Generally, most of the in vitro tests used in neurotoxicology are limited to transformed cell lines which are derived from rodent or human. For an in vitro test to have high rate of predictability of neurotoxicity and teratogenicity it should undergo the important processes of embryological development, such as cell proliferation, cell migration, and differentiation. Human neural stem cells have been proposed for this purpose, which have the ability to divide, differentiate, and migrate. In this study, it was found that double coating of laminin with either poly D lysine or poly L lysine was most suitable for growing human neural stem cells rather than coating with a single extracellular molecule. Several chemicals and drugs were then chosen to assess the utility of neural stem cells as an assay for neurotoxicity: methyl mercury and lead acetate; four anti-epileptics drugs (sodium valproate, phenytoin, carbamazepine, and phenobarbitone); anti-oxidants (folic acid and melatonin). These anti-oxidants were tested alone and when added to sodium valproate and to phenytoin (which are well known in their teratogenicity), and other drugs (lithium, diazepam, and amitriptyline), which are weak teratogens. To assess the effects of these molecules on human neural stem cells cell survival, total cellular protein, neuronal process length, neurosphere sizes, migration distance, Glial Fibrillary Acidic Protein, and tubulin III protein expression were measured. The study shows that methyl mercury caused significant reduction in most of the end points from the dose of 1µM and it led to significant increase in Glial Fibrillary Acidic Protein expression (which is a sign of reactive gliosis). Lead acetate led to a significant reduction in cell migration 48hours after treatment with 10µM. In the case of the anti-epileptics, sodium valproate appeared to reduce neurosphere size significantly from the dose of 500µM and decrease migration distance significantly 48hours after treatment with 1000µM. Moreover, phenytoin treatment resulted in significant reduction in neurosphere sizes from the dose of 25µM and reduced cell migration significantly from the dose of 50µM. However, the other anti-epileptics (carbamazepine and phenobarbitone) revealed their effect only at high doses which are above their therapeutic range. On the other hand, adding the anti-oxidants (Folic acid or Melatonin) to sodium valproate or phenytoin had to some extent beneficial effects, by making their toxic effect appear at doses which were higher than when used alone. Regarding the other drugs (lithium, diazepam, and amitriptyline), it seems that their toxic effect appeared only at doses which are higher than the therapeutic range. Therefore, it can be concluded that human neural stem cells are a sensitive model in detecting the neurotoxicity of methyl mercury and lead acetate at low doses and can predict the neurotoxicity of sodium valproate and phenytoin at their therapeutic doses.

