Effects of group size and space allocation on physiological, behavioural and production-related welfare parameters in farmed silver fox cubs

Selostus: Ryhmäkoon ja käytössä olevan tilan vaikutus tarhattujen hopeakettupentujen hyvinvointiin

Modular continuous crystallizer: operation, experimental arrangement and identification of process parameters

Crystallization is employed in different industrial processes. The method and operation can differ depending on the nature of the substances involved. The aim of this study is to examine the effect of various operating conditions on the crystal properties in a chemical engineering design window with a focus on ultrasound assisted cooling crystallization. Batch to batch variations, minimal manufacturing steps and faster production times are factors which continuous crystallization seeks to resolve. Continuous processes scale-up is considered straightforward compared to batch processes owing to increase of processing time in the specific reactor. In cooling crystallization process, ultrasound can be used to control the crystal properties. Different model compounds were used to define the suitable process parameters for the modular crystallizer using equal operating conditions in each module. A final temperature of 20oC was employed in all experiments while the operating conditions differed. The studied process parameters and configuration of the crystallizer were manipulated to achieve a continuous operation without crystal clogging along the crystallization path. The results from the continuous experiment were compared with the batch crystallization results and analysed using the Malvern Morphologi G3 instrument to determine the crystal morphology and CSD. The modular crystallizer was operated successfully with three different residence times. At optimal process conditions, a longer residence time gives smaller crystals and narrower CSD. Based on the findings, at a constant initial solution concentration, the residence time had clear influence on crystal properties. The equal supersaturation criterion in each module offered better results compared to other cooling profiles. The combination of continuous crystallization and ultrasound has large potential to overcome clogging, obtain reproducible and narrow CSD, specific crystal morphologies and uniform particle sizes, and exclusion of milling stages in comparison to batch processes.

Capital Structure and Firm Growth: R&D Intensive Companies

The purpose of this study is to examine and explain firm`s growth impact on capital structure decision-making in research and development intensive companies. Many studies claim that R&D has a pivotal impact on capital structure decisions, but corporate finance theories have often failed to explain these observed patterns. As sales growth is an important concept and objective for R&D firms, it is logical to assume that it plays a vital role in capital structure decisions. This study applies nomothetic research approach. The theoretical part employs a formal conceptual analysis in order to develop the propositions that are tested with empirical data. The empirical part consists of the analysis of three companies; the data is obtained from the annual reports over the period 2003 – 2008. The companies operate in IT- or ICT-industry and are publicly listed. The method for analyzing the case data is based on the financial indicators, which are obtained from the financials of the case companies. These economic indicators describe the capital structure and the financial decision-making of the firms. The method relates to the quantitative studies. Yet, this study extends the analysis beyond the indicators. Specifically, this study addresses the question of what is behind the economic indicators, therefore combining aspects of quantitative and qualitative analysis. The firms examined in this study seem to prefer internal finance during growth. However, external finance seems to be a catalyst for sales growth. Firms strongly prefer equity financing. In growth, the use of equity per capital either increases or stays in a constant level. Over the period 2003 – 2008, the firms were often associated to equity related transactions and short-term debt. Short-term debt was used as a substitute of long-term debt and equity. The case firms also adjusted their capital structure – these adjustments were carried out with short-term debt or equity. The case data also provides implications for the growth signal theory that was developed in this study. Based on the econometric indicators, arguments can be made that equity investors are `attracted` to growing R&D firms. This is because growth helps investors perceive the true type of firm. The findings of this study are best explained by the trade-off theory and the pecking order theory. These corporate finance theories are considered as mainstream. Little support can be found to the implications of the signaling theory and market timing theory.

