Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation

Introduction: Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection.

Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored.

Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.     

Factors influencing myocardial salvage with primary angioplasty

Background

The purpose of this study was to evaluate the factors influencing the salvage of jeopardized myocardium in patients treated with primary angioplasty for acute myocardial infarction.

Methods and Results

This multicenter study involved 59 patients with acute myocardial infarction who underwent primary angioplasty without antecedent thrombolytic therapy and paired baseline (before angioplasty) and predischarge tomographic perfusion imaging by quantitative ^99mTc-labeled sestamibi techniques for assessing the initial area at risk and eventual infarct size. Of the 59 patients who underwent primary angioplasty, Thrombolysis In Myocardial Infarction (TIMI) level 3 perfusion was restored in the infarct vessel in 54 patients (92%). On average, approximately one third of the left ventricular myocardial mass was initially jeopardized by the infarction in progress; eventual infarct size was 18%±15% of the left ventricle; myocardial salvage was 16%±17% of the left ventricle. Primary angioplasty salvaged 46%±50% of initially jeopardized myocardium. Factors correlated with myocardial salvage included elapsed time from onset of pain to reperfusion, infarct location (anterior infarcts had more myocardial salvage than inferior infarcts), and residual flow to the infarct zone at preangioplasty baseline levels. In the five patients reperfused less than 2 hours from onset of pain, 80% of the jeopardized myocardium was salvaged. Myocardial salvage beyond 2 hours was much more variable.

Conclusion

Primary angioplasty was highly effective at restoring normal perfusion in the infarct vessel and salvaging jeopardized myocardium. The myocardial salvage was highly variable and correlated with elapsed time to reperfusion, baseline residual flow to the infarct zone, and infarct location.     

The anti-nausea effects of CB1 agonists are mediated by an action at the visceral insular cortex

BACKGROUND AND PURPOSE

Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB₁) agonists interfere with the establishment of nausea-induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB₁ receptors.

EXPERIMENTAL APPROACH

We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB₁ agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB₁ receptors.

KEY RESULTS

Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB₁ agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB₁ receptors because it was prevented by co-administration of CB₁ antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.

CONCLUSIONS AND IMPLICATIONS

The nausea-relieving effects of CB₁ agonists, but not the nausea-inducing effects of CB₁ inverse agonists, are mediated, at least in part, by their action at the VIC in rats.     

Pain after barium enema: effect of CO2 and air on double-contrast study

One hundred fifty-one consecutive patients scheduled for double-contrast barium enema studies were assigned randomly to insufflation with either air or carbon dioxide (CO2) in a double-blind, prospective trial. Within 24 hours after the enema study, the patients were contacted by telephone by an interviewer, who completed a standard questionnaire. Radiographs from the enema studies were assessed for quality by two radiologists. Pain experienced after the procedure was graded from 0 (none) to 4 (severe). Clinically relevant (grades 2-4) pain was experienced by 30% of patients after insufflation with room air, compared with 11% of patients in whom CO2 was used for insufflation (P = .005). The mean pain score for CO2 was 0.4, and for room air, 1.2 (P less than .005). Although five patients experienced grade 4 pain after insufflation with air, no patient reported severe pain after CO2 insufflation. Post-evacuation films confirmed there was significantly less residual gas in the CO2 group. The quality of radiographs was equal in the two groups. CO2 has advantages for use in the double-contrast barium enema examination.     

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.     

Mechanism of acute myocardial infarction in patients with prior coronary artery bypass grafting and therapeutic implications

Although acute myocardial infarction (AMI) is usually due to thrombotic occlusion when involving a native coronary artery, the mechanism responsible for AMI in patients with previous coronary artery bypass grafting (CABG) is not well understood. Since knowledge of pathophysiology of AMI may alter subsequent management, angiograms obtained between 1 hour and 7 days of AMI (median 1 day) were reviewed in 50 patients greater than 1 year after CABG. The culprit vessel was identified by the presence of residual stenosis and/or thrombus in the vessel supplying the infarct zone or by reviewing previous angiograms. The infarct vessel was identified as a vein graft in 38 (76%) patients, the native vessel in 8 patients (16%) and could not be accurately determined in 4 patients (8%). Among the 38 vein grafts suspected as the infarct vessel, unequivocal angiographic evidence of residual thrombus (filling defect/persistent staining) was present in 31 (82%) and was greater than 2 cm in length in 15 patients. Successful reperfusion occurred in only 2 of 8 (25%) grafts after intravenous thrombolytic therapy. Intragraft thrombolysis with or without additional angioplasty was successful at restoring flow in 8 of 10 (80%) grafts. Data indicate that in patients who have undergone previous CABG, AMI is usually caused by thrombotic occlusion of a saphenous vein graft and that conventional intravenous thrombolytic therapy may be inadequate to restore flow. The large mass of thrombus and absent flow in the graft may require subselective drug infusion, a higher thrombolytic dose or a mechanical means of recanalization.     