Les UDP-glucuronosyltransférases (UGT) sont des enzymes impliquées dans le métabolisme de plusieurs molécules endogènes et exogènes, entraînant leur inactivation et leur élimination subséquente via la bile et l’urine. Étant donné l’impact potentiel de l’épissage alternatif sur la variabilité de la glucuronidation chez l’humain, nous avons étudié ce processus chez deux membres de la famille des UGT2B, soit UGT2B4 et UGT2B7. Dans le cas d’UGT2B4 nous avons détecté 3 nouveaux exons et 11 nouveaux transcrits principalement exprimés au foie. Les nouvelles protéines dérivées de ces ARNm n’ont pas d’activité de conjugaison, mais trois d’entre elles ayant une extrémité C-terminale alternative (i2, i3 et i5) modulent la capacité de glucuronidation de l’enzyme active UGT2B4_i1. Dans le cas d’UGT2B7 nous avons découvert 6 nouveaux exons retrouvés dans 22 transcrits pleines-longueurs codant pour 7 protéines UGT2B7. Tous les ARNm détectés l’ont été au niveau du rein, mais nous avons observé une grande spécificité tissulaire dans la transcription: les ARNm contenant l’exon 1 classique contrôlés par un promoteur proximal sont exprimés dans les tissus du tractus gastro-intestinal et le foie, alors que les transcrits caractérisés par la présence d’exons 1 alternatifs et distaux sont exprimés en périphérie. De plus, un contrôle de la spécificité d’expression des promoteurs UGT2B7 semble exister au rein, le promoteur associé à l’enzyme active étant absent dans les tissus foetaux et néoplasiques. Les 6 protéines UGT2B7 alternatives sont enzymatiquement inactives, mais deux d’entre elles ayant une extrémité C-terminale tronquée (UGT2B7_i2 et i4) modulent négativement la glucuronidation par l’enzyme i1. Cette régulation a été observée en surexpression mais également lors d’expérimentations de répression des isoformes endogènes d’i2 et i4 par interférence à l'ARN entraînant une augmentation de la conjugaison. Des expériences de co-immunoprécipitation et d’immunofluorescence supportent que cette répression survienne via l'interaction directe des protéines i2 et i4 avec i1 dans la membrane du réticulum, formant des complexes inactifs. Nos résultats démontrent que des évènements d'épissage alternatif des gènes UGT2B humains influenceraient la voie de glucuronidation, ce qui pourrait constituer un nouveau mécanisme d'autorégulation et influencer le métabolisme de substances endogènes et la réponse à des traitements pharmacologiques. / UDP-glucuronosyltransferases (UGT) are enzymes involved in the metabolism of several endogenous and exogenous molecules in the human body via inactivation and further elimination through bile and urine. Because of the potential impact of alternative splicing on the variability of the glucuronidation pathway, we studied this process in two UGT2B family members, UGT2B4 and 2B7. For UGT2B4, we detected 3 novel exons and 11 transcripts mainly expressed in the liver. The novel proteins derived from those mRNAs are enzymatically inactive, but three of them bearing alternative C-terminal ends (UGT2B4_i2, i3 and i5) have the ability to modulate glucuronidation efficiencies of the UGT2B4_i1 enzyme. For UGT2B7 we discovered 6 novel exons in 22 full-length transcripts coding for seven UGT2B7 proteins. All mRNAs were detected at least in the kidney, but a complex tissue-specificity of the transcription of UGT2B7 was observed: mRNAs containing the classical exon 1 are mainly expressed in gastrointestinal tract and liver, whereas transcripts characterized by the presence of alternative exon 1s (derived from the action of the distal promoter 1a) can be found in peripheral tissues. Fine-tuning of the specificity of UGT2B7 expression seems to exist at least in the kidney, this organ having a modulated UGT2B7 expression profile depending if the tissue is embryonic, adult or neoplastic. All six novel UGT2B7 proteins are enzymatically inactive, but two of them with truncated C-terminal ends (UGT2B7_i2 and i4) modulate the glucuronidation activity of the i1 enzyme. This regulation has been observed in overexpressing cellular models, but also in RNA interference experiments where repression of i2 and i4 increased glucuronidation by UGT2B7. Co-immuoprecipitation as well as immunofluorescence experiments support that this repression is related to the interaction of i2 and i4 with the i1 enzyme in the ER membrane, this process forming inactive complexes. The results presented here show that alternative splicing in UGT2B genes in human influences the glucuronidation process, a feature that could constitute an auto-regulation mechanism and could modify the susceptibility to adverse effect and response related to the treatment of several pathologies. Also, this process could influence elimination capacity of endogenous substances like steroid hormones.

