Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.

Interactions of natural products with β-lactoglobulins, members of the lipocalin family

Natural products constitute an important source of new drugs. The bioavailability of the drugs depends on their absorption, distribution, metabolism and elimination. To achieve good bioavailability, the drug must be soluble in water, stable in the gastrointestinal tract and palatable. Binding proteins may improve the solubility of drug compounds, masking unwanted properties, such as bad taste, bitterness or toxicity, transporting or protecting these compounds during processing and storage. The focus of this thesis was to study the interactions, including ligand binding and the effect of pH and temperature, of bovine and reindeer β-lactoglobulin (βLG) with such compounds as retinoids, phenolic compounds as well as with compounds from plant extracts, and to investigate the transport properties of the βLG-ligand complex. To examine the binding interactions of different ligands to βLG, new methods were developed. The fluorescence binding method for the evaluation of ligand binding to βLG was miniaturized from a quartz cell to a 96-well plate. A method of ultrafiltration sampling combined with high-performance liquid chromatography was developed to assess the binding of compounds from extracts. The interactions of phenolic compounds or retinoids and βLG were investigated using the 96-well plate method. The majority of flavones, flavonols, flavanones and isoflavones and all of the retinoids included were shown to bind to bovine and reindeer βLG. Phenolic compounds, contrary to retinol, were not released at acidic pH. Those results suggest that βLG may have more binding sites, probably also on the surface of βLG. An extract from Camellia sinensis (L.) O. Kunze (black tea), Urtica dioica L. (nettle) and Piper nigrum (black pepper) were used to evaluate whether βLG could bind compounds from plant extracts. Piperine from P. nigrum was found to bind tightly and rutin from U. dioica weakly to βLG. No components from C. sinensis bound to βLG in our experiment. The uptake and membrane permeation of bovine and reindeer βLG, free and bound with retinol, palmitic acid and cholesterol, were investigated using Caco-2 cell monolayers. Both bovine and reindeer βLG were able to cross the Caco-2 cell membrane. Free and βLG-bound retinol and palmitic acid were transported equally, whereas cholesterol could not cross the Caco-2 cell monolayer free or bound to βLG. Our results showed that βLG can bind different natural product compounds, but cannot enhance transport of retinol, palmitic acid or cholesterol through Caco-2 cells. Despite this, βLG, as a water-soluble binding protein, may improve the solubility of natural compounds, possibly protecting them from early degradation and transporting some of them through the stomach. Furthermore, it may decrease their bad or bitter taste during oral administration of drugs or in food preparations. βLG can also enhance or decrease the health benefits of herbal teas and food preparations by binding compounds from extracts.

