Accurate mass-based analysis in human sport doping control : Application of liquid chromatography - time-of-flight mass spectrometry

Human sport doping control analysis is a complex and challenging task for anti-doping laboratories. The List of Prohibited Substances and Methods, updated annually by World Anti-Doping Agency (WADA), consists of hundreds of chemically and pharmacologically different low and high molecular weight compounds. This poses a considerable challenge for laboratories to analyze for them all in a limited amount of time from a limited sample aliquot. The continuous expansion of the Prohibited List obliges laboratories to keep their analytical methods updated and to research new available methodologies. In this thesis, an accurate mass-based analysis employing liquid chromatography - time-of-flight mass spectrometry (LC-TOFMS) was developed and validated to improve the power of doping control analysis. New analytical methods were developed utilizing the high mass accuracy and high information content obtained by TOFMS to generate comprehensive and generic screening procedures. The suitability of LC-TOFMS for comprehensive screening was demonstrated for the first time in the field with mass accuracies better than 1 mDa. Further attention was given to generic sample preparation, an essential part of screening analysis, to rationalize the whole work flow and minimize the need for several separate sample preparation methods. Utilizing both positive and negative ionization allowed the detection of almost 200 prohibited substances. Automatic data processing produced a Microsoft Excel based report highlighting the entries fulfilling the criteria of the reverse data base search (retention time (RT), mass accuracy, isotope match). The quantitative performance of LC-TOFMS was demonstrated with morphine, codeine and their intact glucuronide conjugates. After a straightforward sample preparation the compounds were analyzed directly without the need for hydrolysis, solvent transfer, evaporation or reconstitution. The hydrophilic interaction technique (HILIC) provided good chromatographic separation, which was critical for the morphine glucuronide isomers. A wide linear range (50-5000 ng/ml) with good precision (RSD<10%) and accuracy (±10%) was obtained, showing comparable or better performance to other methods used. In-source collision-induced dissociation (ISCID) allowed confirmation analysis with three diagnostic ions with a median mass accuracy of 1.08 mDa and repeatable ion ratios fulfilling WADA s identification criteria. The suitability of LC-TOFMS for screening of high molecular weight doping agents was demonstrated with plasma volume expanders (PVE), namely dextran and hydroxyethylstarch (HES). Specificity of the assay was improved, since interfering matrix compounds were removed by size exclusion chromatography (SEC). ISCID produced three characteristic ions with an excellent mean mass accuracy of 0.82 mDa at physiological concentration levels. In summary, by combining TOFMS with a proper sample preparation and chromatographic separation, the technique can be utilized extensively in doping control laboratories for comprehensive screening of chemically different low and high molecular weight compounds, for quantification of threshold substances and even for confirmation. LC-TOFMS rationalized the work flow in doping control laboratories by simplifying the screening scheme, expediting reporting and minimizing the analysis costs. Therefore LC-TOFMS can be exploited widely in doping control, and the need for several separate analysis techniques is reduced.

Towards real-time understanding of processes in pharmaceutical powder technology

There is a need for better understanding of the processes and new ideas to develop traditional pharmaceutical powder manufacturing procedures. Process analytical technology (PAT) has been developed to improve understanding of the processes and establish methods to monitor and control processes. The interest is in maintaining and even improving the whole manufacturing process and the final products at real-time. Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. New methods are craved for to increase the quality and safety of the final products faster and more efficiently than ever before. The real-time process monitoring demands tools, which enable fast and noninvasive measurements with sufficient accuracy. Traditional quality control methods have been laborious and time consuming and they are performed off line i.e. the analysis has been removed from process area. Vibrational spectroscopic methods are responding this challenge and their utilisation have increased a lot during the past few years. In addition, other methods such as colour analysis can be utilised in noninvasive real-time process monitoring. In this study three pharmaceutical processes were investigated: drying, mixing and tabletting. In addition tablet properties were evaluated. Real-time monitoring was performed with NIR and Raman spectroscopies, colour analysis, particle size analysis and compression data during tabletting was evaluated using mathematical modelling. These methods were suitable for real-time monitoring of pharmaceutical unit operations and increase the knowledge of the critical parameters in the processes and the phenomena occurring during operations. They can improve our process understanding and therefore, finally, enhance the quality of final products.