Este estudo teve como finalidade principal avaliar a qualidade de vida (QV) dos profissionais de saúde que compõem o serviço de radiodiagnóstico de um hospital da cidade de São Paulo. Além disso, objetivou conhecer o perfil desses profissionais, identificando as variáveis que podem influenciar a QV desses profissionais. Trata-se de um estudo descritivo e exploratório com abordagem quali-quantitativa. Os dados foram coletados usando os questionários: o instrumento abreviado de avaliação de QV - World Health Organization Quality of Life Instrument bref (WHOQOL-bref) da Organização Mundial da Saúde e um questionário sobre as variáveis de interesse: sociodemográficas, condições de trabalho e estilo de vida, ambos questionários auto-aplicáveis. A amostra foi constituída de 118 profissionais nas categorias de: médicos, tecnólogos/técnicos de radiologia, enfermeiros, técnicos e auxiliares de enfermagem, entre outros. A análise dos dados envolveu estatística descritiva, testes não paramétricos e o uso de um modelo de regressão linear. O grau de confiabilidade do instrumento foi avaliado por meio do Coeficiente Alfa de Cronbach (α). O WHOQOL-bref demonstrou ser um instrumento adequado, de aplicação fácil e rápida para a aferição da qualidade de vida; mostrou bom desempenho psicométrico e boa consistência interna (α=0,884). O estudo permitiu conhecer a percepção de qualidade de vida do grupo estudado. / The main objective of this study was to evaluate the quality of life (QOL) of diagnostic radiology services workers at a hospital of São Paulo city. It aimed also to draw the profile of these workers identifying the variables, as its influence on their quality of life. A descriptive exploratory study with qualitative and quantitative approaches was carried out. The data were collected using the questionnaires: the abbreviated instrument for the assessment of the QOL, World Health Organization Quality of Life Instrument bref (WHOQOL-bref) and a questionnaire including the social demographic variables, work conditions and the variables that express the lifestyle of individuals, both questionnaires self-applied. The sample was formed by 118 workers, among them: physicians, technologists/technicians in radiology, nurses, technicians and assistants in nursing, and others health professionals. The data analysis included descriptive statistics, nonparametric tests and the use of a linear regression model. The reliability of the instrument for the studied sample was verified by Cronbachs Alpha Coefficient (α). The WHOQOL-bref proved to be an adequate instrument, with a good level of internal consistency (α=0.884), being easily and quickly administrated for the evaluation of the QOL. The study provided an overview of the perception of quality of life of the studied group.

Este estudo teve como finalidade principal avaliar a qualidade de vida (QV) dos profissionais de saúde que compõem o serviço de radiodiagnóstico de um hospital da cidade de São Paulo. Além disso, objetivou conhecer o perfil desses profissionais, identificando as variáveis que podem influenciar a QV desses profissionais. Trata-se de um estudo descritivo e exploratório com abordagem quali-quantitativa. Os dados foram coletados usando os questionários: o instrumento abreviado de avaliação de QV - World Health Organization Quality of Life Instrument bref (WHOQOL-bref) da Organização Mundial da Saúde e um questionário sobre as variáveis de interesse: sociodemográficas, condições de trabalho e estilo de vida, ambos questionários auto-aplicáveis. A amostra foi constituída de 118 profissionais nas categorias de: médicos, tecnólogos/técnicos de radiologia, enfermeiros, técnicos e auxiliares de enfermagem, entre outros. A análise dos dados envolveu estatística descritiva, testes não paramétricos e o uso de um modelo de regressão linear. O grau de confiabilidade do instrumento foi avaliado por meio do Coeficiente Alfa de Cronbach (α). O WHOQOL-bref demonstrou ser um instrumento adequado, de aplicação fácil e rápida para a aferição da qualidade de vida; mostrou bom desempenho psicométrico e boa consistência interna (α=0,884). O estudo permitiu conhecer a percepção de qualidade de vida do grupo estudado. / The main objective of this study was to evaluate the quality of life (QOL) of diagnostic radiology services workers at a hospital of São Paulo city. It aimed also to draw the profile of these workers identifying the variables, as its influence on their quality of life. A descriptive exploratory study with qualitative and quantitative approaches was carried out. The data were collected using the questionnaires: the abbreviated instrument for the assessment of the QOL, World Health Organization Quality of Life Instrument bref (WHOQOL-bref) and a questionnaire including the social demographic variables, work conditions and the variables that express the lifestyle of individuals, both questionnaires self-applied. The sample was formed by 118 workers, among them: physicians, technologists/technicians in radiology, nurses, technicians and assistants in nursing, and others health professionals. The data analysis included descriptive statistics, nonparametric tests and the use of a linear regression model. The reliability of the instrument for the studied sample was verified by Cronbachs Alpha Coefficient (α). The WHOQOL-bref proved to be an adequate instrument, with a good level of internal consistency (α=0.884), being easily and quickly administrated for the evaluation of the QOL. The study provided an overview of the perception of quality of life of the studied group.

