Cyclosporin nephrotoxicity in heart and lung transplant patients

Twenty-two patients with heart, lung or heart and lung transplants maintained on cyclosporin for periods ranging from 3 months to 10 years developed renal insufficiency which was investigated by renal biopsy. The histopathological changes were: (i) severe vascular and glomerular damage due to thrombotic microangiopathy (TM); (ii) a form of focal segmental glomerulosclerosis (FSGS); (iii) glomerular ischaemia. Rather than being separate entities, these changes appeared to represent a spectrum of pathology, some biopsies showing all three forms of glomerular injury. In all cases the glomerular changes were accompanied by arteriolar and arterial pathology, and we identified novel ultrastructural changes in the arteriolar endothelial basal lamina. Tubular atrophy was a consistent feature, the severity of which reflected the severity of the glomerular sclerosis, and which appeared to be a consequence of glomerular loss. Our findings are consistent with the nephrotoxic effects of cyclosporin being mediated chiefly via damage to preglomerular vessels and glomerular capillary endothelium. From an analysis of the clinical aspects of these cases, the effects of cyclosporin appear to be to some extent idiosyncratic, and therefore not entirely preventable, but strict monitoring of blood cyclosporin levels is essential to minimize the risk of permanent renal damage. Monitoring urinary protein in addition to plasma creatinine may detect the onset of FSGS, as proteinuria precedes creatinine elevation.      

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。     

中药癌痛克对人肝癌细胞HepG2增殖、凋亡及Rb基因表达的影响

目的:通过观察不同浓度癌痛克对肝癌细胞株HepG2增殖及凋亡的作用,以及在相应状态下细胞内Rb基因表达量的改变,探讨中药癌痛克抗肝癌的可能作用机制。方法:实验于2005-09/2006-03在广州医学院中心实验室完成。取对数生长期的HepG2细胞,使细胞静止于G0/G1期。随机分为癌痛克2,10,50mg/L组和对照组,癌痛克2,10,50mg/L组分别加入对应浓度癌痛克(购自河南省肿瘤研究所,由金蝎、土元、九香虫、大黄、人参、灵芝、黄芪等纯中药组成的粉状制剂,功能:消癌肿、消癌痛、消积水、升白排毒),对照组不加药物,每组设4个复孔。MTT法检测各组细胞24,48,72h增殖率,细胞增殖率=[(A570癌痛克组-A570对照组)/A570对照组]×100%;以流式细胞术检测各组细胞24,48,72h凋亡率;RT-PCR方法检测各组细胞24,48,72h细胞内Rb基因mRNA表达量。结果:①2～50mg/L癌痛克具有明显的增殖抑制作用,癌痛克2,10,50mg/L组在24,48,72h与对照组比较,差异有显著性意义(P<0.05);3组各时点两两之间比较差异有显著性意义(P<0.05);同组各时点之间比较差异有显著性意义(P<0.05)。②2～50mg/L癌痛克组可诱导HepG2细胞凋亡,相同作用时间癌痛克2,10,50mg/L组与对照组比较差异有显著性意义(P<0.001);同一时点各组比较差异有显著性意义(P<0.05);同组不同作用时间点比较差异有显著性意义(P<0.001)。③2～50mg/L癌痛克可上调Rb基因的表达,各浓度组在各时点与对照组比较,差异均有显著性意义(P<0.05);24,48,72h癌痛克2,10,50mg/L组之间比较差异无显著性意义(P>0.05);3组各时点比较差异有显著性意义(P<0.05)。结论:中药癌痛克可通过抑制HepG2细胞增殖或诱导其凋亡,而发挥抗肝癌作用;且其诱导细胞凋亡的机制之一可能为通过增加Rb基因的表达而实现。     

The midterm experience of tapered stent grafts in the endovascular management of iliac artery aneurysms with unfavorable anatomy

We report our experience and the midterm results of a modern technique for endovascular management of isolated iliac artery aneurysms (IAAs) with unfavorable neck anatomy, which involves the inversion of an iliac leg of a Zenith stent graft. Patients who underwent endovascular IAA repair from 2002 to 2010 were reviewed. A total of 12 patients, with a mean age of 77.6 years, underwent endovascular repair of 13 IAAs. Mean size of the aneurysms was 54.6 mm (range 34-133 mm). Mean proximal neck diameter was 18 mm (range 15-22 mm). In 7 patients, the length of the proximal neck was <15 mm (10-14 mm). Only 1 patient developed thrombosis of the stent graft immediately after the operation. Patients were followed up for a mean of 31.5 months (range 18-72 months). Our midterm results demonstrate the durability of this technique in the management of iliac aneurysms with unfavorable anatomy.     

