteisiin, mikäli niille halutaan antaa selkeä oikeudellinen vaikutus. Tutkielmassa on lisäksi esitetty, että välitystuomioistuimilla olisi laajemmat mahdollisuudet turvautua Unidroit-periaatteisiin, koska välitystuomioistuimilla on lähtökohtaisesti mahdollisuus tukeutua ns. soft law -normistoihin yleisiä tuomioistuimia laajemmassa määrin.
  • Ruotsalainen, Henri (2013)
    Tutkielmassa käsitellään sopimuksen neuvotteluvaiheeseen liittyvää vastuuta voimassa olevan oikeuden ja toisaalta sopimustek-niikan näkökulmasta. Tarkastelu kohdistetaan yrityskaupan valmistelun erityispiirteisiin. Tutkimusaineistona käytetään pääasiassa kotimaista ja muuta pohjoismaista aineistoa, erityisesti oikeustapauksia ja –kirjallisuutta. Huomiota kiinnitetään myös laajemmin oikeusvertailevaan aineistoon, sillä yrityskauppojen sopimuskäytäntö on huomattavan kansainvälistynyttä. Lisäksi tutkielmassa hyödynnetään oikeustaloustieteellisiä reaalisia argumentteja, sillä taloudellisella tehokkuudella voidaan nähdä olevan erityistä merkitystä liiketoimintaympäristössä, kuten juuri yrityskauppojen yhteydessä. Ennen varsinaisten neuvotteluvastuuperusteiden käsittelyä culpa in contrahendo -vastuulle pyritään muodostamaan teoreettinen lähtökohta, jonka valossa neuvottelujen katkeamista jäljempänä tarkastellaan. Vastuun arvioinnissa keskeistä on osapuolen tuot-tamus ja toisen osapuolen luottamus. Tuottamuksen ja luottamuksen välistä suhdetta arvioidaan tutkielmassa neuvotteluvapauden ja neuvottelulojaliteettiperiaatteen avulla. Sopimusvastuu nähdään luottamukseen perustuvana, jolloin neuvotteluvastuukin voi-daan nähdään osana sopimusvastuuta. Sopimusvastuuta ja sopimusneuvotteluja tarkastellaan vaiheittain kehittyvänä prosessina. Tutkielmassa neuvottelut jaetaan sitovuudeltaan kolmeen vaiheeseen, jotka ovat (i) täysi neuvotteluvapaus, (ii) rajoitettu neuvotte-luvapaus sekä (iii) sopimuksentekovelvollisuus. Varsinaisten vastuuperusteiden käsittely aloitetaan yrityskaupan valmistelulle tyypillisistä tekijöistä, jotka vaikuttavat siirtymiseen neuvottelujen sitovuusasteelta toiselle. Tarkastelussa huomioidaan erityisesti yrityskaupan luonne monimutkaisena projektina sekä erilaiset neuvotteluosapuolten käyttämät väli-instrumentit. Monimutkaisten transaktioiden kohdalla vahvana olettamana tavallisesti on, että neuvotteluissa ei synny mitään sitovaa ennen kuin kaikista yksityiskohdista on päästy yksimielisyyteen. Toisaalta erilaiset väli-instrumentit, jotka eivät tavallisesti vielä merkitse täyttä sopimusvastuuta, saattavat rikkoa tämän olettaman. Erityinen merkitys on niin sanotuilla prekontraktuaalisilla sopimuksilla, aiesopimuksilla ja esisopimuksella. Sitovuuden kehittymisen tarkastelun jälkeen huomio kiinnitetään tarkemmin neuvotteluvaiheen velvoitteisiin. Neuvotteluvaiheen velvoitteet jaetaan tutkielmassa negatiivisiin ja positiivisiin lakimääräisiin velvoitteisiin sekä osapuolten keskenään sopimiin velvoit-teisiin. Velvoitteita tarkastellaan suhteessa neuvottelujen vaiheeseen. Osa velvoitteista pysyy voimassa vielä neuvottelujen katket-tuakin. Yrityskaupoissa erityisen merkityksellisiä negatiivisia velvoitteita ovat salassapito- ja hyödyntämiskielto. Positiivisista vel-voitteista tärkein on tiedonantovelvollisuus, jonka todetaan yrityskaupoissa olevan hieman kapeampi kuin tavanomaisessa irtaimen kaupassa. Lakimääräisten velvoitteiden täsmentymättömyyden vuoksi osapuolten keskenään disponoimat velvoitteet saavat eri-tyistä merkitystä. Yrityskaupoissa tärkeimmät sovitut velvoitteet liittyvät salassapidon täsmentämiseen, neuvottelueksklusiviteettiin sekä erilaisiin kaupan strukturointeihin huutokaupan tyylisiksi. Tärkein neuvottelujen katkeamisesta aiheutuva oikeusseuraamus on vahingonkorvausvastuu, joka yleensä mitataan niin sanotun negatiivisen sopimusedun mukaisesti. Korvattavaksi tulee yleensä välittömiä vahinkoja, mutta myös välilliset vahingot voidaan kor-vata. Poikkeuksellisesti kysymykseen saattaa tulla myös positiivisen sopimusedun mukainen vahingonkorvaus tai jopa luontois-suoritusvastuu. Yrityskaupoissa näin ankara vastuu saattaa käytännössä liittyä lähinnä kaupan strukturointeihin.
