BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.

背景与目标： ：由于尚无关于抗微管剂对纤毛虫原虫影响的系统研究，因此我们筛选了多种此类化合物对草履虫草履虫细胞培养物生长的影响。测试的化合物包括化学成分差异很大的试剂，并且据报道对多种细胞类型具有影响。我们可以区分不同的药物作用：（a）鱼藤酮是唯一没有任何可识别作用的药物，（b）与较高的动物细胞相比，另一组化合物（包括秋水仙碱）需要很高的浓度，即接近细胞毒性水平；该组还包括微管唑（出乎意料的是，顺式和反式立体异构体之间没有任何区别）。 （c）第三类药物抑制细胞培养物的生长而没有任何致死作用（苯并咪唑，诺考达唑，苯达达唑； [抗]真菌抗生素，灰黄霉素；除草剂三氟拉林）。 （d）最后，一组试剂在植物（除草剂，APM）或高级动物细胞（包括微管稳定剂，紫杉醇）或两者（长春碱，长春新碱，三乙基铅）的浓度范围内均具有活性。它们在较高浓度下具有细胞毒性（如[b]组化合物）。因此，对于草履虫细胞中可能真正的抗微管作用的更详细的分析，可以进一步考虑组（c）以及可能的组（d）的化合物。 Nocodazole，parbendazole和trifluralin特别令人感兴趣，因为它们可以在相对低的浓度下（与其他细胞类型相比）抑制细胞培养物的生长（经过24小时测试），而不会损害细胞的活力。

BACKGROUND & AIMS: :Direct-acting antiviral (DAA) agents specifically target viral proteins. Two DAAs have been already been approved for the treatment of HCV infection and many more are in development. DAA treatment of HCV infection, however, leads to the selection of viral variants (produced by the error-prone HCV polymerase) that are resistant to the DAA agent in use. The selection of DAA-resistant HCV variants has been studied extensively in vitro and in vivo. Common amino acid substitution sites in each of the non-structural proteins are associated with DAA-resistance: D168, A155, A156 and V36 in NS3 protease; L31 and Y93 in NS5A; S282, S96, P495, M423, M414 and C316 in NS5B. In this review we cover the basic principles of DAA resistance, summarise the available resistance data for the various classes of DAAs and discuss the potential of DAA combination therapy for overcoming DAA-resistance, resulting in major advances in the treatment of HCV.

背景与目标： ：直接作用抗病毒（DAA）剂专门针对病毒蛋白。已经批准了两种DAA用于治疗HCV感染，并且还有更多的药物正在开发中。但是，DAA对HCV感染的治疗导致选择对使用中的DAA剂具有抗性的病毒变体（由易出错的HCV聚合酶产生）。在体外和体内已经广泛研究了抗DAA的HCV变异体的选择。每种非结构蛋白中的常见氨基酸取代位点均与DAA耐药性相关：NS3蛋白酶中的D168，A155，A156和V36。 NS5A中的L31和Y93； NS5B中的S282，S96，P495，M423，M414和C316。在本综述中，我们涵盖了DAA耐药性的基本原理，总结了各种DAA耐药性的可用耐药性数据，并讨论了DAA联合疗法克服DAA耐药性的潜力，从而在HCV的治疗方面取得了重大进展。

BACKGROUND & AIMS: :Mammalian cells respond to their substrates by complex changes in gene expression profiles, morphology, proliferation and migration. We report that substrate nanotopography alters morpohology and proliferation of human embryonic stem cells (hESCs). Fibronectin-coated poly(di-methyl siloxane) substrates with line-grating (600nm ridges with 600nm spacing and 600+/-150nm feature height) induced hESC alignment and elongation, mediated the organization of cytoskeletal components including actin, vimentin, and alpha-tubulin, and reduced proliferation. Spatial polarization of gamma-tubulin complexes was also observed in response to nanotopography. Furthermore, the addition of actin disrupting agents attenuated the alignment and proliferative effects of nanotopography. These findings further demonstrate the importance of interplay between cytoskeleton and substrate interactions as a key modulator of morphological and proliferative cellular response in hESCs on nanotopography.