Correlation of P-glycoprotein expression and function in childhood acute leukemia: a children's cancer group study

Clinical drug resistance may be attributed to the simultaneous selection and expression of genes modulating the uptake and metabolism of chemotherapeutic agents. P-glycoprotein (P-gp) functions as a membrane-associated drug efflux pump whose increased expression results in resistance to anthracyclines, epipodophyllotoxins, vinca alkaloids, and some alkylating agents. This type of resistance occurs as both de novo and acquired resistance to therapy for leukemia. We have studied P- gp expression and function in childhood acute leukemias by developing a series of doxorubicin- and vincristine-selected CEM, T-cell lymphoblastoid cell lines that recapitulate the low levels of expression and resistance seen clinically. These cell lines have been used to develop flow cytometric assays for the semiquantitative measurements of P-gp expression with the MRK16 monoclonal antibody and P-gp function using the enhanced retention of rhodamine 123 in the presence of verapamil, a resistance modulator. Kolmogorov-Smirnov statistics, represented by the D measurement, are used to determine the difference in level of P-gp expression by comparing MRK16 staining to an IgG2a isotype control. When D is > 0.09, there is an excellent correlation (R = 0.82) between P-gp expression and function. The evaluation of 107 bone marrow specimens from 84 children with lymphoblastic or myelogenous leukemia showed a statistically significant (P = .004) increase in P-gp function at relapse. P-gp expression at relapse, however, approached but did not reach a significant level (P = .097). Using this methodology, we can identify patients with levels of P-gp expression and function that we can define clinically, as well as children with discordant multidrug resistance phenotypes. This study supports the role of P-gp-mediated drug resistance in childhood leukemia and confirms that P-gp expression and function are measurable in their leukemic blasts. These assays provide the means for the in vitro testing of resistance modulators and the monitoring of in vivo response to treatment with these agents.     

Distribution of atrial electrogram types during atrial fibrillation: Effect of rapid atrial pacing and intercaval junction ablation

Objectives. This study examined the anatomic distribution types and possible determinant of atrial electrogram types during atrial fibrillation.

Background. Different types of atrial electrograms during atrial fibrillation have been observed and classified, but their anatomic distribution patterns, determinants and potential usefulness in guiding future catheter ablation are unknown.

Methods. Two animal models of atrial fibrillation were used: the sterile pericarditis model (n = 10) and the rapid atrial pacing model (400 beats/min for 6 weeks, N = 6). The atrial electrogram of atrial fibrillation and the atrial effective refractory period were obtained from multiple sites of the right and left atrium. In addition, decremental rapid atrial stimulation was applied to the site of shortest and longest atrial effective refractory periods until atrial fibrillation induction in a subgroup of nine dogs. Ablation of the intereaval junction was performed using the radiofrequency catheter technique in dogs with atrial fibrillation duration > 1 min.

Results. In both models, organized atrial electrograms (type I) were predominantly observed at the left atrial sites and the right atrial appendage, whereas disorganized atrial electrograms (type III) were mainly observed at the right posterolateral atrium. The distribution of the atrial electrogram types closely followed that of the atrial effective refractory period, with the shortest atrial effective refractory period corresponding to organized atrial electrograms (type I) and the longest atrial effective refractory period corresponding to disorganized atrial electrograms (type III). The correlation of atrial electrogram type with the atrial effective refractory period was further demonstrated by the effect of rapid atrial stimulation. When rapid atrial stimulation was applied to the site with the shortest atrial effective refractory period, disorganized atrial electrograms were observed at sites with the longest atrial effective refractory period, whereas 1:1 atrial capture was still present at the stimulation site. Ablation of the intercaval junction made atrial fibrillation noninducible or tended to shorten the atrial fibrillation duration (from 26.4 ± 24.2 to 8.8 ± 22.6 min in the pericarditis group, P = 0.02, and from 33.7 ± 29.2 to 12.1 ± 23.8 min in the rapid pacing group, P = 0.09) bud did not change the atrial electrogram types during atrial fibrillation.

Conclusions. Various types of atrial electrograms are present at different locations during atrial fibrillation. The atrial electrogram characteristics of atrial fibrillation at a specific location are related to the atrial effective refractory period, with short effective refractory periods associated with organized atrial electrograms and long effective refractory periods associated with disorganized electrograms.     

Differential regulation of EHD3 in human and mammalian heart failure

Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.     

Invasion of erythrocytes by Plasmodium falciparum malaria parasites: evidence for receptor heterogeneity and two receptors

Plasmodium falciparum malaria parasites with different capabilities of invading sialic acid-deficient erythrocytes were identified. Thai-2 parasites cultured in Tn erythrocytes invaded neuraminidase-treated and Tn erythrocytes twice as efficiently as Thai-2 parasites cultured in normal erythrocytes and seven to ten times more efficiently than a cloned line of Camp parasites cultured in normal erythrocytes. All three parasite lines required sialic acid for optimal invasion, but Thai-2 parasites cultured in Tn erythrocytes invaded neuraminidase- treated erythrocytes with 45% efficiency whereas Camp parasites invaded neuraminidase-treated erythrocytes with less than 10% efficiency. P falciparum malaria parasites probably possess two receptors: one that binds to a sialic acid-dependent ligand and another that binds to a sialic acid-independent ligand. Parasites may differ in the quantity or affinity of their receptors for the sialic acid-independent ligand.