Delta opioid receptor-mediated analgesia is not altered in preprotachykinin A knockout mice

We have shown that delta opioid receptor (DOPR)-mediated analgesia was enhanced in the complete Freund's adjuvant (CFA) model of inflammation. This effect is thought to originate from translocation of DOPR in the plasma membrane of dorsal root ganglia and spinal cord neurons. Among the putative mechanisms involved in the regulation of DOPR trafficking, an interaction with substance P (SP) in large dense-core vesicles has been described as an essential event for the externalization of DOPR. As we have previously observed that membrane DOPRs were upregulated in small- and medium-sized neurons under inflammatory pain conditions (whereas SP is mainly expressed by small dorsal root ganglia neurons), we raised the hypothesis that an SP-independent mechanism mediates DOPR trafficking and functional emergence in the CFA model. Therefore, we investigated the role of SP in DOPR-mediated analgesia by using preprotachykinin A (precursor of SP) knockout mice (PPTA(-/-) ) in the CFA model of inflammation. First, we confirmed that PPTA(-/-) mice are not expressing SP and have a similar level of CFA-induced inflammation as wildtype mice. Then, using the thermal plantar test, we found that an intrathecal injection of deltorphin II induced DOPR-mediated antihyperalgesia, which was not modified by the absence of SP (similar efficacy and potency in wildtype and PPTA(-/-) mice). We also observed similar analgesia of intrathecal deltorphin II for PPTA(-/-) and wildtype mice in the hot-water immersion tail-flick test. Consequently, our results suggest that SP is not essential for membrane insertion and for the functional emergence of DOPR.     

Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor

The role of each of the four amide bonds in Leu(5)-enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu(5)-enkephalin analogs based on six dipeptide surrogates and two Met(5)-enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biological properties. We observed that an E-alkene can efficiently replace the first amide bond of Leu(5)- and Met(5)-enkephalin without significantly affecting biological activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biologically essential intra- or intermolecular interactions. Finally, we observed that the affinity and activity of analogs containing an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra- or intermolecular interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.     

Presence of task-1 channel in the laryngeal mucosa in the newborn lamb

Nearly 40 potassium channels have been described in respiratory epithelial cells. Of these are found several members of the 4-transmembrane domain, 2-pore K(+) channel family (K2P family), namely Twik-1 and -2, Trek-1 and -2, Task-2, -3, and -4, Thik-1, and KCNK7. The aim of this study was to verify whether the Twik-related acid-sensitive K(+) channel, subtype 1 (Task-1) (also known as KCNK3), is present in the laryngeal mucosa in the newborn lamb. Through the use of immunohistochemistry and nested polymerase chain reaction (PCR) amplification, results indicate that Task-1 protein and mRNA are present in the laryngeal mucosa, in both the ciliated, pseudostratified columnar (respiratory) epithelium and the nonkeratinized, stratified squamous epithelium. The complete ovine Task-1 protein sequence showed high homology levels with previously reported mouse, bovine, and human Task-1 sequences. This includes a complete homology for the C-terminal amino acid sequence, which is mandatory for protein trafficking to the cell membrane. These results represent the first demonstration that Task-1, a pH-sensitive channel responsible for setting membrane potential, is present in the laryngeal mucosa of a newborn mammal.     

A New Dithienylbenzotriazole‐Based Poly(2,7‐carbazole) for Efficient Photovoltaics

A new dithienyl benzotriazole‐based conjugated polymer was synthesized by Suzuki coupling reaction. The polymer was found to be soluble in common organic solvents, such as chloroform, tetrahydrofuran and chlorobenzene, with excellent film‐forming properties. The structure of the polymer was confirmed by ¹H NMR, the molecular weights determined by GPC and the thermal properties investigated by TGA and DSC. The polymer films exhibited an absorption band in the wavelength range 300 to 610 nm. Preliminary photovoltaic cells based on the composite structure of indium tin oxide (ITO)/PEDOT:PSS/ PCDTBTz:PC ₆₀ BM (1:2 w/w)/Al showed an open‐circuit voltage of 0.92 V, a power conversion efficiency of 2.2% and a short circuit current of 5.33 mA cm^?2.

     

Health care providers’ requests to Teratogen Information Services on medication use during pregnancy and lactation

Background  Medication use during pregnancy and lactation is prevalent. However, current knowledge of the risks and benefits of medication use during pregnancy and lactation is incomplete as the best available evidence has been obtained from cohort studies of inadvertent exposures and registries. This situtation may partly explain health care providers’ (HCP) risk perceptions and thus the increasing number of calls to Teratogen Information Services (TIS). Objectives  The objectives of this study were (1) to identify the medication classes for which HCP are seeking counseling from the IMAGe center, a Quebec TIS; (2) to identify the medical conditions for which medication classes were used during pregnancy and lactation; (3) to identify and quantify predictors of medication information requests during pregnancy and lactation. Methods  A retrospective analysis of data was conducted within the population served by the IMAGe center, a TIS based at CHU Ste-Justine in Montreal, Quebec, Canada, that serves the French population of Canada. To be included, calls had to be received between January 1, 2004 and April 30, 2007, and the subject of the call had to be directly associated with the exposure, or not, of a pregnant or breastfeeding woman to medication. Multivariate generalized estimating equation (GEE) regression models were performed to identify the predictors of medication requests. Results  A total of 11, 076 requests regarding medication exposure during pregnancy, 12 055 requests regarding pregnant women before the exposure took place, and 13, 364 requests regarding lactation were included for analyses. Pregnant women were most frequently exposed to antidepressants (17.3), antibiotics (6.3%), and benzodiazepines (5.3%). Prior to drug exposure, the most frequent inquiries by HCP were on antibiotics (11.0%), anti-inflammatory drugs (6.0%), and antiemetics (5.1%). Inquiries concerning lactating women most frequently requested information on the drug classes of antidepressants (10.8%), antibiotics (9.1%), and anti-inflammatory drugs (7.8%). Depressive disorders were an indication of antidepressant, benzodiazepine and antipsychotic exposures reported to IMAGe. Associations were found between medication use and maternal age, previous pregnancies, trimester of pregnancy at the time of the call and lifestyle habits. Conclusions  The IMAGe received frequent inquiries on antidepressant, antibiotic, and benzodiazepine exposures, with depressive disorders being the most frequently declared indication. Predictors of medication requests were identified among exposed women during pregnancy, and breastfeeding women. These results emphasize the need for effective studies on drug use during pregnancy and lactation and for better knowledge transfer programs.     