背景与目标： ：哺乳动物细胞通过基因表达谱，形态，增殖和迁移的复杂变化来响应其底物。我们报告说，基底纳米形貌改变了人类胚胎干细胞（hESCs）的形态和增殖。纤连蛋白涂层的聚二甲基硅氧烷底物具有线栅（间距为600nm，间距为600nm，特征高度为600 / -150nm），诱导hESC对准和伸长，介导包括肌动蛋白，波形蛋白和α-微管蛋白的细胞骨架成分的组织，并减少扩散。响应纳米形貌还观察到了γ-微管蛋白复合物的空间极化。此外，肌动蛋白破坏剂的添加减弱了纳米形貌的排列和增殖作用。这些发现进一步证明了细胞骨架和底物相互作用之间相互作用的重要性，这是纳米地形图上hESCs中形态学和增殖细胞应答的关键调节剂。

BACKGROUND & AIMS: :The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.

背景与目标： ：7-氮杂茚并异喹啉是细胞毒性拓扑异构酶I（Top1）抑制剂。以前报道的代表带有一个3-硝基基团。本报告记录了潜在的具有遗传毒性的3-硝基被3-氯和3-氟取代基取代，从而导致在人类癌细胞培养中具有高Top1抑制活性和强细胞毒性的化合物，并降低了动物模型的致死率。一些新的Top1抑制剂还具有对酪氨酰DNA磷酸二酯酶1（TDP1）和酪氨酰DNA磷酸二酯酶2（TDP2）的中等抑制活性，这两种酶都参与了由Top1抑制剂引起的DNA损伤修复，并且它们产生的DNA明显更多。在癌细胞中的损伤要比正常细胞中的损伤大。 18种新化合物的细胞毒性平均图中点（MGM）GI50值在亚微摩尔（0.033-0.630μM）范围内。化合物16b和17b在人类癌细胞培养物中最有效，其MGM GI50值分别为0.063和0.033μM。通过分子建模研究了与Top1和TDP1可能的结合模式。

BACKGROUND & AIMS: :Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.

背景与目标： ：Suramin是目前正在评估抗肿瘤活性的聚阴离子化合物。临床试验期间遇到的主要问题之一是不良的神经毒性作用，这可能是由于对神经细胞的直接细胞毒性作用所致。还已知苏拉明会触发人结肠癌细胞的分化，但是长期治疗会引起溶酶体贮积症。这项研究的目的是评估苏拉明类似物的作用：（i）对人结肠癌细胞克隆HT29-D4的溶酶体系统； （ii）C6胶质瘤细胞的生长和形态。测试的一种衍生物NF036诱导了HT29-D4细胞的终末分化，而对溶酶体系统没有任何损害。此外，与苏拉明相反，NF036不会改变C6细胞的生长和形态。我们得出结论，苏拉明衍生物在人结肠癌细胞中诱导溶酶体贮积病的能力与其神经毒性作用之间存在关联。在HT29-D4和C6细胞上对苏拉明类似物的双重筛选使我们能够鉴定出新的候选抗肿瘤药：NF036。

BACKGROUND & AIMS: :A set of benzophenone derivatives was evaluated for the antimalarial activity against Plasmodium berghei in mice and the mean survival time of mice for all the compounds was determined. The QSAR analysis was carried out for the fourteen benzophenone derivatives using different physicochemical descriptors. The multiple linear regression analysis was used to correlate the physicochemical descriptors with the antimalarial activity of the benzophenone derivatives from the training set and the best QSAR model was developed, which was further used to predict the antimalarial activity of other compounds from the class of benzophenones. To confirm the predictivity of the best QSAR model, a new set (test set) of six compounds was designed, synthesized and evaluated for the antimalarial activity. A good correlation between the experimental and predicted antimalarial activities was obtained for the test set compounds in the validation procedure, indicating the high predictivity of the developed QSAR model. Five benzophenone derivatives, which showed good antimalarial activity, were further studied for their drug-likeliness characteristic and per cent oral absorption using software "QikProp". It was observed that all the five benzophenone derivatives were found to be good drug candidates and showed good oral absorption.