External signal-activated liposomal drug delivery systems

Modern drug discovery gives rise to a great number of potential new therapeutic agents, but in some cases the efficient treatment of patient may not be achieved because the delivery of active compounds to the target site is insufficient. Thus, drug delivery is one of the major challenges in current pharmaceutical research. Numerous nanoparticle-based drug carriers, e.g. liposomes, have been developed for enhanced drug delivery and targeting. Drug targeting may enhance the efficiency of the treatment and, importantly, reduce unwanted side effects by decreasing drug distribution to non-target tissues. Liposomes are biocompatible lipid-based carriers that have been studied for drug delivery during the last 40 years. They can be functionalized with targeting ligands and sensing materials for triggered activation. In this study, various external signal-assisted liposomal delivery systems were developed. Signals can be used to modulate drug permeation or release from the liposome formulation, and they provide accurate control of time, place and rate of activation. The study involved three types of signals that were used to trigger drug permeation and release: electricity, heat and light. Electrical stimulus was utilized to enhance the permeation of liposomal DNA across the skin. Liposome/DNA complex-mediated transfections were performed in tight rat epidermal cell model. Various transfection media and current intensities were tested, and transfection efficiency was evaluated non-invasively by monitoring the concentration of secreted reporter protein in cell culture medium. Liposome/DNA complexes produced gene expression, but electrical stimulus did not enhance the transfection efficiency significantly. Heat-sensitive liposomal drug delivery system was developed by coating liposomes with biodegradable and thermosensitive poly(N-(2-hydroxypropyl) methacrylamide-mono/dilactate polymer. Temperature-triggered liposome aggregation and contents release from liposomes were evaluated. The cloud point temperature (CP) of the polymer was set to 42 °C. Polymer-coated liposome aggregation and contents release were observed above CP of the polymer, while non-coated liposomes remained intact. Polymer precipitates above its CP and interacts with liposomal bilayers. It is likely that this induces permeabilization of the liposomal membrane and contents release. Light-sensitivity was introduced to liposomes by incorporation of small (< 5 nm) gold nanoparticles. Hydrophobic and hydrophilic gold nanoparticles were embedded in thermosensitive liposomes, and contents release was investigated upon UV light exposure. UV light-induced lipid phase transitions were examined with small angle X-ray scattering, and light-triggered contents release was shown also in human retinal pigment epithelial cell line. Gold nanoparticles absorb light energy and transfer it into heat, which induces phase transitions in liposomes and triggers the contents release. In conclusion, external signal-activated liposomes offer an advanced platform for numerous applications in drug delivery, particularly in the localized drug delivery. Drug release may be localized to the target site with triggering stimulus that results in better therapeutic response and less adverse effects. Triggering signal and mechanism of activation can be selected according to a specific application.

Thin-Layer Chromatography with Ultraviolet and Mass Spectrometric Detection: From Preparative-Layer to Miniaturized Ultra-Thin-Layer Technique

The present challenge in drug discovery is to synthesize new compounds efficiently in minimal time. The trend is towards carefully designed and well-characterized compound libraries because fast and effective synthesis methods easily produce thousands of new compounds. The need for rapid and reliable analysis methods is increased at the same time. Quality assessment, including the identification and purity tests, is highly important since false (negative or positive) results, for instance in tests of biological activity or determination of early-ADME parameters in vitro (the pharmacokinetic study of drug absorption, distribution, metabolism, and excretion), must be avoided. This thesis summarizes the principles of classical planar chromatographic separation combined with ultraviolet (UV) and mass spectrometric (MS) detection, and introduces powerful, rapid, easy, low-cost, and alternative tools and techniques for qualitative and quantitative analysis of small drug or drug-like molecules. High performance thin-layer chromatography (HPTLC) was introduced and evaluated for fast semi-quantitative assessment of the purity of synthesis target compounds. HPTLC methods were compared with the liquid chromatography (LC) methods. Electrospray ionization mass spectrometry (ESI MS) and atmospheric pressure matrix-assisted laser desorption/ionization MS (AP MALDI MS) were used to identify and confirm the product zones on the plate. AP MALDI MS was rapid, and easy to carry out directly on the plate without scraping. The PLC method was used to isolate target compounds from crude synthesized products and purify them for bioactivity and preliminary ADME tests. Ultra-thin-layer chromatography (UTLC) with AP MALDI MS and desorption electrospray ionization mass spectrometry (DESI MS) was introduced and studied for the first time. Because of the thinner adsorbent layer, the monolithic UTLC plate provided 10 100 times better sensitivity in MALDI analysis than did HPTLC plates. The limits of detection (LODs) down to low picomole range were demonstrated for UTLC AP MALDI and UTLC DESI MS. In a comparison of AP and vacuum MALDI MS detection for UTLC plates, desorption from the irregular surface of the plates with the combination of an external AP MALDI ion source and an ion trap instrument provided clearly less variation in mass accuracy than the vacuum MALDI time-of-flight (TOF) instrument. The performance of the two-dimensional (2D) UTLC separation with AP MALDI MS method was studied for the first time. The influence of the urine matrix on the separation and the repeatability was evaluated with benzodiazepines as model substances in human urine. The applicability of 2D UTLC AP MALDI MS was demonstrated in the detection of metabolites in an authentic urine sample.

