Drug cultures in Estonia : contexts, meanings and patterns of illicit drug use.

In Estonia, illicit drug use hardly existed before the social changes of the 1990s when, as a result of economic and cultural transformations, the country became part of a world order centred in the West. On the one hand, this development is due to the spread of international youth culture, which many young people have perceived as being associated with drugs; on the other hand, it results from the marginalisation of a part of the population. The empirical part of the study is based mostly on in-depth interviews with different drug users conducted during between 1998 and 2002. Complementary material includes the results of participant observations, interviews with key experts, and the results of previous quantitative studies and statistics. The young people who started experimenting with illicit drugs from the 1990s and onwards perceived them as a part of an attractive lifestyle - a Western lifestyle, a point which is worth stressing in the case of Estonia. Although the reasons for initiation into drug use were similar for the majority of young people, their drug use habits and the impact of the drug use on their lives began to differ. I argue that the potential pleasure and harm which might accompany drug use is offset by the meanings attached to drugs and the sanctions and rituals regulating drug use. In the study both recreational and problem use have been analysed from different aspects in seven articles. I have investigated different types of drug users: new bohemians, cannabis users, in whose case partying and restrictive drug use is positively connected to their lives and goals within established society; stimulant-using party people for whom drugs are a means of having fun but who do not have the same restrictive norms regulating their drug use as the former and who may get into trouble under certain conditions; and heroin users for whom the drug rapidly progressed from a means of having fun to an obligation due to addiction. The research results point at the importance not only of the drug itself and the socio-economic situation of the user, but also of the cultural and social context within which the drug is used. The latter may on occasions be a crucial factor in whether or not initial drug use eventually leads to addiction.

Pathways to health : Determinants of health, health behaviour and health inequalities in early adulthood

There is increasing evidence that the origins of poor adult health and health inequalities can be traced back to circumstances preceding current socioeconomic position and living conditions. The life-course approach to examining the determinants of health has emphasised that exposure to adverse social and economic circumstances in earlier life or concurrent adverse circumstances due to unfavourable living conditions in earlier life may lead to poor health, health-damaging behaviour, disease or even premature death in adulthood. There is, however, still a lack of knowledge about the contribution of social and economic circumstances in childhood and youth to adult health and health inequalities, and even less is known about how environmental and behavioural factors in adulthood mediate the effects of earlier adverse experiences. The main purpose of this study was to deepen our understanding of the development of poor health, health-damaging behaviours and health inequalities during the life-course. Its aim was to find out which factors in earlier and current circumstances determine health, the most detrimental indicators of health behaviour (smoking, heavy drinking and obesity as a proxy for the balance between nutrition and exercise), and educational health differences in young adults in Finland. Following the ideas of the social pathway theory, it was assumed that childhood environment affects adult health and its proximal determinants via different pathways, including educational, work and family careers. Early adulthood was studied as a significant phase of life when many behavioural patterns and living conditions relevant to health are established. In addition, socioeconomic health inequalities seem to emerge rapidly when moving into adulthood; they are very small or non-existent in childhood and adolescence, but very marked by early middle age. The data of this study were collected in 2000 2001 as part of the Health 2000 Survey (N = 9,922), a cross-sectional and nationally representative health interview and examination survey. The main subset of data used in this thesis was the one comprising the age group 18 29 years (N = 1,894), which included information collected by standardised structured computer-aided interviews and self-administered questionnaires. The survey had a very high participation rate at almost 90% for the core questions. According to the results of this study, childhood circumstances predict the health of young adults. Almost all the childhood adversities studied were found to be associated with poor self-rated health and psychological distress in early adulthood, although fewer associations were found with the somatic morbidity typical of young adults. These effects seemed to be more or less independent of the young adult s own education. Childhood circumstances also had a strong effect on smoking and heavy drinking, although current circumstances and education in particular, played a role in mediating this effect. Parental smoking and alcohol abuse had an influence on the corresponding behaviours of offspring. Childhood circumstances had a role in the development of obesity and, to a lesser extent, overweight, particularly in women. The findings support the notion that parental education has a strong effect on early adult obesity, even independently of the young adult s own educational level. There were marked educational differences in self-rated health in early adulthood: those in the lowest educational category were most likely to have average or poorer health. Childhood social circumstances seemed to explain a substantial part of these educational differences. In addition, daily smoking and heavy drinking contributed substantially to educational health differences. However, the contribution of childhood circumstances was largely shared with health behaviours adopted by early adulthood. Employment also shared the effects of childhood circumstances on educational health differences. The results indicate that childhood circumstances are important in determining health, health behaviour and health inequalities in early adulthood. Early recognition of childhood adversities followed by relevant support measures may play an important role in preventing the unfortunate pathways leading to the development of poor health, health-damaging behaviour and health inequalities. It is crucially important to recognise the needs of children living in adverse circumstances as well as children of substance abusing parents. In addition, single-parent families would benefit from support. Differences in health and health behaviours between different sub-groups of the population mean that we can expect to see ever greater health differences when today s generation of young adults grows older. This presents a formidable challenge to national health and social policy as well as health promotion. Young adults with no more than primary level education are at greatest risk of poor health. Preventive policies should emphasise the role of low educational level as a key determinant of health-damaging behaviours and poor health. Keywords: health, health behaviour, health inequalities, life-course, socioeconomic position, education, childhood circumstances, self-rated health, psychological distress, somatic morbidity, smoking, heavy drinking, BMI, early adulthood

