The acute and chronic administration of the 5-HT(2B/2C) receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.     

The hypertriglyceridemic waist phenotype versus the National Cholesterol Education Program-Adult Treatment Panel III and International Diabetes Federation clinical criteria to identify high-risk men with an altered cardiometabolic risk profile

The hypertriglyceridemic waist phenotype, the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria, and the International Diabetes Federation (IDF) criteria have been proposed as screening tools to identify subjects with features of the metabolic syndrome and therefore at increased cardiometabolic risk. The aim of the present study was to compare the ability of these 3 clinical approaches to identify individuals at increased cardiometabolic risk as suggested by the presence of deteriorated markers such as hyperinsulinemia, elevated apolipoprotein B levels, small low-density lipoprotein particles, high C-reactive protein concentrations, and low adiponectin levels. For that purpose, physical and cardiometabolic characteristics of a sample of 272 white men recruited for various metabolic investigations were studied. The hypertriglyceridemic waist phenotype was defined as having both a high waist circumference (≥90 cm) and increased fasting triglyceride levels (≥2.0 mmol/L). Having at least 3 of the 5 NCEP-ATP III criteria or waist circumference of at least 94 cm plus any 2 of the 4 additional IDF criteria was also used to identify individuals at increased cardiometabolic risk. A large proportion of men with the hypertriglyceridemic waist phenotype also met the NCEP-ATP III (82.7%) or IDF (89.2%) criteria. Men with the hypertriglyceridemic waist phenotype were characterized by alterations in their lipoprotein-lipid profile that included small low-density lipoprotein particles, increased apolipoprotein B and insulin levels, as well as reduced adiponectin concentrations, which were similar to individuals meeting the NCEP-ATP III or the IDF criteria. Moreover, the Framingham risk score of men meeting any of the 3 screening tools criteria was higher and was similar across the 3 approaches (4.2, 3.8, and 3.7, respectively). These results suggest that hypertriglyceridemic waist may be as discriminant as the NCEP-ATP III or the IDF criteria and could be used as an initial screening approach to identify individuals with deteriorated cardiometabolic risk markers.     

Sex differences in postprandial plasma tumor necrosis factor–α, interleukin-6, and C-reactive protein concentrations

Abdominal obesity and insulin resistance are characterized by low-level chronic inflammation most likely implicated in the increased cardiovascular disease risk associated with these conditions. However, not much is known of the acute regulation of circulating inflammatory markers in response to food intake. The aim of this study is to examine changes in inflammatory marker concentrations after the consumption of a high-fat meal in men and women. We measured tumor necrosis factor–α (TNF-α), interleukin-6 (IL-6), and C-reactive protein concentrations in plasma samples collected at 0, 4, and 8 hours after consumption of the meal in 39 men and 41 women. Associations between these variations and physical as well as metabolic variables were then examined. We noted significant increases in plasma IL-6 concentrations at 4 and 8 hours after the meal in men (+34% and +107%, respectively; P < .005 vs 0 hour) and women (+78% and +153%, respectively; P < .0001 vs 0 hour). Postprandial plasma TNF-α concentrations significantly dropped at 4 hours after the high-fat meal in men (−9.5%, P < .0005 vs 0 hour) and women (−5.5%, P < .05 vs 0 hour). Plasma CRP concentrations were not affected by food intake in either men or women. We also found that postprandial plasma concentrations of IL-6 were lower in subjects with a normal glucose tolerance (n = 69) compared with individuals with an impaired glucose tolerance (n = 11). Results of the present study show that consumption of a high-fat meal is associated with a transient reduction in circulating concentrations of TNF-α in both men and women as well as an elevation of plasma IL-6 concentrations that was found to be greater in women than in men.     

Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 Inhibitor

Background: Inherited human aldehyde dehydrogenase 2 (ALDH‐2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH‐2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH‐2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH‐2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co‐crystal structure of ALDH‐2 and daidzin. We tested the efficacy of a highly selective reversible ALDH‐2 inhibitor, CVT‐10216, in models of moderate and high alcohol drinking rats. We studied 2‐bottle choice and deprivation‐induced drinking paradigms in Fawn Hooded (FH) rats, operant self‐administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue‐induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results: CVT‐10216 increases acetaldehyde after alcohol gavage and inhibits 2‐bottle choice alcohol intake in heavy drinking rodents, including deprivation‐induced drinking. Moreover, CVT‐10216 also prevents operant self‐administration and eliminates cue‐induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT‐10216 prevents alcohol‐induced increases in NAc DA without changing basal levels. CVT‐10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion: Our findings suggest that selective reversible ALDH‐2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.     

An Audit of the Activities of the Pediatric Dermatology Nurse Specialist (PDNS)

Abstract:   In the current financial climate where resources in the National Health Service are becoming increasingly limited, it is essential that the role of the pediatric dermatology nurse specialist remains appreciated and supported. Our pediatric dermatology nurse specialist was first employed in September 2002 having had 6 years experience nursing children with a wide variety of dermatologic conditions prior to her employment. She achieved her pediatric community nursing degree in 2003 undertaking the nurse prescribing extended formulary course in 2006, her training history representative of many nurse specialists. We present the results of an audit highlighting how the employment of our pediatric dermatology nurse specialist has led to a decrease in hospital admissions as well as providing a significant positive impact on waiting lists.     

Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat

Understanding tissue distribution and clearance of nanomaterials following different routes of exposure is needed for risk assessment. F344 female rats received single or multiple exposures to 20 nm, 100 nm or 1000 nm latex fluorospheres by intravenous (i.v.) injection or oral pharyngeal aspiration into the airways. The presence of fluorospheres in tissues was assessed up to 90–120 days after the final dose. Blood, perfusion fluid, bone marrow, brain, eyes, feces, gut, heart, kidney, liver, lung, muscle, skin, spleen, thymus, tongue, urine and uterus plus ovaries were collected for analysis. Liver, spleen and lung were the greatest tissue depots for all particles following i.v. injection. The proportion of 100 nm and 1000 nm but not 20 nm spheres significantly increased in the spleen over time. Lung was the greatest tissue depot for all particles following single or repeat airway exposure. Greater than 95% of 1000 nm spheres that were recovered were in the lung in contrast to 70–80% of 20 nm spheres or 89–95% of 100 nm spheres. All 3 sizes were found in gut or gut + feces 1–7 days after lung exposure. The thymus was the largest extra-pulmonary depot for the particles; up to 25% of recovered 20 nm particles were in the thymus up to 4 months after exposure compared to 6% of 100 nm particles and 1–3% of 1000 nm particles. A small proportion of 20 nm particles were detected in kidney following both acute and repeat airway exposure. Low numbers of particles were found in the circulation (blood, perfusion), bone marrow, brain, heart, liver and spleen but not in eye, muscle, skin, tongue, ovaries, uterus or urine. These data show that the tissue targets of nano- and micron-sized spheres are very similar whether exposure occurs systemically or via the airways while the proportion of particles in some tissues and tissue clearance varies based on particle size.     

选择性κ阿片激动剂K-Ⅱ与U-50488的药理作用比较

K-Ⅱ系k阿片激动剂U-50488的同类物。通过部分离体和整体实验比较了K-Ⅱ与U-50488的药理作用。实验发现,K-Ⅱ抑制电刺激兔输精管收缩的IC₅₀值为0.42 nmol/L,U-50488为26.5 nmol/L;K-Ⅱ抑制小鼠运动功能(横筛法)的ED₅₀值为1.7 mg/g,U-50488为15.3 mg/kg;K-Ⅱ的小鼠LD₅₀值为152.5 mg/kg,U-50488为118.4 mg/g;K-Ⅱ明显降低小鼠自发活动的作用比U-50488强5倍。结果表明,K-Ⅱ是一个药理作用较U-50488强的k受体激动剂。