Konstrukcija mnimosti : K poètike "Voskovoj persony" Ju. Tynjanova

The subject of this work is the poetics of «The Wax Effigy», a short novel or novella by Jurii Tynianov, Russian writer, literary critic, historian of literature and prominent literary theoretician. The plot structure of the novel is based upon a real event, the creation by Bartolomeo Carlo Rastrelli in 1725 of a wax sculpture of the first Russian emperor, Peter the Great. «Construction of the Sham» consists of three chapters, an introduction and a conclusion. Due to the fact that Tynianov was at the same time a prose writer and theoretician of literature it seemed important to consider the reception of his prose and his works on literary theory in relationship to each other. The introduction is devoted to this task. The first chapter is about the history of the creation of the novel and its reception. Tynianov stopped writing one short story in order to write the novel; these two works have some common traits. It seems almost obvious that his work on the first text was a real step toward the creation of the second. In the first story there is an opposition of dead/alive which is semantic prefiguring of a central motif in «The Wax Effigy». An analysis of the reception of the novel demonstrated that almost every critic writing about the novel has described it as nonsense. Critics considered Tynianov's work in terms of «devices» and «content» and could not understand how devices are related to the content of the novel: the novel was thought as a signifier without any signified. Implicitly, critics thought the signified of the novel as a traditional one of the historical novel, as the historiosophical «idea», embodied in the system of literary devices. In this case literature becomes something instrumental, a kind of expression of extraliterary content. In contradistinction to that Tynianov considered literary semantics as an effect of the literary structure. From his point of view the literary sense is immanent to the process of signification accomplished inside the literary text. The second chapter is devoted to a rhetorical analysis of the opposition dead/alive. Tynianov systematically compares both terms of the opposition. As a result of this strategy the wax effigy of the dead emperor becomes «as if» alive and the world of living people «as if» dead. The qualifier «as if» refers to the fact that Tynianov creates an ambiguous semantic system. This rhetoric is related to European Romanticism and his «fantastic literature» (Merimé, Hoffmann, Maupassant etc.). But Tynianov demonstrates a linguistic origin of the strange fantoms created by romantics; he demystifies these idols by parodying the fantastic literature, that is, showing «how it was done». At the same time, the opposition mentioned above refers to his idea of «incongruity» which plays a prominent role in Tynianov s theory but has never been conceptualised. The incongruity is a inner collision of the literary text; from Tynianov's point of view the meaning of the work of literature is always a dynamic collision of semantically heterogeneous elements struggling with each other. In «The Wax Effigy» Tynianov creates a metalevel of the work demonstrating the process of creation of the literary sense. The third chapter is a reconstruction of Tynianov's conception of the historical prose, specifically of the mechanisms by which historical facts are transformed into literary events. Tynianov thought that the task of the historical novelist is to depict his hero as an actor, to demonstrate that as a wearer of many masks he is a creator of appearances, ambiguities. Here, in the «figure of fiction» (Andrei Belyi), the very idea of the historical prose and rhetoric employed in «The Wax Effigy», history and literature meet each other. In his last theoretical work, «On parody» Tynianov writes about the so-called sham structure of parody. In his opinion every parody is a text about other texts and «serious» work which could be read at the same time as a text about «reality». This twofold structure of parody is that of «The Wax Effigy»: that text speaks about ambiguities of the history and about ambiguities of the literary sense, about social reality of the past and - about the working of the literature itself. «The Wax Effigy» is written as a autoreflective text, as an experiment in literary semantics, as a system of literary ambiguities - of hero, rhetoric and the text itself. The meaning of the novel is created not by the embodiment extraliterary idea, but by the process of signification accomplished inside the work of literature. In this sense Tynianov's novel is parody, a break with the tradition of the historical novel preceding «The Wax Effigy».

