Immunomodulation of allergic immune response during specific immunotherapy

Atopic, IgE-mediated allergies are one of the major public health problems in Finland and other Western countries. These diseases are characterized by type 2 T helper (Th2) cell predominated immune responses (interleukin-4 (IL-4), IL-5) against ubiquitous environmental allergens. Despite of adequate pharmacological treatment, more than 20% of the patients with allergic rhinitis develop asthma. Allergen specific immunotherapy (SIT) is the only treatment currently available to affect to the natural course of allergic diseases. This treatment involves repeated administration of allergens to the patients either via sublingual route (sublingual immunotherapy, SLIT) or by subcutaneous injections (subcutaneous immunotherapy, SCIT). Successful treatment with SCIT or SLIT has been shown to provide long-term remission in symptoms, and prevent disease progression to asthma, but the immunological mechanisms behind these beneficial effects are not yet completely understood. Increased knowledge of such mechanisms could not only help to improve SIT efficacy, but also provide tools to monitor the development of clinical response to SIT in individual patients, and possibly also, predict the ultimate therapeutic outcome. The aim of this work was to clarify the immunological mechanisms associated with SIT by investigating the specific allergen-induced immune responses in peripheral blood mononuclear cells (PBMC) of allergic rhinitis patients during the course of SLIT and SCIT. The results of this work demonstrate that both therapies induced increases in the protective, Th2-balancing Th1 type immune responses in PBMC, e.g. by up-regulating signaling lymphocytic activation molecule (SLAM) and interferon gamma (IFN-γ) expression, and augmented tolerogenic T regulatory (Treg) cell type responses against the specific allergens, e.g. by increasing IL-10 or Forkhead box P3 (FOXP3) expression. The induction of allergen-specific Th1 and Treg type responses during SLIT were dependent on the treatment dose, favoring high allergen dose SLIT. During SCIT, the early decrease in Th2 type cytokine production - in particular of IL-4 mRNA and IL-4/IFN-γ expression ratio - was associated with the development of good therapeutic outcome. Conversely, increases in both Th2 (IL-5) and Th1 (IFN-γ, SLAM) type responses and IL-10 mRNA production were seen in the patients with less effective outcome. In addition, increase in Th17 type cytokine (IL-17) mRNA production was found in the PBMC of patients with less effective outcome during both SLIT and SCIT. These data strengthen the current hypothesis that immunomodulation of allergen-specific immune responses from the prevailing Th2-biased responses towards a more Th1 type, and induction of tolerogenic Treg cells producing IL-10 represent the two key mechanisms behind the beneficial effects of SIT. The data also give novel insight into the mechanisms why SIT may fail to be effective in some patients by demonstrating a positive correlation between the proinflammatory IL-17 responses, Th2 type IL-5 production and clinical symptoms. Taken together, these data indicate that the analysis of Th1, Th2, Treg ja Th17-associated immune markers such as IL-10, SLAM, IL-4, IL-5 and IL-17 could provide tools to monitor the development of clinical response to SIT, and thereby, predict the ultimate clinical outcome already in the early course of the treatment.

Determining risk potential through accidents and near-accidents: an empirical study in a steel factory

Fatal and permanently disabling accidents form only one per I cent of all occupational accidents but in many branches of industry they account for more than half the accident costs. Furthermore the human suffering of the victim and his family is greater in severe accidents than in slight ones. For both human and economic reasons the severe accident risks should be identified befor injuries occur. It is for this purpose that different safety analysis methods have been developed . This study shows two new possible approaches to the problem.. The first is the hypothesis that it is possible to estimate the potential severity of accidents independent of the actual severity. The second is the hypothesis that when workers are also asked to report near accidents, they are particularly prone to report potentially severe near accidents on the basis of their own subjective risk assessment. A field study was carried out in a steel factory. The results supported both the hypotheses. The reliability and the validity of post incident estimates of an accident's potential severity were reasonable. About 10 % of accidents were estimated to be potentially critical; they could have led to death or very severe permanent disability. Reported near accidents were significantly more severe, about 60 $ of them were estimated to be critical. Furthermore the validity of workers subjective risk assessment, manifested in the near accident reports, proved to be reasonable. The studied new methods require further development and testing. They could be used both in routine usage in work places and in research for identifying and setting the priorities of accident risks.

