4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1

TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous alpha,beta-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.

Safety and quality and stage of distribution

Let 0 denote the level of quality inherent in a food product that is delivered to some terminal market. In this paper, I characterize allocations over 0 and provide an economic rationale for regulating safety and quality standards in the food system. Zusman and Bockstael investigate the theoretical foundations for imposing standards and stress the importance of providing a tractable conceptual foundation. Despite a wealth of contributions that are mainly empirical (for reviews of these works see, respectively, Caswell and Antle), there have been relatively few attempts to model formally the linkages between farm and food markets when food quality and consumer safety are at issue. Here, I attempt to provide such a framework, building on key contributions in the theoretical literature and linking them in a simple model of quality determination in a vertically related marketing channel. The food-marketing model is due to Gardner. Spence provides a foundation for Pareto-improving intervention in a deterministic model of quality provision, and Leland, building on the classic paper by Akerlof, investigates licensing and minimum standards when the information structure is incomplete. Linking these ideas in a satisfactory model of the food markets is the main objective of the paper.

Cooled infrared filters and dichroics for the sea and land surface temperature radiometer (SLSTR)

The Sea and Land Surface Temperature Radiometer (SLSTR) is a nine channel visible and infrared high precision radiometer designed to provide climate data of global sea and land surface temperatures. The SLSTR payload is destined to fly on the Ocean and Medium-Resolution Land Mission for the ESA/EU Global Monitoring for Environment and Security (GMES) Programme Sentinel-3 mission to measure the sea and land temperature and topography for near real-time environmental and atmospheric climate monitoring of the Earth. In this paper we describe the optical layout of infrared optics in the instrument, spectral thin-film multilayer design, and system channel throughput analysis for the combined interference filter and dichroic beamsplitter coatings to discriminate wavelengths at 3.74, 10.85 & 12.0 μm. The rationale for selection of thin-film materials, deposition technique, and environmental testing, inclusive of humidity, thermal cycling and ionizing radiation testing are also described.

Extended Canadian middle atmosphere model: zonal-mean climatology and physical parameterizations

This paper describes the energetics and zonal-mean state of the upward extension of the Canadian Middle Atmosphere Model, which extends from the ground to ~210 km. The model includes realistic parameterizations of the major physical processes from the ground up to the lower thermosphere and exhibits a broad spectrum of geophysical variability. The rationale for the extended model is to examine the nature of the physical and dynamical processes in the mesosphere/lower thermosphere (MLT) region without the artificial effects of an imposed sponge layer which can modify the circulation in an unrealistic manner. The zonal-mean distributions of temperature and zonal wind are found to be in reasonable agreement with observations in most parts of the model domain below ~150 km. Analysis of the global-average energy and momentum budgets reveals a balance between solar extreme ultraviolet heating and molecular diffusion and a thermally direct viscous meridional circulation above 130 km, with the viscosity coming from molecular diffusion and ion drag. Below 70 km, radiative equilibrium prevails in the global mean. In the MLT region between ~70 and 120 km, many processes contribute to the global energy budget. At solstice, there is a thermally indirect meridional circulation driven mainly by parameterized nonorographic gravity-wave drag. This circulation provides a net global cooling of up to 25 K d^-1.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Creating a world class business through a merger of two equals: an interview with Paul Walsh, Chief Executive Officer of Diageo Plc

Purpose – The purpose of this paper is to explore, from a practical point-of-view, a number of key strategic issues that critically influence organisations' competitiveness. Design/methodology/approach – The paper is based on a semi-structured interview with Mr Paul Walsh, CEO of Diageo. Diageo is a highly successful company and Mr Walsh has played a central role in making Diageo the number one branded drink company in the world. Findings – The paper discusses the key attributes of successful merger, lessons from a complex cross boarder acquisition, rationale for strategic alliance with competitors, distinctive resources, and the role of corporate social responsibility. Research limitations/implications – It is not too often that management scholars have the opportunity to discuss with the CEOs of large multinationals the rational of key strategic decisions. In this paper these issues are explored from the perspective of a CEO of a large and successful company. The lessons, while not generalisable, offer unique insights to students of management and management researchers. Originality/value – The paper offers a bridge between theory and practice. It demonstrates that from Diageo's perspective the distinctive capabilities are intangible. It also offers insight into how to successfully execute strategic decision. In terms of originality it offers a view from the top, which is often missing from strategy research.

John Lewis Partnership lessons in logical incrementalism and organic growth: a case study and interview with the Chairman, Mr Charlie Mayfield

Purpose – The purpose of this paper is to demonstrate how strategy is developed and implemented in an organisation with an unusual ownership model. Partnerships are not a prevalent form of ownership but as this case demonstrates they can be extremely effective. Furthermore this case demonstrates how logical incrementalism can be used to implement major strategic decisions. Design/methodology/approach – The paper draws on company documentary evidence and a semi-structured interview with Mr Charlie Mayfield, Chairman of John Lewis Partnership. A chairman has a helicopter view of business whose perspectives are rarely captured by strategy researchers. This case study offers an insight into strategic thinking of a chairman and chief executive of a successful company. Research limitations/implications – The case study and interview offer a unique insight into the rationale behind strategic decisions within a successful partnership that has grown organically in a highly competitive retail market without high gearing. Originality/value – This case study sheds light on strategic moves within partnership. Furthermore, very few case studies offer insight into the thinking of a chief executive who has successfully managed a business in a turbulent environment.