  • Heikkilä, Tero (Helsingin yliopisto, 2003)
  • Juutistenaho, Sari (Helsingin yliopisto, 2010)
    Cord blood is a well-established alternative to bone marrow and peripheral blood stem cell transplantation. To this day, over 400 000 unrelated donor cord blood units have been stored in cord blood banks worldwide. To enable successful cord blood transplantation, recent efforts have been focused on finding ways to increase the hematopoietic progenitor cell content of cord blood units. In this study, factors that may improve the selection and quality of cord blood collections for banking were identified. In 167 consecutive cord blood units collected from healthy full-term neonates and processed at a national cord blood bank, mean platelet volume (MPV) correlated with the numbers of cord blood unit hematopoietic progenitors (CD34+ cells and colony-forming units); this is a novel finding. Mean platelet volume can be thought to represent general hematopoietic activity, as newly formed platelets have been reported to be large. Stress during delivery is hypothesized to lead to the mobilization of hematopoietic progenitor cells through cytokine stimulation. Accordingly, low-normal umbilical arterial pH, thought to be associated with perinatal stress, correlated with high cord blood unit CD34+ cell and colony-forming unit numbers. The associations were closer in vaginal deliveries than in Cesarean sections. Vaginal delivery entails specific physiological changes, which may also affect the hematopoietic system. Thus, different factors may predict cord blood hematopoietic progenitor cell numbers in the two modes of delivery. Theoretical models were created to enable the use of platelet characteristics (mean platelet volume) and perinatal factors (umbilical arterial pH and placental weight) in the selection of cord blood collections with high hematopoietic progenitor cell counts. These observations could thus be implemented as a part of the evaluation of cord blood collections for banking. The quality of cord blood units has been the focus of several recent studies. However, hemostasis activation during cord blood collection is scarcely evaluated in cord blood banks. In this study, hemostasis activation was assessed with prothrombin activation fragment 1+2 (F1+2), a direct indicator of thrombin generation, and platelet factor 4 (PF4), indicating platelet activation. Altogether three sample series were collected during the set-up of the cord blood bank as well as after changes in personnel and collection equipment. The activation decreased from the first to the subsequent series, which were collected with the bank fully in operation and following international standards, and was at a level similar to that previously reported for healthy neonates. As hemostasis activation may have unwanted effects on cord blood cell contents, it should be minimized. The assessment of hemostasis activation could be implemented as a part of process control in cord blood banks. Culture assays provide information about the hematopoietic potential of the cord blood unit. In processed cord blood units prior to freezing, megakaryocytic colony growth was evaluated in semisolid cultures with a novel scoring system. Three investigators analyzed the colony assays, and the scores were highly concordant. With such scoring systems, the growth potential of various cord blood cell lineages can be assessed. In addition, erythroid cells were observed in liquid cultures of cryostored and thawed, unseparated cord blood units without exogenous erythropoietin. This was hypothesized to be due to the erythropoietic effect of thrombopoietin, endogenous erythropoietin production, and diverse cell-cell interactions in the culture. This observation underscores the complex interactions of cytokines and supporting cells in the heterogeneous cell population of the thawed cord blood unit.
  • Veijola, Lea (Helsingin yliopisto, 2007)
    Aims: Helicobacter pylori infection, although the prevalence is declining in Western world, is still responsible for several clinically important diseases. None of the diagnostic tests is perfect and in this study, the performance of three stool antigen tests was assessed. In areas of high H. pylori prevalence, the definition of patients with the greatest benefit from eradication therapy may be a problem; the role of duodenal gastric metaplasia in categorizing patients at risk for duodenal ulcer was evaluated in this respect. Whether persistent chronic inflammation and elevated H. pylori antibodies after successful eradication are associated with each other or with atrophic gastritis, a long term sequelae of H. pylori infection, were also studied. Patients and methods: The three stool antigen tests were assessed in pre- and post-eradication settings among 364 subjects in two studies as compared to the rapid urease test (RUT), histology, culture, the 13C-urea breath test (UBT) and enzyme immunoassay (EIA) based H. pylori serology. The association between duodenal gastric metaplasia with duodenal ulcer was evaluated in a retrospective study including 1054 patients gastroscopied due to clinical indications and 154 patients previously operated for duodenal ulcer. The extent of duodenal gastric metaplasia was assessed from histological specimens in different patient groups formed on the basis of gastroscopy findings and H. pylori infection. Chronic gastric inflammation (108 patients) and H. pylori antibodies and serum markers for atrophy (77 patients) were assessed in patients earlier treated for H. pylori. Results: Of the stool antigen tests studied, the monoclonal antibody-based EIA-test showed the highest sensitivity and specificity both in the pre-treatment setting (96.9% and 95.9%) and after therapy (96.9% and 97.8%). The polyclonal stool antigen test and the in-office test had at baseline a sensitivity of 91% and 94%, and a specificity of 96% and 89%, respectively and in a post-treatment setting, a sensitivity of 78% and 91%, and a specificity of 97%, respectively. Duodenal gastric metaplasia was strongly associated with H. pylori positive duodenal ulcer (odds ratio 42). Although common still five years after eradication, persistent chronic gastric inflammation (21%) and elevated H. pylori antibodies (33%) were neither associated with each other nor with atrophic gastritis. Conclusions: Current H. pylori infection can feasibly be diagnosed by a monoclonal antibody-based EIA test with the accuracy comparable to that of reference methods. The performance of the polyclonal test as compared to the monoclonal test was inferior especially in the post-treatment setting. The in-office test had a low specificity for primary diagnosis and hence positive test results should probably be confirmed with another test before eradication therapy is prescribed. The presence of widespread duodenal gastric metaplasia showed promising results in detecting patients who should be treated for H. pylori due to an increased risk of duodenal ulcer. If serology is used later on in patients with earlier successfully treated for H. pylori, it should be taken into account that H. pylori antibodies may persist elevated for years for unknown reason. However, this phenomenon was not found to be associated with persistent chronic inflammation or atrophic changes.