Liquid Chromatography-Mass Spectrometry in Studies of Drug Metabolism and Permeability

Poor pharmacokinetics is one of the reasons for the withdrawal of drug candidates from clinical trials. There is an urgent need for investigating in vitro ADME (absorption, distribution, metabolism and excretion) properties and recognising unsuitable drug candidates as early as possible in the drug development process. Current throughput of in vitro ADME profiling is insufficient because effective new synthesis techniques, such as drug design in silico and combinatorial synthesis, have vastly increased the number of drug candidates. Assay technologies for larger sets of compounds than are currently feasible are critically needed. The first part of this work focused on the evaluation of cocktail strategy in studies of drug permeability and metabolic stability. N-in-one liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods were developed and validated for the multiple component analysis of samples in cocktail experiments. Together, cocktail dosing and LC/MS/MS were found to form an effective tool for increasing throughput. First, cocktail dosing, i.e. the use of a mixture of many test compounds, was applied in permeability experiments with Caco-2 cell culture, which is a widely used in vitro model for small intestinal absorption. A cocktail of 7-10 reference compounds was successfully evaluated for standardization and routine testing of the performance of Caco-2 cell cultures. Secondly, cocktail strategy was used in metabolic stability studies of drugs with UGT isoenzymes, which are one of the most important phase II drug metabolizing enzymes. The study confirmed that the determination of intrinsic clearance (Clint) as a cocktail of seven substrates is possible. The LC/MS/MS methods that were developed were fast and reliable for the quantitative analysis of a heterogenous set of drugs from Caco-2 permeability experiments and the set of glucuronides from in vitro stability experiments. The performance of a new ionization technique, atmospheric pressure photoionization (APPI), was evaluated through comparison with electrospray ionization (ESI), where both techniques were used for the analysis of Caco-2 samples. Like ESI, also APPI proved to be a reliable technique for the analysis of Caco-2 samples and even more flexible than ESI because of the wider dynamic linear range. The second part of the experimental study focused on metabolite profiling. Different mass spectrometric instruments and commercially available software tools were investigated for profiling metabolites in urine and hepatocyte samples. All the instruments tested (triple quadrupole, quadrupole time-of-flight, ion trap) exhibited some good and some bad features in searching for and identifying of expected and non-expected metabolites. Although, current profiling software is helpful, it is still insufficient. Thus a time-consuming largely manual approach is still required for metabolite profiling from complex biological matrices.

Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Japanese Video Game Localization : A Case Study of Sony's Sairen Series

This thesis is a comparative case study in Japanese video game localization for the video games Sairen, Sairen 2 and Sairen Nyûtoransurêshon, and English-language localized versions of the same games as published in Scandinavia and Australia/New Zealand. All games are developed by Sony Computer Entertainment Inc. and published exclusively for Playstation2 and Playstation3 consoles. The fictional world of the Sairen games draws much influence from Japanese history, as well as from popular and contemporary culture, and in doing so caters mainly to a Japanese audience. For localization, i.e. the adaptation of a product to make it accessible to users outside the original market it was intended for in the first place, this is a challenging issue. Video games are media of entertainment, and therefore localization practice must preserve the games’ effects on the players’ emotions. Further, video games are digital products that are comprised of a multitude of distinct elements, some of which are part of the game world, while others regulate the connection between the player as part of the real world and the game as digital medium. As a result, video game localization is also a practice that has to cope with the technical restrictions that are inherent to the medium. The main theory used throughout the thesis is Anthony Pym’s framework for localization studies that considers the user of the localized product as a defining part of the localization process. This concept presupposes that localization is an adaptation that is performed to make a product better suited for use during a specific reception situation. Pym also addresses the factor that certain products may resist distribution into certain reception situations because of their content, and that certain aspects of localization aim to reduce this resistance through significant alterations of the original product. While Pym developed his ideas with mainly regular software in mind, they can also be adapted well to study video games from a localization angle. Since modern video games are highly complex entities that often switch between interactive and non-interactive modes, Pym’s ideas are adapted throughout the thesis to suit the particular elements being studied. Instances analyzed in this thesis include menu screens, video clips, in-game action and websites. The main research questions focus on how the games’ rules influence localization, and how the games’ fictional domain influences localization. Because there are so many peculiarities inherent to the medium of the video game, other theories are introduced as well to complement the research at hand. These include Lawrence Venuti’s discussions of foreiginizing and domesticating translation methods for literary translation, and Jesper Juul’s definition of games. Additionally, knowledge gathered from interviews with video game localization professionals in Japan during September and October 2009 is also utilized for this study. Apart from answering the aforementioned research questions, one of this thesis’ aims is to enrich the still rather small field of game localization studies, and the study of Japanese video games in particular, one of Japan’s most successful cultural exports.

