The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.

BACKGROUND AND OBJECTIVE Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process. METHODS In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples. RESULTS The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms. CONCLUSIONS This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms.

More volunteers in football clubs. An evaluation of a method to increase the number of volunteers

An increasing number of clubs experience difficulties in recruiting and retaining sufficient numbers of volunteers to manage and staff their clubs (Lamprecht, Fischer, & Stamm, 2012). In order to facilitate volunteer recruitment, sport clubs need a specific strategy to recruit and retain volunteers for both formal positions and ad hoc tasks. Therefore, the intervention “More Volunteers in Football Clubs” was designed and its impact was evaluated in detail. The question this evaluation research wants to address is: Can football clubs recruit and retain volunteers successfully by implementing the intervention “More Volunteers in Football Clubs”? The designed intervention is based on the different expectations and needs of volunteers, as well as non-profit human resource management and organisational development management, with a strong emphasis on club-specific counseling and support. Task forces of the twelve participating football clubs attended four workshops in which they received tailor made counseling to reach the desired number of volunteers. The intervention has been implemented and its effectiveness tested in cooperation with the Swiss Football Federation with twelve Swiss football clubs following a pretest, intervention, posttest design Data have been gathered and analysed using a combination of qualitative and quantitative methods. Outcome measurements are: volunteer rate, number of recruited volunteers, number of filled volunteer positions and volunteer satisfaction. Four months after the intervention all clubs that completed the proposed intervention were successful in recruiting the desired number of volunteers. Further, all participating clubs found the intervention helpful and would recommend other clubs to participate as well. With the development of this practical intervention a solution for football clubs is provided to overcome the difficulties in recruiting and retaining sufficient numbers of volunteers. Lamprecht, M., Fischer, A., & Stamm, H.-P. (2012). Sportvereine in der Schweiz. Strukturen, Leistungen, Herausforderungen. Zürich, Switzerland: Seismo.

Mechanical Loading Promoted Discogenic Differentiation of Human Mesenchymal Stem Cells Incorporated in 3D-PEG Scaffolds with RhGDF5 and RGD

Hydrogels have been described as ideal scaffolds for cells of 3D tissue constructs and hold strong promises with respect to in vitro 3D-cell-culture, where cells are isolated from native extracellular matrix (ECM). Synthesized polyethyleneglycol (PEG) hydrogels are appealing with regard to potential for cell therapy or as vehicles for drug delivery or even to regenerate tissue with similar hydrogel-like properties such as the nucleus pulposus of the intervertebral disc (IVD). Here, we tested whether incorporation of RGD motive would hinder discogenic differentiation of primary bone marrow-derived human mesenchymal stem cells (hMSCs) but favor proliferation of undifferentiated hMSCs. HMSCs were embedded in +RGD containing or without RGD PEG hydrogel and pre-conditioned with or without growth and differentiation factor-5 (rhGDF-5) for 13 days. Afterwards, all hMSCs-PEG gels were subsequently cyclically loaded (15% strain, 1Hz) for 5 consecutive days in a bioreactor to generate an IVD-like phenotype. Higher metabolic activity (resazurin assay) was found in groups with rhGDF5 in both gel types with and without RGD. Cell viability and morphology measured by confocal laser microscopy and DNA content showed decreased values (~60%) after 18 days of culture. Real-time RT-PCR of an array of 15 key genes suspected to be distinctive for IVD cells revealed moderate response to rhGDF5 and mechanical loading as also shown by histology staining. Preconditioning and mechanical loading showed relatively moderate responses revealed from both RT-PCR and histology although hMSCs were demonstrated to be potent to differentiate into chondrocyte-progenitor cells in micro- mass and 3D alginate bead culture.