  • Liu, Liwei (Helsingin yliopisto, 2014)
    Cyanobacteria are one of the most widespread microorganisms on earth, and they are found in almost all ecosystems, from fresh and marine water to terrestrial environments. Cyanobacteria received a great deal of attention as prolific producers of bioactive secondary metabolites. The aim of this study was to screen and characterize novel bioactive natural products, which present biological activity against acute myeloid leukemia (AML) cells, trypsin, and hepatotoxin microcystin/nodularin, from cyanobacteria isolated from different habitats. Of 40 cyanobacteria strains isolated from the Baltic Sea shore and lichen symbiosis were used to look for anti-cancer compounds which could induce apoptosis of AML cells. Half of these cyanobacteria strains contain apoptosis-inducing anti-AML activity, and seven cell extracts contain potent apoptosis-induced activities against AML. Two of apoptogens were confirmed to be new variants of hassallidin and scytophycin. Cyanobacteria produce a plethora of serine protease inhibitors with a broad range of chemical structures. Nostosins, new trypsin inhibitors, were discovered through the analysis of secondary metabolites in methanol extracts of Nostoc sp. FSN. The data showed that they were linear peptides with three residues: Hhpba, L-Ile and L-argininal/argininol. Nostosin A and B inhibited trypsin with IC50 values of 0.35 μM and 55 μM, respectively. Computer docking data indicated that the argininal aldehyde and guanidino groups played the most crucial role in the efficient inhibition of trypsin. The bloom-forming cyanobacterium Nodularia spumigena has been reported to produce several bioactive peptides. In this study, Nodularia spumigena strains from the Baltic Sea were discovered to produce new hybrid peptides named as pseudoaeruginosins. Because of the low abundance in cyanobacteria strains, pseudoaeruginosins were chemically synthesized and the structure was confirmed with LC-MS and NMR. Pseudoaeruginosins contained all the structure blocks of aeruginosin NAL2 except that the Choi was replaced by 4-methylproline (4-mPro), which is a specific subunit of spumigins in N. spumigena. The aldehyde group containing pseudoaeruginosin NS1 exhibited IC50 of 0.19 μM against porcine trypsin. The biosynthesis of pseudoaerugnosins was proposed to be a joint action of aeruginosin and spumigin biosynthesis pathways in N. spumigena. 4-mPro is a rare non-proteinogenic amino acid, which has been found in a small number of bioactive compounds identified from cyanobacteria. A combination of PCR and LC-MS were used to screen 116 cyanobacteria strains for the production of 4-mPro. A total of 12 strains were confirmed to produce 4-mPro, and eleven new cyclic peptides belonging to two groups were identified from two Nostoc spp. XPORK 5A and UK2aImI strains, respectively. Among 11 peptides, the tested five could inhibit the organic anion transporters OATP1B1/B3 to block the induction of apoptosis of hepatocytes by microcystin/nodularin. In this research, a total of two new trypsin inhibitors and five new cyclic peptides with the antitoxic bioactivity against microcystin/nodularin were identified. It was shown that cyanobacteria from both marine and terrestrial environments are a good resource for discovering new bioactive compounds. These findings increased the diversity of bioactive secondary metabolites characterized from cyanobacteria and provide new leads for drug research.
  • Haimila, Sanna (2007)
    This paper examines the question of when employees become entrepreneurs from an economic theory perspective. It focuses on new company formation as a decision between spin-out, spin-off or internal venture, especially from employee’s point of view. It addresses the question of how pre-entry organizational structures and availability of outside financing influence both employee and company decisions, taking into account the fundamental questions of when employees generate innovations, how companies react to them, and whether they are eventually developed inside or outside the company. The starting point is the situation when an employee has a new business idea while working in a company as an employee. It is also assumed that the idea or innovation is out side employer company’s core business. The question is, under what circumstances does the employee start a new business. Intellectual property right regime influences the outcome, but not so that it pre-determines the outcome. This paper will be based mainly on the work of Klepper, Anton, Yao and Hellman. Anton and Yao’s (1995) and Klepper’s (2001) work form a base for the economical approach on the formation of spin-outs and spin-offs. Anton and Yao’s work focuses on inventions that don’t require much start up capital and for which property rights are very weak or missing all together. In such settings, the employee will sometimes form a new company even though joint profits would have been larger had the invention been developed with the original company. They study the incentives faced by an employer and an employee when the employee privately discovers a significant invention. Most of the definitions of new entrants and employee motivations in this thesis are adaptations of Klepper’s previous work. Besides the work of Anton and Yao, this thesis is based on Hellman’s model on new company formation (Hellman; 2001). Hellman has combined different approaches in his paper, by forming a model that is based on four main elements; Alternative regimes of intellectual property rights, differences in the entrepreneurial environment, endogenous corporate strategy and employee-driven innovations. The model aims to explain why some companies let their employees go, others develop their innovations internally, turning employees into intrapreneurs, while some use their employees’ innovations to create spin-offs Hellman (2002). Helman’s paper differs from most of the other previous work in that it considers a larger set of development alternatives, explaining spin-outs (voluntary or not, with or without intellectual property rights), internal ventures, spin-offs, and even refusals to develop an innovation. The analysis does not rely on incomplete contracts, but instead uses a multi-task incentive framework to characterize the employee’s incentive problem. Most importantly, Hellman’s paper introduces corporate strategy into the analysis. This approach builds on the work by Rotemberg and Saloner (1994), who examine the benefits of narrow business strategy. Some other aspects of spin-off and spin-out motives are visited briefly in this paper.
