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991.
Herman D Lim Maristella Adami Elena Guaita Thomas Werfel Rogier A Smits Iwan JP de Esch Remko A Bakker Ralf Gutzmer Gabriella Coruzzi Rob Leurs 《British journal of pharmacology》2009,157(1):34-43
Background and purpose:
We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine.Experimental approach:
Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity.Key results:
Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430.Conclusions and implications:
Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors. 相似文献992.
CZ Zhu JP Mikusa Y Fan PR Hollingsworth M Pai P Chandran AV Daza BB Yao MJ Dart MD Meyer MW Decker GC Hsieh P Honore 《British journal of pharmacology》2009,157(4):645-655
Background and purpose:
Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain.Experimental approach:
WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB1 and CB2 receptor antagonists.Key results:
WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB1 versus CB2 receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB1 receptor antagonist, but not with a CB2 receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB1 and CB2 antagonists blocked systemic WIN-induced analgesic activity.Conclusions and implications:
Both CB1 and CB2 receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB1 but not CB2 receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB1 receptors in the brain.British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009 相似文献993.
JP Garner SK Sood J Robinson W Barber K Ravi 《Annals of the Royal College of Surgeons of England》2009,91(1):39-42
INTRODUCTION
Biliary symptoms whilst awaiting elective cholecystectomy are common, resulting in hospital admission, further investigation and increased hospital costs. Immediate cholecystectomy during the first admission is safe and effective, even when performed laparoscopically, but acute laparoscopic cholecystectomy has only recently become increasingly commonplace in the UK. This study was designed to quantify this problem in our hospital and its cost implications.PATIENTS AND METHODS
The case notes of all patients undergoing laparoscopic cholecystectomy in our hospital between January 2004 and June 2005 were examined for details of hospital admissions with biliary symptoms or complications whilst waiting for elective cholecystectomy. Additional bed occupancy and radiological investigations were recorded and these costs to the trust calculated. We compared the potential tariff income to the hospital trust for the actual management of these patients and if a policy of acute laparoscopic cholecystectomy on first admission were in place.RESULTS
In the 18-month study period, 259 patients (202 females) underwent laparoscopic cholecystectomy. Of these, 147 presented as out-patients and only 11% required hospital admission because of biliary symptoms whilst waiting for elective surgery. There were 112 patients who initially presented acutely and were managed conservatively. Twenty-four patients were re-admitted 37 times, which utilised 231 hospital bed-days and repeat investigations costing over £40,000. There would have been a marginal increase in tariff income if a policy of acute laparoscopic cholecystectomy had been in place.CONCLUSIONS
Adoption of a policy of acute laparoscopic cholecystectomy on the index admission would result in substantial cost savings to the trust, reduce elective cholecystectomy waiting times and increase tariff income. 相似文献994.
Yu L Boulware DC Beam CA Hutton JC Wenzlau JM Greenbaum CJ Bingley PJ Krischer JP Sosenko JM Skyler JS Eisenbarth GS Mahon JL;Type Diabetes TrialNet Study Group 《Diabetes care》2012,35(6):1213-1218
OBJECTIVE
We assessed diabetes risk associated with zinc transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A).RESEARCH DESIGN AND METHODS
For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives.RESULTS
ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA+ vs. 8 of 911 [0.8%] BAA−, P < 0.001) and BAA number (177 of 1,683 [10.5%] single-, 221 of 384 [57.6%] double-, and 150 of 189 [79.4%] triple-BAA positivity, P < 0.001). The 4-year diabetes risk was higher in single BAA+ relatives with ZnT8A than ZnT8A− relatives (31 vs. 7%, P < 0.001). In multivariable analysis, age ≤20 years (hazard ratio 2.13, P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not (P = 0.81 and 0.86, respectively).CONCLUSIONS
In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.Type 1 diabetes is usually preceded by a subclinical prodrome marked by islet cell antibodies (ICA) and biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and the insulinoma-associated protein 2 antigen (IA-2A/ICA512A) (1). The predictive validity of the autoantibodies for diabetes in relatives of people with type 1 diabetes has made autoantibody positivity an entry criterion for type 1 diabetes secondary prevention trials (2–5) and a surrogate outcome in primary prevention trials (6). Autoantibodies to the islet antigen zinc transporter-8 (ZnT8A) recently were found to predict type 1 diabetes (7–9). However, the relationship between diabetes risk and ZnT8A in combination with other risk markers, including ICA, the standard BAA, HLA genotype, and age, remains unclear.We therefore measured ZnT8A in a large cohort of relatives being followed in the TrialNet Natural History Study of Type 1 Diabetes (NHS). We hypothesized that ZnT8A positivity would increase diabetes risk in relatives positive for a single BAA—a group that accounts for most autoantibody-positive relatives but whose members are at much lower risk compared with relatives with two or more autoantibodies (10). We also assessed whether ZnT8A increased diabetes risk independently of ICA, the BAA, HLA class II genotype, and age. 相似文献995.
996.
997.
Lafanechère A Pène F Goulenok C Delahaye A Mallet V Choukroun G Chiche JD Mira JP Cariou A 《Critical care (London, England)》2006,10(5):R132-8
Introduction
Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (ΔPP) to predict fluid responsiveness.Methods
We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%.Results
Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A ΔPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively.Conclusion
The PLR-induced increase in ABF and a ΔPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading. 相似文献998.
The quantification of cardiac dimensions derived from echocardiographyis important in paediatric cardiac practice. Evaluation of thesize and growth of cardiac chambers, valves, and great vesselsplays a key role in the management of congenital heart disease,from the initial decision-making in the neonatal period to thenature and timing of subsequent interventions. It may also beimportant in the assessment and risk stratification of childrenwith acquired heart disease such as hypertrophiccardiomyopathy or coronary artery involvement in Kawasaki disease.Body size and cardiac dimensions change dramatically duringnormal growth and development. Therefore, it is necessary toplace in context the measured size of a given cardiac structureby correcting for body size, through the process of normalization. 相似文献
999.
1000.
Monitoring adverse events (AEs) is an important part of clinical research and a crucial target for data standards. The representation of adverse events themselves requires the use of controlled vocabularies with thousands of needed clinical concepts. Several data standards for adverse events currently exist, each with a strong user base. The structure and features of these current adverse event data standards (including terminologies and classifications) are different, so comparisons and evaluations are not straightforward, nor are strategies for their harmonization. Three different data standards - the Medical Dictionary for Regulatory Activities (MedDRA) and the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) terminologies, and Common Terminology Criteria for Adverse Events (CTCAE) classification - are explored as candidate representations for AEs. This paper describes the structural features of each coding system, their content and relationship to the Unified Medical Language System (UMLS), and unsettled issues for future interoperability of these standards. 相似文献