Upregulation and Functionality of Neuronal Nicotinic Acetylcholine Receptors

Cigarette smoking is, in developed countries, the leading cause of premature death. In tobacco smoke, the main addictive compound is nicotine, which in the brain binds to neuronal nicotinic acetylcholine receptors (neuronal nAChRs). These have been implicated in addiction, but also in several neurological disorders including Alzheimer's and Parkinson's diseases, Tourette's syndrome, attention-deficit hyperactivity disorder (ADHD), schizophrenia, pain, depression, and autosomal-dominant noctural frontal lobe epilepsy; all of which makes nAChRs an intriguing target of study. Chronic treatment with nicotine leads to an increase in the number of nAChRs (upregulation) in the brain and changes their functionality. Changes in the properties of nAChRs are likely to occur in smokers as well, since they are exposed to nicotine for long periods of time. Several nAChR subtypes likely play a role in the formation of nicotine addiction by participating in the release of dopamine in the striatum. The aim of this study was to clarify at cellular level the changes in nAChR characteristics resulting from chronic nicotine treatment. SH-SY5Y cells, endogenously several nAChR-expressing, and SH-EP1-h-alfa7 cells, transfected with the alfa 7 nAChR subunit gene were treated chronically with nicotine. The localisation of alfa 7 and beta2 subunits was studied with confocal and electron microscopy. Functionality of nAChRs was studied with calcium fluorometry. Effects of long-term treatment with opioid compounds on nAChRs were studied by means of ligand binding. Confocal microscopy showed that in SH-SY5Y cells, alfa7 and beta2 subunits formed clusters, unlike the case in SH-EP1-h alfa7 cells, where alfa7 nAChRs were distributed more diffusely. The majority of nAChR subunits localised on endoplasmic reticulum (ER). The isomers of methadone acted as agonists at alfa7 nAChRs. Acute morphine challenge also stimulated nAChRs. Chronic treatment with methadone or morphine led to an increased number of nAChRs. In animal studies, mice received nicotine for 7 weeks. Electron microscopical analysis of the localisation of nAChRs showed in the striatum that alfa7 and beta2 nAChR subunits localised synaptically, extrasynaptically, and intracellularly, with the majority localising extrasynaptically. Chronic nicotine treatment caused an increase in the number of nAChR subunits at all studied locations. These results suggest that the alfa7 nAChR and beta2 subunit-containing nAChRs respond to chronic nicotine treatment differently. This may indicate that the functional balance of various nAChR subtypes in control of the release of dopamine is altered as a result of chronic nicotine treatment. Compounds binding both to opioid and nACh receptors may be of clinical importance.

Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

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.

Community Pharmacies and the Needs of Mobile EU Citizens - A study on Finns living in Spain

Migration within the European Union (EU) has increased since the Union was established. Community pharmacies provide open access to health care services and can be the first, most frequently used or even the only contact with a nation s health care system among mobile community residents. In some of the mass-migration areas in Southern Europe, most of the customers may represent mobile citizens of foreign background. This has not always been taken into consideration in the development of community pharmacy services. Mobile patients have been on the EU's health policy agenda, but they have seldom been mentioned in the context of community pharmacies. In most of the EU member states, governments control the specific legislation concerning community pharmacies and there is no harmonised pharmaceutical policy or consistent minimal standards for community pharmacy services in the EU. The aim of this study was to understand medication use, the role of community pharmacies and the symptom mitigation process of mobile community residents. Finns living in Spain were used as an example to examine how community pharmacies in a EU member state meet the needs of mobile community residents. The data were collected by a survey in 2002 (response rate 53%, n= 533) and by five focus group discussions in 2006 (n=30). A large number (70%) of the respondents had moved to Spain for health reasons and suffered from chronic morbidity. Community pharmacies had an important role in the healthcare of mobile community residents and the respondents were mostly satisfied with these services. However, several medication safety risks related to community pharmacy practices were identified: 1) Availability of prescription medicines without prescription (e.g., antibiotics, sleeping pills, Viagra®, asthma medications, cardiovascular medicines, psoriasis medicines and analgesics); 2) Irrational use of medicines (e.g., 41% of antibiotic users had bought their antibiotics without a prescription, and the most common reasons for antibiotic self-medication were symptomatic common colds and sore throats); 3) Language barriers between patients and pharmacy professionals; 4) Lack of medication counselling; 5) Unqualified pharmacy personnel providing pharmacotherapy. A fifth of the respondents reported experiencing problems during pharmacy visits in Spain, and the lack of a common language was the source of most of these problems. The findings of this study indicate that regulations and their enforcement can play a crucial role in actually assuring the rational and safe use of medicines. These results can be used in the development of pharmaceutical and healthcare policies in the EU. It is important to define consistent minimum standards for community pharmacy services in the EU. Then, the increasing number of mobile community residents could access safe and high quality health care services, including community pharmacy services, in every member state within the EU.