  • Haimila, Sanna (2007)
    Tämä tutkielma pyrkii selvittämään mitkä seikat voimakkaimmin vaikuttavat työntekijän päätökseen jättää työpaikkansa ja ryhtyä yrittäjäksi vaihtoehtona yhteistyölle työnantajayrityksen (emoyhtiö) kanssa. Tutkielma keskittyy asetelmaan jossa työntekijä keksii liikeidean työskennellessään toisen yrityksen (emoyhtiö) palveluksessa. Uusi yritys (spin-out) perustetaan työntekijän toimesta vaihtoehtona innovaation sisäiselle kehittämiselle ja kaupallistamiselle emoyhtiössä, tai emoyhtiön perustamalle uudelle yritykselle (spin-off). Oletus on, että työntekijän isea tai innovaatio ei liity suoraan yrityksen ydinliiketoimintaan, mutta yrityksen on kuitenkin mahdollista hyödyntää innovaatio omassa liiketoiminassaan. Tutkielma perustuu pääasiassa Klepperin, Antonin, Yaon ja Hellmanin aikaisempaan työhön. Antaonin ja Yaon (1995) sekä Klepperin (2001) työt muodostavat perustan taloudelliselle lähestymistavalle spin-out ja spin-off yritysten synnyn analysoinnille. Antonin ja Yaon työ keskittyy innovaatioihin joidenka kaupallistaminen ei riipu voimakkaasti ulkopuolisen pääoman saannista ja joidenka osalta omistusoikeudet ovat heikosti suojattu. Tällaisessa tilanteessa työntekijä usein päätyy perustamaan uuden yrityksen siitäkin huolimatta, että yhteenlaskettu tuotto olisi selvästi suurempi tilanteessa jossa innovaatio kaupallistetaan yhteistyössä emoyhtiön kanssa. Antonin ja Yaon malliin perustuen tutkielma selvittää insentiivejä sekä työntekijän että työnantajan näkökulmasta tilanteessa jossa työntekijällä on hallussaan arvokkaaksi oletettu innovaatio. Loppuosa perustuu Hellmanin malliin uusien yritysten sytymisestä neljän muuttujan kautta. Mallissa käytettävät muuttujat ovat immateriaaliset omistusoikeudet, toimintaympäristö yrittäjyyden näkökulmasta, yrityksen strategia sekä työntekijöistä lähtevät innovaatiot ja niiden synty. Mallin avulla tutkielma selittää miksi yritykset ja työntekijät päätyvät erilaisiin ratkaisuihin innovaation kaupallistamisen suhteen. Malli ei perustu epätäydellisiin sopimuksiin vaan selittää työntekijän ja emoyhtiön valintaongelmaa toimintaympäristön ja yrityksen startegian kautta.
  • Sakko, Arto (Helsingin yliopisto, 2011)
    Inelastic x-ray scattering spectroscopy is a versatile experimental technique for probing the electronic structure of materials. It provides a wealth of information on the sample's atomic-scale structure, but extracting this information from the experimental data can be challenging because there is no direct relation between the structure and the measured spectrum. Theoretical calculations can bridge this gap by explaining the structural origins of the spectral features. Reliable methods for modeling inelastic x-ray scattering require accurate electronic structure calculations. This work presents the development and implementation of new schemes for modeling the inelastic scattering of x-rays from non-periodic systems. The methods are based on density functional theory and are applicable for a wide variety of molecular materials. Applications are presented in this work for amorphous silicon monoxide and several gas phase systems. Valuable new information on their structure and properties could be extracted with the combination of experimental and computational methods.
