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Translational value of liquid chromatography coupled with tandem mass spectrometry-based quantitative proteomics for in vitro-in vivo extrapolation of drug metabolism and transport and considerations in selecting appropriate techniques
No full textIntroduction: Drug-metabolizing enzymes and transporters play an important role in drug absorption, distribution, metabolism and excretion and, consequently, they influence drug efficacy and toxicity. Quantification of drug-metabolizing enzymes and transporters in various tissues is therefore essential for comprehensive elucidation of drug absorption, distribution, metabolism and excretion. Recent advances in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) have improved the quantification of pharmacologically relevant proteins. Areas covered: This report presents an overview of mass spectrometry-based methods currently used for the quantification of drug-metabolizing enzymes and drug transporters, mainly focusing on applications and cost associated with various quantitative strategies based on stable isotope-labeled standards (absolute quantification peptide standards, quantification concatemers, protein standards for absolute quantification) and label-free analysis. Expert opinion: In mass spectrometry, there is no simple relationship between signal intensity and analyte concentration. Proteomic strategies are therefore complex and several factors need to be considered when selecting the most appropriate method for an intended application, including the number of proteins and samples. Quantitative strategies require appropriate mass spectrometry platforms, yet choice is often limited by the availability of appropriate instrumentation. Quantitative proteomics research requires specialist practical skills and there is a pressing need to dedicate more effort and investment to training personnel in this area. Large-scale multicenter collaborations are also needed to standardize quantitative strategies in order to improve physiologically based pharmacokinetic models
Designing for the dichotomy of immersion in location based games
No full textThe interaction design of mixed reality location based games typically focuses upon the digital content of the mobile screen, as this is characteristically the primary navigational tool players use to traverse the game space. This emphasis on the digital over the physical means the opportunity for player immersion in mixed reality games is often limited to the single (digital) dimension. This research seeks to redress this imbalance, which is caused, in part, by the requirement for the player’s attention to be systematically switched between the two worlds, defined in this research as the ‘Dichotomy of Immersion’. Using different design strategies we propose minimising the reliance of the player upon the mobile screen by encouraging greater observation of their physical surroundings. Using a ‘research through design’ approach for the mixed reality game PAC-LAN: Zombie Apocalypse, we illustrate design strategies for increasing immersion in location based games, which we believe will aid designers in enabling players to more readily engage with the physical context of the game and thus facilitate richer game experiences
The quality and implications of Balance of Care studies: lessons from a systematic literature review
No full textThe Balance of Care approach provides a framework for assessing the relative costs and outcomes of changes in the mix of services provided for a particular client group in a defined geographical area. A 2008/2009 systematic literature review explored how five key aspects of the framework had been operationalised detailing past studies’ methods. However, little has been reported about the quality of these applications, whilst the (positive and negative, internal and external) issues associated with organisations’ capacity to implement study findings (i.e. reconfigure provision) have not been appraised. Against this background, this paper reports the results of a new review that sought to address these gaps and identified 38 examples of the approach’s use since 1970. Reporting standards appeared to have improved over time, but there was no clear relationship between study quality and year of publication. Recent applications generally had large samples, used credible case types and engaged appropriate personnel in specifying optimal care. However, they rarely considered comprehensive costs, cost shifting or outcomes. Factors perceived to assist service reconfiguration included the high quality data the approach provided and the momentum for change it generated. Negative factors were predominantly financial, including increased average unit costs and the need for bridging funds
Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy:comparing corneal confocal microscopy with intraepidermal nerve fiber density
No full textObjective: Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard. Research design and methods: Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy. RESULTS: Manual and automated corneal nerve fiber density (CNFD) (P <0.0001), branch density (CNBD) (P <0.0001) and length (CNFL) (P <0.0001), and IENFD (P <0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14). Conclusions: This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN
Hymer's analysis of the multinational organization: Power retention and the demise of the federative MNE