背景与目标： ：评估了一组二苯甲酮衍生物对小鼠伯氏疟原虫的抗疟活性，并确定了所有化合物的小鼠平均存活时间。使用不同的理化指标对十四种二苯甲酮衍生物进行了QSAR分析。使用多元线性回归分析将物理化学指标与训练集中二苯甲酮衍生物的抗疟活性相关联，并开发了最佳QSAR模型，该模型进一步用于预测二苯甲酮类其他化合物的抗疟活性。为了确认最佳QSAR模型的可预测性，设计，合成了一套新的（测试集）六种化合物，并评估了其抗疟活性。在验证过程中，测试化合物的实验和预测的抗疟活性之间具有良好的相关性，表明所开发的QSAR模型具有很高的预测性。使用软件“ QikProp”进一步研究了五种显示出良好抗疟活性的二苯甲酮衍生物的类药物特性和口服吸收百分比。观察到所有五种二苯甲酮衍生物均被认为是良好的候选药物，并表现出良好的口服吸收性。

BACKGROUND & AIMS: :A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.

背景与目标： ：设计，合成并评估了一系列小ber碱-硫代苯基杂化物，作为乙酰胆碱酯酶（AChE），丁酰胆碱酯酶（BuChE）和β-淀粉样蛋白（Aβ）聚集的抑制剂和抗氧化剂。在这些杂种中，观察到化合物4f和4i（通过2碳间隔基与邻甲基硫代苯基和邻氯硫代苯基连接的小ber碱）是有效的AChE抑制剂，IC50值分别为0.077和0.042μM。在测试的化合物中，4i也是BuChE的最强抑制剂，IC50值为0.662μM。 AChE-抑制剂复合物的动力学研究和分子建模模拟表明，这些小碱衍生物存在混合竞争结合模式。生物学研究还表明，这些杂种表现出有趣的活性，包括抑制Aβ聚集和抗氧化性能。

BACKGROUND & AIMS: :The effect of ketamine on myocardial contractile force was examined in rabbit papillary muscles in order to determine the underlying mechanism of action of the anesthetic. Ketamine HCl (20 and 40 mg/L) inhibited rested-state contractions that are dependent on the transsarcolemmal influx of Ca2+ for activation and reduced the upstroke velocity of the slow action potential, which reflects Ca2+ influx through the slow Ca2+ channel. On the other hand, ketamine had a relatively small effect on potentiated-state contractions and no effect on rapid cooling induced contractures, both of which are activated by the release of Ca2+ stored in the sarcoplasmic reticulum. These results suggest that ketamine inhibition of transsarcolemmal Ca2+ influx plays a major role in the negative inotropic action of the anesthetic.

背景与目标： ：检查氯胺酮对兔乳头肌中心肌收缩力的作用，以确定麻醉剂的潜在作用机理。盐酸氯胺酮（20和40 mg / L）抑制了静息状态的收缩，而静息状态的收缩依赖于Ca2的跨膜层流入激活，并降低了慢动作电位的上冲程速度，这反映了Ca2通过缓慢的Ca2通道流入。另一方面，氯胺酮对增强状态的收缩影响相对较小，而对快速冷却引起的挛缩没有影响，两者均通过肌浆网中储存的Ca2释放而被激活。这些结果表明氯胺酮抑制跨肌膜Ca2内流在麻醉剂的负性肌力作用中起主要作用。