Vyra enie obob čёnno-ličnogo značenija v russkom jazyke

Expressing generalized-personal meaning in Russian Based on data from Russian, this doctoral dissertation examines generalized-personal meaning that is, generic expressions referring to all human beings, people in general, each or any person (e.g. S vozrastom načinae cenit prostye ve či With age you start to appreciate simple things ). The study shares its basic theoretical orientation with functional approaches going from meaning to form . The objective of the thesis is to determine and describe the various linguistic means which can be used by the speaker to express generalized-personal meaning. The main material of the study consists of 2,000 examples collected from modern Russian literature, newspapers, and magazines. The linguistic means of expressing generalized-personal meaning are divided into three main classes. Morphological and lexico-grammatical means (22% of the material) include the use of personal pronouns and personal verbal endings. In Russian, all personal forms except the 3rd person singular can be used in a generalized-personal meaning. Lexical means (14% of the material) involve, above all, pronouns like vse all , ka dyj everyone , nikto no one , as well as the nouns čelovek man and ljudi people . In emotional speech, generalized-personal meaning can also be conveyed lexically by using utterances like da e idiot znaet even an idiot knows . In rhetorical questions the pronoun kto who can appear in this meaning (cf. Kto ne ljubit moro enoe?! Who doesn t like ice cream?! ). The third main class, syntactic means (64% of the material), consists of constructions in which the generic person is not expressed at the surface level. This class mainly includes two-component structures in which the infinitive relates to a modal predicative adverb (e.g. mo no can, be allowed to , nado must ), modal verb (e.g. stoit be worth(while) , sleduet must, be obliged to ), or predicative adverb ending in -о (e.g. trudno it is hard to , neprilično is not appropriate ). Other syntactic means are: one-component infinitive structures, so-called embedded structures, structures with a processual noun, passive constructions, and gerund constructions. The different forms of expression available in Russian are not interchangeable in all contexts. Even if a given context tolerates the substitution of one construction for another, the two expressions are never entirely synonymous. In addition to determining the range of forms which can express generalized-personal meaning, the study aims to compare these forms and to specify the conditions and possible restrictions (contextual, semantic, syntactic, stylistic, etc.) associated with the use of each construction. In Russian linguistics, the generalized-personal meaning has not been extensively studied from a functional perspective. The advantage of a meaning-based functional approach is that it gives a comprehensive picture of the diversity and distribution of the phenomenon.

Suomen rautakautiset kulkuset, kellot ja kelloriipukset : äänimaiseman arkeologiaa