In recent years evidence has emerged that the endocannabinoid system (ECS) may have a significant role in metabolism and energy homeostasis. Several studies have identified upregulation of the peripheral ECS in obesity and type 2 diabetes, but the mechanisms behind this and the consequences of upregulation are unclear. The aim of this thesis was to further elucidate the role of the ECS in mature adipocytes, and its activity in obesity and related metabolic dysfunction. Three adipose tissue depots were dissected from lean, obese and obese diabetic Zucker rats (n=6-8). In human studies, written informed consent was obtained from healthy volunteers within the University of Nottingham and obese surgical patients at the Royal Derby Hospital. Anthropometric measurements and venous blood samples were obtained. In these studies, subcutaneous abdominal adipose tissue was taken from all subjects (n=28 healthy study; n=27 surgical study), and visceral adipose tissue was obtained from some of the surgical patients (n=14). In all studies, collagenase was used to isolate mature adipocytes from the adipose tissue, and FAAH and MGL activities in the adipocytes were assayed using tritium labelled substrates. Human subcutaneous preadipocytes (Promocell, Germany) were cultured and differentiated. Adipocytes were cultured with high concentrations of glucose (15 mM) and/or insulin (1 μM) for 24 hours, in combination with anandamide or 2-AG for 2 or 24 hours. Adiponectin, leptin and resistin in the cell culture media were then measured using sandwich ELISAs. In another study, anandamide and 2-AG uptake were measured in differentiated adipocytes after 2 or 24 hours’ stimulation with glucose and/or insulin. FAAH and MGL activities in the cultured adipocytes were also measured in this study. In rats, FAAH and MGL activities correlated with body mass. In healthy humans, FAAH activity in subcutaneous adipocytes correlated with BMI and waist circumference, but not with other anthropometric measurements, serum glycaemic markers or adipokines. In obese patients, the enzyme activities had no relationships with any of the anthropometric or metabolic markers investigated. Furthermore, there were no differences in activity between patients with metabolic syndrome or diabetes and those without. In both rats and humans, there were no significant differences in FAAH and MGL activities between subcutaneous and visceral adipocytes. In the cell culture studies, anandamide and 2-AG did not alter adipokine secretion under normal, high glucose or high insulin conditions. Chronic insulin exposure increased anandamide uptake, but none of the other acute or chronic treatments with glucose and/or insulin affected anandamide or 2-AG uptake. Glucose and insulin were found to reduce MGL activity. These studies suggest that the rate of anandamide hydrolysis in mature adipocytes is increased in obesity. This relationship was not apparent in a morbidly obese sample. MGL activity in humans does not have relationships with adiposity or metabolic markers, and this may reflect its role as a major component of lipid metabolism, particularly lipolysis. Anandamide and 2-AG are unlikely to be direct mediators of adipokine secretion, at least in cell culture. Insulin may affect endocannabinoid signalling in adipocytes by increasing anandamide uptake and suppressing MGL activity. Overall, these results support the notion that the ECS in adipocytes is dysregulated in obesity, but this is not driven by specific factors associated with obesity.