BACKGROUND & AIMS: BACKGROUND:A possible negative role of pre-operative use of antitumour necrosis factor-alpha (anti-TNF-α) agents on post-operative outcomes in Crohn's disease (CD) patients is still debated. AIM:To examine the impact of pre-operative anti-TNF-α agents on post-operative outcomes 30 and 60 days after CD surgery in a nationwide Danish cohort. Outcomes were death, reoperation, anastomosis leakage, intra-abdominal abscess and bacteraemia. METHODS:We identified all patients having surgical procedures from 1 January 2000 to 31 December 2010 (n = 2293). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery (exposed) or not (unexposed). Outcomes were obtained from nationwide registries and a bacteraemia registry. Sub-analyses were performed for bacteraemia and for impact of pre-operative timing of anti-TNF-α agents. RESULTS:Among surgical procedures for CD, 214 were exposed and 2079 were not. We found no increased relative risks of death or abscess drainage 30 or 60 days after follow-up. Among exposed, 7.5% had a reoperation within 30 days vs. 8.6% among unexposed, adjusted odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.52-1.63. Among exposed, 3.8% had an anastomosis leakage within 30 days after surgery vs. 2.8% among unexposed, adjusted OR = 1.33, 95% CI: 0.59-3.02. No further cases of anastomosis leakages appeared within 60 days. Sub-analyses indicated no increased risk of bacteraemia after 30 days and no increased risks when anti-TNF-α agents were given ≤14 days before surgery. CONCLUSION:We found no significantly increased relative risks of post-operative complications after use of anti-TNF-α agents either 12 weeks or ≤14 days before surgery for Crohn's disease.

背景与目标： 背景：在克罗恩病（CD）患者中，术前使用抗肿瘤坏死因子-α（anti-TNF-α）药物对术后结局的可能负面作用仍在争论中。
目的：探讨丹麦全国队列CD手术后30和60天的术前抗TNF-α药物对术后结局的影响。结果是死亡，再次手术，吻合口漏，腹腔内脓肿和菌血症。
方法：我们确定了从2000年1月1日至2010年12月31日（n = 2293）的所有接受外科手术治疗的患者。根据手术前（未暴露）或未手术（未暴露）前12周内使用抗TNF-α药物对患者进行分类。结果是从全国性注册机构和菌血症注册机构获得的。对菌血症和抗TNF-α药物的术前时机的影响进行了亚分析。
结果：在CD的外科手术中，有214例暴露，而2079例则没有。随访后30或60天，我们没有发现死亡或脓肿引流的相对风险增加。在暴露的患者中，有7.5％在30天内进行了再次手术，而未暴露的，调整后的优势比（OR）= 0.92,95％的置信区间（CI）：0.52-1.63为8.6％。在暴露的人群中，有3.8％的患者在术后30天内发生了吻合口漏，而在未暴露的，调整后的OR = 1.33、95％CI：0.59-3.02的患者中，则为2.8％。在60天内没有其他病例发生吻合口漏。子分析表明，术后30天内细菌菌血症的风险没有增加，并且在手术前≤14天给予抗TNF-α药物的风险也没有增加。
结论：我们发现克罗恩病患者在手术前12周或≤14天使用抗TNF-α药物后，术后并发症的相对风险没有显着增加。

BACKGROUND & AIMS: :NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.

背景与目标： ：NO是大脑中重要的信使分子，尤其是通过ERK / CREB信号通路在学习和记忆中起着重要作用。 NO也是一种神经保护剂。随着年龄的增长，抗氧化剂和营养因子的水平降低，多种机制已被证明可以促进细胞存活。模仿NO的生物活性的小分子，包括NO供体，可能会改善认知并提供神经保护作用。有几条证据将阿尔茨海默氏病的神经退行性疾病和痴呆症与β-淀粉样蛋白在α7-烟碱乙酰胆碱受体上的作用联系起来。 Abeta与通过ERK信号级联反应起作用的α7-烟碱型ACh受体之间的相互作用将淀粉样蛋白级联反应和胆碱能假说联系在一起，从而影响突触可塑性和记忆力。这种相互作用还提供了与AD中NO / cGMP信号破坏的联系，此外，最近发现的直接证据表明Abeta下调了NO / cGMP / CREB途径。大脑中可溶性鸟苷酰环化酶升高cGMP的激活代表了治疗AD和其他神经退行性疾病的治疗方法的核心要素，此外，有证据表明NO可能显示cGMP非依赖性活性，并可能通过多种生化信号通路起作用以确保承受压力的神经元的存活。 GT 1061是一种NO嵌合体，一种NO模仿化合物，其中包含辅助的协同药效团，目前正在阿尔茨海默氏症的临床试验中。没有嵌合体和杂合硝酸盐有望作为具有多种作用位点的AD疗法。

