Is the generation of neo-antigenic determinants by free radicals central to the development of autoimmune rheumatoid disease?

Biomolecules are susceptible to many different post-translational modifications that have important effects on their function and stability, including glycosylation, glycation, phosphorylation and oxidation chemistries. Specific conversion of aspartic acid to its isoaspartyl derivative or arginine to citrulline leads to autoantibody production in models of rheumatoid disease, and ensuing autoantibodies cross-react with native antigens. Autoimmune conditions associate with increased activation of immune effector cells and production of free radical species via NADPH oxidases and nitric oxide synthases. Generation of neo-antigenic determinants by reactive oxygen and nitrogen species ROS and RNS) may contribute to epitope spreading in autoimmunity. The oxidation of amino acids by peroxynitrite, hypochlorous acid and other reactive oxygen species (ROS) increases the antigenicity of DNA, LDL and IgG, generating ligands for which autoantibodies show higher avidity. This review focuses on the evidence for ROS and RNS in promoting the autoimmune responses observed in diseases rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It considers the evidence for ROS/RNS-induced antigenicity arising as a consequence of failure to remove or repair ROS/RNS damaged biomolecules and suggests that an associated defect, probably in T cell signal processing or/or antigen presentation, is required for the development of disease.

Strategies and therapeutic opportunities for the delivery of drugs to the esophagus

Targeting of drugs and therapies locally to the esophagus is an important objective in the development of new and more effective dosage forms. Therapies that are retained within the oral cavity for both local and systemic action have been utilized for many years, although delivery to the esophagus has been far less reported. Esophageal disease states, including infections, motility disorders, gastric reflux, and cancers, would all benefit from localized drug delivery. Therefore, research in this area provides significant opportunities. The key limitation to effective drug delivery within the esophagus is sufficient retention at this site coupled with activity profiles to correspond with these retention times; therefore, a suitable formulation needs to provide the drug in a ready-to-work form at the site of action during the rapid transit through this organ. A successfully designed esophageal-targeted system can overcome these obstacles. This review presents a range of dosage form approaches for targeting the esophagus, including bioadhesive liquids and orally retained lozenges, chewing gums, gels, and films, as well as endoscopically delivered therapeutics. The techniques used to measure efficacy both in vitro and in vivo are also discussed. Drug delivery is a growing driver within the pharmaceutical industry and offers benefits both in terms of clinical efficacy, as well as in market positioning, as a means of extending a drug's exclusivity and profitability. Emerging systems that can be used to target the esophagus are reported within this review, as well as the potential of alternative formulations that offer benefits in this exciting area.

Directions for a troubled discipline:strategy research, teaching and practice introduction to the dialog

This Dialog responds to a growing debate about the relevance of business schools generally and the value of strategy theory and research for strategic management practice. The authors propose that academic theory and management practice can be better connected through management education. The academy researches practice, derives theory, and returns it to practice through the development of teaching materials and the teaching of current and future practitioners. The three articles in this Dialog examine how different approaches to strategy research inform strategy teaching and its application to practice. Joseph Bower explains the rise of business policy and the process research approach that informed that teaching tradition at Harvard Business School. Robert Grant responds by emphasizing the economic theory underpinnings of strategic management research and its impact on teaching. Paula Jarzabkowski and Richard Whittington conclude by proposing a strategyas-practice perspective and suggesting ways to better incorporate strategy-as-practice research into strategy teaching.

Does business environment matter to the development of a market orientation?

Developing a market orientation is one of the key issues in market-orientation research. In this study, based on a survey of top managers from 143 Chinese hotels and 72 travel services—two tourism sectors with distinctly different business environments—we explore the effects of environmental conditions on the development of market orientation. In particular we examine whether environmental conditions have a direct impact on the level of market orientation or whether they moderate the relationship between market orientation and its antecedents. We find that the effectiveness of top management emphasis varies under different environmental conditions but that the impact of other antecedents is not influenced by environmental conditions.

