再发性低血糖对幼鼠脑内GLUT1及GLUT3表达的影响

目的观察再发性低血糖后脑内葡萄糖转运蛋白1(glucose transporter 1,GLUT1)及葡萄糖转运蛋白3(GLUT3)表达的变化,从而探讨无症状低血糖的发生机制。方法将80只15日龄野生型小鼠随机分为正常对照组及低血糖组,每组40只。低血糖组给予正规胰岛素腹腔注射3次,每次剂量为5U/kg,对照组注射等体积生理盐水。两组分别在最后1次注射后12、24、48及72 h处死小鼠取脑组织(每组每时间点10只),应用免疫组化方法观察小鼠脑内GLUT1及GLUT3表达的变化。结果低血糖后脑内微血管上GLUT1表达有增加趋势,皮质增加高于海马,72 h皮质GLUT1表达显著高于对照组;低血糖后48、72 h皮质及海马GLUT3表达均显著高于相应对照组。结论再发性低血糖后脑内GLUT1及GLUT3适应性增高,这种适应既能节省神经元的能量代谢,但也能削减神经元对低血糖的反应。     

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma

Introduction: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic.

Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm.

Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.     

Safety of a quadrivalent meningococcal serogroups A,C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: Results of an open-label,randomized, phase 3b controlled study in healthy infants

Background

The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants.

Methods

Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1–7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%).

Results

A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI −0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference −0.1% [95% CI −4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups.

Conclusion

In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone.     

提高大鼠心肌梗死后心力衰竭模型存活率的实验研究

目的建立大鼠心肌梗死后心力衰竭模型,并进行评估,以提高存活率和成功率。方法分批对70只SD大鼠行冠状动脉左前降支结扎术,同时设15只假手术组,并计算死亡率。于4周时行血流动力学检查,检测心率(HR)、左心室舒张末压(LVEDP)、左室压力最大上升速率(+dp/dtmax)以及左室压力最大下降速率(-dp/dtmax)。结果4周时模型组HR、+dp/dtmax和-dp/dtmax绝对值均低于假手术组(P<0.05),LVEDP则高于假手术组(P<0.05)。随着手术大鼠例数增多,存活率得到提高(P<0.05)。结论心肌梗死后4周形成心力衰竭模型,通过经口气管插管法、选择结扎冠状动脉分支末梢部位、增加手术操作熟练程度,可提高动物存活率。     

鞍区Rathke囊肿的MRI诊断价值

目的探讨鞍区Rathke囊肿的MRI表现及其诊断价值。方法回顾性分析5例经手术病理证实的鞍区Rathke囊肿的MRI资料。结果 5例囊肿均由鞍内向鞍上延伸,呈哑铃型,边界清楚,囊壁菲薄。囊液T1WI低信号T2WI高信号3例,T1WIT2WI囊液均为高信号2例,囊壁见线样增强1例。结论典型鞍区Rathke囊肿的MRI表现具有一定的特征性,术前正确诊断有可能,但需密切结合临床,并与垂体瘤、颅咽管瘤鉴别。     

污水中汞的微波消解冷原子吸收测定法

目的 改进冷原子吸收法测定污水中汞的消解方法。方法 采用王水（1＋1）微波消解法代替KMnO4-K2S2O8消解法测定污水中的汞。结果 王水（1＋1）微波消解水样测定污水中汞，方法的线性范围为0~10.0μg／L，检出限为0.25μg／L，相对标准偏差小于2.7％，加标回收率为95.0％-102.0%。结论 与KMnO4-K2S2O8消解法相比，该方法具有较高的灵敏度和精密度，操作简单，结果可靠，适用于环境监测分析。     

Therapeutic potential of histamine H4 receptor agonists in triple-negative human breast cancer experimental model

Background and Purpose

The presence of the histamine H₄ receptor (H₄R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H₄R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.

Experimental Approach

Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H₄R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹).

Results

Data indicate that developed tumours were highly undifferentiated, expressed H₄R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H₄R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis.

Conclusions and Implications

Histamine through the H₄R exhibits a crucial role in tumour progression. Therefore, H₄R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1     

同种异体大鼠小肠移植中监测CD4+ T细胞和CD8+ T细胞数比值的意义

目的 探讨CD4+T细胞数/CD8+T细胞数作为大鼠同种异体小肠移植急性免疫排斥反应指标的可行性.方法 选取健康雄性成年SD、Wistar大鼠建立同种异体小肠移植模型,于大鼠术前和术后1、3、5、7、9d共6个时间段静脉取血,应用免疫荧光染色技术及流式细胞仪检测CD4+T细胞和CD8+T细胞百分率,并计算其比值.同期取移植小肠标本做组织学检测.结果 术后CD4+T细胞数和CD8+T细胞数比值前期增高后期降低.组织病理学检测发现术后小肠移植物的排斥反应由轻到重,术后第5天始CD4+T细胞数和CD8+T细胞数比值与急性免疫排斥反应程度呈正相关.结论 CD4+T细胞和CD8+T细胞数比值作为大鼠同种异体小肠移植术后急性免疫排斥反应的监测指标的可行性较大.