BACKGROUND & AIMS: OBJECTIVES:To assess the clinical effectiveness and cost-effectiveness of central venous catheters (CVCs) treated with anti-infective agents in preventing catheter-related bloodstream infection (CRBSI). DATA SOURCES:Major electronic databases were searched from 1985 to August 2005. REVIEW METHODS:The systematic clinical and economic reviews were conducted according to accepted procedures. Only full economic evaluations (synthesis of costs and benefits) comparing the use of anti-infective central venous catheters (AI-CVCs) with untreated CVCs or other treated catheters were selected for inclusion in the economic review. RESULTS:A total of 32 trials met the clinical inclusion criteria. Seven different types of AI-CVC were identified, with the most frequently tested being chlorhexidine and silver sulfadiazine (CHSS) (externally treated), CHSS (externally and internally treated) and minocycline rifampicin (internally and externally treated). In general, the trials were of a poor quality in terms of reported methodology, microbiological relevance and control of confounding variables. The pooled result suggests a statistically significant advantage for AI-CVCs in comparison to standard catheters in reducing CRBSI [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.34 to 0.60, 24 studies, I-squared = 0%, fixed effects]. Analysis by subgroups of catheters demonstrates that antibiotic-treated catheters and catheters treated internally and externally decrease CRBSI rates significantly (OR 0.26, 95% CI 0.15 to 0.46, six studies, I-squared = 0%, fixed effects, and OR 0.43, 95% CI 0.26 to 0.70, nine studies, I-squared = 0%, fixed effects, respectively). Catheters treated only externally demonstrate a wider CI and non-significant effect (OR 0.67, 95% CI 0.43 to 1.06, nine studies, I-squared = 0%, fixed effects). A treatment effect was also found for trials with an average duration of between 5 and 12 days, and for the one study with a mean duration of over 20 days. There was a statistically significant treatment effect for both femoral and jugular insertion sites and for those studies reporting a mix of insertion sites. The treatment effect was not observed in trials using exclusively subclavian insertion sites. Of the four trials that compared treated catheters, one reported a benefit of antibiotic-treated catheters over catheters treated externally with CHSS. All three sensitivity analyses testing for study design differences reported a statistically significant treatment effect. The review was limited owing to the quality of the trials included, marked differences in the definitions and methods of diagnosis of CRBSI, and inconsistent reporting of risk factors and patient population factors. Furthermore, two-thirds of trials were commercially funded. The economic performance (cost-effectiveness and potential cost-savings) of using AI-CVCs to reduce the number of CRBSIs in patients requiring a CVC was also reviewed. Results show that the use of AI-CVCs instead of standard CVCs can lead to a reduction in CRBSIs and decreased medical costs. To complement the reviews, a basic decision-analytic model was constructed to explore a range of possible scenarios for the NHS in England and Wales. Results show that for every patient who receives an AI-CVC there is an estimated cost-saving of 138.20 pounds. The multivariate sensitivity analyses estimate potentially large cost-savings, depending on the size of the population, under a wide range of cost and clinical assumptions. However, those considering the purchase of AI-CVCs should ensure that their patient populations and the important characteristics of local clinical practice are indeed similar to those described in this economic evaluation. CONCLUSIONS:Overall, AI-CVCs are clinically effective and relatively inexpensive and therefore their integration into clinical practice can be justified. However, the use of these anti-infective catheters without the appropriate use of other practical care initiatives will have only a limited success on the prevention of CRBSIs. Comparative trials are required to determine which, if any, of the treated catheters is the most effective. Pragmatic research related to the effectiveness of bundles of care that may reduce rates of CRBSI is also warranted.