Natural history of celiac disease-associated antibodies and progression to overt disease in children at increased genetic risk

Background: Celiac disease is a lifelong, gluten-sensitive, autoimmune-mediated chronic enteropathy, tightly associated with risk alleles at the HLA class II genes. Aims: This study was carried out as a part of the population-based Type 1 Diabetes Prediction and Prevention (DIPP) Project. The first aim was to study the natural history of celiac disease-associated antibodies before the diagnosis of celiac disease was made. The second aim was to describe when and in which order celiac disease-associated and type 1 diabetes-associated antibodies appeared in children with genetic risk for both diseases. Subjects and Methods: Antibodies against tissue transglutaminase (TGA) and other celiac disease-associated antibodies were measured in serum samples collected at 3- to 12-month intervals of children at genetic risk for celiac disease who participated in the DIPP project. Celiac disease was confirmed by duodenal biopsy. Type 1 diabetes-associated antibodies were measured in all samples that had been collected. Overt disease was diagnosed according to World Health Organization criteria. Follow-up continued until a diagnosis of type 1 diabetes or until the end of a defined follow-up period. Results: TGA appeared in children at genetic risk for celiac disease only after the first year of life, but anti-gliadin antibodies often emerged significantly earlier, at age 6 months. The data show that spontaneous disappearance of celiac disease-associated antibodies, transient or persisting, is a common phenomenon, at least in prepubertal children. In children with genetic susceptibility to type 1 diabetes and celiac disease, celiac disease-associated antibodies usually develop earlier than the type 1 diabetes-associated antibodies. Conclusions: The transient nature of celiac disease-associated antibodies emphasizes the significance of establishing seropositivity repeatedly in screening detected celiac disease before gastroscopy and duodenal biopsy are considered and emphasized the importance of duodenal biopsy for diagnosing celiac disease.

A platform for assessing the current state of data repositories in Korea, Japan and China

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Design and evaluation of web interface signs to improve web usability : a semiotic framework

Technological innovations, the development of the internet, and globalization have increased the number and complexity of web applications. As a result, keeping web user interfaces understandable and usable (in terms of ease-of-use, effectiveness, and satisfaction) is a challenge. As part of this, designing userintuitive interface signs (i.e., the small elements of web user interface, e.g., navigational link, command buttons, icons, small images, thumbnails, etc.) is an issue for designers. Interface signs are key elements of web user interfaces because ‘interface signs’ act as a communication artefact to convey web content and system functionality, and because users interact with systems by means of interface signs. In the light of the above, applying semiotic (i.e., the study of signs) concepts on web interface signs will contribute to discover new and important perspectives on web user interface design and evaluation. The thesis mainly focuses on web interface signs and uses the theory of semiotic as a background theory. The underlying aim of this thesis is to provide valuable insights to design and evaluate web user interfaces from a semiotic perspective in order to improve overall web usability. The fundamental research question is formulated as What do practitioners and researchers need to be aware of from a semiotic perspective when designing or evaluating web user interfaces to improve web usability? From a methodological perspective, the thesis follows a design science research (DSR) approach. A systematic literature review and six empirical studies are carried out in this thesis. The empirical studies are carried out with a total of 74 participants in Finland. The steps of a design science research process are followed while the studies were designed and conducted; that includes (a) problem identification and motivation, (b) definition of objectives of a solution, (c) design and development, (d) demonstration, (e) evaluation, and (f) communication. The data is collected using observations in a usability testing lab, by analytical (expert) inspection, with questionnaires, and in structured and semi-structured interviews. User behaviour analysis, qualitative analysis and statistics are used to analyze the study data. The results are summarized as follows and have lead to the following contributions. Firstly, the results present the current status of semiotic research in UI design and evaluation and highlight the importance of considering semiotic concepts in UI design and evaluation. Secondly, the thesis explores interface sign ontologies (i.e., sets of concepts and skills that a user should know to interpret the meaning of interface signs) by providing a set of ontologies used to interpret the meaning of interface signs, and by providing a set of features related to ontology mapping in interpreting the meaning of interface signs. Thirdly, the thesis explores the value of integrating semiotic concepts in usability testing. Fourthly, the thesis proposes a semiotic framework (Semiotic Interface sign Design and Evaluation – SIDE) for interface sign design and evaluation in order to make them intuitive for end users and to improve web usability. The SIDE framework includes a set of determinants and attributes of user-intuitive interface signs, and a set of semiotic heuristics to design and evaluate interface signs. Finally, the thesis assesses (a) the quality of the SIDE framework in terms of performance metrics (e.g., thoroughness, validity, effectiveness, reliability, etc.) and (b) the contributions of the SIDE framework from the evaluators’ perspective.

