In vivo feasibility study of ultrasound potentiated collagenase therapy of chronic total occlusions

Arterial chronic total occlusions (CTOs) pose considerable challenges for percutaneous interventions, due primarily to the presence of stiff proximal fibrous caps (PFCs) which act as a barrier to the penetration of guide wires. A new approach under development for improving the success rate of guide wire crossing in CTOs is to employ collagenase to degrade the mechanical integrity of the PFCs. This has been shown to be feasible in preclinical work and in a Phase 1 clinical trial. In a recent study we demonstrated using ex vivo experimental CTO specimens that ultrasound-stimulated microbubbles (USMBs) could potentiate the effects of collagenase and result in increased mechanical degradation of the PFCs of CTOs. Here we report the results of the first in vivo study examining the feasibility of this approach, which demonstrates that the force required to puncture through the PFCs of CTOs is reduced with combined USMB + collagenase treatments relative to collagenase only treatments. This approach has the potential to further improve the efficacy of the emerging technique of collagenase facilitation of percutaneous interventions for CTO.     

治疗慢性淋巴细胞白血病的突破性新药Venetoclax的合成进展

Venetoclax为首个获美国FDA批准的靶向B细胞淋巴瘤因子2的选择性抑制剂和突破性药物,用于治疗携带17p删除突变以及之前已接受至少一种疗法的慢性淋巴细胞白血病。本文综述了迄今为止文献报道的Venetoclax的4条合成工艺路线,并进行了相应的评价。通过对这些合成工艺路线的比较和分析,发现Venetoclax的合成为汇聚式,关键在于4类中间体的合成。从Venetoclax的合成工艺路线改进来看,其合成工艺路线总体上向着采用价廉易得原料、反应选择性高的原料或合成方式、更加温和的反应条件以及提高收率的方向进行。Venetoclax的4条合成工艺路线不可避免地采用了贵金属钯和配体催化,探索将它们负载在高聚物上,便于回收,简化分离过程和降低成本,也是Venetoclax工业化合成改进的方向。在此基础上,Venetoclax的合成路线4具有较好的工业化前景。     

Determination of creatinine-related molecules in saliva by reversed-phase liquid chromatography with tandem mass spectrometry and the evaluation of hemodialysis in chronic kidney disease patients

The serum concentrations of creatinine (Cre) and urea are used for the determination of the renal function. However, the use of blood is not always suitable due to the invasive, hygienic and infection problems during its sample collection and handling. In contrast, saliva is relatively clean and the samples can be quickly and noninvasively collected and easily stored. Therefore, the simultaneous determination of Arginine (Arg), creatine (Cr) and Cre in the saliva of chronic kidney disease (CKD) patients was performed by UPLC-ESI-MS/MS together with the saliva of healthy volunteers. The evaluation of hemodialysis of CKD patients was also carried out by the determinations before and after the dialysis. An HS-F5 column was used for the simultaneous determination of Arg, Cr and Cre in the saliva. These molecules were rapidly separated within 4 min and sensitively determined by the multiple reaction monitoring (MRM) of the precursor ion [M+H]⁺ → product ions (m/z 175.1 → 70.1 for Arg; m/z 132.0 → 44.1 for Cr; m/z 114.0 → 44.1 for Cre). The concentration of Cre in the CKD patients was higher than that in the healthy persons. The concentrations of Cre in the saliva of the patients before hemodialysis were moderately correlated with the serum Cre concentrations (R² = 0.661). Furthermore, the concentration in the saliva obviously decreased after hemodialysis (before 0.73 mg/dL, after 0.25 mg/dL; p < 0.02). Thus, the proposed detection method using saliva by UPLC-MS/MS is useful for the evaluation of the renal function in CKD patients. The present method offers a new option for monitoring the hemodialysis of CKD patients.     