The thesis addresses the problem of Finnish Iron Age bells, pellet bells and bell pendants, previously unexplored musical artefacts from 400–1300 AD. The study, which contributes to the field of music archaeology, aims to provide a gateway to ancient soundworlds and ideas of music making. The research questions include: Where did these metal artefacts come from? How did they sound? How were they used? What did their sound mean to the people of the Iron Age? The data collected at the National Museum of Finland and at several provincial museums covers a total of 486 bells, pellet bells and bell pendants. By means of a cluster analysis, each category was divided into several subgroups. The subgroups, which all seem to have a different dating and geographical distribution, represent a spread of both local and international manufacturing traditions. According to an elemental analysis, the material varies from iron to copper-tin, copper-lead and copper-tin-lead alloys. Clappers, pellets and pebbles prove that the bells and pellet bells were indisputably instruments intended for sound production. Clusters of small bell pendants, however, probably produced sound by jingling against each other. Spectrogram plots reveal that the partials of the still audible sounds range from 1 000 to 19 850 Hz. On the basis of 129 inhumation graves, hoards, barrows and stray finds, it seems evident that the bells, pellet bells and bell pendants were fastened to dresses and horse harnesses or carried in pouches and boxes. The resulting acoustic spaces could have been employed in constructing social hierarchies, since the instruments usually appear in richly furnished graves. Furthermore, the instruments repeatedly occur with crosses, edge tools and zoomorphic pendants that in the later Finnish-Karelian culture were regarded as prophylactic amulets. In the Iron Age as well as in later folk culture, the bell sounds seem to have expressed territorial, social and cosmological boundaries.

Kirjan tie lukijalle : Kirjakauppojen vakiintuminen Suomessa 1740 - 1860

Books Paths to Readers describes the history of the origins and consolidation of modern and open book stores in Finland 1740 1860. The thesis approaches the book trade as a part of a print culture. Instead of literary studies choice to concentrate on texts and writers, book history seeks to describe the print culture of a society and how the literary activities and societies interconnect. For book historians, printed works are creations of various individuals and groups: writers, printers, editors, book sellers, censors, critics and finally, readers. They all take part in the creation, delivery and interpretation of printed works. The study reveals the ways selling and distributing books have influenced the printed works and the literary and print culture. The research period 1740 1860 covers the so-called second revolution of the book, or the modernisation of the print culture. The thesis describes the history of 60 book stores and their 96 owners. The study concentrates on three themes: firstly, how the particular book trade network became a central institution for printed works distribution, secondly what were the relations between cosmopolitan European book markets and the national cultural sphere, and thirdly how book stores functioned as cultural institutions and business enterprises. Book stores that have a varied assortment and are targeted to all readers became the main institution for book trade in Finland during 1740 1860. It happened because of three features. First, the book binders monopoly on selling bound copies in Sweden was abolished in 1740s. As a consequence entrepreneurs could concentrate solely to trade activities and offer copies from various publishers at their stores. Secondly the common business model of bartering was replaced by selling copies for cash, first in the German book trade centre Leipzig in 1770s. The change intensified book markets activities and Finnish book stores foreign connections. Thirdly, after Finland was annexed to the Russian empire in 1809, the Grand duchy s administration steered foreign book trade to book stores (because of censorship demands). Up to 1830 s book stores were available only in Helsinki and Turku. During next ten years book stores opened in six regional centres. The early entrepreneurs ran usually vertical businesses consisting of printing, publishing and distribution activities. This strategy lowered costs, eased the delivery of printed works and helped to create elaborated centres for all book activities. These book stores main clientele consisted of the Swedish speaking gentry. During late 1840s various opinion leaders called for the development of a national Finnish print culture, and also book stores. As a result, during the five years before the beginning of the Crimean war (1853 1856) book stores were opened in almost all Finnish towns: at the beginning of the war 36 book stores operated in 21 towns. The later book sellers, mainly functioning in small towns among Finnish speaking people, settled usually strictly for selling activities. Book stores received most of their revenues from selling foreign titles. Swedish, German, French and Belgian (pirate editions of popular French novels) books were widely available for the multilingual gentry. Foreign titles and copies brought in most of the revenues. Censorship inspections or unfavourable custom fees would not limit the imports. Even if the local Finnish print production steadily rose, many copies, even titles, were never delivered via book stores. Only during the 1840 s and 1850 s the most advanced publishers would concentrate on creating publishing programmes and delivering their titles via book stores. Book sellers regulated commissions were small. They got even smaller because of large amounts of unsold copies, various and usual misunderstandings of consignments and accounts or plain accidents that destroyed shipments and warehouses. Also, the cultural aim of a creating large and assortments and the tendency of short selling periods demanded professional entrepreneurship, which many small town book sellers however lacked. In the midst of troublesome business efforts, co-operation and mutual concern of the book market s entrepreneurs were the key elements of the trade, although on local level book sellers would compete, sometimes even ferociously. The difficult circumstances (new censorship decree of 1850, Crimean war) and lack of entrepreneurship, experience and customers meant that half of the book stores opened in 1845 1860 was shut in less than five years. In 1858 the few leading publishers established The Finnish Book Publishers Association. Its first task was to create new business rules and manners for the book trade. The association s activities began to professionalise the whole network, but at the same time the earlier independence of regional publishing and selling enterprises diminished greatly. The consolidation of modern and open book store network in Finland is a history of a slow and complex development without clear signs of a beginning or an end. The ideal book store model was rarely accomplished in its all features. Nevertheless, book stores became the norm of the book trade. They managed to offer larger selections, reached larger clienteles and maintained constant activity better than any other book distribution model. In essential, the book stores methods have not changed up to present times.