Natriumsilikaatin liuotuslaitoksen kapasiteetin nosto

Tässä työssä tutkittiin natriumsilikaatin (vesilasi) liuotukseen ja suodatukseen vaikuttavia tekijöitä. Työssä pyrittiin optimoimaan natriumsilikaatin liuotus- ja suodatuskapasiteetti J. M. Huber Finland Oy:n Haminan tehtaan liuotuslaitoksella. Kirjallisuusosassa perehdyttiin kiinteän natriumsilikaatin ja natriumsilikaatin vesiliuoksen ominaisuuksiin, sekä käsiteltiin soveltuvin osin liuotuksen ja suodatuksen teoriaa. Kokeellisessa osassa vertailtiin kahden eri valmistajan natriumsilikaatteja toisiinsa, sekä pyrittiin löytämään molemmille laseille optimaalisimmat prosessiparametrit liuotus- ja suodatuskokeiden avulla. Erilaisia prosessiparametreja ja ajotapoja testattiin tehdasmittakaavan koeajoilla todellisilla prosessilaitteilla. Eri natriumsilikaattien vertailu tehtiin tehdasmittakaavan koeajojen sekä laboratorioanalyysien avulla. Koeajojen tulosten perusteella Taavetista toimitettu vesilasi liukenee nopeammin kuin Puolasta toimitettu ostolasi, mutta puolalaisesta lasista liuotettu silikaatti suodattuu helpommin kuin Taavetin lasista liuotettu silikaatti. Liukenemisnopeuden eroon selitettävissä Taavetin lasin suuremmalla ominaispinta-alalla sekä hauraammalla rakenteella. Suodatuseroon ei löytynyt yksiselitteistä syytä, joten sen löytämiseksi vaadittaisiin jatkotutkimuksia. Kokeiden perusteellaparas keino puolalaisen lasin liuotuksen nopeuttamiseen olisi pitää liuotussäiliön lasiylimäärä mahdollisimman korkeana jokaisessa panoksessa ja nopeuttaa liuotussäiliön panostusta lasin ja veden yhtäaikaisella annostelulla. Tulosten perusteella paras keino Taavetin lasista liuotetun silikaatin suodatuksen helpottamiseen olisi laskea liuoksen tavoitetiheyttä nykyisestä arvostaan, jolloin viskositeetti pienenee merkittävästi ja suodatus onnistuu liuotuslaitoksen kapasiteetin kannalta paremmin. Edellä mainituilla ajotavoilla tehtyjen koeajojen perusteella, molemmilla laseilla on mahdollista päästä 150 MT/d tavoitekapasiteettiin, mutta varmin tapa kyseisen kapasiteetin saavuttamiseksi olisi lisätä suodatuskapasiteettia investoimalla toiseen silikaattisuodattimeen.

Tuotealustapohjaisen suunnittelun vaikutukset risteilijän suunnitteluaikatauluihin