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.

Neuro- and immunotoxic effects of fumonisin B1 in cells

Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species can also be found in moisture-damaged buildings, and therefore there may also be human exposure to Fusarium mycotoxins, including FB1. FB1 affects the metabolism of sphingolipids by inhibiting the enzyme ceramide synthase. It is neuro-, hepato- and nephrotoxic, and it is classified as possibly carcinogenic to humans. This study aimed to clarify the mechanisms behind FB1-induced neuro- and immunotoxicity. Four neural and glial cell lines of human, rat and mouse origin were exposed to graded doses of FB1 and the effects on the production of reactive oxygen species, lipid peroxidation, intracellular glutathione levels, cell viability and apoptosis were investigated. Furthermore, the effects of FB1, alone or together with lipopolysaccharide (LPS), on the mRNA and protein expression levels of different cytokines and chemokines were studied in human dendritic cells (DC). FB1 induced oxidative stress and cell death in all cell lines studied. Generally, the effects were only seen after prolonged exposure at 10 and 100 µM of FB1. Signs of apoptosis were also seen in all four cell lines. The sensitivities of the cell lines used in this study towards FB1 may be classified as human U-118MG glioblastoma > mouse GT1-7 hypothalamic > rat C6 glioblastoma > human SH-SY5Y neuroblastoma cells. When comparing cell lines of human origin, it can be concluded that glial cells seem to be more sensitive towards FB1 toxicity than those of neural origin. After exposure to FB1, significantly increased levels of the cytokine interferon-γ (IFNγ) were detected in human DC. This observation was further confirmed by FB1-induced levels of the chemokine CXCL9, which is known to be regulated by IFNγ. During co-exposure of DC to both LPS and FB1, significant inhibitions of the LPS-induced levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1β, and their regulatory chemokines CCL3 and CCL5 were observed. FB1 can thus affect immune responses in DC, and therefore, it is rather likely that it also affects other types of cells participating in the immune defence system. When evaluating the toxicity potential of FB1, it is important to consider the effects on different cell types and cell-cell interactions. The results of this study represent new information, especially about the mechanisms behind FB1-induced oxidative stress, apoptosis and immunotoxicity, as well as the varying sensitivities of different cell types towards FB1.

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.

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

"Do Not Celebrate Your Feast without Your Neighbours" : A Study of References to Feasts and Festivals in Non-Literary Documents from Ramesside Period Deir el-Medina