  • Korkea-aho, Emilia (2011)
    The dissertation examines the role of the EU courts in new governance. New governance has raised unprecedented interest in the EU in recent years. This is manifested in a plethora of instruments and actors at various levels that challenge more traditional forms of command-and-control regulation. New governance and political experimentation more generally is thought to sap the ability of the EU judiciary to monitor and review these experiments. The exclusion of the courts is then seen to add to the legitimacy problem of new governance. The starting point of this dissertation is the observation that the marginalised role of the courts is based on theoretical and empirical assumptions which invite scrutiny. The theoretical framework of the dissertation is deliberative democracy and democratic experimentalism. The analysis of deliberative democracy is sustained by an attempt to apply theoretical concepts to three distinctive examples of governance in the EU. These are the EU Sustainable Development Strategy, the European Chemicals Agency, and the Common Implementation Strategy for the Water Framework Directive. The case studies show numerous disincentives and barriers to judicial review. Among these are questions of the role of courts in shaping governance frameworks, the reviewability of science-based measures, the standing of individuals before the courts, and the justiciability of soft law. The dissertation analyses the conditions of judicial review in each governance environment and proposes improvements. From a more theoretical standpoint it could be said that each case study presents a governance regime which builds on legislation that lays out major (guide)lines but leaves details to be filled out at a later stage. Specification of detailed standards takes place through collaborative networks comprising members from national administrations, NGOs, and the Commission. Viewed this way, deliberative problem-solving is needed to bring people together to clarify, elaborate, and revise largely abstract and general norms in order to resolve concrete and specific problems and to make law applicable and enforceable. The dissertation draws attention to the potential of peer review included there and its profound consequences for judicial accountability structures. It is argued that without this kind of ongoing and dynamic peer review of accountability in governance frameworks, judicial review of new governance is difficult and in some cases impossible. This claim has implications for how we understand the concept of soft law, the role of the courts, participation rights, and the legitimacy of governance measures more generally. The experimentalist architecture of judicial decision-making relies upon a wide variety of actors to provide conditions for legitimate and efficient review.
  • Kluger, Nicolas (Helsingin yliopisto, 2015)
    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene located on chromosome 21 (21q22.3). AIRE deficiency causes a loss in central immune tolerance, leading to the failure to eliminate autoreactive T cells in the thymus and allowing their escape to the periphery. Because of a founder effect, APECED is particularly prevalent in Finland (1/25,000) but is observed worldwide with variable prevalence. APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine autoimmune diseases such as primary hypoparathyroidism, adrenal insufficiency, primary hypogonadism, type 1 diabetes, hypothyroidism, and hypophysitis. They may also develop additional nonendocrine autoimmune diseases, such as alopecia areata/totalis, vitiligo, gastro-intestinal (GI) diseases, keratitis or tubulointerstitial nephritis (TIN). In addition, the patients typically develop a variety of serum tissue-specific autoantibodies, which are predictive of the development of autoimmune disease and anticytokine antibodies such as those against type I interferons and Th17-related interleukin IL-17 and IL-22. The aim of this thesis was to study such manifestations of APECED that have not been well characterized before and also, to study health-related quality of life among Finnish APECED and Addison s disease/APS2 patients. We evaluated the clinical GI features and searched for novel markers of GI dysfunction in a Finnish cohort of 31 APECED patients. The main upper GI symptoms were dysphagia and retrosternal pain (45%) and the lower GI symptoms were constipation (48%), diarrhoea (45%) and malabsorption (16%). Previously, L-amino-acid decarboxylase (AADC) and tryptophan hydroxylase type 1 (TPH-1) antibodies have been demonstrated in APECED. AADC antibodies were found in 51% and TPH-1 antibodies in 39% of all patients. Also, a T cell response to AADC was detected in 43%. One third of the patients had autoimmune enteropathy (AIE)-related 75 kDa antigen (AIE-75, 33%) and villin (29%) autoantibodies, and antibodies against brush borders and Paneth cells (PCs) were detected in 29% and 20%, respectively. Mucosal intestinal IL-17 expression was decreased or negative in 77% of the intestinal samples. Duodenal chromogranin A and serotonin expression was absent or decreased in 50% and 66% of the patients, respectively. Of the clinical symptoms, constipation correlated with negative serotonin staining (p less than 0.05) and with AADC antibodies (p = 0.019). Importantly, we found a correlation between autoantibodies against AADC, which are critical for serotonin and DOPA synthesis, and constipation. Constipation was also associated with a lack of serotonin expression in the enteroendocrine cells (EECs). Paneth cells (PCs) were lacking in the duodenum in 20% of our intestinal samples, even though this was not associated with GI symptoms. In this Finnish APECED patient cohort, 17% (5/30) had moderate-to-severe renal failure, including 10% (3/30) with TIN requiring transplantation, haemodialysis or immunosuppressive treatment. However, the latter did not seem to be efficient in controlling disease progression. All 3 patients with TIN had circulating antibodies against the distal part of the nephron, as did 30% of all cohort cases. The pathogenic relevance of such circulating antibodies is still unclear. The immunological basis of hypoparathyroidism in APECED was explored by studying circulating calcium-sensing receptor (CaSR) and NALP5 antibodies. Although they were detected in 16 of 44 (36%) and 13 of 44 (30%) patients, respectively, we failed to find any clinically relevant statistical association. These APECED patients did not present circulating antibodies for other autoimmune diseases such as rheumatoid arthritis, celiac disease, bullous pemphigoid or pemphigus vulgaris. Some patients had antinuclear antibodies at a low-titre without clinical significance. Secondly, we evaluated the health-related quality of life among Finnish APECED and Addison s disease/APS2 patients and sought to determine which factors may predict a possible impairment. Using health-related quality of life (HRQoL) questionnaires for APECED (SF-36) and Addison s disease/APS2 patients (SF-36, 15D), we indeed observed impaired HRQoL. For the APECED patients, general health, emotional well-being and energy/vitality were the most diminished aspects of HRQoL. Among the patients with Addison s disease/APS2, compared to a large control population, physical or emotional role functioning, energy/vitality and general health were most affected. Discomfort and symptoms, vitality, and sexual activity were the most affected dimensions of the 15D scores. Affiliation with a patients association, female gender, the presence of non-APS2 inflammatory comorbidities, lower educational level and a longer disease duration were independent predictors of impaired HRQoL in these patients. Taken together, the results of this thesis show that APECED patients are genetically prone to develop autoantibodies to a multitude of tissue antigens but are still tolerant to some common autoantigens. The true clinical and biological relevance of these circulating autoantibodies has not yet been elucidated, and it is possible that they are only a reflection of T cell-mediated immunity. They may, however, have a cumulative effect and clinical disease may arise only in patients with a combination of circulating antibodies, as seen in diabetes type 1. This may explain why we failed to find any association between any single type of antibody and a given symptom. For the lower GI track manifestations, we hypothesise a cumulative effect of the autoimmunity directed against both the enteroendocrine cells and the Paneth cells, leading to a dysfunction in both the secretion of serotonin in the gut and the secretion of antimicrobiobial defensins. Such a disturbance would have an effect on the gut microbiota. The question of whether the neutralising antibodies against cytokines may have a paradoxical protective effect is open to debate. Lastly, despite having a high number of manifestations, patients with APECED seem to cope with their disease. Patients with Addison s disease have significantly impaired HRQoL compared to the general population.