Merchandising Strategies and Retail Performance for Seasonal Fashion Products

This study presents mathematical methods for evaluation of retail performance with special regard to product sourcing strategies. Forecast accuracy, process lead time, offshore / local sourcing mix and up front / replenishment buying mix are defined as critical success factors in connection with sourcing seasonal products with a fashion content. As success measures, this research focuses on service level, lost sales, product substitute percentage, gross margin, gross margin return on inventory and mark down rate. The accuracy of demand forecast is found to be a fundamental success factor. Forecast accuracy depends on lead time. Lead times are traditionally long and buying decisions are made seven to eight months prior to the start of the selling season. Forecast errors cause stockouts and lost sales. Some of the products bought for the selling season will not be sold and have to be marked down and sold at clearance, causing loss of gross margin. Gross margin percentage is not the best tool for evaluating sourcing decisions and in the context of this study gross margin return on inventory, which combines profitability and assets management, is used. The findings of this research suggest that there are more profitable ways of sourcing products than buying them from low cost offshore sources. Mixing up front and inseason replenishment deliveries, especially when point of sale information is used for improving forecast accuracy, results in better retail performance. Quick Response and Vendor Managed Inventory strategies yield better results than traditional up front buying from offshore even if local purchase prices are higher. Increasing the number of selling seasons, slight over buying for the season in order to

Tuotannonohjauksen kehittäminen piensarjatuotannossa

Tämä diplomityö käsittelee teollisen yrityksen tuotannonohjauksen kehittämistä piensarjatuotannossa. Työn kohteena on ABB Oy:n Tuulivoimageneraattorit-tulosyksikkö, joka valmistaa vakiotuotteita asiakasohjautuvasti. Työssä esitellään aluksi tuotannon ja tuotannonohjauksen teoriaa. Lävitse käydään perusasioiden kuten määritelmien, tavoitteiden ja tehtävien lisäksi tuotannonohjausprosessia sekä tuotannonohjauksen tietotekniikkaa. Teorian jälkeisessä empiriaosuudessa esitellään työssä kehitettyjä keinoja tuotannonohjauksen parantamiseksi. Tutkimus on toteutettu teoreettisen ja empiirisen tutkimustyön avulla. Teoreettiseen tutkimustyöhön sisältyi suomalaisiin ja ulkomaalaisiin kirjallisuuslähteisiin perehtyminen. Empiirinen tutkimustyö suoritettiin itsenäisen ongelman ratkaisutyön avulla. Tämä sisälsi kehittämiskohteiden analysoinnin, tarkempien kehittämistarpeiden määrityksen sekä kokeilujen kautta tapahtuneen kehittämistyön. Tutkimuksen päätavoitteena oli selvittää, miten tuotannonohjauksen kehittämisellä voidaan parantaa kohteena olevan tulosyksikön tuottavuutta ja kannattavuutta. Päätavoitteen pohjalta muodostettiin kuusi osatavoitetta: toimitusvarmuuden parantaminen, kapasiteetin kuormitusasteen nostaminen, kapasiteetin suunnittelun kehittäminen, läpäisyaikojen lyhentäminen, uuden ERP-järjestelmän vaatimusmäärittely sekä tuotannonohjausprosessin määrittäminen. Työssä rakennettiin neljään ensiksi mainittuun osatavoitteeseen tietotekniset sovellukset, jotka mahdollistavat osatavoitteiden suunnittelun ja ohjaamisen. Sovelluksia varten kullekin tuotteelle määriteltiin esimerkiksi työnvaiheketjut läpäisyaikoineen, kuormitusryhmät, kuormitusryhmien kapasiteetit, tuotteiden kuormittavuudet sekä kriittiset työvälineet. Työ osoitti, että tietotekniikka auttaa suuresti tuotannonohjauksessa. Lisääntynyt läpinäkyvyys, parantunut tiedonkulku, simulointimahdollisuudet sekä graafinen esitystapa helpottavat erilaisten suunnitelmien teossa ja parantavat siten päätöksenteon laatua. Tietotekniikan hyväksikäytön pohjana toimii tuotannon perus- ja tapahtumatietojen kurinalainen päivitys. Tämän vuoksi tietojärjestelmistä kannattaa rakentaa mahdollisimman yksinkertaisia.

Sinfonia piccola

Soitinnus: Ork.

Sudenmorsian : radio-ooppera 1940 [!]

Äänitetty: 1968, Yleisradio.

Mestarin nuuskarasia

Digitoitu 21. 8. 2008.

Kaarle Kuninkaan metsästys

Digitoitu 29. 12. 2008

Hoffmannin kertomukset

Esityskieli: suomi.

Juha

Digitoitu 11. 10. 2007.