This dissertation is a study of the forms and functions of feasts and feasting in the ancient Egyptian village of Deir el-Medina in Thebes (modern Luxor). This particular village, during the New Kingdom (c. 1550 1069 BC), was inhabited by the men (and their families) who constructed the Royal Tombs in the Valley of the Kings and the Valley of the Queens. The royal artisans were probably more literate than the average Egyptians and the numerous Ramesside Period (c. 1295 1069 BC) non-literary texts found in the excavations of the village and its surroundings form the source material for this study. In this study, the methods used are mainly Egyptological and the references to feasts and feasting are considered in view of what is known of New Kingdom Egypt, Thebes, and Deir el-Medina. Nevertheless, it is the use of the methodological concept local vernacular religion that has resulted in the division of the research findings into two sections, i.e., references to feasts celebrated both in and outside the community and other references to feasts and feasting in the village. When considering the function of the feasts celebrated at Deir el-Medina, a functional approach to feasts introduced by anthropologists and archaeologists is utilized. The Deir el-Medina feasts which were associated with the official religion form a festival calendar of feasts celebrated annually on the same civil calendar day. The reconstructed festival calendar of Deir el-Medina reflects the feasts celebrated around Thebes or, at least, in Western Thebes. The function of the nationally and regionally observed feasts (which, at least at Deir el-Medina, resulted in a work-free day) may have been to keep people content so that they would continue to work which was to the advantage of the king and the elite surrounding him. Local feasts appear to have been observed more irregularly at Deir el-Medina or perhaps according to the lunar calendar. Feasts celebrated by the community as a whole served to maintain the unity of the group. In addition to feasts celebrated by the entire community, the inhabitants of Deir el-Medina could mark their own personal feasts and organize small gatherings during public feasts. Through such feasts, an individual man might form alliances and advance his chances of a favourable marriage or of acquiring a position on the work crew.

The Saintly Madman : A Study of the Scholarly Reception History of Buile Shuibhne

This study examines the scholarly reception history of an early Irish text, Buile Shuibhne (The Frenzy of Suibhne), by focusing on the various theoretical and methodological presuppositions which have determined the scholars’ understanding of the text’s religious allegorical significance in the course of the 20th century. The reception-oriented inquiry takes the intersubjective aspect of literary interpretation as the basis for accentuating the importance of communally shared presumptions and reading strategies in the explication of interpretive variety. The materials of the study have been divided into four frameworks of interpretation: historical, pre-Christian, Christian and anthropological. This heuristic division does not denote mutually exclusive paradigms, but rather refers to perceived similarities within each group regarding the questions posed, and the evidence adduced, in textual analysis. The historical framework concentrates on the issues of the origins of the tale and the possible historicity of its main protagonist. The pre-Christian framework covers the theories of the shamanic, Indo-European and Celtic elements in the text, whereas the Christian framework includes readings emphasising the biblical, monastic and ascetic aspects of the tale. The anthropological framework in turn focuses on the parallels drawn between the narrative and the universal structure of the rites of passage. In addition to the examination of these four frameworks, the study also links the question of methodology with wider issues of authorship and textual integrity, and critically reconsiders the manner in which J.G. O'Keeffe's 1913 edition of the text has been reified in previous scholarship as a representation of a 12th century authorial original. The overall objective of the present case-study is to relate theoretical conceptions of literary theory, comparative religion and historiography to the study of early Irish narrative material by considering the communal and institutional dimension of meaning-making, and the implications of comparative methodology for historical research. In this aim, the prevailing methodological presuppositions informing the scholarly discourse on Buile Shuibhne are set against the wider context of Celtic Studies scholarship, in order to draw attention to the need to critically reflect upon the operations of knowledge production in future research.

