The development of palliative care for people with progressive neurological disease

The role of palliative care for people with neurological disease has been developing for over 50 years, and was described from the early days of the modern hospice movement. This thesis considers my papers and studies which have helped in establishing the need for palliative care, the involvement of specialist palliative care services, the effectiveness of palliative care for neurological patients, the importance of complex decision making for this patient group and the development of guidelines, to enable care to be more widely established for patients and families. These papers have developed from the evidence from earlier research and the experience of hospices and specialist palliative care teams and helped to encourage further research. They have been important in providing an evidence-base for neurological palliative care and support-ed a wider recognition of the role of palliative care for people with neurological disease. The re-search reported here demonstrates how the increasing collaboration between specialist palliative care services and neurology can result in improved care of patients with neurological dis-ease, together with their families

Stress-Induced Cocaine Seeking Requires a Beta-2 Adrenergic Receptor-Regulated Pathway from the Ventral Bed Nucleus of the Stria Terminalis That Regulates CRF Actions in the Ventral Tegmental Area

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the β-2 AR antagonist, ICI-118,551, but not the β-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of the β-2 AR agonist, clenbuterol, but not the β-1 agonist, dobutamine, reinstated cocaine seeking, suggesting that activation of vBNST β-2 AR is both necessary for stress-induced reinstatement and sufficient to induce cocaine seeking. The contribution of a β-2 AR-regulated vBNST-to-VTA pathway that releases CRF was investigated using a disconnection approach. Injection of ICI-118,551 into the vBNST in one hemisphere and antalarmin into the VTA of the contralateral hemisphere prevented footshock-induced reinstatement, whereas ipsilateral manipulations failed to attenuate stress-induced cocaine seeking, suggesting that β-2 AR regulate vBNST efferents that release CRF into the VTA, activating CRF receptors, and promoting cocaine use. Last, reinstatement by clenbuterol delivered bilaterally into the vBNST was prevented by bilateral vBNST pretreatment with antalarmin, indicating that β-2 AR-mediated actions in the vBNST also require local CRF receptor activation. Understanding the processes through which stress induces cocaine seeking should guide the development of new treatments for addiction

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 s; range 10–70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 μg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts

Towards the 3D Web with Open Simulator

Continuing advances and reduced costs in computational power, graphics processors and network bandwidth have led to 3D immersive multi-user virtual worlds becoming increasingly accessible while offering an improved and engaging Quality of Experience. At the same time the functionality of the World Wide Web continues to expand alongside the computing infrastructure it runs on and pages can now routinely accommodate many forms of interactive multimedia components as standard features - streaming video for example. Inevitably there is an emerging expectation that the Web will expand further to incorporate immersive 3D environments. This is exciting because humans are well adapted to operating in 3D environments and it is challenging because existing software and skill sets are focused around competencies in 2D Web applications. Open Simulator (OpenSim) is a freely available open source tool-kit that empowers users to create and deploy their own 3D environments in the same way that anyone can create and deploy a Web site. Its characteristics can be seen as a set of references as to how the 3D Web could be instantiated. This paper describes experiments carried out with OpenSim to better understand network and system issues, and presents experience in using OpenSim to develop and deliver applications for education and cultural heritage. Evaluation is based upon observations of these applications in use and measurements of systems both in the lab and in the wild

Neurological palliative care — who, how, when?

There is increasing collaboration between palliative care and neurology, intending to improve the qualityof care and quality of life of people with neurological disease and their families.

Complete intersections and mod p cochains

We give homotopy invariant definitions corresponding to three well known properties of complete intersections, for the ring, the module theory and the endomorphisms of the residue field, and we investigate them for the mod p cochains on a space, showing that suitable versions of the second and third are equivalent and that the first is stronger. We are particularly interested in classifying spaces of groups, and we give a number of examples. This paper follows on from arXiv:0906.4025 which considered the classical case of a commutative ring and arXiv:0906.3247 which considered the case of rational homotopy theory.Comment: To appear in AG

CB1 Receptor Antagonism Blocks Stress-Potentiated Reinstatement of Cocaine Seeking in Rats

Rationale Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior. Objectives The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats. Methods Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement. Results Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher dose (i.e., 3 mg/kg) and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 h access/day) was affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex. Conclusions These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related