Nicotine improves probabilistic reward learning in wildtype but not alpha7 nAChR null mutants,yet alpha7 nAChR agonists do not improve probabilistic learning

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n?=?84) were treated with vehicle, 0.03, or 0.3?mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3?mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.     

Selective ablation of dorsal horn NK1 expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones

Activity in descending systems from the brainstem modulates nociceptive transmission through the dorsal horn. Intrathecal injection of the neurotoxin saporin conjugated to SP (SP-SAP) into the lumbar spinal cord results in the selective ablation of NK(1) receptor expressing (NK(1)+ve) neurones in the superficial dorsal horn (lamina I/III). Loss of these NK(1)+ve neurones attenuates excitability of deep dorsal horn neurones due to a disruption of both intrinsic spinal circuits and a spino-bulbo-spinal loop, which activates a descending excitatory drive, mediated through spinal 5HT(3) receptors. Descending inhibitory pathways also modulate spinal activity and hence control the level of nociceptive transmission relayed to higher centres. To ascertain the spinal origins of the major descending noradrenergic inhibitory pathway we studied the effects of a selective alpha2-adrenoceptor antagonist, atipamezole, on neuronal activity in animals pre-treated with SP-SAP. Intrathecal application of atipamezole dose dependently facilitated the mechanically evoked neuronal responses of deep dorsal horn neurones to low intensity von Frey hairs (5-15 g) and noxious thermal (45-50 degrees C) evoked responses in SAP control animals indicating a physiological alpha2-adrenoceptor control. This facilitatory effect of atipamezole was lost in the SP-SAP treated group. These data suggest that activity within noradrenergic pathways have a dependence on dorsal horn NK(1)+ve cells. Further, noradrenergic descending inhibition may in part be driven by lamina I/III (NK(1)+ve) cells, and mediated via spinal alpha2-adrenoceptor activation. Since the same neuronal population drives descending facilitation and inhibition, the reduced excitability of lamina V/VI WDR neurones seen after loss of these NK(1)+ve neurones indicates a dominant role of descending facilitation.     

Behaviour of postnatally growth-impaired mice during malnutrition and after partial weight recovery

Abstract

Objectives

Early malnutrition is a highly prevalent condition in developing countries. Different rodent models of postnatal early malnutrition have been used to approach the subject experimentally, inducing early malnutrition by maternal malnutrition, temporal maternal separation, manipulation of litter size or the surgical nipple ligation to impair lactation. Studies on the behaviour of (previously) malnourished animals using animal models have produced sometimes contradictory results regarding the effects of early postnatal malnutrition and have been criticized for introducing potential confounding factors.

The present paper is a first report on the behavioural effects of early malnutrition induced by an alternative approach: mice nursed by α-casein-deficient knockout dams showed a severe growth delay during early development and substantial catch-up growth after weaning when compared with animals nursed by wild-type females.

Methods

Established behavioural tests were used to study the consequences of early postnatal malnutrition on mouse pups at weaning and after partial weight recovery.

Results

Despite the impaired growth, the only behavioural difference between malnourished and normally growing animals was found in exploratory behaviour during acute malnutrition at the time of weaning. After partial catch-up in weight early protein malnourished animals showed no indication of lasting effects on general activity, emotionality and exploration, memory, and pain reactivity.

Discussion

These results suggest that the role of early nutrition on behavioural development after recovery in animal models may have been overestimated. Further careful examination of this animal model in terms of maternal care and offspring behaviour will be necessary to confirm if mice nursed by α-casein-deficient dams offer an alternative to existing models while eliminating potential confounding factors.     

拍摄高质量大体标本图像的方法

探讨使用数码照相机拍摄大体标本,应用于教医研,提出了拍摄高质量大体标本图像所需要的条件、方法和注意事项。     

冠脉循环中血小板活化状态对冠心病致病作用的研究

目的：探讨冠脉循环中血小板活化状态在冠心病（ＣＨＤ）发病学中的意义。方法：用放免等方法对受试冠状静脉窦（ＣＳ）及升主动脉（ＡＯ）血行血小板膜表面α－颗粒膜蛋白（α－ＧＭＰ－１４０）和循环内皮细胞（ＣＥＣ）等测定。结果：ＣＨＤ患冠脉循环中α－ＧＭＰ－１４０含量和ＣＥＣ浓度均明显升高（Ｐ〈０．０１）,以急心肌梗塞（ＡＭＩ）组为明显,冠脉狭窄愈严重,二升高愈明显,病灶多发比单发升高明显。结论：ＣＨＤ患冠脉循环中血小板高度激活,在ＣＨＤ的发生发展中有一定的意义。     

A Bayesian Sequential Design for Clinical Trials With Time-to-Event Outcomes

Abstract

There is increasing interest in Bayesian group sequential design because of its potential to improve efficiency in clinical trials, to shorten drug development time, and to enhance statistical inference precision without undermining the clinical trial’s integrity or validity. We propose a Bayesian sequential design for clinical trials with time-to-event outcomes and use alpha spending functions to control the overall Type I error rate. Bayes factor is adapted for decision-making at interim analyses. Algorithms are presented to make decision rules and to calculate power of the proposed tests. Sensitivity analysis is implemented to evaluate the impact of different choices of prior parameters on choosing critical values. The power of tests, the expected event size of the proposed design, and the quality of estimators are studied through simulations, and compared with the frequentist group sequential design. Simulations show that at fixed total number of events, the proposed design can achieve greater power and require smaller expected event size when appropriate priors are chosen, compared with the frequentist group sequential design. The feasibility of the proposed design is further illustrated on a real dataset. Supplementary materials for this article are available online.     