  • Lilius, Tuomas (Helsingin yliopisto, 2014)
    Opioid analgesics are effective in relieving acute and chronic pain. However, adverse effects and the development of opioid dependence and tolerance may restrict the use of opioids and result in inadequate pain relief. The effects of four structurally and functionally different drugs already on the market, ibudilast, atipamezole, spironolactone, and ketamine, were studied in coadministration with morphine, the prototypical mu-opioid receptor agonist. Experiments were conducted using thermal and mechanical tests of nociception in male Sprague-Dawley rats. Morphine tolerance was produced during four days by subcutaneous or intrathecal delivery of morphine. Drug and metabolite concentrations were measured using high-pressure liquid chromatography-tandem mass spectrometry. The objective of the thesis study was to search for potential drugs to augment morphine antinociception and prevent opioid tolerance. Ibudilast, a phosphodiesterase and macrophage inhibitory factor inhibitor, had transient sedative effects, but it restored the antinociceptive effect of morphine in morphine-tolerant rats after single and repeated administration. It did not prevent the development of opioid tolerance. Atipamezole, an alpha-2-adrenoceptor antagonist used for the reversal of sedation in animals during anesthesia, was effective in augmenting intrathecal morphine antinociception in both opioid-naïve and opioid-tolerant animals. These effects were observed at doses lower than those required for the antagonism of alpha-2-adrenoceptors. In subcutaneous administration, low doses of atipamezole did not influence morphine antinociception. The mineralocorticoid receptor antagonist spironolactone dose-dependently enhanced morphine antinociception. This effect was mediated via the increased access of morphine to the central nervous system by the inhibition of the efflux protein P-glycoprotein. Spironolactone did not inhibit the metabolism of morphine to the pronociceptive metabolite morphine-3-glucuronide, and it did not prevent the development of opioid tolerance. The effects of ketamine in augmenting opioid analgesia in tolerance are thought to result from a beneficial pharmacodynamic interaction. When acute ketamine was administered to rats under chronic morphine treatment, the brain concentrations of morphine, ketamine and norketamine were increased compared with the situation where either morphine treatment or acute ketamine were administered alone. The results indicate a potentially beneficial pharmacokinetic interaction between the two drugs. The results of the thesis study demonstrate that ibudilast and atipamezole modulate nociception at systemic and spinal levels in preclinical models of pain, and they may prove advantageous as an adjuvant to opioid therapy. Spironolactone had a pharmacokinetic interaction with morphine, leading to increased morphine concentrations in the central nervous system. Ketamine, a drug used for the treatment of opioid tolerance in cancer patients, may undergo previously unrecognized beneficial pharmacokinetic interactions with morphine.
  • Savolainen, Marja (Helsingin yliopisto, 2008)
    There is a growing interest in the amorphous state in the field of pharmaceutics. The amorphous state is a high energy state and thus, it offers one possible solution to overcome the poor water solubility problem related to many drug molecules. Amorphous material can be created during several pharmaceutical processing steps both unintentionally as well as intentionally. Therefore, there is a need for techniques that can be used to obtain more information about the amorphous state as well as to monitor process induced changes associated with it. The aim of this thesis was to combine spectroscopic techniques with multivariate data analysis tools to gain molecular level understanding of the differences in the amorphous state caused by preparation method and the initial polymorphic form used to prepare the amorphous sample. The same techniques were used to obtain information about the solid-state transformations that could occur during the lifecycle of an amorphous drug, from preparation with different processing steps to storage and dissolution testing. Vibrational spectroscopy techniques combined with multivariate data analysis were well suited for the analysis of amorphous or partly amorphous systems. They also enabled quantification of the amorphous form in presence of several different solid-state forms. However, the major source of error was related to sampling and, thus, systems where the sampling area is increased for example by rotating the sample, are of great benefit. The preparative technique as well as the original polymorphic form of the drug used to prepare the amorphous sample influenced the amorphous state. Molecular level differences were noted in the amorphous state. In particular, amorphous material obtained through a solid-state transition resembled the original crystalline form more closely. Principal component analysis could be used to screen for these molecular level differences and give an indication of stability differences already on the day of preparation. The solid-state transitions related to amorphous state that occur during processing, storage or dissolution testing, were monitored and quantified successfully with both NIR and Raman spectroscopy using multivariate data analysis tools. In situ Raman spectroscopy offered a valuable tool for a better understanding of the phenomena that occur during dissolution.