Naiset rajalla : Kyöpeli, Nainen, Naara(s), Neitsyt, Morsian, Akka ja Ämmä Suomen paikannimissä

Women at the boundary. Kyöpeli ( ghost, devil, elf, fairy, enchantress, witch ), Nainen ( woman ), Naara(s) ( female animal, derogatory term for a woman ), Neitsyt ( young, [virgin] woman ), Morsian ( bride ), Akka ( old woman, wife, grandmother ) and Ämmä ( [old] woman, wife, grandmother ) in Finnish place names This study examines a total of about 4,000 Finnish place names which include a specific that refers to a woman: Kyöpeli, Nainen, Naara(s), Neitsyt, Morsian, Akka or Ämmä. The study has two main objectives. First, to interpret the place names in the data, that is, to examine the words included in the data and establish their background and to differentiate names of different ages. In establishing the background of a name, the type of place (e.g. lake, hill or marsh) and its location, as well as the semantics of the feminine specific, are taken into account. The connotations of words referring to a woman are also studied. Words that refer to a woman are often affective and susceptible to changes in meaning, which is reflected in the history of place names. The second main objective is to recognise and highlight mythological place names. Mythology is pivotal for the interpretation of many place names with a feminine specific. The criteria for mythological names have not been explicitly discussed in Finnish onomastics until now, and I seek to determine such criteria in this study with the help of the data. Mythological place names often refer to large and significant natural localities, which are in many cases important boundaries for the community. Names for smaller localities may also be mythological if they refer to a place with a key location or a special topography (e.g. steep or rocky places). I also discuss the stories involved with specific places in the data, such as stories about supernatural beings. Each of the name groups discussed in the study has its own profile. For example, Naara(s) names are so old that naara is no longer understood to refer to a woman. These names have thus often been misinterpreted in onomastics. Names beginning with Morsian, on the other hand, appear to be of fairly recent origin and may be attributed to an international cautionary tale. Names beginning with Nais, Neitsyt, Akka and Ämmä highlight the duality of the data. They include both old names for important natural localities or boundaries and more recent names for modest dwellings, small cultivated areas and useless marshy ponds. This distribution of place names may reflect a cultural shift that changed the status of women in the community.