Mass spectrometry and n-in-one analytics in early drug discovery: Combinatorial chemistry libraries, lipophilicity and absorption screening

This thesis describes current and past n-in-one methods and presents three early experimental studies using mass spectrometry and the triple quadrupole instrument on the application of n-in-one in drug discovery. N-in-one strategy pools and mix samples in drug discovery prior to measurement or analysis. This allows the most promising compounds to be rapidly identified and then analysed. Nowadays properties of drugs are characterised earlier and in parallel with pharmacological efficacy. Studies presented here use in vitro methods as caco-2 cells and immobilized artificial membrane chromatography for drug absorption and lipophilicity measurements. The high sensitivity and selectivity of liquid chromatography mass spectrometry are especially important for new analytical methods using n-in-one. In the first study, the fragmentation patterns of ten nitrophenoxy benzoate compounds, serial homology, were characterised and the presence of the compounds was determined in a combinatorial library. The influence of one or two nitro substituents and the alkyl chain length of methyl to pentyl on collision-induced fragmentation was studied, and interesting structurefragmentation relationships were detected. Two nitro group compounds increased fragmentation compared to one nitro group, whereas less fragmentation was noted in molecules with a longer alkyl chain. The most abundant product ions were nitrophenoxy ions, which were also tested in the precursor ion screening of the combinatorial library. In the second study, the immobilized artificial membrane chromatographic method was transferred from ultraviolet detection to mass spectrometric analysis and a new method was developed. Mass spectra were scanned and the chromatographic retention of compounds was analysed using extract ion chromatograms. When changing detectors and buffers and including n-in-one in the method, the results showed good correlation. Finally, the results demonstrated that mass spectrometric detection with gradient elution can provide a rapid and convenient n-in-one method for ranking the lipophilic properties of several structurally diverse compounds simultaneously. In the final study, a new method was developed for caco-2 samples. Compounds were separated by liquid chromatography and quantified by selected reaction monitoring using mass spectrometry. This method was used for caco-2 samples, where absorption of ten chemically and physiologically different compounds was screened using both single and nin- one approaches. These three studies used mass spectrometry for compound identification, method transfer and quantitation in the area of mixture analysis. Different mass spectrometric scanning modes for the triple quadrupole instrument were used in each method. Early drug discovery with n-in-one is area where mass spectrometric analysis, its possibilities and proper use, is especially important.

Porlyl oligopeptidase in development

Prolyl oligopeptidase (POP, prolyl endopeptidase, EC 3.4.21.26) is a serine-type peptidase (family S9 of clan SC) hydrolyzing peptides shorter than 30 amino acids. POP has been found in various mammalian and bacterial sources and it is widely distributed throughout different organisms. In human and rat, POP enzyme activity has been detected in most tissues, with the highest activity found mostly in the brain. POP has gained scientific interest as being involved in the hydrolyzis of many bioactive peptides connected with learning and memory functions, and also with neurodegenerative disorders. In drug or lesion induced amnesia models and in aged rodents, POP inhibitors have been able to revert memory loss. POP may have a fuction in IP3 signaling and it may be a possible target of mood stabilizing substances. POP may also have a role in protein trafficking, sorting and secretion. The role of POP during ontogeny has not yet been resolved. POP enzyme activity and expression have shown fluctuation during development. Specially high enzyme activities have been measured in the brain during early development. Reduced neuronal proliferation and differentation in presence of POP inhibitor have been reported. Nuclear POP has been observed in proliferating peripheral tissues and in cell cultures at the early stage of development. Also, POP coding mRNA is abundantly expressed during brain ontogeny and the highest levels of expression are associated with proliferative germinal matrices. This observation indicates a special role for POP in the regulation of neurogenesis during development. For the experimental part, the study was undertaken to investigate the expression and distribution of POP protein and enzymatic activity of POP in developing rat brain (from embryonic day 14 to post natal day 7) using immunohistochemistry, POP enzyme activity measurements and western blot-analysis. The aim was also to find in vivo confirmation of the nuclear colocalization of POP during early brain ontogeny. For immunohistochemistry, cryosections from the brains of the fetuses/rats were made and stained using specific antibody for POP and fluorescent markers for POP and nuclei. The enzyme activity assay was based on the fluorescence of 7- amino-4-methylcoumarin (AMC) generated from the fluorogenic substrate succinyl-glycyl-prolyl-7-amino-4-methylcoumarin (Suc-Gly-Pro-AMC) by POP. The amounts of POP protein and the specifity of POP antibody in rat embryos was confirmed by western blot analysis. We observed that enzymatic activity of POP is highest at embryonic day 18 while the protein amounts reach their peak at birth. POP was widely present throughout the developmental stages from embryonic day 14 to parturition day, although the POP-immunoreactivity varied abundantly. At embryonic days 14 and 18 notably amounts of POP was distributed at proliferative germinal zones. Furthermore, POP was located in the nucleus early in the development but is transferred to cytosol before birth. At P0 and P7 the POP-immunoreactivity was also widely observed, but the amount of POP was notably reduced at P7. POP was present in cytosol and in intercellular space, but no nuclear POP was observed. These findings support the idea of POP being involved in specific brain functions, such as neuronal proliferation and differentation. Our results in vivo confirm the previous cell culture results supporting the role of POP in neurogenesis. Moreover, an inconsistency of POP protein amounts and enzymatic activity late in the development suggests a strong regulation of POP activity and a possible non-hydrolytic role at that stage.