Talking About Time in Russian and Finnish

In this study I look at what people want to express when they talk about time in Russian and Finnish, and why they use the means they use. The material consists of expressions of time: 1087 from Russian and 1141 from Finnish. They have been collected from dictionaries, usage guides, corpora, and the Internet. An expression means here an idiomatic set of words in a preset form, a collocation or construction. They are studied as lexical entities, without a context, and analysed and categorized according to various features. The theoretical background for the study includes two completely different approaches. Functional Syntax is used in order to find out what general meanings the speaker wishes to convey when talking about time and how these meanings are expressed in specific languages. Conceptual metaphor theory is used for explaining why the expressions are as they are, i.e. what kind of conceptual metaphors (transfers from one conceptual domain to another) they include. The study has resulted in a grammatically glossed list of time expressions in Russian and Finnish, a list of 56 general meanings involved in these time expressions and an account of the means (constructions) that these languages have for expressing the general meanings defined. It also includes an analysis of conceptual metaphors behind the expressions. The general meanings involved turned out to revolve around expressing duration, point in time, period of time, frequency, sequence, passing of time, suitable time and the right time, life as time, limitedness of time, and some other notions having less obvious semantic relations to the others. Conceptual metaphor analysis of the material has shown that time is conceptualized in Russian and Finnish according to the metaphors Time Is Space (Time Is Container, Time Has Direction, Time Is Cycle, and the Time Line Metaphor), Time Is Resource (and its submapping Time Is Substance), Time Is Actor; and some characteristics are added to these conceptualizations with the help of the secondary metaphors Time Is Nature and Time Is Life. The limits between different conceptual metaphors and the connections these metaphors have with one another are looked at with the help of the theory of conceptual integration (the blending theory) and its schemas. The results of the study show that although Russian and Finnish are typologically different, they are very similar both in the needs of expression their speakers have concerning time, and in the conceptualizations behind expressing time. This study introduces both theoretical and methodological novelties in the nature of material used, in developing empirical methodology for conceptual metaphor studies, in the exactness of defining the limits of different conceptual metaphors, and in seeking unity among the different facets of time. Keywords: time, metaphor, time expression, idiom, conceptual metaphor theory, functional syntax, blending theory

Idyll eller verklighet? : Albert Edelfelt och Gunnar Berndtson i det moderna genombrottets ambivalens

Idyll or Reality? Albert Edelfelt, Gunnar Berndtson and the ambivalent breakthrough of modernity Albert Edelfelt (1854-1905) and Gunnar Berndtson (1854-1895) have much in common. In this dissertation, I study their paintings of local peasants and fishermen and of the gentry’s summer in the county of Uusimaa in southern Finland, in the context of Nordic history of ideas. The breakthrough of modernity, with its attention on debating social problems, provides a novel angle into the oeuvres of the two artists. My focus is on the paintings which emerge in the collision of the public discussion of social matters and the values of the artists’ manorial milieu. The artists’ relation to the public discussion is scrutinized through two of the main topics: the question of the common people and democracy, and the question of equality between men and women. My dissertation is a contextual study which is based on the analysis of the artworks of Edelfelt and Berndtson, on their letters, and on the study of drama and fiction of their time. The notion “liberté, egalité, fraternité” is linked to the breakthrough of modernity. Both artists were aware of the ideal of equality. They used the means and the themes of contemporary art in their presentations, but their pictures contain the ideal of an earlier epoch: the hardworking, but still complacent common people. This conception of the common people is also reflected in the poems of J. L. Runeberg. Women of the late 19th century challenged woman’s primary role as wife and mother. In Edelfelt’s and Berndtson’s depictions of the gentry enjoying summer, women and children have the main role. Notwithstanding the debate of the breakthrough of modernity they depicted women almost without exception as good mothers. Their paintings often depict lazy days in the sunshine, which were, in reality, rare moments for the mistress of the house. Edelfelt’s and Berndtson’s subjects from the Uusimaa countryside coincide with the topics of the breakthrough of modernity, but both the pictures of the common people and the depictions of the gentry enjoying summer, are a retouched picture of reality, often an idyll, in which the public discussion of social matters is evident only materially or not at all.

Methodological and Empirical Advances in the Quantitative Analysis of Spontaneous Responses in Psychophysiological Time Series

The aim of the present study was to advance the methodology and use of time series analysis to quantify dynamic structures in psychophysiological processes and thereby to produce information on spontaneously coupled physiological responses and their behavioral and experiential correlates. Series of analyses using both simulated and empirical cardiac (IBI), electrodermal (EDA), and facial electromyographic (EMG) data indicated that, despite potential autocorrelated structures, smoothing increased the reliability of detecting response coupling from an interindividual distribution of intraindividual measures and that especially the measures of covariance produced accurate information on the extent of coupled responses. This methodology was applied to analyze spontaneously coupled IBI, EDA, and facial EMG responses and vagal activity in their relation to emotional experience and personality characteristics in a group of middle-aged men (n = 37) during the administration of the Rorschach testing protocol. The results revealed new characteristics in the relationship between phasic end-organ synchronization and vagal activity, on the one hand, and individual differences in emotional adjustment to novel situations on the other. Specifically, it appeared that the vagal system is intimately related to emotional and social responsivity. It was also found that the lack of spontaneously synchronized responses is related to decreased energetic arousal (e.g., depression, mood). These findings indicate that the present process analysis approach has many advantages for use in both experimental and applied research, and that it is a useful new paradigm in psychophysiological research. Keywords: Autonomic Nervous System; Emotion; Facial Electromyography; Individual Differences; Spontaneous Responses; Time Series Analysis; Vagal System