A sequential analysis of "nú" and "núna" in Icelandic conversation

This thesis is an empirical study of how two words in Icelandic, "nú" and "núna", are used in contemporary Icelandic conversation. My aims in this study are, first, to explain the differences between the temporal functions of "nú" and "núna", and, second, to describe the non-temporal functions of "nú". In the analysis, a focus is placed on comparing the sequential placement of the two words, on their syntactical distribution, and on their prosodic realization. The empirical data comprise 14 hours and 11 minutes of naturally occurring conversation recorded between 1996 and 2003. The selected conversations represent a wide range of interactional contexts including informal dinner parties, institutional and non-institutional telephone conversations, radio programs for teenagers, phone-in programs, and, finally, a political debate on television. The theoretical and methodological framework is interactional linguistics, which can be described as linguistically oriented conversation analysis (CA). A comparison of "nú" and "núna" shows that the two words have different syntactic distributions. "Nú" has a clear tendency to occur in the front field, before the finite verb, while "núna" typically occurs in the end field, after the object. It is argued that this syntactic difference reflects a functional difference between "nú" and "núna". A sequential analysis of "núna" shows that the word refers to an unspecified period of time which includes the utterance time as well as some time in the past and in the future. This temporal relation is referred to as reference time. "Nú", by contrast, is mainly used in three different environments: a) in temporal comparisons, 2) in transitions, and 3) when the speaker is taking an affective stance. The non-temporal functions of "nú" are divided into three categories: a) "nú" as a tone particle, 2) "nú" as an utterance particle, and 3) "nú" as a dialogue particle. "Nú" as a tone particle is syntactically integrated and can occur in two syntactic positions: pre-verbally and post-verbally. I argue that these instances are employed in utterances in which a speaker is foregrounding information or marking it as particularly important. The study shows that, although these instances are typically prosodically non-prominent and unstressed, they are in some cases delivered with stress and with a higher pitch than the surrounding talk. "Nú" as an utterance particle occurs turn-initially and is syntactically non-integrated. By using "nú", speakers show continuity between turns and link new turns to prior ones. These instances initiate either continuations by the same speaker or new turns after speaker shifts. "Nú" as a dialogue particle occurs as a turn of its own. The study shows that these instances register informings in prior turns as unexpected or as a departure from the normal state of affairs. "Nú" as a dialogue particle is often delivered with a prolonged vowel and a recognizable intonation contour. A comparative sequential and prosodic analysis shows that in these cases there is a correlation between the function of "nú" and the intonation contour by which it is delivered. Finally, I argue that despite the many functions of "nú", all the instances can be said to have a common denominator, which is to display attention towards the present moment and the utterances which are produced prior or after the production of "nú". Instead of anchoring the utterances in external time or reference time, these instances position the utterance in discourse internal time, or discourse time.

Toiminta ja tarkoite : Tutkimus suomen pronominista

The study describes the use and meaning of the Finnish demonstrative pronouns, focus being on the pronoun "tämä" (roughly 'this'). The Finnish demonstrative system is a three way one, the other two demonstratives are "tuo" ('that') and "se" ('it'). The data consisted of 12 half hours of video- and tape-recorded face-to-face and telephone conversations. The method for the study was ethnomethodological conversation analysis (CA); in addition to CA, the theoretical framework consisted of functional linguistics and linguistic anthropology. First, the study dealt with the syntactic distribution of the three demonstratives. The pronouns were analysed according to whether they are before or after the verb, and whether they compose an NP on their own or are determinants of a lexical NP. The study suggested that the form and the placement of the NP presents the referent as continuous/discontinuous or given/new. Givenness of a referent was defined as "identified adequately for the purposes of the on-going action". The so-called dislocated utterances were considered separately. It was found that left-dislocations are used for inserting referents in a particular relation to the on-going activity. Right-dislocations offer a solution for the sometimes competing motivations of newness and continuity: they are used for securing the identifiability of a referent that is implied to be continuous. Second, the study focussed on analysing the meaning of the pronouns according to three dimensions of reference: referential, indexical and relational. It was found that the demonstratives can organize interactional or spatial context. When organizing interactional context, the demonstrative pronouns express the role of identifying the referent in relation to the on-going activity. The pronoun "tämä" expresses that the referent is referentially open and the characterization of the referent is given in the on-going turn. Furthermore, it expresses asymmetry of the indexical ground: it expresses that the participants of a conversation do not share a mutual understanding of the activity at that particular time. In addition, the referent of the pronoun "tämä" is central for understanding the on-going action. Centrality could be understood as the relational feature of the pronoun. However, it is a consequence of the referential and indexical features of "tämä". The pronoun "tuo" also expresses referential openness, but it implies indexical symmetry. The pronoun "se" implies that the referent is known enough, and implies indexical symmetry. When used spatially, the pronouns may refer to a physical space or to a situation. They express or imply that the speaker is inside or outside the referent. The pronoun "tämä" implies inclusion, and the pronoun "tuo" expresses exclusion.