背景与目标： 目的：评估用抗感染药治疗的中心静脉导管（CVC）在预防导管相关的血流感染（CRBSI）方面的临床效果和成本效益。
数据来源：从1985年到2005年8月，检索了主要的电子数据库。
审查方法：根据公认的程序进行系统的临床和经济审查。只有将将抗感染中心静脉导管（AI-CVC）与未经治疗的CVC或其他经过治疗的导管进行比较的全面经济评估（成本和收益的综合）才被选入经济评估。
结果：总共32项试验符合临床纳入标准。鉴定出七种不同类型的AI-CVC，最常测试的是洗必太和磺胺嘧啶银（CHSS）（外部治疗），CHSS（外部和内部治疗）和米诺环素利福平（内部和外部治疗）。总体而言，就报告的方法学，微生物学相关性和混杂变量的控制而言，这些试验的质量较差。汇总结果表明，与标准导管相比，AI-CVC在降低CRBSI方面具有统计学上的显着优势[比值比（OR）0.45，95％置信区间（CI）0.34至0.60，24个研究，I平方= 0％，固定效果]。导管亚组的分析表明，抗生素治疗过的导管和内外治疗过的导管显着降低了CRBSI率（OR 0.26，95％CI 0.15至0.46，六项研究，I平方= 0％，固定效应，OR 0.43，95 ％CI 0.26至0.70，九项研究，I平方= 0％，分别为固定效应）。仅经外部治疗的导管显示出较宽的置信区间，且无显着影响（OR为0.67，95％置信区间为0.43至1.06，九项研究，I平方= 0％，固定效应）。对于平均持续时间为5至12天的试验以及平均持续时间超过20天的一项研究，也发现了治疗效果。股骨和颈静脉插入部位以及报告混合插入部位的研究在统计学上均具有显着的治疗效果。在仅使用锁骨下插入位点的试验中未观察到治疗效果。在比较经治疗的导管的四项试验中，有一项报告指出，与经CHSS外部治疗的导管相比，经抗生素治疗的导管有益处。针对研究设计差异的所有三个敏感性分析测试均报告了统计学上显着的治疗效果。由于包括的试验质量，CRBSI的诊断定义和诊断方法存在明显差异以及危险因素和患者人群因素的报告不一致，因此该审查受到了限制。此外，三分之二的试验是由商业资助的。还回顾了使用AI-CVC减少需要CVC的患者的CRBSI数量的经济表现（成本效益和潜在的成本节省）。结果表明，使用AI-CVC代替标准CVC可以减少CRBSI并降低医疗成本。为了补充评论，构建了基本的决策分析模型，以探索英格兰和威尔士的NHS的各种可能方案。结果表明，每位接受AI-CVC的患者估计可节省138.20磅。多元敏感性分析估计，在广泛的成本和临床假设下，取决于人群的规模，可能会节省大量成本。但是，考虑购买AI-CVC的人员应确保其患者人数和当地临床实践的重要特征确实与本经济评估中所述的相似。
结论：总体而言，AI-CVC具有临床效果且相对便宜，因此可以证明将其整合到临床实践中是合理的。但是，在没有适当使用其他实践护理措施的情况下使用这些抗感染导管在预防CRBSI方面仅会取得有限的成功。需要进行比较试验，以确定哪一种治疗过的导管最有效。还必须进行与可能降低CRBSI发生率的护理捆绑的有效性相关的务实研究。

