Dynamic regulation of the endocannabinoid system: implications for analgesia

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics

Raman spectroscopy: elucidation of biochemical changes in carcinogenesis of oesophagus

Several techniques are under development to diagnose oesophageal adenocarcinoma at an earlier stage. We have demonstrated the potential of Raman spectroscopy, an optical diagnostic technique, for the identification and classification of malignant changes. However, there is no clear recognition of the biochemical changes that distinguish between the different stages of disease. Our aim is to understand these changes through Raman mapping studies. Raman spectral mapping was used to analyse 20-μm sections of tissue from 29 snap-frozen oesophageal biopsies. Contiguous haematoxylin and eosin sections were reviewed by a consultant pathologist. Principal component analysis was used to identify the major differences between the spectra across each map. Pseudocolour score maps were generated and the peaks of corresponding loads identified enabling visualisation of the biochemical changes associated with malignancy. Changes were noted in the distribution of DNA, glycogen, lipids and proteins. The mean spectra obtained from selected regions demonstrate increased levels of glycogen in the squamous area compared with increased DNA levels in the abnormal region. Raman spectroscopy is a highly sensitive and specific technique for demonstration of biochemical changes in the carcinogenesis of Barrett's oesophagus. There is potential for in vivo application for real-time endoscopic optical diagnosis

Biotic resistance to invasion along an estuarine gradient

Biotic resistance is the ability of native communities to repel the establishment of invasive species. Predation by native species may confer biotic resistance to communities, but the environmental context under which this form of biotic resistance occurs is not well understood. We evaluated several factors that influence the distribution of invasive Asian mussels (Musculista senhousia) in Mission Bay, a southern California estuary containing an extensive eelgrass (Zostera marina) habitat. Asian mussels exhibit a distinct spatial pattern of invasion, with extremely high densities towards the back of Mission Bay (up to 4,000 m−2) in contrast with near-complete absence at sites towards the front of the bay. We established that recruits arrived at sites where adult mussels were absent and found that dense eelgrass does not appear to preclude Asian mussel growth and survival. Mussel survival and growth were high in predator-exclusion plots throughout the bay, but mussel survival was low in the front of the bay when plots were open to predators. Additional experiments revealed that consumption by spiny lobsters (Panulirus interruptus) and a gastropod (Pteropurpura festiva) likely are the primary factors responsible for resistance to Asian mussel invasion. However, biotic resistance was dependent on location within the estuary (for both species) and also on the availability of a hard substratum (for P. festiva). Our findings indicate that biotic resistance in the form of predation may be conferred by higher order predators, but that the strength of resistance may strongly vary across estuarine gradients and depend on the nature of the locally available habitat

GPR80/99, proposed to be the P2Y15 receptor activated by adenosine and AMP, is not a P2Y receptor

The orphan receptor GPR80 (also called GPR99) was recently reported to be the P2Y15 receptor activated by AMP and adenosine and coupled to increases in cyclic AMP accumulation and intracellular Ca2+ mobilization (Inbe et al. J Biol Chem 2004; 279: 19790–9[12]). However, the cell line (HEK293) used to carry out those studies endogenously expresses A2A and A2B adenosine receptors as well as multiple P2Y receptors, which complicates the analysis of a potential P2Y receptor. To determine unambiguously whether GPR80 is a P2Y receptor subtype, HA-tagged GPR80 was either stably expressed in CHO cells or transiently expressed in COS-7 and HEK293 cells, and cell surface expression was verified by radioimmunoassay (RIA). COS-7 cells overexpressing GPR80 showed a consistent twofold increase in basal inositol phosphate accumulation. However, neither adenosine nor AMP was capable of promoting accumulation of either cyclic AMP or inositol phosphates in any of the three GPR80-expressing cells. A recent paper (He et al. Nature 2004; 429: 188–93 [15]) reported that GPR80 is a Gq-coupled receptor activated by the citric acid cycle intermediate, α-ketoglutarate. Consistent with this report, α-ketoglutarate promoted inositol phosphate accumulation in CHO and HEK293 cells expressing GPR80, and pretreatment of GPR80-expressing COS-7 cells with glutamate dehydrogenase, which converts α-ketoglutarate to glutamate, decreased basal levels of inositol phosphates. Taken together, these data demonstrate that GPR80 is not activated by adenosine, AMP or other nucleotides, but instead is activated by α-ketoglutarate. Therefore, GPR80 is not a new member of the P2Y receptor family

Perceived barriers to integrated care in rheumatoid arthritis: views of recipients and providers of care in an inner-city setting

