Designer broad-spectrum polyimidazolium antibiotics

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

AMPs and AMP mimics have attracted considerable attention as candidates for therapeutic development (1). The basic design elements include a region of charged residues, generally cationic residues, enabling interaction with bacterial cell surfaces, combined with a hydrophobic nature in AMPs (2). Unfortunately, AMPs and related polymers, in general, have one or more issues that limit their use as broad-spectrum antibiotics. Some are quite toxic to human cells, the potency of some is not adequate for human administration, others are sensitive to salt at levels present in human fluids, and some are too difficult and expensive to synthesize (3, 4). One broad-spectrum antimicrobial peptide, CST has seen increased recent use as a last resort antibiotic. CST is believed to kill bacteria by virtue of its ability to disrupt membrane integrity (5). This antibiotic requires intravenous administration and is nephrotoxic (6). The emergence of CST-resistant pathogens has also become a significant problem (7). We are unaware of any new broad-spectrum AMPs that have advanced to clinical trials.Imidazolium (IM) salts are antimicrobials (8), and there is an emerging literature on antimicrobial activity of side-chain and main-chain polyimidazolium (PIM) salts with chemical structures that are in some ways similar to those we describe. Although PIMs are potent antimicrobials, there are biocompatibility problems hindering their development, and some have somewhat limited activity spectra. As with other AMPs, there have been toxicity issues, potency issues, and delivery issues as many have large molecular masses, and there is little known about mammalian cell toxicity or mechanism of action (9–12).Here we show that members of a series of PIMs we designed and synthesized are potent broad-spectrum antibacterial compounds. We selected two for further analysis and showed they retain activity even against pan-antibiotic-resistant bacteria. Unlike CST and many other AMPs, which disrupt bacterial membranes, our model PIM is bactericidal without disrupting bacterial membranes. Our experiments provide insights about mechanism of action, the potential for the emergence of PIM resistance, and indicate PIMs are effective against a model gram-negative and a model gram-positive pathogen in murine infection models.     

健康急进高原者纤溶系统变化的研究

目的：探讨健康急进高原者纤溶系统的变化。方法：总共50名青年男性入选本试验，均为从四川省（海拔400m）招募的新兵。在乘飞机从四川进入拉萨（海拔3658m）之前及之后3d，测定血凝血酶原时间（PT）、凝血酶时间（TT）、活化部分凝血活酶时间（APTT）、纤维蛋白原（Fg）、纤溶酶原（Plg）、纤溶酶抑制物、D-二聚体（DD）含量。结果：进入高原后，PT、TT、APTT、DD比在平原时增高，FIB、Plg、纤溶酶抑制物降低（P〈0．05）。结论：健康人急进高原后纤溶系统变化显著。     

乙型肝炎病毒多聚酶末端蛋白重链可变区抗体体外抑制病毒的复制

目的用蛋白片段互补法(PCA)选择HBV多聚酶末端蛋白(TP)重链可变区(VH)抗体,研究特异性VH抗体体外抑制HBV的复制与分泌。方法以HBV多聚酶TP区为抗原,用PCA法进行特异性VH抗体筛选。特异性VH抗体基因定向亚克隆人真核表达载体pZeoSV2( ),构建pZeoSV2( )-VH重组质粒,用脂质体介导的转染技术,将其导入HepG 2.2.15细胞,观察特异性抗体的生物学活性。结果用PCA法从抗体库中选择出3个特异性抗体:VH1、VH2和VH3,其中与抗原亲和力最高的是VH1。转染pZeoSV2( )-VH1的HepG 2.2.15细胞比未转染pZeoSV2 ( )-VH1或只转染空载体pZeoSV2( )的HepG 2.2.15细胞病毒颗粒分泌明显减少,上清液内为2.978 7±0.276 1比5.150 4±0.276 1和5.295 1±0.241 0(P<0.05);细胞内为5.283 9±0.162 9比8.300 4±0.323 2和8.532 1±0.138 3(P<0.05)。结论用PCA法可从抗体库中选择出HBV多聚酶TP区特异性VH抗体,该抗体在体外可抑制HBV的复制与分泌。     

Signal‐Averaged P Wave Duration and the Dimensions of the Atria

Background: Delay of atrial electrical conduction measured as prolonged signal‐averaged P wave duration (SAPWD) could be due to atrial enlargement. Here, we aimed to compare different atrial size parameters obtained from echocardiography with the SAPWD measured with a signal‐averaged electrocardiogram (SAECG). Methods: In 74 patients scheduled for elective echocardiography, an SAECG was recorded directly after the echocardiogram. We measured the SAPWD and registered clinical characteristics. The correlation between the SAPWD and the left atrial diameter (LAD), left atrial volume (LAV), right atrial volume (RAV), and total atrial volume (TAV) was analyzed by linear regression analyses. The effect of concomitant risk factors on TAV and the SAPWD was examined. Results: Linear regression analysis showed that the correlation between the SAPWD and the LAD was significant (R²= 0.11, P = 0.03). However, LAV (R²= 0.15, P = 0.009), RAV (R²= 0.27, P = 0.0003), and TAV (R²= 0.37, P < 0.0001) were more strongly correlated to the SAPWD. The TAV and the SAPWD were not significantly associated with coexisting risk factors. Conclusions: The SAPWD is significantly correlated to the atrial size; most strongly to the TAV. The size of the right atrium, with the sinus node area, appears to affect the SAPWD.     