医院与社区联合对慢性心力衰竭患者的院外干预研究

目的探索医院与社区联合,对慢性心力衰竭患者进行院外规范化管理干预的有效途径和方式。方法选择出院的心力衰竭患者1894例,随机分为3组：医院社区联合组630例,其中男352例,女278例,平均年龄（69.39±12.46）岁;医院对社区全科医师进行心力衰竭诊疗技能及规范化管理知识的培训,医院与社区共同制定心力衰竭患者的干预方案,社区全科医师对心力衰竭患者进行防治管理。医院组631例,其中男359例,女272例,平均年龄（68.51±12.15）岁;由专科医师对心力衰竭患者进行院外随访干预。社区组633例,其中男356例,女277例,平均年龄（68.50±12.51）岁;不开展对社区全科医师的培训,由社区医师对心力衰竭患者进行随访。所有病例平均随访（12.0±1.6）个月。结果医院社区联合组、医院组患者的一级终点事件总病死率、心血管病死率、心力衰竭再住院率、心力衰竭急诊率较社区组分别下降17.53﹪、15.71﹪、19.11﹪、18.15﹪,差异均有统计学意义（均P＜0.05）;二级终点事件患者的心功能级别、左心室射血分数（LVEF）、依从性、生活质量均明显高于社区组,心力衰竭恶化率较社区组下降15.59﹪（均P＜0.05）;平均住院日较社区组减少4.56d（P＜0.05）;社区全科医师的心力衰竭诊治及管理水平明显提高。结论通过医院与社区联合对院外心力衰竭患者进行规范化管理干预,提高社区全科医师的心力衰竭诊治及管理水平,可显著降低心力衰竭患者的病死率、再次住院率、心力衰竭急诊率,改善患者的心功能、依从性、生活质量及预后,降低医疗费用。     

COPD急性加重合并活动性肺结核患者的危险因素及临床特征分析

目的分析慢性阻塞性肺疾病（COPD）急性加重合并活动性肺结核患者的危险因素及临床特征,以指导临床治疗。方法选取COPD急性发作合并活动性肺结核患者42例（合并组）及同期单纯COPD急性发作的患者72例（对照组）,比较两组患者的临床特征,并采用单因素分析及logistic回归分析其危险因素。结果两组患者的部分临床特征有统计学差异（均P＜0.05）。单因素分析表明,吸烟史、营养不良、长期吸入糖皮质激素史及既往有肺结核史是COPD急性发作合并活动性肺结核的主要危险因素（均P＜0.05）。多因素分析发现,营养不良（OR=4.100,95%CI：1.471～11.431）、长期吸入糖皮质激素史（OR=2.695,95%CI：1.078～6.739）及既往肺结核史（OR=11.102,95%CI：3.076～40.065）为独立危险因素（均P＜0.05）。结论根据危险因素早期识别合并活动性肺结核的高危COPD患者,可尽早明确诊断,给予积极治疗。     

Can preoperative diffusion-weighted MRI predict postoperative hepatic insufficiency after curative resection of HBV-related hepatocellular carcinoma? A pilot study

Liver fibrosis determines the functional liver reserve. Several studies have reported that the apparent diffusion coefficient (ADC) values of diffusion-weighted magnetic resonance imaging (DW-MRI) can assess liver fibrosis. We investigated whether DW-MRI predicts postoperative hepatic insufficiency and liver fibrosis in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Twenty-six patients with HBV-related HCC who received preoperative DW-MRI on a 3-T MRI system were enrolled between July and December 2008. ADC values were measured twice by two observers. Three “b values” were used: 50, 400 and 800 s/mm². Postoperative hepatic insufficiency was defined as persistent hyperbilirubinemia (total bilirubin level >5 mg/dl for more than 5 days after surgery) or postoperative death without other causes. The mean age (21 men and 5 women) was 51.4 years. Three patients experienced postoperative hepatic insufficiency. liver stiffness measurement predicted postoperative hepatic insufficiency, advanced fibrosis (F3–4), and cirrhosis significantly [area under the receiving operator characteristic curve (AUROC)=0.942, 0.771 and 0.818, respectively, with P=.047, 0.048 and 0.006, respectively]; ADC values of DW-MRI, however, did not (AUROC=0.797, 0.648 and 0.491, respectively, with P=.100, 0.313 and 0.938, respectively). Reliability of ADC values between right and left hepatic lobes (ρ=0.868 and ρ=0.910 in the first and second measures of Observer A; ρ=0.865 and ρ=0.831 in the first and second measures of Observer B) was high and the intra- and interobserver reliability (ρ=0.958 in observer A and ρ=0.977 in observer B; ρ=0.929 in the first measure and ρ=0.978 in the second measure between the two observers) were high. All reliability was significant (P<.001). Our results suggest that DW-MRI on a 3-T MRI system is not suitable for predicting postoperative hepatic insufficiency, advanced liver fibrosis, and cirrhosis in patients with HBV-related HCC, despite significantly high reliability.     