Measuring aggressiveness and anger, but not aggression? A response to the CAAS critique

Objectives: The Competitive Aggressiveness and Anger Scale (CAAS) was developed to measure antecedents of aggression in sport. The critique attacks the CAAS on three points: (1) the definition of aggression in sport adopted, (2) the‘‘one size fits all’’ element in the thinking behind the scale’s development, (3) the nature of the CAAS Anger and Aggressiveness items. The objectives of this response is to address misunderstandings in the critique. Methods: We identified a number of false assumptions that undermine the validity of the critique and attempt to clarify our position with respect to the criticisms made. Results: (1) The CAAS is being criticised for a definition that it did not use. (2) We accepted that the CAAS may not be suitable for everyone in our limitations section and fully accept the limitations of any scale. We have since undertaken a large research project to establish whether the scale is valid across and within specific sports. (3) The fundamental misunderstanding inherent throughout the critique is that the CAAS was designed as a measure of aggression, rather than anger and aggressiveness, rendering the critique of its items redundant. Conclusions: The critique misrepresents the authors of the CAAS and fails to present a coherent argument against its use. We hope to clarify our position here. The evidence to date suggests that the CAAS is a valid measure of anger and aggressiveness in many sports and that these concepts reliably differentiate players who admit unsanctioned aggression from those who do not.

Does the balanced scorecard make a difference to the strategy development process?

A great number of strategy tools are being taught in strategic management modules. These tools are available to managers for use in facilitating strategic decision-making and enhancing the strategy development process in their organisations. A number of studies have been published examining which are the most popular tools; however there is little empirical evidence on how their utilisation influences the strategy process. This paper is based on a large scale international survey on the strategy development process, and seeks to examine the impact of a particular strategy tool, the Balanced Scorecard, upon the strategy process. The Balanced Scorecard is one of the most popular strategy tools whose use has evolved since its introduction in the 1990’s. Recently, it has been suggested that as a strategy tool, Balanced Scorecard can influence all elements of the strategy process. The results of this study indicate that although there are significant differences in some elements of the strategy process between the organisations that have implemented the Balanced Scorecard and those that have not, the impact is not comprehensive.

From local to global: feminist and postcolonial approaches to the relationship between the Antipodes (Galicia-Australia)

Starting from the exploration of the common features related to a postcolonial and feminist analysis, I will attempt to establish new relationships and to open up new perspectives within the cultural exchanges between the two nations, Galicia and Australia, within a global world. On the one hand, this will be new relationships in favour of a non-sexist language which contributes to overcoming gender discrimination; and on the other hand, new relationships which favour a re-evaluation of voices which have been silenced by hegemonic and centralised discourses.

Putting service relations to the test:how can negative consumer reactions of price increases be reduced?

Price increases seem to be an adequate way to improve the earnings of companies. This fact becomes especially crucial because of increased price competition in many markets. Price increases might lead to negative customer reactions, such as a lower perceived utility or a lower loyalty intention. Therefore, the question for managers remains how prices can be increased without losing customers. Results of our experimental study suggest that customers of energy suppliers rate the perceived utility of the offer relatively better when the price increase is combined with an additional modification of the product or accompanied by a new service. It becomes clear that intensifying service relations can offset the negative effects of price increases.

A comparative study on applying the method of fundamental solutions to the backward heat conduction problem

We investigate an application of the method of fundamental solutions (MFS) to the backward heat conduction problem (BHCP). We extend the MFS in Johansson and Lesnic (2008) [5] and Johansson et al. (in press) [6] proposed for one and two-dimensional direct heat conduction problems, respectively, with the sources placed outside the space domain of interest. Theoretical properties of the method, as well as numerical investigations, are included, showing that accurate and stable results can be obtained efficiently with small computational cost.

Linking comprehensive performance assessment to the balanced scorecard:evidence from Hertfordshire County Council

Over the course of the last twenty years there has been a growing academic interest in performance management, particularly in respect of the evolution of new techniques and their resulting impact. One important theoretical development has been the emergence of multidimensional performance measurement models that are potentially applicable within the public sector. Empirically, academic researchers are increasingly supporting the use of such models as a way of improving public sector management and the effectiveness of service provision (Mayston, 1985; Pollitt, 1986; Bates and Brignall, 1993; and Massey, 1999). This paper seeks to add to the literature by using both theoretical and empirical evidence to argue that CPA, the external inspection tool used by the Audit Commission to evaluate local authority performance management, is a version of the Balanced Scorecard which, when adapted for internal use, may have beneficial effects. After demonstrating the parallels between the CPA framework and Kaplan and Norton's public sector Balanced Scorecard (BSC), we use a case study of the BSC based performance management system in Hertfordshire County Council to demonstrate the empirical linkages between a local scorecard and CPA. We conclude that CPA is based upon the BSC and has the potential to serve as a springboard for the evolution of local authority performance management systems.