  • Gylfe, Alexandra (Helsingin yliopisto, 2014)
    Colorectal cancer (CRC) is the third most common cancer, and the second most common cause of cancer mortality. The aim of this thesis work was to gain novel insight into the molecular mechanisms behind CRC predisposition, as well as tumor progression and development. Microsatellite instability (MSI) arises due to a defective mismatch repair system and is characteristic for a subset of all CRCs. Here, we aimed to identify novel MSI target genes with potential oncogenic effects. We characterized all genes overexpressed in MSI CRCs and predicted to escape nonsense-mediated decay when mutated. The mitotic checkpoint kinase TTK was identified with protein-elongating mutations in 59% of MSI CRCs. TTK has an essential role in spindle assembly checkpoint (SAC) signaling, however, the mutated protein did not show SAC weakening. While no evidence of oncogenic mechanisms was observed, the high mutation frequency of TTK argues for biological significance. In another screening effort on MSI CRCs, we sought to identify novel oncogenes with activating hotspot mutations. The exomes of 25 tumor and respective healthy colon tissues were sequenced. A total of 15 candidate oncogenes with hotspot mutations were identified. Three genes, ZBTB2, PSRC1 and RANBP2, displayed hotspot mutations also in the validation set of 86 MSI CRCs. Interestingly, the CRC-associated mutant form of ZBTB2 increased cell proliferation. Additional work is needed to further clarify the role of the identified somatic mutations in CRC tumorigenesis. The candidate oncogenes identified in this thesis work might be used to develop personalized tumor profiling and therapy. Inherited susceptibility is estimated to be involved in approximately one-third of all CRCs. However, the great majority of inherited CRC susceptibility remains still molecularly unexplained. A recent systematic sequencing study on CRC reported a set of somatically mutated genes, termed candidate cancer (CAN) genes. We examined the mutational profiles of 15 top-ranked CAN genes for somatic mutations as well as for germline variants in 45 familial CRC cases. In our tumor set, six of the CAN genes were somatically mutated. In germline, three private missense variants were identified in CSMD3, EPHB6 and c10orf137. In another effort, we exome sequenced 96 independent cases with familial CRC. We identified 11 novel candidate CRC susceptibility genes with rare putative LoF variants. Seven loss-of-heterozygosity events, involving four genes, were observed in the data. In each occasion, the losses targeted the wild-type allele (P=0.0078), providing further support that true culprits are among the eleven genes. This study provides an interesting set of candidate predisposing genes, which might explain a subset of common familial CRC. The identified germline variants need to be validated in larger sample sets to provide firm evidence for disease predisposition. Additional work is also needed to characterize the detailed functional and clinical relevance of the identified candidate CRC predisposing genes. This information, then, can ultimately be translated into tools for cancer prevention and early diagnosis in individuals carrying true predisposition alleles.
  • Peltonen, Iida (Helsingin yliopisto, 2012)
    Prolyl oligopeptidase (PREP, also known as POP; EC 3.4.21.26) is an 80-kDa serine protease hydrolyzing peptides smaller than 30-mer at the carboxyl side of an internal proline-residue. PREP is widely distributed in the body and the cytosolic form is abundantly expressed also in the brain. Several neuropeptides have been suggested to be hydrolyzed by PREP, such as arginine-vasopressin (AVP), oxytocin and substance P (SP), through which PREP has been connected to central nervous system (CNS) functions including learning, memory and mood. However, the break-down of these peptides by PREP has not been conclusively demonstrated in vivo. One of the major criticisms against the neuropeptide theory has been the different locations of intracellular PREP and the mainly extracellular neuropeptides. Although PREP has mostly been studied as a neuropeptide-cleaving enzyme, there are also other connections between PREP and brain diseases, such as the altered levels of PREP in the plasma of patients with CNS disorders and the location of PREP in neurons connected to important brain functions. Recent studies show that PREP may have effects on intracellular protein aggregation via protein-protein interactions. The purpose of this study was to find novel actions and elucidate the relevance of proposed physiological roles of PREP in the rodent brain using different neurochemical and behavioural methods. Brain penetrating PREP inhibitors were used as tools in many of the studies. First, we studied the PREP inhibition capabilities of common psychoactive drugs. Since the pathophysiology of CNS diseases is not fully understood, we tested whether PREP could be a physiological target for these compounds. Second, we examined the colocalization and interaction of PREP with several neurotransmitter systems by lesioning the major nuclei of these transmitters with neurotoxins and then studying the effects of the lesions on PREP activity and immunoreactivity in the respective projection areas. Third, the colocalization and functional interaction of PREP with neurotensin and its receptor NTS1 were studied in the midbrain dopaminergic pathways. Finally, the effect of PREP inhibition on behaviour was tested in animal models of memory, locomotor activity and Parkinson s disease. We found that psychoactive compounds did not considerably inhibit PREP at concentrations achieved in the human therapy. Lesioning of the major neurotransmitter nuclei did not affect PREP activity or immunoreactivity in the projection areas indicating that PREP is not present in the long projection neurons or not connected to their functions. PREP was highly colocalized with neurotensin and NTS1 in the ventral tegmental area (VTA) and with NTS1 in the substantia nigra (SN). In addition, PREP inhibitor was shown to increase the dopamine levels in the SN and VTA in a NTS1-dependent manner. We found also that PREP inhibition increases locomotor activity in rats, but does not improve memory or affect rotational behaviour in a rat model of Parkinson s disease. Conclusively, although the precise role of PREP in the brain remains unclear, our studies substantiated the view that the major physiological role for PREP in the brain is not the improvement of memory. Interestingly, our results suggested that PREP may be involved in motor functions and in the neurotensin-mediated dopaminergic signalling in the SN and VTA through intracellular mechanisms.