Costs of COPD in Sweden according to disease severity

OBJECTIVES: COPD is a common and disabling disease that entails high costs for society. The objectives of this study were to measure the societal costs of COPD in Sweden, and to examine the relationship between severity of illness and costs. METHODS: The costs of COPD were examined using a well-defined and representative cohort of subjects with mild, moderate, and severe COPD. Regular telephone interviews regarding resource utilization were made to a cohort of 212 subjects with COPD derived from studies of the general population in Northern Sweden. RESULTS: The annual per capita cost for COPD in Swedish crowns (SEK) was estimated at SEK 13,418 (1,284 US dollars (USD); 1,448 euros (EUR). The direct and indirect costs were SEK 5,592 (42%) and SEK 7,828 (58%), respectively. A highly significant relationship was found between severity of disease and costs. Costs for severe disease were 3 times as high as costs for moderate disease and > 10 times as high as for mild disease. Large individual variations in the level of costs were found. CONCLUSION: Assuming that the prevalence and treatment patterns are representative of Sweden as a whole, the total costs of COPD to society in 1999 were estimated at SEK 9.1 billion (USD 871 million; EUR 982 million). Subjects with mild disease (83%) accounted for 29%, while subjects with moderate disease (13%) accounted for 41% of the total costs. The subjects with severe disease (4%) accounted for the remainder (30%). Prevention, early diagnosis, and postponement of disease progression should have large monetary and policy implications.     

MR淋巴造影显影兔VX2乳腺癌模型内乳前哨淋巴结

目的 探讨MR淋巴造影（MR-LG）显影兔VX2乳腺癌内乳前哨淋巴结（SLN）的可行性。方法 将75只新西兰大白兔分别建立兔VX2乳腺癌（肿瘤组）及炎性（炎症组）实验动物模型,并对其行MR-LG检查,检查后进行淋巴结清扫术。记录内乳SLN及淋巴管的显示情况,分析影响其显像的因素。结果 实验兔建模成功率为97.33%（73/75）;MR-LG对内乳SLN及淋巴管的显示率分别为15.94%（11/69）和75.36%（52/69）,其在肿瘤组与炎症组差异均无统计学意义（P均>0.05）。肿瘤组内乳SLN显示与未显示实验兔间体质量,肿瘤生长时间,肿瘤长径,腋窝SLN数目、大小及阳性数目,内乳淋巴管显影情况差异均无统计学意义（P均>0.05）;内乳淋巴管显示与未显示实验兔间肿瘤大小及腋窝SLN数目差异有统计学意义（P均<0.05）。MR-LG检出内乳SLN的准确率、敏感度、特异度、假阴性率及假阳性率分别为76.81%（53/69）、39.13%（9/23）、95.65%（44/46）、60.86%（14/23）和4.35%（2/46）。结论 MR-LG可有效显像兔VX2乳腺癌模型内乳SLN及淋巴管。     

肝脏血管平滑肌脂肪瘤的CT及MRI表现

目的 分析肝脏血管平滑肌脂肪瘤的CT及MRI征象特点。方法 回顾性分析经手术病理证实的7例肝脏血管平滑肌脂肪瘤患者的CT和/或MRI表现,并与病理结果进行对照。结果 CT及MRI平扫共8个病灶,CT显示6个病灶中,5个呈稍低密度,1个病灶大部分呈低密度,其内可见小片状等密度。MR显示的4个病灶中,2个脂肪抑制T2WI呈低信号,T1WI呈较均匀低信号,1病灶未显示脂肪信号特点,病灶内未见囊变、血肿、坏死等信号。增强扫描动脉期7个病灶表现为明显不均匀强化,1个病灶呈均匀强化;3个病灶呈"快进快出"强化改变,5个病灶呈持续强化改变;3个病灶内部见粗大畸形血管,5个病灶可见引流静脉。结论 肝脏血管平滑肌脂肪瘤的影像学表现有一定特征性,影像学检查有助于诊断和鉴别诊断。     

踝臂指数和颈动脉斑块积分预测冠脉病变的价值

目的 探讨踝臂指数(ABI)和颈动脉斑块积分(Crouse积分)预测冠状动脉病变的价值.方法 选择2013年12月～2014年5月在解放军总医院心内科住院并首次行冠状动脉造影的194例患者,根据冠状动脉造影结果按病变狭窄程度(Gensini积分)分为严重病变组(64例)和非严重病变组(130例),分析ABI及颈动脉Crouse积分与冠脉病变的关系.结果 严重病变组和非严重病变组的ABI和颈动脉Crouse积分差异均有统计学意义(P＜ 0.05或P＜ 0.01);相关性分析结果,ABI与冠脉病变情况呈负相关(r=-0.518,P＜0.01),颈动脉Crouse积分与冠脉病变情况呈正相关(r=0.616,P＜0.01).ABI诊断严重冠脉病变的受试者工作特征曲线(ROC曲线)下面积为0.278,以ABI≤0.9为截断值,其预测冠脉严重病变的敏感性为23.4％,特异性为95.4％;颈动脉Crouse积分诊断严重冠脉病变的ROC曲线下面积为0.627,以颈动脉Crouse积分≥1.9为截断值,其预测冠脉严重病变的敏感性为70.3％,特异性为41.5％.结论 ABI和颈动脉Crouse积分与冠状动脉的病变程度密切相关,对于预测严重病变的冠状动脉,二者具有很高的应用价值.     

中药房规范化管理研究刍议

中药作为我国的"国宝",影响广泛且倍受国人的青睐,而中药房又是中草药及中成药面对患者的终端,因而对中药房实施规范化管理具有重要意义。该文就目前中药房规范化管理方面存在的主要问题,提出了相应的对策及建议,以提高中药房工作效率,使用药安全得到保障。