Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

“THE PATIENT SURVIVED DESPITE THE TREATMENT”. A study of Finnish health policy and New Public Management. Case: The Government Resolution on the Health 2015 public health programme.

Internationally, Finland has been among the most respected countries during several decades in terms of public health. WHO has had the most significant influence on Finnish health policy and the relationship has traditionally been warm. However, the situation has slightly changed in the last 10-20 years. The objectives of Finnish national health policy have been to secure the best possible health for the population and to minimize disparities in health between different population groups. Nevertheless, although the state of public health and welfare has steadily improved, the socioeconomic disparities in health have increased. This qualitative case study will demonstrate why health is political and why health matters. It will also present some recommendations for research topics and administrative reforms. It will be argued that lack of political interest in health policy leads to absence of health policy visions and political commitment, which can be disastrous for public health. This study will investigate how Finnish health policy is defined and organised, and it will also shed light on Finnish health policy formation processes and actors. Health policy is understood as a broader societal construct covering the domains of different ministries, not just Ministry of Social Affairs and Health (MSAH). The influences of economic recession of the 1990s, state subsidy reform in 1993, globalisation and the European Union will be addressed, as well. There is not much earlier Finnish research done on health policy from political science viewpoint. Therefore, this study is interdisciplinary and combines political science with administrative science, contemporary history and health policy research with a hint of epidemiology. As a method, literature review, semi-structured interviews and policy analysi will be utilised. Institutionalism, policy transfer, and corporatism are understood as the theoretical framework. According to the study, there are two health policies in Finland: the official health policy and health policy generated by industry, media and various interest organisations. The complex relationships between the Government and municipalities, and on the other hand, the MSAH and National Institute for Health and Welfare (THL) seemed significant in terms of Finnish health policy coordination. The study also showed that the Investigated case, Health 2015, does not fulfil all necessary criteria for a successful public health programme. There were also several features both in Health 2015 and Finnish health policy, which can be interpreted in NPM framework and seen having NPM influences.

Työn fyysinen ja psyykkinen kuormittavuus vanhustenhoidossa - seurantatutkimus ergonomisen kehittämistyön tuloksista

Tutkimuksen tarkoituksena oli analysoida vanhusten ympärivuorokautisen hoidon yksiköissä työskentelevien työntekijöiden työn fyysistä ja psyykkistä kuormittavuutta ja työhön liittyviä fyysisiä riskejä. Lisäksi haluttiin selvittää, millaisia vaikutuksia fyysisen kuormittavuuden vähentämistä tavoitelleella ergonomisella kehittämisinterventiolla saadaan aikaan. Tutkimuksessa hyödynnettiin Turun kaupungin vanhuspalveluissa vuosina 2010–2012 toteutuneessa ergonomisessa kehittämisinterventiossa (47 työyksikköä) kertynyttä ja vuosien 2010 ja 2012 Kunta10-kyselyn (120 työyksikköä) tuottamaa tietoa. Intervention ydin oli Työterveyslaitoksen Fyysisten riskien hallintamalli hoitoalalla -mallin käyttööotto. Käytetyt mittarit olivat seuraavat: Työn kuormitus- ja työtyytyväisyyskysely työntekijöille, asiakkaiden toimintakykyä mittaava RAVATM -indeksi, fyysistä kuormitusta ja työn riskejä mittava Care ThermometerTM-menetelmä, potilassiirtojen turvallisuusjohtamisen (PHOQS) arviointi sekä esimies- ja ergonomiavastaavien kysely. Lisäksi käytössä olivat Kunta10-kyselyn tulokset valittujen muuttujien osalta kaikista tutkimukseen osallistuvista kaupungeista sekä ympärivuorokautisen hoidon asiakkaita ja hoitohenkilöstöä kuvaavia tilastoja. Työ vanhusten ympärivuorokautisessa hoidossa on fyysisesti ja psyykkisesti kuormittavaa. Interventiotoimenpiteistä huolimatta koettu fyysinen ja psyykkinen kuormittavuus kasvoivat, tosin fyysinen psyykkistä vähemmän. Kuormittavuus vaihteli toimintamuodoittain ja ammattiryhmittäin. Fyysisesti kuormittavimmaksi työ koettiin pitkäaikaissairaanhoidossa, psyykkinen kuormitus kasvoi eniten tehostetussa palveluasumisessa. Vanhainkodit sijoittuivat näiden väliin. Lähihoitajat kokivat työnsä fyysisesti kuormittavimmaksi, kun taas sairaanhoitajien työ oli psyykkisesti lähihoitajien työtä kuormittavampaa. Ergonomiakoulutus vähensi eniten koettua fyysistä kuormittavuutta. Kehityskeskustelut ja aiempaa paremmaksi arvioitu työkyky vähensivät mutta tyytymättömyys työhön lisäsi koettua fyysistä ja psyykkistä kuormittavuutta. Työntekijöiden ikä, RAVATM -indeksi, Care ThermometerTM -mittaukset ja PHOQS-pisteet eivät olleet tilastollisesti merkitsevästi yhteydessä kuormittavuuden muutoksiin. Työn kuormittavuuden vähentäminen ja turvallisen työskentelyn edistäminen vaativat pitkäkestoista toimintaa ja hyvää johtamista erityisesti lähiesimiehiltä. Fyysisten riskien hallintamallin käyttöönotto ja ergonomiavastaavien toiminnan vakiinnuttaminen tukevat tavoitteiden saavuttamista.