Fragmentation of Natural Resources Management: Experiences from Lake Kariba

This book is an output of the Defragmenting African Resources Management (DARMA) Project. Lake Kariba and its environs are a complex transboundary ecosystem with multiple, competing and often contested resource uses. The individual chapters in the book describe the current sectoral approach to natural resource management, the interconnections, and the need to adopt an ecosystem approach. The book is an essential reading for students, researchers, academics and managers in the environmental and natural resources sectors interested in advancing the ecosystems approach in management of commons in general and Southern Africa in particular. - See more at: http://www.plaas.org.za/plaas-publication/DARMA-Kariba-LV#sthash.7giSiWiB.dpuf

Shaping Institutions for Natural Resource Management

This InfoResources Focus tries to clarify challenges people face when shaping institutions for sustainable NRM and discusses key elements for implementing processes of institutional change. Emphasis is put on local institutions embedded in national, regional and global institutional schemes.

Amadir: Livelihood and Resource Management in an Eritrean Highland Community: A development baseline

This publication presents the results of a study conducted in 2003 in Amadir, a village in the Central Highlands of Eritrea. It gives an overview of the natural resource base, livelihoods, farm management, and institutions that are important to the local community. The report concludes with a chapter on options for development as discussed with the village community and local administration. This report supports Eritrea's efforts to promote rural development. It contains an extensive summary in Tigrinya, as well as a large-scale satellite image and a large-scale land use map of the study area. The appendix presents a summary of the methods used in the study.

The Role of Artefacts in the Process of Replication

This paper investigates the role of artefacts for the replication or routines in organizations. Drawing on data of a large franchise organization in the UK, we show that actors' engagement with a portfolio of different primary (e.g. software, tools) and secondary (e.g. manuals) artefacts that are part of the business format, gives rise to five artefact enabled practices of replication (activity scoping, time patterning, practical enquiry, use in practice and contextual enquiry). Importantly, these practices of replication enable three different types of franchisee agency (iterational, practical evaluative and projective agency) that support but partly also challenge replication in terms of the similarity of organizational routines across units. Our findings have several theoretical contributions for the growing literature on replication as well as materiality and artefacts in organizations.

The Impact of Human Asset Specificity on the Sourcing of Application Services

The question concerning the circumstances under which it is advantageous for a company to outsource certain information systems functions has been a controversial issue for the last decade. While opponents emphasize the risks of outsourcing based on the loss of strategic potentials and increased transaction costs, proponents emphasize the strategic benefits of outsourcing and high potentials of cost-savings. This paper brings together both views by examining the conditions under which both the strategic potentials as well as savings in production and transaction costs of developing and maintaining software applications can better be achieved in-house as opposed to by an external vendor. We develop a theoretical framework from three complementary theories and test it empirically based on a mail survey of 139 German companies. The results show that insourcing is more cost efficient and advantageous in creating strategic benefits through IS if the provision of application services requires a high amount of firm specific human assets. These relationships, however, are partially moderated by differences in the trustworthiness and intrinsic motivation of internal versus external IS professionals. Moreover, capital shares with an external vendor can lower the risk of high transaction costs as well the risk of loosing the strategic opportunities of an IS.

An Exploratory Study of Data Quality Management Practices in the ERP Software Systems Context

Quality data are not only relevant for successful Data Warehousing or Business Intelligence applications; they are also a precondition for efficient and effective use of Enterprise Resource Planning (ERP) systems. ERP professionals in all kinds of businesses are concerned with data quality issues, as a survey, conducted by the Institute of Information Systems at the University of Bern, has shown. This paper demonstrates, by using results of this survey, why data quality problems in modern ERP systems can occur and suggests how ERP researchers and practitioners can handle issues around the quality of data in an ERP software Environment.

The Process of Starting a Business

Many students are inspired to start their own business venture after taking some courses in school or simply just taking an idea and turning it into a business. The beginning process is usually most difficult in terms of establishing a functioning business, getting the right connections, and avoiding discouragement to follow through with the business. That is why many businesses fall into the categories of starting, failing along the process, or failing to get started. There is a lot to be learned from the process of starting a business venture. In addressing this issue, some of the questions this research study aims to explore and study are how people go about their new venture efforts? Second, what steps they undertake? Third, from whom do they get information? And fourth, how do they use that information? This study will seek a variety of insights that can help answer these questions and improve our understanding of why some businesses fail, succeed, or never get started.