Metaphors in complexity theory and planning

This article reviews the use of complexity theory in planning theory using the theory of metaphors for theory transfer and theory construction. The introduction to the article presents the author's positioning of planning theory. The first section thereafter provides a general background of the trajectory of development of complexity theory and discusses the rationale of using the theory of metaphors for evaluating the use of complexity theory in planning. The second section introduces the workings of metaphors in general and theory-constructing metaphors in particular, drawing out an understanding of how to proceed with an evaluative approach towards an analysis of the use of complexity theory in planning. The third section presents two case studies – reviews of two articles – to illustrate how the framework might be employed. It then discusses the implications of the evaluation for the question ‘can complexity theory contribute to planning?’ The concluding section discusses the employment of the ‘theory of metaphors’ for evaluating theory transfer and draws out normative suggestions for engaging in theory transfer using the metaphorical route.

Evaluating the interdependencies between managing business change, IT sourcing and IT governance

Organisations need the right business and IT capabilities in order to achieve future business success. It follows that the sourcing of these capabilities is an important decision. Yet, there is a lack of consensus on the approach to decid-ing where and how to source the core operational capabilities. Furthermore, de-veloping its dynamic capability enables an organisation to effectively manage change its operational capabilities. Recent research has proposed that analysing business capabilities is a key pre-requisite to defining its Information Technology (IT) solutions. This research builds on these findings by considering the interde-pendencies between the dynamic business change capability and the sourcing of IT capabilities. Further it examines the decision-making oversight of these areas as implemented through IT governance. There is a good understanding of the direct impact of IT sourcing decision on operational capabilities However, there is a lack of research on the indirect impact to the capability of managing business change. Through a review of prior research and initial pilot field research, a capability framework and three main propositions are proposed, each examining a two-way interdependency. This paper describes the development of the integrated capa-bility framework and the rationale for the propositions. These respectively cover managing business change, IT sourcing and IT governance. Firstly, the sourcing of IT affects both the operational capabilities and the capability to manage business change. Similarly a business change may result in new or revised operational ca-pabilities, which can influence the IT sourcing decision resulting in a two-way rela-tionship. Secondly, this IT sourcing is directed under IT governance, which pro-vides a decision-making framework for the organisation. At the same time, the IT sourcing can have an impact on the IT governance capability, for example by out-sourcing key capabilities; hence this is potentially again a two-way relationship. Finally, there is a postulated two-way relationship between IT governance and managing business change in that IT governance provides an oversight of manag-ing business change through portfolio management while IT governance is a key element of the business change capability. Given the nature and novelty of this framework, a philosophical paradigm of constructivism is preferred. To illustrate and explore the theoretical perspectives provided, this paper reports on the find-ings of a case study incorporating eight high-level interviews with senior execu-tives in a German bank with 2300 employees. The collected data also include or-ganisational charts, annual reports, project and activity portfolio and benchmark reports for the IT budget. Recommendations are made for practitioners. An understanding of the interdependencies can support professionals in improving business success through effectively managing business change. Additionally, they can be assisted to evaluate the impact of IT sourcing decisions on the organisa-tion’s operational and dynamic capabilities, using an appropriate IT governance framework.

Conscience, discretion and the creation of property rights

This paper considers the utility of the concept of conscience or unconscionable conduct as a contemporary rationale for intervention in two principles applied where a person seeks to renege on an informal agreement relating to land: the principle in Rochefoucauld v Boustead; and transfers 'subject to' rights in favour of a claimant. By analysing the concept in light of our current understanding of the nature of judicial discretion and the use of general principles, it responds to arguments that unconscionability is too general a concept on which to base intervention. In doing so, it considers the nature of the discretion that is actually in issue when the court intervenes through conscience in these principles. However, the paper questions the use of constructive trusts as a response to unconscionability. It argues that there is a need, in limited circumstances, to separate the finding of unconscionability from the imposition of a constructive trust. In these limited circumstances, once unconscionability is found, the courts should have a discretion as to the remedy, modelled on that developed in the context of proprietary estoppel. The message underlying this paper is that many of the concerns expressed about unconscionability that have led to suggestions of alternative rationales for intervention can in fact be addressed whilst retaining an unconscionability analysis. Unconscionability remains a preferable rationale for intervention as it provides a common thread that links apparently separate principles and can assist our understanding of their scope.