高龄冠心病患者经皮冠状动脉介入治疗与冠状动脉旁路移植术的比较

目的比较高龄患者经皮冠状动脉介入治疗（PCI）支架术与冠状动脉旁路移植术（CABG）对住院与临床随访结果的影响。方法212例高龄（年龄〉75岁）患者,根据血运重建方式的不同将其分为PCI支架组149例和CABG组63例,记录其临床与造影特征、血运重建情况和住院临床结果等资料,并进行临床随访。主要观察终点为住院与随访主要不良心脑血管事件（MACCE）。所有资料采用SPSS13．0软件进行统计分析,以P〈0．05为差异有统计学意义。结果与CABG组相比,PCI组的院内MACCE发生率较低（2．0％vs12．7％,χ2=10．3,P〈0．05）;院内死亡率较低（2．O％V87．9％,χ^2=4．3,P〈0．05）。多因素Logistic回归分析显示,CABG组院内MACCE发生的风险显著高于PCI组（P〈0．05）。平均随访19个月（中位时间579d）显示,2组MACCE（17．2％VS13．7％,P=0．57）、再次血运重建（P〉0．05）、卒中发生率均无统计学意义（P〉0．05）。多因素Cox回归分析表明,与CABG组相比,PCI组随访期间MACCE风险较低（P〈0．05）。结论与CABG相比,高龄冠心病患者PCI术后的院内及随访主要不良心脑血管事件发生率较低。     

家兔动脉成形术后血管内膜增殖与普伐他汀联合阿司匹林的干预效应

目的:观察普伐他汀、阿司匹林联用对家兔颈动脉血管成形术后内膜增殖进展的影响及其作用机制。方法:实验于2002-03/12在北京中医药大学教育部中医内科学重点学科实验室完成。雄性日本大耳白兔30只,体质量1.8～2.0kg,动物适应性喂养1周后随机数字表法分为正常对照组(n=9)、假手术组(n=6)、模型组(n=9)、治疗组(n=6)。模型组和治疗组动物氯胺酮、速眠新混合肌注麻醉,沿气管正中切开皮肤,剥离颈总动脉,给予电刺激。术后第2天开始饲喂高脂饲料(胆固醇:0.7%,猪油:3%,普通饲料96.3%);正常对照组无任何干预措施;假手术组仅剥离颈总动脉,不做电刺激,喂高脂饲料;动物连续喂养8周后超声评价颈总动脉,根据B超选择颈总动脉有斑块或血流明显改变者作颈总动脉球囊扩张术。正常对照组、模型组、假手术组喂普通饲料,治疗组喂普伐他汀与阿司匹林含药饲料(普伐他汀5.046mg/kg,阿司匹林2.268g/kg),4周后测血脂和C-反应蛋白浓度、血清一氧化氮及转化生长因子β水平,观察颈动脉组织病理形态学改变,半定量分析增生内膜中胶原含量的变化,免疫组织化学方法分析增生内膜中巨噬细胞和平滑肌细胞阳性百分率。结果:纳入大耳白兔30只,正常对照组中途死亡1只,死因为牙齿畸型影响进食;模型组1只因电刺激8周时超声评价颈动脉未形成斑块及血流无明显改变而剔出实验,进入分析28只。与模型组比,普伐他汀与阿司匹林联用4周后,治疗组胆固醇及三酰甘油水平明显下降[(4.12±2.30),(0.74±0.17)mmol/L;(0.47±0.27),(0.39±0.14)mmol/L;P<0.05],血清C-反应蛋白水平和转化生长因子β水平均降低[(0.86±0.27),(0.57±0.30)mg/L;(3.45±0.77),(3.23±0.34)ng/L;P<0.05],一氧化氮水平升高[(41.79±35.78),(90.14±32.54)mmol/L;P<0.05],动脉内膜增殖程度明显减轻,管腔狭窄率降低,内中膜厚度及内中膜面积比降低[(71.91±14.90)%,(47.20±18.74)%;(0.41±0.17),(0.26±0.04)mm;1.66±0.63,0.78±0.34;P均<0.05],动脉内膜胶原含量减少(30.92±10.05,21.93±5.81,P<0.01),动脉内膜巨噬细胞阳性百分率降低[(13.94±4.91)%,(7.29±7.28)%,P<0.05],平滑肌细胞含量无明显差异(38.37±5.67,35.79±10.68,P>0.05)。结论:普伐他汀与阿司匹林联用具有抑制内膜增生和减少新生内膜胶原含量的作用,其机制与两药抑制炎症反应、保护内皮功能及抑制细胞外基质生成等有关。