Functional and physical associations of beta1 integrins in the activation of human T lymphocytes

Adhesion involves interactions between cells or cells with extracellular matrix components and is a fundamental process for all multicellular organisms as well as many pathogenic microbes. Integrins are heterodimeric transmembrane proteins that function as adhesion molecules and transduce signals between the extracellular environment and the intracellular cytoskeletal machinery. β1 integrin subfamily is highly expressed on T lymphocytes and mediates cell spreading, adhesion and coactivation. T lymphocytes have an important role in the regulation and homeostasis of the immune system therefore, the goals of this study were to first to investigate β1 integrin interaction with fibronectin binding protein A (FnbpA), a surface protein expressed on gram-negative bacteria Staphylococcus aureus. Second, characterize the association and function of a non-integrin surface protein, CD98, with β1 integrins on T lymphocytes. ^ FnbpA binds to fibronectin (FN), also a ligand for α5β1 and α4β1 integrins on T lymphocytes. Since both bacterial proteins FnbpA and T cell integrins utilize FN, it was of interest to determine the effects FnbpA on T cell activation. Results demonstrated that recombinant FnbpA (rFnbpA) coimmobilized with OKT3 mediated T cell coactivation in a soluble FN-dependent manner. Integrin α5β1 was identified as the main integrin utilized by Staphylococcus aureus FnbpA from studies using soluble antibodies to inhibit T cell proliferation and parallel plate flow chamber assays. The mechanism of rFnbpA-mediated coactivation was one that used soluble FN as a bridge between rFnbpA and integrin α5β1 on the T lymphocyte. ^ Since integrins are utilized by T lymphocytes and bacterial proteins, it was of interest to identify proteins involved in integrin regulation. Anti-CD98 mAb 80A10 was identified and characterized from a screen to identify surface proteins involved in integrin signaling and functions. CD98 is a non-integrin protein that was sensitive to integrin inhibition in human T lymphocyte aggregation and activation, thus suggested that CD98 shared a common signaling pathway with integrins. These results led to the question of whether CD98 physically associates with β1 integrins. Fluorescence microscopy and biochemical analysis determined that CD98 is specifically associated with β1 integrin on human T lymphocytes and may be part of a larger multimolecular signaling complex. ^

Molecular markers of human papillomavirus (HPV) infection and epidemiologic risk factors for squamous intraepithelial lesions (SIL) of the cervix

Infection with certain types of HPV is a necessary event in the development of cervical carcinoma; however, not all women who become infected will progress. While much is known about the molecular influence of HPV E6 and E7 proteins on the malignant transformation, little is known about the additional factors needed to drive the process. Currently, conventional cervical screening is insufficient at identifying women who are likely to progress from premalignant lesions to carcinoma. Aneuploidy and chromatin texture from image cytometry have been suggested as quantitative measures of nuclear damage in premalignant lesions and cancer, and traditional epidemiologic studies have identified potential factors to aid in the discrimination of those lesions likely to progress. ^ In the current study, real-time PCR was used to quantitate mRNA expression of the E7 gene in women exhibiting normal epithelium, LSIL, and HSIL. Quantitative cytometry was used to gather information about the DNA index and chromatin features of cells from the same women. Logistic regression modeling was used to establish predictor variables for histologic grade based on the traditional epidemiologic risk factors and molecular markers. ^ Prevalence of mRNA transcripts was lower among women with normal histology (27%) than for women with LSIL (40%) and HSIL (37%) with mean levels ranging from 2.0 to 4.2. The transcriptional activity of HPV 18 was higher than that of HPV 16 and increased with increasing level of dysplasia, reinforcing the more aggressive nature of HPV 18. DNA index and mRNA level increased with increasing histological grade. Chromatin score was not correlated with histology but was higher for HPV 18 samples and those with both HPV 18 and HPV 16. However, chromatin score and DNA index were not correlated with mRNA levels. The most predictive variables in the regression modeling were mRNA level, DNA index, parity, and age, and the ROC curves for LSIL and HSIL indicated excellent discrimination. ^ Real-time PCR of viral transcripts could provide a more efficient method to analyze the oncogenic potential within cells from cervical swabs. Epidemiological modeling of malignant progression in the cervix should include molecular markers, as well as the traditional epidemiological risk factors. ^