Tuotealustapohjaisella suunnittelulla pyritään hyödyntämään jo kertaalleen hyväksi todettuja kokonaisuuksia ja moduuleja, joiden avulla voidaan nopeasti suunnitella uusia tuotteita. Tarkoituksena on suunnitella asiakkaan näkökulmasta monia erilaisia tuotteita jopa sarjatuotannon kustannustehokkuudella. Tutkimuksessa esitetään risteilijän tuotealustapohjainen suunnitteluprosessi. Lisäksi työn tavoitteena on tutkia uuden suunnitteluprosessin vaikutukset risteilijän suunnitteluaikatauluihin. Tutkimuksessa haastateltiin Turun telakan suunnitteluosaston ja kehitysosaston johtajia. Haastatteluilla selvitettiin nykyisen suunnitteluprosessin haasteita, joiden nähtiin erityisesti viivästyttävät suunnitteluaikatauluja. Keskeisiä haasteita ovat suunnitteluresurssien ylikuormitus ja suunnittelulaadun huonontuminen. Lisäksi kartoitettiin tavoitteet risteilijän tuotealustaratkaisulle ja suunnitteluaikataululle. Haastattelukierroksen pohjalta ja teoriaa soveltaen analysoitiin risteilijän modulaariseen tuotealustaan perustuva suunnitteluprosessi. Tätä suunnitteluprosessia tutkittiin edelleen case-tutkimuksessa jääasemien osalta, jossa haastateltiin kyseisten alueiden suunnittelijoita. Lisäksi case-tutkimuksessa verrattiin jääaseman ja baaripentterin perussuunnittelun vaiheita toisiinsa. Näistä saatuja tutkimustuloksia verrattiin hyttialueen vakioidun perussuunnitteluohjeen vaikutuksiin suunnitteluprosessissa. Onnistunut tuotealustapohjainen suunnittelu vaatii sitoutumista jokaisella organisaation tasolla, jotta tuotealustassa olevien vakioituja moduuleja myös käytettäisiin. Modulaarisesta toiminnasta siirtyminen tuotealustapohjaiseen suunnitteluun vaatii vakioituja moduuleja ja vakioituja rajapintoja risteilijässä. Case-tutkimuksessa ja johtopäätöksissä on todettu uuden suunnitteluprosessin lyhentävän ja tuovan kustannussäästöjä tuotteen valmistusprosessissa.

Training system for conceptual design and evaluation for wastewater treatment

Rising population, rapid urbanisation and growing industrialisation have severely stressed water quality and its availability in Malawi. In addition, financial and institutional problems and the expanding agro industry have aggravated this problem. The situation is worsened by depleting water resources and pollution from untreated sewage and industrial effluent. The increasing scarcity of clean water calls for the need for appropriate management of available water resources. There is also demand for a training system for conceptual design and evaluation for wastewater treatment in order to build the capacity for technical service providers and environmental practitioners in the country. It is predicted that Malawi will face a water stress situation by 2025. In the city of Blantyre, this situation is aggravated by the serious pollution threat from the grossly inadequate sewage treatment capacity. This capacity is only 23.5% of the wastewater being generated presently. In addition, limited or non-existent industrial effluent treatment has contributed to the severe water quality degradation. This situation poses a threat to the ecologically fragile and sensitive receiving water courses within the city. This water is used for domestic purposes further downstream. This manuscript outlines the legal and policy framework for wastewater treatment in Malawi. The manuscript also evaluates the existing wastewater treatment systems in Blantyre. This evaluation aims at determining if the effluent levels at the municipal plants conform to existing standards and guidelines and other associated policy and regulatory frameworks. The raw material at all the three municipal plants is sewage. The typical wastewater parameters are Biochemical Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), and Total Suspended Solids (TSS). The treatment target is BOD5, COD, and TSS reduction. Typical wastewater parameters at the wastewater treatment plant at MDW&S textile and garments factory are BOD5 and COD. The treatment target is to reduce BOD5 and COD. The manuscript further evaluates a design approach of the three municipal wastewater treatment plants in the city and the wastewater treatment plant at Mapeto David Whitehead & Sons (MDW&S) textile and garments factory. This evaluation utilises case-based design and case-based reasoning principles in the ED-WAVE tool to determine if there is potential for the tool in Blantyre. The manuscript finally evaluates the technology selection process for appropriate wastewater treatment systems for the city of Blantyre. The criteria for selection of appropriate wastewater treatment systems are discussed. Decision support tools and the decision tree making process for technology selection are also discussed. Based on the treatment targets and design criteria at the eight cases evaluated in this manuscript in reference to similar cases in the ED-WAVE tool, this work confirms the practical use of case-based design and case-based reasoning principles in the ED-WAVE tool in the design and evaluation of wastewater treatment 6 systems in sub-Sahara Africa, using Blantyre, Malawi, as the case study area. After encountering a new situation, already collected decision scenarios (cases) are invoked and modified in order to arrive at a particular design alternative. What is necessary, however, is to appropriately modify the case arrived at through the Case Study Manager in order to come up with a design appropriate to the local situation taking into account technical, socio-economic and environmental aspects. This work provides a training system for conceptual design and evaluation for wastewater treatment.