维生素K缺乏或拮抗剂Ⅱ诱导的蛋白质在原发性肝细胞癌临床诊断中的应用

目的 研究血清维生素K缺乏或拮抗剂Ⅱ诱导的蛋白质(PIVKA-Ⅱ)检测在原发性肝细胞癌(HCC)临床诊断中的价值.方法 收集北京大学第一医院门诊及住院患者共97例,其中HCC患者27例(均为肝硬化患者),非HCC患者70例(包括肝硬化患者47例,非肝硬化患者23例).检测不同组间患者的AFP和PIVKA-Ⅱ,比较两者的灵敏度和特异性,绘制受试者工作特征曲线(ROC)分析曲线下面积,对所有入组患者做AFP和PIVKA-Ⅱ的相关性分析.结果 HCC组血清AFP和PIVKA-Ⅱ水平均明显高于非HCC组(Z=-3.244、-3.329,P均＜0.01).血清AFP单独诊断HCC的灵敏度和特异性分别为81.48％、42.86％,血清PIVKA-Ⅱ单独诊断HCC的灵敏度和特异性分别为74.04％、48.57％,两者差异无统计学意义(P均＞0.05).采用AFP和PIVKA-Ⅱ不同的联合诊断方案,可将诊断HCC的灵敏度和特异性分别提高到100.00％和91.43％.ROC分析结果显示,AFP、PIVKA-Ⅱ和AFP×PIVKA-Ⅱ(AFP和PIVKA-Ⅱ之积)曲线下面积分别为0.713(95％CI:0.594～0.832)、0.719 (95％CI:0.607～0.831)、0.751 (95％CI:0.636～0.867).所有患者的AFP和PIVKA-Ⅱ的Pearson相关系数为0.370(P＜0.01),HCC患者的Pearson相关系数为0.400(P＜0.05).结论 血清PIVKA-Ⅱ用于HCC的诊断价值与血清AFP相当,可作为临床诊断HCC的血清学标记物.血清PIVKA-Ⅱ与AFP联合检测可明显提高对HCC的诊断效能.     

化学免疫治疗对肝癌患者血液甲胎蛋白 mRNA表达的影响

目的探讨肝动脉化疗栓塞（transcatheterarterial chemoembolization,TACE）联合静脉滴注化学免疫治疗（chemoimmunotherapy,CI）对原发性肝癌患者外周血甲胎蛋白（AFP）mRNA表达的影响及其临床意义。方法应用巢式逆转录聚合酶链反应（nestedRT-PCR）检测36例肝癌患者血液AFPmRNA表达在TACE＋CI前后的变化,并与单纯接受TACE的35例患者比较。结果在治疗后1周和4周,TACE组血AFPmRNA阳性率分别为54.3％和57.1％,与治疗前的51.4％（18/35）比较,差异无显著性（P均>0.05）;而TACE＋CI组血AFPmRNA阳性率各为22.2％和33.3％,分别显著低于治疗前（58.3％,21/36）和TACE组（P<0.01和P<0.05）。经过6～12个月随访,TACE＋CI组平均缓解期为(5.8±2.8)月,有6例出现门脉癌栓或肝外转移（16.7％）,而TACE组为(3.7±2.6)月和13例（37.1％）,差异均有显著性（P<0.001和P<0.05）。结论应用RTPCR技术检测原发性肝癌患者外周血AFPmRNA的动态变化对判断TACE等方法治疗肝癌的疗效有重要参考价值。联合静脉化学免疫治疗能显著降低肝癌患者外周血AFPmRNA的阳性率,可能对防止肝癌细胞的血行播散有积极意义。     

甲胎蛋白启动子调控表达p53基因的肝癌细胞靶向性基因治疗？…

目的 利用含有人甲胎蛋白启动子的腺相关病毒载体,构建能在人肝癌细胞株中特异表达目的的基因的质粒。方法 通过设计含有特定酶切点位点的引物,选择性地从人基因组中扩增出人甲胎蛋启动子（ＡＦＰ ｐｒｏｍｏｔｅｒ）主列并克琶含有绿色荧光蛋白（ＧＦＰ报基因的质粒,ｐＲＴ－ＵＦ５上,构建成含报告基因的重组腺相关病毒质粒ｒＡＡＶ－ＡＦＰ－ＧＦＰ转染表达ＡＦＰ的Ｈｅｐ Ｇ２细胞株和不表达ＡＦＰ的２９３因的质粒ｒＡＡ