紫杉醇药物涂层支架植入术后患者外周血单核细胞中热休克蛋白70的变化：生物材料临床应用近期效果随访

目的:植入材料、靶血管病变特征、术前状态、炎症因子及急性期蛋白均对急性冠状动脉综合征接受支架材料介入治疗后的效果有影响,为验证紫杉醇涂层支架临床应用后材料及宿主的相关反应,实验观察了接受紫杉醇涂层支架介入治疗的急性冠状动脉综合征患者的外周血热休克蛋白70水平变化,并分析其临床意义。方法:①连续性入选2004-12/2006-03在江苏大学附属人民医院行经皮冠状动脉介入治疗的78例急性冠状动脉综合征患者,全部病例均置入紫杉醇药物涂层支架。采用流式细胞仪测定症状发作平均(34.1±16.2)h的外周血单核细胞热休克蛋白70阳性表达水平。②所有患者随访至术后6个月,出现心源性死亡、再次心肌梗死、再发心绞痛、再次血运重建术和继发心衰等主要心脏不良事件者为近期预后不良组,无上述情况者判定为近期预后良好组,用logistic多元回归法分析术前状态、靶血管病变特征、植入支架的各项参数及外周血热休克蛋白70水平与主要心脏不良事件发生率的关系,并以同期健康体检者20例为正常对照组。结果:68例患者完成随访进入结果分析。①外周血热休克蛋白70水平:急性心肌梗死患者和不稳定型心绞痛患者比较差异无统计学意义(P>0.05),但均显著高于正常对照组(P<0.05)。②在多变量的logistic回归分析中,外周血热休克蛋白70独立于其危险因素,能预测急性冠状动脉综合征患者经皮冠状动脉介入治疗后近期主要心脏不良事件发生率(OR值为0.904,P<0.05)。结论:回归分析结果提示,应用紫杉醇涂层支架临床治疗近期效果评估中,外周血热休克蛋白70水平高的急性冠状动脉综合征患者近期心脏事件发生率较高,说明外周血热休克蛋白70可能成为判断紫杉醇涂层支架介入治疗后不良事件发生率的独立因素之一。     

骨唾液酸蛋白在体外培养人骨髓间充质干细胞向成骨细胞分化中的角色

目的：骨唾液酸蛋白在骨矿化形成方面扮演重要角色，实验观察其是否能诱导体外培养的人骨髓间充质干细胞向成骨细胞分化。方法：实验于2005—10／2006—12在解放军广州军区广州总医院医学实验科完成。①材料来源：选取在本院体检的健康志愿者2人，对本实验均知情同意。采用Ni-NTA亲和纯化技术，从本室构建的毕赤酵母GS115／pPICZaA-hbsp发酵上清中纯化重组人骨唾液酸蛋白。②实验方法：对健康志愿者进行髂骨穿刺抽取骨髓液，采用贴壁法培养得到骨髓间充质干细胞。设立4组：骨唾液酸蛋白组添加0．1nmol／L骨唾液酸蛋白；成骨诱导液组添加10nmol／L地塞米松、10mmol／L磷酸甘油、50mg／L抗坏血酸；联合组添加上述两组的所有试剂；空白对照组不添加任何处理因素；各组均处理细胞12d。⑧实验评估：光镜及电镜观察培养的细胞形态；以细胞计数法测定生长曲线，应用流式细胞仪分析细胞周期，采用免疫荧光细胞化学法和流式细胞分析检测干细胞标志物STRO-1的表达；生化试剂盒测定碱性磷酸酶活性；von Kossa染色法检测钙沉积。结果：①单个骨髓间充质干细胞为长梭形，经骨唾液酸蛋白处理后细胞大而扁平，原来密集的克隆分散开。②与空白对照组比较，骨唾液酸蛋白组引起细胞生长曲线右移，细胞Go／G，期比例平均增加12．09％（P〈0．01），S期比例减少65．92％（P〈0．01），STRO-1阳性细胞百分率下降26．54％（P〈0．01）。⑧与空白对照组比较，骨唾液酸蛋白组细胞碱性磷酸酶活性增加50．0％，成骨诱导液组增加59．5％，联合组增加71．43％，并且随着处理时间的延长，活性增加越显著。④空白对照组细胞vonKossa染色呈阴性，其余各组均呈阳性。其中联合组的黑色矿化结节体积最大、数目最多；骨唾液酸蛋白组的结节体积较小、数目较少；成骨诱导液组居中。结论：骨唾液酸蛋白对人骨髓间充质干细胞有促进成骨分化和矿化作用，且与成骨诱导液联用效果更佳。