Production of Mg(OH)2 from Mg-silicate rock for CO2 mineral sequestration

Sequestration of carbon dioxide in mineral rocks, also known as CO2 Capture and Mineralization (CCM), is considered to have a huge potential in stabilizing anthropogenic CO2 emissions. One of the CCM routes is the ex situ indirect gas/sold carbonation of reactive materials, such as Mg(OH)2, produced from abundantly available Mg-silicate rocks. The gas/solid carbonation method is intensively researched at Åbo Akademi University (ÅAU ), Finland because it is energetically attractive and utilizes the exothermic chemistry of Mg(OH)2 carbonation. In this thesis, a method for producing Mg(OH)2 from Mg-silicate rocks for CCM was investigated, and the process efficiency, energy and environmental impact assessed. The Mg(OH)2 process studied here was first proposed in 2008 in a Master’s Thesis by the author. At that time the process was applied to only one Mg-silicate rock (Finnish serpentinite from the Hitura nickel mine site of Finn Nickel) and the optimum process conversions, energy and environmental performance were not known. Producing Mg(OH)2 from Mg-silicate rocks involves a two-staged process of Mg extraction and Mg(OH)2 precipitation. The first stage extracts Mg and other cations by reacting pulverized serpentinite or olivine rocks with ammonium sulfate (AS) salt at 400 - 550 oC (preferably < 450 oC). In the second stage, ammonia solution reacts with the cations (extracted from the first stage after they are leached in water) to form mainly FeOOH, high purity Mg(OH)2 and aqueous (dissolved) AS. The Mg(OH)2 process described here is closed loop in nature; gaseous ammonia and water vapour are produced from the extraction stage, recovered and used as reagent for the precipitation stage. The AS reagent is thereafter recovered after the precipitation stage. The Mg extraction stage, being the conversion-determining and the most energy-intensive step of the entire CCM process chain, received a prominent attention in this study. The extraction behavior and reactivity of different rocks types (serpentinite and olivine rocks) from different locations worldwide (Australia, Finland, Lithuania, Norway and Portugal) was tested. Also, parametric evaluation was carried out to determine the optimal reaction temperature, time and chemical reagent (AS). Effects of reactor types and configuration, mixing and scale-up possibilities were also studied. The Mg(OH)2 produced can be used to convert CO2 to thermodynamically stable and environmentally benign magnesium carbonate. Therefore, the process energy and life cycle environmental performance of the ÅAU CCM technique that first produces Mg(OH)2 and the carbonates in a pressurized fluidized bed (FB) were assessed. The life cycle energy and environmental assessment approach applied in this thesis is motivated by the fact that the CCM technology should in itself offer a solution to what is both an energy and environmental problem. Results obtained in this study show that different Mg-silicate rocks react differently; olivine rocks being far less reactive than serpentinite rocks. In summary, the reactivity of Mg-silicate rocks is a function of both the chemical and physical properties of rocks. Reaction temperature and time remain important parameters to consider in process design and operation. Heat transfer properties of the reactor determine the temperature at which maximum Mg extraction is obtained. Also, an increase in reaction temperature leads to an increase in the extent of extraction, reaching a maximum yield at different temperatures depending on the reaction time. Process energy requirement for producing Mg(OH)2 from a hypothetical case of an iron-free serpentine rock is 3.62 GJ/t-CO2. This value can increase by 16 - 68% depending on the type of iron compound (FeO, Fe2O3 or Fe3O4) in the mineral. This suggests that the benefit from the potential use of FeOOH as an iron ore feedstock in iron and steelmaking should be determined by considering the energy, cost and emissions associated with the FeOOH by-product. AS recovery through crystallization is the second most energy intensive unit operation after the extraction reaction. However, the choice of mechanical vapor recompression (MVR) over the “simple evaporation” crystallization method has a potential energy savings of 15.2 GJ/t-CO2 (84 % savings). Integrating the Mg(OH)2 production method and the gas/solid carbonation process could provide up to an 25% energy offset to the CCM process energy requirements. Life cycle inventory assessment (LCIA) results show that for every ton of CO2 mineralized, the ÅAU CCM process avoids 430 - 480 kg CO2. The Mg(OH)2 process studied in this thesis has many promising features. Even at the current high energy and environmental burden, producing Mg(OH)2 from Mg-silicates can play a significant role in advancing CCM processes. However, dedicated future research and development (R&D) have potential to significantly improve the Mg(OH)2 process performance.