Èto i to v povesti Staruha Daniila Harmsa

This dissertation focuses on the short story Starukha (The Old Woman), one of the last works of the Russian writer Daniil Kharms (1905-1942). The story, written in 1939, is analysed using the Kharmsian concepts èto and to (this and that) as a heuristic interpretative model. The first chapter gives a detailed analysis of this model, as well as a survey of the critical work done to date on Kharms and Starukha. In the second chapter the model is applied to study the different states of consciousness of the male protagonist. This is significant, because he is the "I" of the work, from whose point of view everything is being told. The third chapter takes a closer look at the reality of the world that exists independently of the consciousness of the protagonist. Physical objects can be said to bear - besides their everyday meaning - a hidden symbolic meaning. Similarly, the characters can be considered as representatives of everyday reality and otherworldliness. The fourth chapter deals with the narrative devices of Starukha. The problematics of the relation between fact and fiction plays an essential role in the story. Kharms's use of Ich-Erzählung and different tenses, which contributes to achieving a complicated elaboration of this kind of problematics, is examined in detail. The fifth chapter provides an intertextual reading of Starukha, based on its allusions to the Bible and the Christian tradition. As a result, the whole story can be seen as a kind of meditation on the Passion of Christ. The final chapter examines how the important Kharmsian concepts of the grotesque and the absurd manifest themselves in Starukha. The old woman represents in a grotesque way two opposite systems: the religious and the totalitarian. The absurdity of Starukha can be claimed to be illusory. Therefore, it is better to speak about paradoxicality. Starukha itself is a kind of paradox, in the sense that it tries to say something of the ultimate truth of reality, which inevitably remains ineffable.

Andegraund : Istorija i mify leningradskoj neoficial'noj literatury

The history of the Leningrad underground is one of the key themes of late socialism. Samizdat, "black humour", religious syncretism, dissidence, apolitical bohemianism, the pathos of freedom of individuality and the mechanics of literature are closely interlinked with the cultural mythology of this passed epoch. Describing conceptions that, when taken together, form the contemporary understanding of unofficial culture, the author creates a historical portrait of this environment. Amongst the central figures here, there are well-known writers (Bitov, Brodsky, Dovlatov, Khvostenko, Krivulin) and literary activists who still await recognition. The analysis of works, many of which were only distributed in typewritten publications in the 1960s-1980s, gives a preliminary definition of the key factors that united the authors of the unofficial community. The book begins with a critique of the identification of the Soviet underground with political dissidence or with a society living in autonomous independence with regard to the state. Describing the historical development of the various names for this environment (the underground, samizdat, unofficial culture, podpolie and others), the author follows the genesis of the community from its appearance, in the years of "the Thaw", through to perestroika, when it dissolved. Taking the history of the publication of Bitov's "The Pushkin House" as an example, the concept of the unofficial is interpreted as a risky interaction with the authorities. Unofficial culture is then viewed as a late Soviet reflection of the Western underground in the 1950s-1960s. Unlike the radical-utopian-anarchistic source, it proclaimed a liberalist and democratic ideology in the context of the destruction of the socialist utopia. The historical portrait of the community is built up from the perceptions of its members regarding literature practice and rhetorical approaches, with the aid of which these perceptions are expressed. Taking typewritten publications as source material, four main representations are given: privacy, deviancy, criticism and irrationality. An understanding of literature as a private affair, neo-avant-garde deviancy in social and literary behaviour and the pathos of the critical relationship with officialdom and irrational message of literary work, comprise the basis for the worldview of unofficial authors, as well as the poetic system, genre preferences and dictums. An analysis of irrationality, based on the texts of Khvostenko and Bogdanov, leads to a review of the cultural mythologies that were crucial to the unofficial conception of the absurd. Absurd is an homonym. It contains ideas that are important for the worldview of unofficial authors and the poetics of their works. The irrationality of the Soviet order is reflected in the documentary nature of the satirical prose of Dovlatov. The existential absurd of Camus is perceived here as the pointlessness of social realities and the ontological alienation of man, while existentialist practices for consciousness in the "atmosphere of absurd" remain bracketed off. The third homonym of absurd - the conception of reality as an illusion - is a clear demonstration of religious syncretism, where neo-Christian ideas are interweaved with a modernized version of Hinduism, as taken from Rolland s books on Ramakrishna and Vivekananda. The unofficial community was influenced by the ideology of westernization. Even "the East" arrived here via French retellings and accounts. As a whole, unofficial Leningrad culture can be understood as a neo-modernist phenomenon which, unlike the western neo-modernism of the 1940s and 1950s, arose in the years of the Thaw and ended its existence in the mid-1980s.

