Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis

Background: Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade. Methods: Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund’s adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis. Results: Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage. Conclusions: By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis

The Combined Roles of Moral Emotion and Moral Rules in Explaining Acts of Violence Using a Situational Action Theory Perspective

The roles of shame and guilt, and their relationships to empathy, have not been modeled adequately as key factors in moral decision-making in the study of violence. The role of moral emotion has been neglected in existing criminological research and this study seeks to develop current explanations of the comprehensive myriad of factors that play a role in moral crime decision-making. This research will test the different roles of empathy, shame, and guilt in violence decision-making using a situational action theory (SAT) perspective. Data taken from the Peterborough Adolescent and Young Adult Development Study (PADS+), a longitudinal study with a large representative sample, provide quantitative questionnaire indices to enable comparison of a persistent and frequent violent offender subsample (N = 48) with the remaining PADS+ study sample (N = 607). A striking majority of violent offenders report that they do not think it is wrong to commit violence, and do not care about it, that is, they lack shame and guilt, and report that violence comes as a morally acceptable and natural action alternative. Furthermore, violent offenders do not register the predicament of their victims; there is a distinct lack of empathy. This article demonstrates a key finding which has rarely been explored to date; regression analyses reveal an interaction effect whereby individuals with weak shame and guilt, combined specifically with weak moral rules, are more likely to commit acts of violence. The study findings provide strong support for the SAT of the role of weak morality in violence decision-making. To reduce the possibility of crime being seen as an action alternative, moral development programs should be developed and administered in childhood

PRIME Deliverable D3.1: PReventing, Interdicting and Mitigating Extremist events: Defending against lone actor extremism

Led by UCL, the purpose of this deliverable is to set out an analytical framework, which will 1) guide and motivate the project's data collection activities; and 2) provide the 'bare frame' around which to build LAEE scripts by identifying key categories of indicators associated with LAEEs, which are theorised to signposts opportunities for the prevention, disruption or mitigation of these events. The theoretical model described herein, based on prior work by the first author (Bouhana, UCL) is intended for use as a risk analysis framework (i.e. a model which sets out the relationships between categories of risk factors and indicators at different analytical levels)

Developing an alternative formulation of SCP principles – the Ds (11 and counting)

Background The 25 Techniques of Situational Crime Prevention remain one of the bedrocks of research in Crime Science and play a key role in managing knowledge of research and practice. But they are not the only way of organising, transferring and applying this knowledge. Discussion Taking the 25 Techniques and their theoretical underpinnings as our starting point, this paper presents the (currently) 11 Ds, a set of intervention principles which focus specifically on how the interventions are intended to influence the offender in the proximal crime situation. The context of this work was a project to help security managers detect and control attempts to undertake 'hostile reconnaissance' of public places by those planning to commit crimes or acts of terrorism. We discuss why we judged 25 Techniques as a model for emulation in general terms but unsuitable in detail for the present purpose. We also describe the process of developing the principles, which involved both reflection, and capture of new knowledge from theory and practice, including the security domain. The distinctive contribution of professional design to this process is noted. We then present the Ds themselves and show how, as generic principles, they relate to practical methods of prevention; how they can be further organised to aid their learning and their use; how they relate to other formulations such as the Conjunction of Criminal Opportunity; and how they might apply, with expansion perhaps, to the wider field of SCP. Summary We discuss the process and the wider benefits of developing alternative – but rigorously linked – perspectives on the same theories and phenomena both for transferring existing research knowledge to practice and for sparking leading-edge theory and research

Dynamics of electric field screening in photoconductive THz sources with spatially patterned excitation

65nm n-MOSFETs show state-of-the-art cutoff frequency with ft =210 GHz and microwave low noise and high gain properties(NFmin= 0.8dB and Gass=17.3 dB at 12 GHz). As compared with the previous nodes, the high frequency properties of these MOSFETs continue to be in agreement with the downscaling trends