TOTEM early measurements

The status of the TOTEM experiment is described as well as the prospects for the measurements in the early LHC runs. The primary goal of TOTEM is the measurement of the total p-p cross section, using a method independent of the luminosity. A final accuracy of 1% is ex- pected with dedicated β∗ = 1540 m runs, while at the beginning a 5% resolution is achievable with a β∗ = 90 m optics. Accordingly to the running scenarios TOTEM will be able to measure the elastic scattering in a wide range of t and to study the cross-sections and the topologies of diffractive events. In a later stage, physics studies will be extended to low-x and forward physics collaborating with CMS as a whole experimental apparatus.

Organisation Carescapes: Researching Organisations, Work and Care

This working paper develops an approach to the analysis of care as it is evident in the policies and practices of employing organisations. We identify how notions of care are incorporated in myriad and multi-faceted ways that may support, survey and control workers, as well as having implications for employers, managers, employees and workers. Aspects of care can be found in a range of statutory duties, policies and related activities, including: health and safety, equality and diversity, parental leave, religious observance, bullying and harassment, personal development, voluntary redundancy, early retirement, employer pension schemes, grievance procedures, and dismissal. The conceptual framework of organisation carescapes is offered as an aid to the analysis of employee policies and services. These policies and services are transformed by shifts in supranational and national policies such as European Union (EU) economic strategies and national legislation on disability rights legislation, age discrimination and flexible working, and changes in labour market competitiveness. In conclusion, we consider how the framework of organisation carescapes is informing research design in our and our colleagues’ ongoing programme of research.

Philosophy as a Path to Happiness : Attainment of Happiness in Arabic Peripatetic and Ismaili Philosophy

The aim of the dissertation is to explore the idea of philosophy as a path to happiness in classical Arabic philosophy. The starting point is in comparison of two distinct currents between the 10th and early 11th centuries, Peripatetic philosophy, represented by al-Fārābī and Ibn Sīnā, and Ismaili philosophy represented by al-Kirmānī and the Brethren of Purity. They initially offer two contrasting views about philosophy in that the attitude of the Peripatetics is rationalistic and secular in spirit, whereas for the Ismailis philosophy represents the esoteric truth behind revelation. Still, they converge in their view that the ultimate purpose of philosophy lies in its ability to lead man towards happiness. Moreover, they share a common concept of happiness as a contemplative ideal of human perfection, which refers primarily to an otherworldly state of the soul s ascent to the spiritual world. For both the way to happiness consists of two parts: theory and practice. The practical part manifests itself in the idea of the purification of the rational soul from its bodily attachments in order for it to direct its attention fully to the contemplative life. Hence, there appears an ideal of philosophical life with the goal of relative detachment from the worldly life. The regulations of the religious law in this context appear as the primary means for the soul s purification, but for all but al-Kirmānī they are complemented by auxiliary philosophical practices. The ascent to happiness, however, takes place primarily through the acquisition of theoretical knowledge. The saving knowledge consists primarily of the conception of the hierarchy of physical and metaphysical reality, but all of philosophy forms a curriculum through which the soul gradually ascends towards a spiritual state of being along an order that is inverse to the Neoplatonic emanationist hierarchy of creation. For Ismaili philosophy the ascent takes place from the exoteric religious sciences towards the esoteric philosophical knowledge. For Peripatetic philosophers logic performs the function of an instrument enabling the ascent, mathematics is treated either as propaedeutic to philosophy or as a mediator between physical and metaphysical knowledge, whereas physics and metaphysics provide the core of knowledge necessary for the attainment of happiness.