Modeling the Chagas’ disease after stem cell transplantation

A recent model for Chagas’ disease after stem cell transplantation is extended for a three-dimensional multi-agent-based model. The computational model includes six different types of autonomous agents: inflammatory cell, fibrosis, cardiomyocyte, proinflammatory cytokine tumor necrosis factor-α, Trypanosoma cruzi, and bone marrow stem cell. Only fibrosis is fixed and the other types of agents can move randomly through the empty spaces using the three-dimensional Moore neighborhood. Bone marrow stem cells can promote apoptosis in inflammatory cells, fibrosis regression and can differentiate in cardiomyocyte. T. cruzi can increase the number of inflammatory cells. Inflammatory cells and tumor necrosis factor-α can increase the quantity of fibrosis. Our results were compared with experimental data giving a fairly fit and they suggest that the inflammatory cells are important for the development of fibrosis.     

网络建模研究生物质烟雾引起的导致慢性阻塞性肺病的炎症反应动力学

慢性阻塞性肺病（COPD）是一种由慢性炎症引起的气道阻塞和渐进性的肺组织损伤.目前在全球范围内大概有30亿人使用生物质燃料进行烹饪和加热取暖,生物质烟雾被认为是慢性阻塞性肺病一个重要的危险因素.最近的临床数据表明,与吸烟引起的慢性阻塞性肺病不同,生物质烟雾引起的慢性阻塞性肺病（BS-COPD）病人有Th2类型的抗炎反应特征.然而,由于促炎反应是慢性阻塞性肺病的一个基本特征,人们对生物质烟雾引起的慢性阻塞性肺病的Th2类型的抗炎特征形成机理还不是很清楚.本文应用多尺度网络模型计算研究了生物质烟雾引起的炎症反应动力学.本文的网络模型涉及几个不同的正反馈通路,激活这些正反馈通路分别对应不同的慢性阻塞性肺病临床表现的形成机制.建模研究确定在一部分BS-COPD病人具有混合的M1（促炎）和Th2炎症反应特征.本文的计算结果与临床试验吻合得很好,而且计算敲除模拟显示几种重要的网络组成部分对COPD疾病形成起着重要作用.研究对BS-COPD的形成机制提供了新的见解,为未来利用标靶和个性化治疗慢性阻塞性肺病提供了可能的理论基础.     

Polymorphisms in the interleukin-8 gene in patients with chronic obstructive pulmonary disease

Airway inflammation is the main pathophysiological feature of patients with chronic obstructive pulmonary disease (COPD). Interleukin-8 (IL-8) is a potent chemoattractant for neutrophils and eosinophils. Increased IL-8 levels were observed in bronchoalveolar lavage (BAL) and induced sputum in patients with COPD. To evaluate the role of the IL-8 gene, we genotyped blood samples of 122 COPD-patients and 385 healthy controls for a known polymorphism in the promoter region (-251 A/T) of the IL-8 gene. Additionally, we screened the coding region for further polymorphisms by SSCP analyses. Comparison of the allele and genotype frequencies among each group revealed no significant differences between patients and controls. Although IL-8 plays an important role in the chemotaxis of inflammatory cells, the polymorphisms investigated here do not seem to be involved in the genetic predisposition to COPD.