  • Wirén, Sini (2013)
    On the basis of technological advances, changing economic conditions and heightened audience expectations for openness and credibility, it has been suggested that transparency should be a new ethical norm for professional online journalism. While theoretical knowledge on this topic is constantly expanding, comprehensive empirical analysis of the practical implementation of transparency measures in news production is still rather scarce, particularly in Finland. To fill this gap in the existing research, this study focuses on transparency in the content of ten leading news websites in Finland. The content is examined with a mixed-methods approach that incorporates both a quantitative and a qualitative analysis. While the quantitative analysis examines a total of 70 front-page articles from each of these news websites with a focus on systematic techniques that reflect transparency, the qualitative analysis scrutinizes these websites in their entirety by concentrating on the larger structures and elements that foster transparency through disclosure of information and supporting audience participation in news production. The results indicate that the level of transparency in the leading online media sources is still relatively low, and that there are no significant differences in transparency measures between the different kinds of mainstream news outlets, although certain techniques seem to be more popular in the tabloid media and others are more widely used by online-only or public service media. As practicing editorial and journalistic transparency does not usually require large financial investments, or involve legal restrictions, the discussion suggests that the main limitations for the utilization of transparency measures are the lack of audience demand on one hand and attitudinal resistance from the media professionals and organisations on the other. This study manages to add new knowledge to prior research on this topic by providing a comprehensive account of both the level and the nature of media transparency. At the same time, it clearly indicates that both transparency and online news publishing are such multi-dimensional and constantly evolving matters that comprehensive measurement of their prevalence would require much further research through a more diverse methodology. In addition to its academic contribution, this study introduces different transparency techniques that would benefit journalism practitioners. It also focuses the attention of consumers on the quality of online journalism and provides them with comparable information on the performance of different news outlets with regards to openness and public participation.
  • Tigerstedt, Nina-Maria (Helsingin yliopisto, 2009)
    Vascular intimal hyperplasia is a major complication following angioplasty. The hallmark feature of this disorder is accumulation of dedifferentiated smooth muscle cells (SMCs) to the luminal side of the injured artery, cellular proliferation, migration, and synthesis of extracellular matrix. This finally results in intimal hyperplasia, which is currently considered an untreatable condition. According to current knowledge, a major part of neointimal cells derive from circulating precursor cells. This has outdated the traditional in vitro cell culture methods of studying neointimal cell migration and proliferation using cultured medial SMCs. Somatostatin and some of its analogs with different selectivity for the five somatostatin receptors (sst1 through sst5) have been shown to have vasculoprotective properties in animal studies. However, clinical trials using analogs selective for sst2/sst3/sst5 to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) have failed to show any major benefits. Sirolimus is a cell cycle inhibitor that has been suggested to act synergistically with the protein-tyrosine kinase inhibitor imatinib to inhibit intimal hyperplasia in rat already at well-tolerated submaximal oral doses. The mechanisms behind this synergy and its long-term efficacy are not known. The aim of this study was to set up an ex vivo vascular explant culture model to measure neointimal cell activity without excluding the participation of circulating progenitor cells. Furthermore, two novel potential vasculoprotective treatment strategies were evaluated in detail in rat models of intimal hyperplasia and in the ex vivo explant model: sst1/sst4-selective somatostatin receptor analogs and combination treatment with sirolimus and imatinib. This study shows how whole vessel explants can be used to study the kinetics of neointimal cells and their progenitors, and to evaluate the anti-migratory and anti-proliferative properties of potential vasculoprotective compounds. It also shows how the influx of neointimal progenitor cells occurs already during the first days after vascular injury, how the contribution of cell migration is more important in the injury response than cell proliferation, and how the adventitia actively contribute in vascular repair. The vasculoprotective effect of somatostatin is mediated preferentially through sst4, and through inhibition of cell migration rather than of proliferation, which may explain why sst2/sst3/sst5-selective analogs have failed in clinical trials. Furthermore, a brief early oral treatment with the combination of sirolimus and imatinib at submaximal doses results in long-term synergistic suppression of intimal hyperplasia. The synergy is a result of inhibition of post-operative thrombocytosis and leukocytosis, inhibition of neointimal cell migration to the injury-site, and maintenance of cell integrity by inhibition of apoptosis and SMC dedifferentiation. In conclusion, the influx of progenitor cells already during the first days after injury and the high neointimal cell migratory activity underlines the importance of early therapeutic intervention with anti-migratory compounds to prevent neointimal hyperplasia. Sst4-selective analogs and the combination therapy with sirolimus and imatinib represent potential targets for the development of such vasculoprotective therapies.