No full textChapter Reprinted from International Business Review, Vol. 15 (2006), 166–179, ‘Hymer’s Analysis of the Multinational Organization: Power Retention and the Demise of the Federative MNE’, by Mohammad Yamin and Mats Forsgren. Copyright © 2005 by Elsevier Ltd. With kind permission from Elsevier. All Rights Reserved // This book presents more than four decades of research in international business at the Department of Business Studies, Uppsala University. Gradually, this research has been recognized as 'The Uppsala School'. The work in Uppsala over the years reflects a broad palette of issues and approaches. There are, though, some common characteristics of most of the contributions which motivates the 'school' label, beyond the fact that all have their origin in Uppsala. We claim that the dominating work has been devoted to three basic themes; knowledge as an asset and as a problem, markets as business networks and power within and between organizations. In this book these three themes have been discussed relation to firms' internationalization process and the multinational firm as an organization. A dominating feature of the work done in Uppsala is also its strong emphasis on empirical data as a base for theory development, which often has been collected through personal interviews with Swedish firms. // PART I: INTRODUCTION Knowledge, Networks And Power - The Uppsala School Of International Business; Mats Forsgren, Jan Johanson And Ulf Holm PART II: THE INTERNATIONALIZATION PROCESS OF THE FIRM 1. Experiential Knowledge And Cost In The Internationalization Process; Eriksson K., Johanson J., Majkgard A. and Sharma D 2. A Note On The Criticisms Against The Internationalization Process Model; Hadjikhani A. 3. The Concept Of Learning In The Uppsala Internationalization Process: A Critical Review; Forsgren, M. 4. Internationalisation In Industrial Systems - A Network Approach; Johanson J. and Mattsson L.G. 5. Business Networks And Cooperation In International Business Relationships; Blankenburg Holm, Eriksson and Johanson 6. The Uppsala Internationalization Process Model Revisited: From Liability Of Foreignness To Liability Of Outsidership; Johanson J. and Vahlne J-E. 7. Network Knowledge And Business-Relationship Value In The Foreign Market; Hohenthal J., Johanson J. and Johanson M. 8. Division Headquarters Go Abroad - A Step In The Internationalization Of The Multinational-Corporation; Forsgren M., Holm U. And Johanson J. PART III: THE MULTINATIONAL CORPORATION 9. Headquarters Knowledge Of Subsidiary Network Contexts In The Multinational Corporation; Holm U., Johanson J. and Thilenius P. 10. Rationality Vs Ignorance: The Role Of MNE Headquarters In Subsidiaries' Innovation Processes; Ciabuschi F., Forsgren M. and Martin Martin O. 11. Internal Embeddedness, Headquarters Involvement, And Innovation Importance In Multinational Enterprises; Ciabuschi F., Dellestrand H. and Martin Martin O. 12. The Strategic Impact Of External Networks - Subsidiary Performance And Competence Development In The Multinational Corporation; Andersson U., Forsgren M., and Holm U. 13. Competence Development Through Business Relationships Or Competitive Environment?: Subsidiary Impact On MNC Competitive Advantage; Holm U., Holmstrom C. and Sharma D. 14. Cultural Distance Or Cultural Positions? Analysing The Effect Of Culture On The HQ-Subsidiary Relationship; Drogendijk, R. and Holm, U., International Business Review, (2012), Pp. 383-396. 15. Balancing Subsidiary Influence In The Federative MNC: A Business Network View; Andersson A., Forsgren M. and Holm, U. 16. Quo Vadis? The Entry Into New Technologies In Advanced Foreign Subsidiaries Of The Multinational Enterprise; Blomkvist K., Kappen P. and Zander I. 17. Hymer's Analysis Of The Multinational Organization: Power Retention And The Demise Of The Federative; MNE. Yamin, M. and Forsgren, M. /
Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
No full textBACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs
Development of an Urban Health Impact Assessment methodology: indicating the health equity impacts of urban policies.
No full textBACKGROUND: An overarching recommendation of the global Commission on Social Determinants of Health was to measure and understand health inequalities and assess the impact of action. In a rapidly urbanising world, now is the time for Urban HIA. This article describes the development of robust and easy-to-use HIA tools to identify and address health inequalities from new urban policies. METHODS: Rapid reviews and consultation with experts identified existing HIA screening tools and methodologies which were then analyzed against predefined selection criteria. A draft Urban HIA Screening Tool (UrHIST) and Urban HIA methodology (UrHIA) were synthesised. The draft tools were tested and refined using a modified Delphi approach that included input from urban and public health experts, practitioners and policy makers. RESULTS: The outputs were two easy-to-use stand-alone urban HIA tools. The reviews and consultations identified an underpinning conceptual framework. The screening tool is used to determine whether a full HIA is required, or for a brief assessment. Urban health indicators are a readily available and efficient means of identifying variations in the health of populations potentially affected by policies. Indicators are, however, currently underutilised in HIA practice. This may limit the identification of health inequalities by HIA and production of recommendations. The new tools utilise health indicator data more fully. UrHIA also incorporates a hierarchy of evidence for use during impact analysis. CONCLUSION: The new urban HIA tools have the potential to enhance the rigour of HIAs and improve the identification and amelioration of health inequalities generated by urban policies
Characterisation and modelling of defect formation in direct-chill cast AZ80 alloy
No full textWrought magnesium alloys for demanding structural applications require high quality defect free cast feedstock. The aim of this study was to first identify and characterise typical defects in direct chill cast magnesium aluminium zinc (AZ) alloy billet and then use modelling to understand the origins of these defects so they can be prevented. Defects were first located using ultrasonic inspection and were then characterised using X-ray computed tomography (XCT) and serial sectioning, establishing the presence of oxide films and intermetallic particles Al8Mn5 in all defects. A model was developed to predict the flow patterns and growth kinetics of the intermetallic phases during casting, which influence the formation of defects. Simulation of the growth of the intermetallic particles demonstrated that precipitation from the liquid occurs in the mould. The combination of the entrained oxide films and intermetallic particles recirculates in the liquid metal and continues to grow, until large enough to settle, which is predicted to occur at the centre of the mould where the flow is the slowest. Based on these predictions, strategies to reduce the susceptibility to defect formation are suggested. (C) 2015 Elsevier Inc. All rights reserved