Top single nucleotide polymorphisms affecting carbohydrate metabolism in Metabolic Syndrome: from the LIPGENE study

Rationale:Metabolic Syndrome (MetS) is a high prevalence condition characterized by altered energy metabolism, insulin resistance and elevated cardiovascular risk.Objectives:Although many individual single nucleotide polymorphisms (SNPs) have been linked to certain MetS features, there are few studies analyzing the influence of SNPs on carbohydrate metabolism in MetS.Methods:904 SNPs (tag SNPs and functional SNPs) were tested for influence in eight fasting and dynamic markers of carbohydrate metabolism, performing an intravenous glucose tolerance test in 450 participants of the LIPGENE study.Findings:From 382 initial gene-phenotype associations between SNPs and any phenotypic variables, 61 (a 16 % of the pre-selected) remained significant after Bootstrapping. Top SNPs affecting glucose metabolism variables were as follows: fasting glucose: rs26125 (PPARGC1B); fasting insulin: rs4759277 (LRP1); C peptide: rs4759277 (LRP1); HOMA-IR: rs4759277 (LRP1); QUICKI: rs184003 (AGER); SI: rs7301876 (ABCC9), AIRg: rs290481 (TCF7L2) and DI: rs12691 (CEBPA).Conclusions:We describe here the top SNPs linked to phenotypic features in carbohydrate metabolism among aproximately 1000 candidate gene variations in fasting and postprandial samples of 450 patients with MetS from the LIPGENE study.

User's manual

'Typeform dialogues', as originally planned for publication, was an interactive CD-based screen interface presenting a comparative survey of typeform history and description. The CD was to be held inside a printed book that included two essays and a User’s Manual. Although 'Typeform dialogues' (CD+book) was not completed as planned, a PDF file was published containing the User’s Manual, together with background information about the interface and the project it was part of. The User's Manual presents all interface sections and features (using screen grabs) and explains their editorial rationale, design, and function.

Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity

Rationale: Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood. Objectives: The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli. Methods: We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design. Results: Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula. Conclusions: These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity.

Effects of pramipexole on the processing of rewarding and aversive taste stimuli

Rationale: Pramipexole, a D2/D3 dopamine receptor agonist, has been implicated in the development of impulse control disorders in patients with Parkinson's disease. Investigation of single doses of pramipexole in healthy participants in reward-based learning tasks has shown inhibition of the neural processing of reward, presumptively through stimulation of dopamine autoreceptors. Objectives: This study aims to examine the effects of pramipexole on the neural response to the passive receipt of rewarding and aversive sight and taste stimuli. Methods: We used functional magnetic resonance imaging to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 16 healthy volunteers who received a single dose of pramipexole (0.25 mg) and placebo in a double-blind, within-subject, design. Results: Relative to placebo, pramipexole treatment reduced blood oxygen level-dependent activation to the chocolate stimuli in the areas known to play a key role in reward, including the ventromedial prefrontal cortex, the orbitofrontal cortex, striatum, thalamus and dorsal anterior cingulate cortex. Pramipexole also reduced activation to the aversive condition in the dorsal anterior cingulate cortex. There were no effects of pramipexole on the subjective ratings of the stimuli. Conclusions: Our results are consistent with an ability of acute, low-dose pramipexole to diminish dopamine-mediated responses to both rewarding and aversive taste stimuli, perhaps through an inhibitory action of D2/3 autoreceptors on phasic burst activity of midbrain dopamine neurones. The ability of pramipexole to inhibit aversive processing might potentiate its adverse behavioural effects and could also play a role in its proposed efficacy in treatment-resistant depression.

The D2 antagonist sulpiride modulates the neural processing of both rewarding and aversive stimuli in healthy volunteers.

Rationale: Animal studies indicate that dopamine pathways in the ventral striatum code for the motivational salience of both rewarding and aversive stimuli, but evidence for this mechanism in humans is less established. We have developed a functional magnetic resonance imaging (fMRI) model which permits examination of the neural processing of both rewarding and aversive stimuli. Objectives: The aim of the study was to determine the effect of the dopamine receptor antagonist, sulpiride, on the neural processing of rewarding and aversive stimuli in healthy volunteers. Methods: We studied 30 healthy participants who were randomly allocated to receive a single dose of sulpiride (400 mg) or placebo, in a double-blind, parallel-group design. We used fMRI to measure the neural response to rewarding (taste or sight of chocolate) and aversive stimuli (sight of mouldy strawberries or unpleasant strawberry taste) 4 h after drug treatment. Results: Relative to placebo, sulpiride reduced blood oxygenation level-dependent responses to chocolate stimuli in the striatum (ventral striatum) and anterior cingulate cortex. Sulpiride also reduced lateral orbitofrontal cortex and insula activations to the taste and sight of the aversive condition. Conclusions: These results suggest that acute dopamine receptor blockade modulates mesolimbic and mesocortical neural activations in response to both rewarding and aversive stimuli in healthy volunteers. This effect may be relevant to the effects of dopamine receptor antagonists in the treatment of psychosis and may also have implications for the possible antidepressant properties of sulpiride.