Recipient v russkom razgovore : o raspredelenii funkcij mezhdu otvetami da, nu i tak

The study investigates actions by recipients in spontaneous Russian conversations by focusing on DA, NU and TAK, when they are used as responses to the main speaker's larger on-going turn. The database for the study consists of some 7 hours of spontaneous conversations. The participants of the conversations come from different parts of Russia. The use of DA, NU and TAK was analyzed by applying the method of ethnomethodological conversation analysis from the point of view of the type of the context, the sequential placement of the response and its manner of production. The particles were analyzed both in contexts in which they responded to an informing and in affective contexts. The particles NU and TAK were used by the speakers almost exclusively in informing contexts, whereas DA was the central response type in affective contexts. DA was also the most common response to information with affective implications. The information, to which the particle NU provided as response, was often unspesific and projected a spesification or explanation by its speaker as the next action. DA and TAK, by contrast, treated the information as one that could be followed and was sufficient in its local context. As a response to parenthetical information NU responded to information that was only loosely connected with the mainline of talk. The particle DA, by contrast, was used as a response to such parenthetical information, which was more crucial for the larger on-going activity. Only NU was used as a response that invited the main speaker to continue a turn that she or he had offered as possibly complete. NU was also used by the recipient after her or his own contribution as a continuer. In affective contexts, DA expressed, depending on its more spesific context, not only agreement but also other functions, such as giving up arguing or prior knowledge on the topic being discussed. In addition DA responses were used to display empathy and identification with the state of affairs expressed by the co-participant. NU, by contrast, was seldom used as a response to a turn that expressed affect. When it was used in affective contexts, it displayed agreement with the co-participant or just registered an assessment by her or him.

Ivanov-mistik : Okkul'tnye motivy v poèzii i proze Vjačeslava Ivanova (1907-1919)

The subject of this work is the mysticism of Russian poet, critic and philosopher Vjacheslav Ivanov (1866-1949). The approach adopted involves the textual and discourse analysis and findings of the history of ideas. The subject has been considered important because of Ivanov's visions of his dead wife, writer Lydia Zinovieva-Annibal, which were combined with audible messages ("automatic writings"). Several automatic writings and descriptions of the visions from Ivanov's archive collections in St.Petersburg and Moscow are presented in this work. Right after the beginning of his hallucinations in the autumn of 1907, Ivanov was totally captivated by the theosophical ideas of Anna Mintslova, the background figure for this work. Anna Mintslova, a disciple of Rudolf Steiner's Esoteric School, offered Ivanov the theosophical concept of initiation to interpret paranormal phenomena in his intimate life. The work is divided into three main chapters, an introduction and aconclusion. The first chapter is called The Mystical Person: Anthropology of Ivanov and describes the role of the inner "Higher Self" in Ivanov's views on the nature of human consciousness. The political implications of the concepts, "mystical anarchism" and "sobornost" (religious unity) are also examined. The acquaintance and contacts with Anna Mintslova during 1906-1907 gave a framework to Ivanov's search for an organic society and personal religious experience. The second part, Mystics of Initiation and Visionary Aesthetics describes the influence of the initiation concept on Ivanov's aesthetic views (mainly "realistic symbolism"). On the other hand, some connections between the imagery of his visions and symbols in his verses of that period are established. Since Mintslova represented the ideas of Rudolf Steiner in Russia, several symbols shared by Steiner and Ivanov ("rose", "rose and cross") have been another subject of investigation. The preference for strict verse form in the lyrics of Ivanov's visionary period is interpreted as an attempt to place his own poetic creation within two traditions, a mystical and literary one. The third part of this work, Mystics of Hope and Terror, examines Ivanov's conception of Russia in connection with Mintslova's ideas of occult danger from the East. Ivanov's view of the "Russian idea" and his nationalistic idea during World War I are considered as a representation of the fear of the danger. Ivanov's interpretation of the October revolution is influenced by the theosophical concept of the "keeper of the threshold" which occurs in the context of the discourse of occult danger.