<p>Abstract</p> <p>Background</p> <p>A number of recent reports published in the UK have put the quality of care of adults with Rheumatoid Arthritis (RA) centre stage. These documents set high standards for health care professionals and commissioning bodies that need to be implemented into routine clinical practice. We therefore have obtained the views of recipients and providers of care in inner city settings as to what they perceive are the barriers to providing integrated care.</p> <p>Methods</p> <p>We conducted focus groups and face to face interviews between 2005-8 with 79 participants (patients, carers, specialist medical and nursing outpatient staff and general practitioners (GPs)) working in or attending three hospitals and three primary care trusts (PCT).</p> <p>Results</p> <p>Three barriers were identified that stood in the way of seamless integrated care in RA from the perspective of patients, carers, specialists and GPs: (i) early referral (e.g. 'gate keeper's role of GPs); (ii) limitations of ongoing care for established RA (e.g. lack of consultation time in secondary care) and (iii) management of acute flares (e.g. pressure on overbooked clinics).</p> <p>Conclusion</p> <p>This timely study of the multi-perspective views of recipients and providers of care was conducted during the time of publications of many important reports in the United Kingdom (UK) that highlighted key components in the provision of high quality care for adults with RA. To achieve seamless care across primary and secondary care requires organisational changes, greater personal and professional collaboration and GP education about RA.</p

Does the Effectiveness of Control Measures Depend on the Influenza Pandemic Profile?

BACKGROUND: Although strategies to contain influenza pandemics are well studied, the characterization and the implications of different geographical and temporal diffusion patterns of the pandemic have been given less attention. METHODOLOGY/MAIN FINDINGS: Using a well-documented metapopulation model incorporating air travel between 52 major world cities, we identified potential influenza pandemic diffusion profiles and examined how the impact of interventions might be affected by this heterogeneity. Clustering methods applied to a set of pandemic simulations, characterized by seven parameters related to the conditions of emergence that were varied following Latin hypercube sampling, were used to identify six pandemic profiles exhibiting different characteristics notably in terms of global burden (from 415 to >160 million of cases) and duration (from 26 to 360 days). A multivariate sensitivity analysis showed that the transmission rate and proportion of susceptibles have a strong impact on the pandemic diffusion. The correlation between interventions and pandemic outcomes were analyzed for two specific profiles: a fast, massive pandemic and a slow building, long-lasting one. In both cases, the date of introduction for five control measures (masks, isolation, prophylactic or therapeutic use of antivirals, vaccination) correlated strongly with pandemic outcomes. Conversely, the coverage and efficacy of these interventions only moderately correlated with pandemic outcomes in the case of a massive pandemic. Pre-pandemic vaccination influenced pandemic outcomes in both profiles, while travel restriction was the only measure without any measurable effect in either. CONCLUSIONS: our study highlights: (i) the great heterogeneity in possible profiles of a future influenza pandemic; (ii) the value of being well prepared in every country since a pandemic may have heavy consequences wherever and whenever it starts; (iii) the need to quickly implement control measures and even to anticipate pandemic emergence through pre-pandemic vaccination; and (iv) the value of combining all available control measures except perhaps travel restrictions

Fitness, motor competence and body composition as correlates of adolescent neck/shoulder pain: an exploratory cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Adolescent neck/shoulder pain (NSP) is a common and sometimes debilitating problem. Several risk factors for this condition have been investigated, but no studies have previously evaluated associations between fitness, motor competence, body composition and adolescent NSP.</p> <p>Methods</p> <p>1608 males and females of mean age 14 years answered questions on their history of NSP (4 measures), and were tested for aerobic fitness, upper and lower limb power, trunk endurance, grip strength, shoulder flexibility, motor competence and anthropometric factors. Univariate and multivariate logistic regressions were used to test for associations between NSP and physical variables.</p> <p>Results</p> <p>There were significant gender differences for most physical and pain variables. After multivariate analysis, males had lower odds of NSP if they had reduced back endurance [OR: 0.66 (95% CI: 0.46–0.97)], reduced persistent control [0.42 (0.19–0.95], and increased muscle power [0.33 (0.12–0.94)], and higher odds of NSP if they had a higher basketball throw [2.47 (1.22–5.00)] and jump performance [3.47 (1.55–7.74)]. Females had lower odds for NSP if they had a reduced jump performance [0.61(0.41–0.92)], a better basketball throw [0.60(0.40–0.90)], lower shoulder flexibility [0.54 (0.30–0.98)] and a higher aerobic capacity [0.61 (0.40–0.93)], and higher odds for NSP if they had greater abdominal endurance [1.57(1.07–2.31)] and greater bimanual dexterity [1.77(1.18–2.65)]. Females showed a U shaped relationship between NSP and back endurance [low: 2.12 (1.20–3.74); high 2.12 (1.18–3.83)].</p> <p>Conclusion</p> <p>Adolescent NSP was associated with fitness and motor competence, although the associations varied with gender, and their strength was limited.</p

Residential Radon and Brain Tumour Incidence in a Danish Cohort

BACKGROUND: Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. OBJECTIVE: To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. METHODS: During 1993-1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. RESULTS: Median estimated radon was 40.5 Bq/m(3). The adjusted IRR for primary brain tumour associated with each 100 Bq/m(3) increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. CONCLUSIONS: We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies