Tei指数评估妊娠晚期正常胎儿心室功能的研究

目的探讨正常胎儿左、右心室的Tei指数在评价胎儿心脏收缩和舒张功能中的作用及其影响因素。方法应用多普勒超声心动图测量61例孕龄28~40周的胎儿左、右心室多普勒时间间期,获得等容收缩及舒张时间和射血时间,计算左、右心室Tei指数,分析孕龄、心率对此指数的影响及左、右心室Tei指数的相关性。结果妊娠晚期正常胎儿左心室平均Tei指数为0.360±0.089,右心室平均Tei指数为0.351±0.097,两者具有相关性,但无明显差异(P>0.05)。孕龄与左心室、右心室Tei指数不相关。胎心率与左心室、右心室Tei指数不相关。结论Tei指数不受孕龄及胎心率的影响,可用来观察各种情况下的胎儿心功能变化。     

生肌红粉膏促进家兔背部创面愈合的实验研究

目的:通过将生肌红粉膏、生肌玉红膏、凡士林的疗效进行对比,进而阐述生肌红粉膏促进家兔感染性创面愈合的作用机制。方法:将健康的普通大耳白兔12只,按照改良付小兵全层皮肤缺损法制成创伤感染性动物体表溃疡模型,分别予生肌红粉膏、生肌玉红膏及凡士林换药,分别测定换药前、换药后第3、71、4天时创面分泌物中pH值、蛋白含量及各个阶段创面面积减小率,以探讨生肌红粉膏促进创面愈合的作用机理。结果:各组分泌物pH值在换药前、换药第3、71、4天组间比较无显著性差异(P>0.05),但其均呈逐渐下降的趋势,且生肌红粉膏在术后创面的pH值相对较低;各组创面蛋白含量在换药前、换药第3、71、4天,均呈逐渐下降的趋势,但换药第3、7天生肌红粉膏组分泌物蛋白含量相对最高;从各组创面面积减小率看,生肌红粉膏组快于生肌玉红膏组,生肌玉红膏组快于凡士林组。结论:生肌红粉膏可能通过酸化创面、提高创面蛋白含量、增强抗感染作用,达到促进创面快速愈合的目的。     

酚氨咖敏片溶出度方法的建立及国内产品质量的考察

目的建立酚氨咖敏片的溶出度检查方法并对国内产品进行质量现状考察。方法采用转篮法,100r·min-1,以900mL0.1mol·L-1盐酸为溶出介质,高效液相色谱法测定,检测波长272nm。结果经方法学验证,对乙酰氨基酚、咖啡因和氨基比林的检测质量浓度分别在0.034 9～0.244 0,0.006 2～0.043 7和0.022 5～0.157 4mg·L-1范围内线性关系良好(r>0.999 8),平均回收率均大于97.0%(RSD小于1.0%)。结论所建立的方法准确可靠,可作为酚氨咖敏片中各组分溶出度测定方法。     

Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions

Genetic screens can identify synthetic lethal (SL) interactions and uncover potential anticancer therapeutic targets. However, most SL screens have utilized knockout or knockdown approaches that do not accurately mimic chemical inhibition of a target protein. Here, we test whether missense mutations can be utilized as a model for a type of protein inhibition that creates a dominant gain-of-function cytotoxicity. We expressed missense mutations in the FEN1 endonuclease and the replication-associated helicase, CHL1, that inhibited enzymatic activity but retained substrate binding, and found that these mutations elicited a dominant SL phenotype consistent with the generation of cytotoxic protein–DNA or protein–protein intermediates. Genetic screens with nuclease-defective hFEN1 and helicase-deficient yCHL1 captured dominant SL interactions, in which ectopic expression of the mutant form, in the presence of the wild-type form, caused SL in specific mutant backgrounds. Expression of nuclease-defective hFEN1 in yeast elicited DNA binding-dependent dominant SL with homologous recombination mutants. In contrast, dominant SL interactions with helicase-deficient yCHL1 were observed in spindle-associated, Ctf18-alternative replication factor C (Ctf18-RFC) clamp loader complex, and cohesin mutant backgrounds. These results highlight the different mechanisms underlying SL interactions that occur in the presence of an inhibited form of the target protein and point to the utility of modeling trapping mutations in pursuit of more clinically relevant SL interactions.

Tumor-specific genetic alterations represent vulnerabilities that can be leveraged to selectively target tumors with therapeutics (1). This can be achieved by exploiting the concept of synthetic lethality (SL), which occurs when cells carrying perturbations of two genes individually are viable but combining those perturbations results in cell lethality (2). However, while the concept of SL holds great promise, and many cancer-relevant SL genetic interactions have been identified over the past two decades, only one SL-based therapeutic has reached the clinic (3).A number of factors confound the development of SL-based therapies, such as the context dependency of genetic interactions and the complexity of overlapping functions between different complexes and pathways in the DNA damage response (3). The success rate of SL-based therapeutics could conceivably be improved by analyzing the properties of PARP inhibitors, which are the only SL-based therapeutic currently in the clinic. Inhibitors of the proteins PARP-1 and PARP-2, which are implicated in DNA repair and genome maintenance (4), were specifically developed as SL-based therapeutics for the treatment of homologous recombination (HR) repair-deficient tumors (5–7). Research into the mechanism of PARP SL has found that the cytotoxicity of PARP inhibitors derives not from the loss of PARP activity, per se, but rather from the trapping of PARP protein on DNA generating a PARP–DNA cytotoxic lesion. The trapped protein–DNA lesion not only generates a potentially cytotoxic lesion, it may also prevent other repair proteins from accessing the DNA damage. The PARP-DNA lesion requires BRCA-mediated HR for error-free resolution or bypass during replication. Consistent with this model, PARP inhibitors are more effective at killing BRCA-mutated cancer cells than PARP knockout or knockdown, and the cytotoxicity of PARP inhibitors correlates with their trapping ability (8–10).Another class of anticancer therapeutic that traps protein targets on DNA is topoisomerase inhibitors. Many topoisomerase inhibitors act as interfacial inhibitors and interfere with the catalytic cycle, preventing the resolution of a DNA–topoisomerase intermediate, thereby creating a trapped topoisomerase–DNA adduct (11). Although they were not developed as SL-based therapeutics, their efficacy is due in part to SL interactions with tumor-specific mutations affecting replication, checkpoints, or repair (12). For both PARP and topoisomerase inhibitors, the cytotoxicity derives from the formation of a toxic intermediate in the form of an inhibited protein complexed with DNA. In effect, the small molecule inhibitors when bound to their targets convert wild-type protein to a cytotoxic form that creates a “gain-of-function” DNA-damaging agent. The creation of cytotoxic protein–DrNA complexes may be generalizable to other DNA-associated proteins, and it is also possible that inhibitors may result in cytotoxic protein–protein intermediates that indirectly impact DNA processes.Most SL screens have relied on loss-of-function knockout/mutation collections, or CRISPR-knockout and RNA interference (RNAi)-based libraries that result in loss- or reduction-of-function phenotypes (3). These approaches may often not accurately model SL interactions between cancer mutations and the chemically inhibited forms of SL partner proteins. An alternative to knockout-based SL modeling is to utilize missense mutations that mimic inhibitors. Missense-derived SL genetic interactions may be more clinically relevant than interactions that are based on complete knockouts as they are assessed when the target protein is present, and retains DNA and/or protein interactions, but is inactivated. For example, specific missense mutations in Saccharomyces cerevisiae Top1 enhance the stability of the covalent topoisomerase–DNA intermediate and phenocopy the effect of the topoisomerase inhibitor camptothecin (13). These camptothecin mimetic mutations cause a dominant phenotype and have been used to screen for mutations that sensitize cells to topoisomerase trapping (14).In both DNA- and protein-trapping scenarios, the trapped inactivated protein would be predicted to elicit a dominant phenotype. This may occur when the trapped protein competes with wild-type protein for substrate and blocks the activity of the wild-type protein. In this way, dominant SL interactions can capture genetic interactions that occur in the presence of the wild-type or residual noninhibited protein. Even trapping of a small percentage of a protein target pool could catalyze a SL interaction and may provide a mechanism by which essential proteins could be exploited to elicit SL.The efficacy of PARP and topoisomerase inhibitors that trap their targets on DNA suggest that other DNA damage response-associated proteins, in particular those associated with the response to replicative stress, would be good targets for inhibition that causes trapping. The DNA flap endonuclease 1 (FEN1) and the helicase DDX11 are critical enzymes that maintain genome stability during replication and are attractive targets for the development of anticancer therapeutics. FEN1 functions in DNA replication and repair and is required for Okazaki fragment maturation. Due to its key role in DNA replication, FEN1 supports rapid proliferation of cancer cells and is overexpressed in many tumor types (15). DDX11 is a member of the iron sulfur DEAD/DEAH helicase family (16). DDX11 is up-regulated in some primary and metastatic melanomas, and suppression of DDX11 in these melanomas curtails proliferation and induces apoptosis (17). SL interaction screens, utilizing knockout mutants of the yeast ortholog rad27Δ, have identified FEN1 as a broad-spectrum target for anticancer therapeutic development (18), especially for HR-deficient tumors (19). The knockout mutant of the DDX11 yeast ortholog chl1Δ is also SL with cohesin mutations (20), which are a common genetic vulnerability in a broad range of tumors (21, 22).In proof-of-principle experiments utilizing yeast-based high-throughput genetic approaches, we used missense mutations in FEN1 and the yeast DDX11 ortholog, Chl1, to mimic a specific case of chemical inhibition in which protein activity was inhibited, but substrate binding was unaffected (23). These mutants were screened for dominant SL interactions with a panel of DNA-associated knockout mutants. Expression of these mutant proteins generated nonoverlapping dominant SL genetic interaction networks and were consistent with the formation of cytotoxic lesions that impacted DNA processes.     

