Differential effects of single versus repeated alcohol withdrawal on the expression of endocannabinoid system-related genes in the rat amygdala

Background: Endogenous cannabinoids such as anandamide and 2‐arachidonoylglycerol (2‐AG) exert important regulatory influences on neuronal signaling, participate in short‐ and long‐term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity, and affective control. Methods: The consequence of long‐term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT‐PCR analyses of amygdala tissue. Two groups of ethanol (EtOH)‐exposed rats were generated by maintenance on an EtOH liquid diet (10%): the first group received continuous access to EtOH for 15 days, whereas the second group was given intermittent access to the EtOH diet (5 d/wk for 3 weeks). Control subjects were maintained on an isocaloric EtOH‐free liquid diet. To provide an initial profile of acute withdrawal, amygdala tissue was harvested following either 6 or 24 hours of EtOH withdrawal. Results: Acute EtOH withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2‐AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) were evident, as were reductions in mRNA expression for CB₁, CB₂, and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent EtOH exposure, alterations in MAGL and cannabinoid receptor‐related mRNA (e.g., CB₁, CB₂, GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal‐associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in 2‐AG biosynthesis (e.g., diacylglicerol lipase‐α/β) were found in any condition. Conclusions: These findings suggest that EtOH dependence and withdrawal are associated with dysregulated endocannabinoid signaling in the amygdala. These alterations may contribute to withdrawal‐related dysregulation of amygdalar neurotransmission.     

Developments in the prevention of transfusion-associated graft-versus-host disease

The transfusion of blood products can result in a variety of consequences, including transfer of pathogens and the induction of immune responses, such as the almost invariably fatal transfusion-associated graft-versus-host disease (TA-GVHD). Exposure of blood products to γ-irradiation is currently the standard of care for the prevention of TA-GVHD. Regulatory, technical and clinical challenges associated with the use of γ-irradiators are driving efforts to develop alternatives. Initially, pathogen reduction methods were developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and leucocytes. These methods have been found to be as effective as γ-irradiation in preventing T lymphocyte proliferation and TA-GVHD responses. Additional benefits of pathogen reduction protocols potentially include inhibition of antigen presentation, cytokine production and activation of lymphocytes.     

The reinforcing effect of exercise in anorexia nervosa: Clinical correlates and relationship to outcome

ABSTRACT

The purpose of the current study was to examine the relative reinforcing effect of exercise compared to a non-monetary alternative reinforcer (leisure activity), and to money, before and after weight restoration in an inpatient population with anorexia nervosa (AN). Sixty-two inpatients with AN completed a progressive ratio (PR) task to earn exercise, leisure activities, or cash at low weight and after weight restoration. Measures of pathology and motivation to exercise were completed and post-treatment discharge weights were collected. Patients worked harder for exercise at low weight than after weight restoration (df = 46, t = 5.50, p < .001). PR task performance was weakly associated with a measure of commitment to exercise (low weight: r = 0.31, weight restored: r = 0.36, p < .05), but not with other clinical measures or follow-up weights. Contrary to prior suggestions, measurement of the reinforcing value of exercise among individuals with AN via a PR task does not appear valuable in assessing clinical severity or outcome. Other, simpler, self-report measures of commitment to exercise may have greater value in assessing these outcomes.     

Minimum clinically significant VAS differences for simultaneous (paired) interval serial pain assessments

We conducted two studies to determine whether the minimum clinically significant difference in the visual analog scale (VAS) for nearly simultaneous and brief-interval serial assessments of pain is less than that for pain assessment at 20- to 30-minute intervals, using a 10-cm VAS. The first study was a blinded, randomized, placebo-controlled paired trial comparing the pain of intravenous cannulation in both hands (20-minute application of a eutectic mixture of local anesthetics v placebo) of study subjects. The second study was a non-blinded, randomized, paired trial of different treatments for jellyfish stings. In the first study, 37 of 40 subjects indicated that one hand experienced more pain than the other. Eleven of these 37 subjects (30%) indicated differences in VAS values of 1.0 cm or less, with a minimum value of 0.5 cm. In the second study, for all the VAS-based pain comparisons, VAS differences of 相似文献   

Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma

BACKGROUND: Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. OBJECTIVE: To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. METHODS: Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. RESULTS: After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a -0.18 doubling dilution shift (95% CI, -1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction (P < .005) of total and low-density lipoprotein cholesterol. CONCLUSION: There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. CLINICAL IMPLICATIONS: Simvastatin is not useful for the treatment of asthma.