Incorporating team context into research and practice concerning team effectiveness in multinational organizations still remains an ongoing challenge. The purpose of this dissertation was to explore the influence of industry, corporate culture, structure, strategy and task characteristics on MNTs in business organizations and to develop a more comprehensive framework connecting the internal dynamics with contextual aspects of MNTs functioning in companies in Europe and the USA. The study was conducted in an Austrian (VA TECH), a German (Henkel) and an American company (K&M International). Forty-two problem-centered interviews were conducted with 22 team members and 20 team leaders. Levels of uncertainty, stress and turbulence influence organizations and MNTs since teams and organizations have to reshape their strategies. Multinational strategy has a positive impact on MNTs while companies with a global strategy assign low value to diversity. MNT norms in companies with a strong corporate culture are reflective of the organizational culture. MNTs at companies with a weak corporate culture develop their own unique cultures and deviate from the values and norms set by the organization. Team composition, size and length of cooperation have a moderating effect on MNTs. We could identify several team leader competences that contribute to team success. The results show how teams reduce the complexity of operations by facilitating the creation and transfer of explicit and tacit knowledge and by transferring appropriate dimensions of the HQ corporate culture between geographically dispersed business units. (author's abstract)

(kein Abstract vorhanden) / Series: Working Papers on Information Systems, Information Business and Operations

(kein Abstract vorhanden) / Series: Working Papers / Institut für Sozialpolitik

In our fast changing global village, the wealth of nations and the wealth of individuals are to some extent determined by a production factor which is called human capital. Nations are seen to be more competitive and therefore create a higher level of wealth if they have a better educated workforce. On an individual basis human capital, which is seen as ones skills and competencies, also define the success on the labor market. This success on the labor market generates individual wealth. The probability of an individual receiving a proper job is assumed to be higher, if the skills, competencies and signals of the employee reflect the skills, competencies and signals required at the job market. This dissertation wants to explore the required skills, competencies and signals by screening job announcements and analyze them via text mining techniques. (author's abstract) Part I chapter I gives an overview of relevant literature, which deals with the economic dimension of knowledge. Starting from the idea of the knowledge based economy the question: "What is useful knowledge?" is raised and discussed with the ideas of Mokyr (2005). These ideas form the framework of the heuristic model for job announcement based competence classification (see chapter: 2.5). This classification is the foundation of the first application of curricular investigation 8. To fill the framework with content, the historical development of the role of skills, competencies and signals is shortly discussed. Starting with the competence and skill dimension in the famous book "Wealth of Nations" from Smith (1868) the dissertation focuses on the 1960's where Schultz (1961) (re-) invented the idea of human capital and the importance of investing in this factor. Theodore W. Schultz received a nobel prize for his ideas. Additionally disparities and similarities according to the approaches of Bourdieu (2005) as a famous sociologist and nobel laureate Spence (1973) are disputed. Chapter 2 debates personal competence from an educational perspective. After discussing "What is educational quality" and "Who is interested in high quality education" it is argued, that employability seems to be important for all stakeholder groups. Basic concepts of employability skills and competencies are defined. Theory comparison in chapter 2.5 leads to a heuristic model for job announcement based competence classification. However, this model could be applied for different problems. Chapter 3 defines the role of the job announcements (and its contained skills and competencies) and critical assumptions which lie behind the analysis of job announcements. Part II explains the used methodology by explaining how the data were harvested from the internet (chapter 4). Data were pre- and post processed (chapter 5) and job announcements were connected with their regional origin (chapter 7). Part III shows two possible applications. The first application is a text mining based context analysis of financial related job announcements to help finding strategies to support curriculum planning focused on employability (see chapter 8). The second application shows (regional) credential inflation effects based on the core/periphery model of Krugman (1991) which are seen as an "adverse reaction" of the knowledge based economy idea (see chapter 9). (author's abstract)

In nonprofit organizations (NPOs) volunteers often work alongside paid workers. Such a coproduction setting can lead to tension between the two worker groups. This paper examines for the first time if and how volunteers influence the separation of paid employees, and thus it contributes to the debate over whether volunteers can substitute paid workers. Using Austrian data on an organizational level we find a significant impact of volunteers on the separations of paid workers in NPOs facing increased competition. These findings support the assumption that a partial substitution effect exists between paid workers and volunteers. (authors' abstract) / Series: Working Papers / Institut für Sozialpolitik