Oxidation rates of carbon and nitrogen in char residues from solid fuels

Computational fluid dynamics (CFD) modeling is an important tool in designing new combustion systems. By using CFD modeling, entire combustion systems can be modeled and the emissions and the performance can be predicted. CFD modeling can also be used to develop new and better combustion systems from an economical and environmental point of view. In CFD modeling of solid fuel combustion, the combustible fuel is generally treated as single fuel particles. One of the limitations with the CFD modeling concerns the sub-models describing the combustion of single fuel particles. Available models in the scientific literature are in many cases not suitable as submodels for CFD modeling since they depend on a large number of input parameters and are computationally heavy. In this thesis CFD-applicable models are developed for the combustion of single fuel particles. The single particle models can be used to improve the combustion performance in various combustion devices or develop completely new technologies. The investigated fields are oxidation of carbon (C) and nitrogen (N) in char residues from solid fuels. Modeled char-C oxidation rates are compared to experimental oxidation rates for a large number of pulverized solid fuel chars under relevant combustion conditions. The experiments have been performed in an isothermal plug flow reactor operating at 1123-1673 K and 3-15 vol.% O2. In the single particle model, the char oxidation is based on apparent kinetics and depends on three fuel specific parameters: apparent pre-exponential factor, apparent activation energy, and apparent reaction order. The single particle model can be incorporated as a sub-model into a CFD code. The results show that the modeled char oxidation rates are in good agreement with experimental char oxidation rates up to around 70% of burnout. Moreover, the results show that the activation energy and the reaction order can be assumed to be constant for a large number of bituminous coal chars under conditions limited by the combined effects of chemical kinetics and pore diffusion. Based on this, a new model based on only one fuel specific parameter is developed (Paper III). The results also show that reaction orders of bituminous coal chars and anthracite chars differ under similar conditions (Paper I and Paper II); reaction orders of bituminous coal chars were found to be one, while reaction orders of anthracite chars were determined to be zero. This difference in reaction orders has not previously been observed in the literature and should be considered in future char oxidation models. One of the most frequently used comprehensive char oxidation models could not explain the difference in the reaction orders. In the thesis (Paper II), a modification to the model is suggested in order to explain the difference in reaction orders between anthracite chars and bituminous coal chars. Two single particle models are also developed for the NO formation and reduction during the oxidation of single biomass char particles. In the models the char-N is assumed to be oxidized to NO and the NO is partly reduced inside the particle. The first model (Paper IV) is based on the concentration gradients of NO inside and outside the particle and the second model is simplified to such an extent that it is based on apparent kinetics and can be incorporated as a sub-model into a CFD code (Paper V). Modeled NO release rates from both models were in good agreement with experimental measurements from a single particle reactor of quartz glass operating at 1173-1323 K and 3-19 vol.% O2. In the future, the models can be used to reduce NO emissions in new combustion systems.

On state and parameter estimation in chaotic systems

State-of-the-art predictions of atmospheric states rely on large-scale numerical models of chaotic systems. This dissertation studies numerical methods for state and parameter estimation in such systems. The motivation comes from weather and climate models and a methodological perspective is adopted. The dissertation comprises three sections: state estimation, parameter estimation and chemical data assimilation with real atmospheric satellite data. In the state estimation part of this dissertation, a new filtering technique based on a combination of ensemble and variational Kalman filtering approaches, is presented, experimented and discussed. This new filter is developed for large-scale Kalman filtering applications. In the parameter estimation part, three different techniques for parameter estimation in chaotic systems are considered. The methods are studied using the parameterized Lorenz 95 system, which is a benchmark model for data assimilation. In addition, a dilemma related to the uniqueness of weather and climate model closure parameters is discussed. In the data-oriented part of this dissertation, data from the Global Ozone Monitoring by Occultation of Stars (GOMOS) satellite instrument are considered and an alternative algorithm to retrieve atmospheric parameters from the measurements is presented. The validation study presents first global comparisons between two unique satellite-borne datasets of vertical profiles of nitrogen trioxide (NO3), retrieved using GOMOS and Stratospheric Aerosol and Gas Experiment III (SAGE III) satellite instruments. The GOMOS NO3 observations are also considered in a chemical state estimation study in order to retrieve stratospheric temperature profiles. The main result of this dissertation is the consideration of likelihood calculations via Kalman filtering outputs. The concept has previously been used together with stochastic differential equations and in time series analysis. In this work, the concept is applied to chaotic dynamical systems and used together with Markov chain Monte Carlo (MCMC) methods for statistical analysis. In particular, this methodology is advocated for use in numerical weather prediction (NWP) and climate model applications. In addition, the concept is shown to be useful in estimating the filter-specific parameters related, e.g., to model error covariance matrix parameters.

The alpha2C-adrenoceptor as a neuropsychiatric drug tar-get - PET studies in human subjects

Positron emission tomography imaging has both academic and applied uses in revealing the distribution and density of different molecular targets in the central nervous system. Following the significant progress made with the dopamine D2 receptor, advances have been made in developing PET tracers to allow analysis of receptor occupancy of many other receptor types as well as evaluating changes in endogenous synaptic transmitter concentrations of transmitters e.g. serotonin and noradrenaline. Noradrenergic receptors are divided into α1-, α2- and β-adrenoceptor subfamilies, in humans each of which is composed of three receptor subtypes. The α2-adrenoceptors have an important presynaptic auto-inhibitory function on noradrenaline release but they also have postsynaptic roles in modulating the release of other neurotransmitters, such as serotonin and dopamine. One of the subtypes, the α2C-adrenoceptor, has been detected at distinct locations in the central nervous system, most notably the dorsal striatum. Several serious neurological conditions causing dementia, Alzheimer’s disease and Parkinson’s disease have been linked to disturbed noradrenergic signaling. Furthermore, altered noradrenergic signaling has also been implicated in conditions like ADHD, depression, anxiety and schizophrenia. In order to benefit future research into these central nervous system disorders as well as being useful in the clinical development of drugs affecting brain noradrenergic neurotransmission, validation work of a novel tracer for positron emission tomography studies in humans was performed. Altogether 85 PET imaging experiments were performed during four separate clinical trials. The repeatability of [11C]ORM-13070 binding was tested in healthy individuals, followed by a study to evaluate the dose-dependent displacement of [11C]ORM-13070 from α2C-adrenoceptors by a competing ligand, and the final two studies examined the sensitivity of [11C]ORM-13070 binding to reflect changes in endogenous noradrenaline levels. The repeatability of [11C]ORM-13070 binding was very high. The binding properties of the tracer allowed for a reliable estimation of α2C-AR occupancy by using the reference tissue ratio method with low test-retest variability. [11C]ORM-13070 was dose-dependently displaced from its specific binding sites by the subtype-nonselective α2-adrenoceptor antagonist atipamezole, and thus it proved suitable for use in clinical drug development of novel α2C-adrenoceptor ligands e.g. to determine the best doses and dosing intervals for clinical trials. Convincing experimental evidence was gained to support the suitability of [11C]ORM-13070 for detecting an increase in endogenous synaptic noradrenaline in the human brain. Tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, although statistical significance was not reached. Thus, the investigation was unable to fully validate [11C]ORM-13070 for the detection of pharmacologically evoked reductions in noradrenaline levels.