Yhteisöllisyys voimavarana yliopisto-opetuksen ja -opiskelun kehittämisessä

A sense of community as a resource for developing university teaching and learning The aim of this doctoral research was to determine how a sense of community can be a resource for developing university teaching and learning. The theoretical background is linked to social sciences, social psychology, university pedagogy and educational sciences. The thesis is comprised of two separate studies. Study I consisted of an action research project in which a model of cooperatively developing a teaching and learning culture was created and tested. The focus of study I was the university pedagogy programme of the Faculty of Agriculture and Forestry. The results demonstrated that the theoretical framework and the methods of cooperative learning provide useful tools for developing an academic learning and teaching culture. The approach helps to create a benevolent learning atmosphere. The cooperative learning culture used in the action research project reflected the traditional academic learning culture and also caused a collision between the two cultures. The aim of study II was to determine how Open University students and Bachelor’s degree students experience their teaching-learning environment and the importance of the learning community and peer support to their studies. The results indicated that, with the exception of support from other students, the Open University students experienced their teaching-learning environments on average more positively than the Bachelor’s degree students. According to the Open University students, their own motivation and interest was the most important factor that enhanced studying. Furthermore, the most common factors delaying their studies were their life situation and a lack of time. The sense of community and social relations mainly promoted studying. Open University students experienced that they were supported by their teachers, tutors, other students, the working community, family and hobbies. The research demonstrated that the methods that make good use of communal resources are negotiation of shared goals and rules, working in various small groups, emphasis on shared and individual responsibilities and assessment of the product and the process of learning. The resources of the academic community can be developed if the members of the community develop, in addition to the communal working methods, their communal sensitivity. In other words, they should have an understanding of social psychological and sociological concepts that they can use for observing communal phenomena.

Effect of waiting time on health outcomes and service utilization : A prospective randomized study on patients admitted to hospital for hip or knee replacement

Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services

Management of multi-scale forest resource data over time

During the last decades there has been a global shift in forest management from a focus solely on timber management to ecosystem management that endorses all aspects of forest functions: ecological, economic and social. This has resulted in a shift in paradigm from sustained yield to sustained diversity of values, goods and benefits obtained at the same time, introducing new temporal and spatial scales into forest resource management. The purpose of the present dissertation was to develop methods that would enable spatial and temporal scales to be introduced into the storage, processing, access and utilization of forest resource data. The methods developed are based on a conceptual view of a forest as a hierarchically nested collection of objects that can have a dynamically changing set of attributes. The temporal aspect of the methods consists of lifetime management for the objects and their attributes and of a temporal succession linking the objects together. Development of the forest resource data processing method concentrated on the extensibility and configurability of the data content and model calculations, allowing for a diverse set of processing operations to be executed using the same framework. The contribution of this dissertation to the utilisation of multi-scale forest resource data lies in the development of a reference data generation method to support forest inventory methods in approaching single-tree resolution.

Stiffer Optical Tweezers through Real-Time Feedback Control

This thesis integrates real-time feedback control into an optical tweezers instrument. The goal is to reduce the variance in the trapped bead s position, -effectively increasing the trap stiffness of the optical tweezers. Trap steering is done with acousto-optic deflectors and control algorithms are implemented with a field-programmable gate array card. When position clamp feedback control is on, the effective trap stiffness increases 12.1-times compared to the stiffness without control. This allows improved spatial control over trapped particles without increasing the trapping laser power.

Power Aware Real Time Scheduling in Constrained Devices

Real-time scheduling algorithms, such as Rate Monotonic and Earliest Deadline First, guarantee that calculations are performed within a pre-defined time. As many real-time systems operate on limited battery power, these algorithms have been enhanced with power-aware properties. In this thesis, 13 power-aware real-time scheduling algorithms for processor, device and system-level use are explored.