Agonist-Specific Regulation of -Opioid Receptor Desensitization and Recovery from Desensitization □ S

ABSTRACT Agonist-selective actions of opioids on the desensitization of -opioid receptors (MORs) have been well characterized, but few if any studies have examined agonist-dependent recovery from desensitization. The outward potassium current induced by several opioids was studied using whole-cell voltage-clamp recordings in locus ceruleus neurons. A brief application of the irreversible opioid antagonist ␤-chlornaltrexamine (␤-CNA) was applied immediately after treatment of slices with saturating concentrations of opioid agonists. This approach permitted the measurement of desensitization and recovery from desensitization using multiple opioid agonists, including [Met] 5 enkephalin (ME), [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO), etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone, and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with ␤-CNA. The amount of desensitization was measured as the decrease in current during a 10-min application of a saturating agonist concentration and was a good predictor of the extent of receptor protection from irreversible inactivation with ␤-CNA. After desensitization with ME or DAMGO and treatment with ␤-CNA, there was an initial profound inhibition of MOR-induced current that recovered significantly after 45 min. There was, however, no recovery of MOR-mediated current with time after treatment with agonists that did not cause desensitization, such as oxycodone. These results demonstrate that desensitization prevents irreversible inactivation of receptors by ␤-CNA

Toward a structural understanding of turbulent drag reduction: nonlinear coherent states in viscoelastic shear flows

Nontrivial steady flows have recently been found that capture the main structures of the turbulent buffer layer. We study the effects of polymer addition on these "exact coherent states" (ECS) in plane Couette flow. Despite the simplicity of the ECS flows, these effects closely mirror those observed experimentally: Structures shift to larger length scales, wall-normal fluctuations are suppressed while streamwise ones are enhanced, and drag is reduced. The mechanism underlying these effects is elucidated. These results suggest that the ECS are closely related to buffer layer turbulence.Comment: 5 pages, 3 figures, published version, Phys. Rev. Lett. 89, 208301 (2002

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Genetic erosion over time of rice landrace agrobiodiversity

Changes in global biodiversity at the genetic level have proved difficult to determine for most organisms because of lack of standardized, repeated or historical data; this hampers the attempts to meet the convention on biological diversity (CBD) 2010 targets of reducing loss of genetic diversity, particularly of crop species. For rice, where germplasm and genetic data have been collected throughout South and Southeast Asia over many decades, contrary to popular opinion, we have been unable to detect a significant reduction of available genetic diversity in our study material. This absence of a decline may be viewed positively; over the 33-year timescale of our study, genetic diversity amongst landraces grown in traditional agricultural systems was still sufficiently abundant to be collected for ex situ conservation. However, if significant genetic erosion does take place in the future as a result of accelerating global warming and/or major changes in land use or agricultural practices, will it be catastrophic or gradual, and how will it be detected? We have shown a strong link between numbers of landraces collected (and therefore extant) and genetic diversity; hence, we have a clear indicator to detect loss of genetic diversity in the future. Our findings lend considerable support for ex situ conservation of germplasm; the more than substantial genetic resources already in genebanks are now safe. On the other hand, it is the germplasm growing in farmers' fields, continually adapting genetically to changing environmental conditions and evolving novel genetic forms, whose future has been much less certain but can now be effectively monitored using our criteria