清气化瘀养阴汤治疗温病气分证的实验研究

通过清气汤，清气化瘀汤，清气养阴汤，清气化瘀养阴汤治疗温病气分证动物的实验研究，并与正常组，对照组比较，结果显示：对照组动物脏器组织病理形态学观察几瘀血，出血，微血栓形成及严重炎性改变等指标，证实温病气分证实验动物已出现ＤＩＣ，属高凝状态。气分阶段不但伤津，且耗血。“耗血”的实质不仅限于血液量的减少，更重要的是表现为血液中血细胞及其它成分的减少，并有功能的严重障碍。各组比较，清气化瘀养阴汤疗效最佳     

粉刺净颗粒剂中盐酸小檗碱的双波长薄层扫描测定

采用双波长薄层扫描法,测定粉刺净颗粒剂中盐酸小檗碱的含量.展开剂为正丁醇-醋酸-水(7∶1∶2),回归方程为M=1.423×104A+2.566×103,r=0.9915,线性范围1～5μg/ml.     

清热止血汤联合鼻腔填塞术治疗鼻衄100例

目的 观察清热止血汤联合鼻腔填塞术对脏腑热结而引起鼻衄的临床疗效。方法 根据中医五脏热法之鼻衄理论将100例鼻衄病人随机分为2组,治疗组给清热止血汤加减,每日1剂,煎服。必要时联合鼻腔填塞术。对照组给三七粉6g,1日3次,口服。观察疗效,疗程均为2周。结果 治疗组总有效率98.55％,对照组总有效率87.10％,两组比较差异有显著性(x~2=5.91,P<0.05)。结论 清热止血汤联合鼻腔填塞术治疗鼻衄疗效非常满意。     

微波联合安达芬栓治疗慢性宫颈炎的治疗体会

目的探讨微波联合安达芬栓治疗慢性宫颈炎治疗效果。方法分析我院慢性宫颈炎患者临床资料,依据治疗方式不同分为对照组30例和观察组30例。结果观察组出血量、愈合时间、复发率均高于对照组,观察组临床治疗总有效率明显高于对照组,P<0.05,差异均有统计学意义。结论微波联合安达芬栓治疗慢性宫颈炎临床效果明显,预后良好,值得临床推广应用。     

芬舒雅对冠心病心绞痛微循环障碍的治疗作用

芬舒雅是由桂枝、丹参等配伍精制的吸入型中药制剂。将其用于42例冠心病心绞痛患者的微循环障碍,并与使用速效救心丸的30例同类患者进行对照比较。结果发现:芬舒雅与速效救心丸对上述患者心绞痛及微循环障碍的总有效率分别为85.7%,92.9%和83.3%,73.3%,提示:芬舒雅是优于速效救心丸等临床常用药剂的新型制剂。