Opportunity Exploration and Exploitation in International New Ventures: A Study of Relationships’ Involvement in Early Entrepreneurial and Internationalisation Events

International new ventures (INVs) are firms that engage very early after their foundation, if not immediately, in inter-national activities. INVs are a relatively recent phenomenon that deviates from earlier theories on international business. In order to develop our understanding of the emergence and early internationalisation of INVs three different research areas are built upon in the dissertation: International Entrepreneurship, Entrepreneurship and Networks. Net-works have been identified as important for INVs. However, there is a lack of more profound studies regarding the way different types of relationships influence INVs. Few studies are concerned with exploration and exploitation of opportunities and research on the benefits and drawbacks of entrepreneurs’ relationships for the international opportunity recognition process has been called for. By taking a network approach to opportunity exploration and exploitation, the dissertation develops our under-standing of how entrepreneurs’ relationships are involved in exploring and exploiting opportunities during an INV’s early and critical entrepreneurial and internationalisation events. The critical events are studied during three phases: pre-founding, start-up and early internationalisation. Since internationalisation is present from the very beginning, the early internationalisation phase may be parallel to both the pre-founding and the start-up phase. The dissertation contributes to international entrepreneur-ship research in mainly two ways. First, by offering a deep insight into which opportunity exploration and exploitation activities entrepreneurs’ relationships are involved. Second, by adding to our understanding of what the relationships contribute to these activities, mainly in the sense of benefits gained through the relationships. Studying micro firms in real time in their early development towards INVs is considered a unique contribution of the study as it offers valuable insights into pre-founding, start-up, pre-internationalisation as well as early internationalisation. The study shows that in order to understand the development of INVs, it is beneficial to go back to times when there was no thought of starting the INV. By focusing on the entrepreneurs’ background and relationships a more complete picture of the INV is gained. Relationships created at former workplaces or during school time might be the ones that develop business opportunities and set off internationalisation. By focusing on the pre-founding phase, the study also contributes to entrepreneurship literature as this stage has often been neglected or assumed obvious in earlier research. This dissertation shows that an important and mostly lengthy pre-founding phase precedes the decision to start a f rm. In addition, the integration of entrepreneurs’ real experiences with existing theory to develop a continuum for the strength of relationships allows for contributions to network theory.

Texts "Con and Pro" : The Early Modern Medical Controversy over Tobacco

The habit of "drinking smoke" , meaning tobacco smoking, caused a true controversy in early modern England. The new substance was used both for its alleged therapeutic properties as well as its narcotic effects. The dispute over tobacco continues the line of written controversies which were an important means of communication in the sixteenth and seventeenth century Europe. The tobacco controversy is special among medical controversies because the recreational use of tobacco soon spread and outweighed its medicinal use, ultimately causing a social and cultural crisis in England. This study examines how language is used in polemic discourse and argumentation. The material consists of medical texts arguing for and against tobacco in early modern England. The texts were compiled into an electronic corpus of tobacco texts (1577 1670) representing different genres and styles of writing. With the help of the corpus, the tobacco controversy is described and analyzed in the context of early modern medicine. A variety of methods suitable for the study of conflict discourse were used to assess internal and external text variation. The linguistic features examined include personal pronouns, intertextuality, structural components, and statistically derived keywords. A common thread in the work is persuasive language use manifested, for example, in the form of emotive adjectives and the generic use of pronouns; the latter is especially pronounced in the dichotomy between us and them. Controversies have not been studied in this manner before but the methods applied have supplemented each other and proven their suitability in the study of conflictive discourse. These methods can also be applied to present-day materials.

Publishing for the Masses : Early Modern English Witchcraft Pamphlets

This study is a pragmatic description of the evolution of the genre of English witchcraft pamphlets from the mid-sixteenth century to the end of the seventeenth century. Witchcraft pamphlets were produced for a new kind of readership semi-literate, uneducated masses and the central hypothesis of this study is that publishing for the masses entailed rethinking the ways of writing and printing texts. Analysis of the use of typographical variation and illustrations indicates how printers and publishers catered to the tastes and expectations of this new audience. Analysis of the language of witchcraft pamphlets shows how pamphlet writers took into account the new readership by transforming formal written source materials trial proceedings into more immediate ways of writing. The material for this study comes from the Corpus of Early Modern English Witchcraft Pamphlets, which has been compiled by the author. The multidisciplinary analysis incorporates both visual and linguistic aspects of the texts, with methodologies and theoretical insights adopted eclectically from historical pragmatics, genre studies, book history, corpus linguistics, systemic functional linguistics and cognitive psychology. The findings are anchored in the socio-historical context of early modern publishing, reading, literacy and witchcraft beliefs. The study shows not only how consideration of a new audience by both authors and printers influenced the development of a genre, but also the value of combining visual and linguistic features in pragmatic analyses of texts.