Käsityksistä ajatuksen poluille : Ammattikorkeakoulun tutkimus- ja kehitystoiminnan kehittäminen

This study deals with the formation of the idea of research and development (r&d) activity at one particular university of applied sciences in Finland. In this study I proceed from examining the conceptions of management regarding r&d-activities to exploring the development of the complex concept that guides these r&d-activities. The aim of this study is, first, to describe conceptions of r&d-activities, and then, second, to describe the formation of a new concept for r&d-activities in one field of study at the university of applied sciences. I used phenomenographic analysis to elucidate the conceptions and collected the data in interviews of personnel (22) who belong to the management of the university of applied sciences. The data for analysing the obstacles faced and the ways of overcoming them during the formation process of the new concept consist of the video-recorded material from ten change laboratory sessions held for the specific field of study at the university of applied sciences. In researching the formation of the concept of the activity, such research and analysis methods are used in which the concept is understood as a material construction, and with the help of which one can work out the formation of the concept during the development process. When the systematic development of the r&d-work was underway, the management of the university of applied sciences held differing views regarding the content, target, factors and organisation of the r&d-activities, as well as regarding the position of dissertations as a part of r&d-activity. Obstacles for developing rd concerned the unclear object and outcomes of the new activity, not having the tools (such as adequate know-how) for the new activity and not having found the necessary solutions for the distribution of work. In addition the rules that quide the activities of the university of applied sciences did not support working according to the new way. To improve r&d-activity, the school’s management defined three development strategies to encourage adequate rd-activity to support working life, regional development and learning. The strategies were based on the expansion of existing methods, such as service activities, dissertation work and the research activities of the teachers. Of the three possible routes, the concept of dissertation in this study was expanded to integrate the services of organisation development and the occupational growth of the students. A group of teachers in the field of social and health studies participated in the development work. The change laboratory method was used as a tool for this work. Analysis of the cognitive trails indicated that, in addition to the cycle of expansive learning activities, microcycles with different purposes can exist. According to Cussins (1992), something already in existence in each microcycle is destabilised, and something else is stabilised to replace it. In this study three microcycles were identified, during which the teachers first destabilised the existing concepts of dissertation work that guided their thinking, and then began to use new concepts to structure their thinking. Secondly, they undermined the existing concepts with material structure that defined their practical work, and developed new practical models to replace them. Thirdly, the problems accumulating in researching and testing the new activities caused the developers to destabilise the r&d-strategies of the university of applied sciences and to define a new conceptual model for r&d-work in the field. During this third cycle, the teachers developed a research arena model, which was a significant expansive innovation. In the cognitive trails developing the new concept for the r&d-activity, the teachers indeed faced the obstacles the management had described as their conceptions. These obstacles manifested themselves as contradictions. During the development process, the nature of the obstacles (i.e. contradictions) changed as the development proceeded. Solving the first and second degree contradictions highlighted the third and fourth degree contradictions. To overcome the obstacles, the teachers had to to articulate the value and motive of the development work throughout the development process. Developing the new concept for r&d-activity required many reconfigurations of practical solutions to overcome the obstacles. Developing the new concept for r&d-activity, both at the level of representations and of new practices, requires universities of applied sciences to adopt new methods in which the actors are partake in construction of new concepts of activity through adequate discussion, analysis and debate. R&d -activity can progress, if instead of implementing partial solutions, the totality of the activities (i.e. the group of partial solutions acting together) will be constructed. The development of the activity system requires many simultaneous changes as well as wide-ranging know-how and discussion related to these changes. What is perhaps most important, however, is that the group of developers mature into a determined collective actor which can engage in many agentive actions. The development of the agency is fundamental to progress.