BACKGROUND & AIMS: :Five dichlorinated 8-quinolinols (2,5- 5,6-, 3,5-, 3,7-, and 4,5-dichloro-8-quinolinol) were tested against Candida albicans and C. tropicalis in Sabouraud dextrose broth with and without bovine serum. The 5,6-, 3,5-, and 3,7-dichloro-8-quinolinols proved to be more effective than the control, 5-fluorocytosine. In cytotoxicity tests employing baby hamster kidney (BHK) cells, all test agents proved to be more cytotoxic than the control. However, the minimum inhibitory concentration (MIC) of 3,5-dichloro-8-quinolinol to both fungi was only one tenth the cytotoxic dose, suggesting that the compound may be useful as a topical or systemic antifungal agent.

背景与目标： ：在Sabouraud葡萄糖肉汤中测试了五种二氯8-喹啉醇（2,5- 5,6-，3,5-，3,7-和4,5-二氯8-喹啉醇）对白色念珠菌和热带念珠菌的抵抗力有和没有牛血清。 5,6-，3,5-和3,7-二氯-8-喹啉醇被证明比对照的5-氟胞嘧啶更有效。在使用小仓鼠肾脏（BHK）细胞的细胞毒性测试中，所有测试药物均被证明比对照更具细胞毒性。但是，3,5-二氯-8-喹啉醇对两种真菌的最小抑制浓度（MIC）仅是细胞毒性剂量的十分之一，表明该化合物可用作局部或全身性抗真菌剂。

BACKGROUND & AIMS: BACKGROUND:Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. METHODS:We prospectively measured liver iron concentration by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA, in keeping with current guidelines. RESULTS:Mild to severe hepatic iron overload was observed in 100 patients (84%; confidence interval, [CI] 76%-90%), of whom 36% (CI, 27%-46%) had severe hepatic iron overload (liver iron concentration >201 μmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin, and C-reactive protein values correlated with hepatic iron stores in both univariate analysis (P<.05, Spearman test) and binary logistic regression (P <.05). In 11 patients who were monitored closely during parenteral iron therapy, the iron dose infused per month correlated strongly with both the overall increase and the monthly increase in liver iron concentration (respectively, rho=0.66, P=.0306 and rho=0.85, P=0.0015, Spearman test). In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 μmol/g (range: 60-340); last MRI: 50 μmol/g (range: 5-210); P <.0001, Wilcoxon's paired test). CONCLUSIONS:Most hemodialysis patients receiving ESA and intravenous iron supplementation have hepatic iron overload on MRI. These findings call for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and noninvasive methods for monitoring iron stores.

背景与目标： 背景：大多数接受促红细胞生成素（ESA）治疗的透析患者也接受肠胃外补铁。在这种情况下，有关铁血黄素沉着症风险的数据很少。
方法：我们按照119例患者的标准，通过无without的T1和T2 *对比磁共振成像（MRI），对119名接受肠胃外注射铁和ESA的健康血液透析患者进行了前瞻性测量。
结果：在100例患者中观察到轻至重度肝铁超负荷（84％；置信区间，[CI] 76％-90％），其中36％（CI，27％-46％）有严重肝铁超负荷（肝）铁浓度> 201μmol/ g干重）。在横断面研究中，在单变量分析（P <.05，Spearman检验）和二元逻辑回归（P <.05）中，注入的铁，铁调素和C反应蛋白值均与肝铁储量相关。在肠胃外铁疗期间接受密切监测的11例患者中，每月输注的铁剂量与肝铁浓度的总体增加和每月增加密切相关（分别为rho = 0.66，P = .0306和rho = 0.85，P = 0.0015，Spearman检验）。在33名铁超负荷患者中，铁撤出或铁剂量大幅减少后铁存储显着下降（首次MRI：220μmol/ g（范围：60-340）;最后MRI：50μmol/ g（范围:) 5-210）； P <.0001，Wilcoxon配对测试）。
结论：大多数接受ESA和静脉补铁的血液透析患者在MRI检查中均存在肝铁超负荷。这些发现要求在这种情况下修订铁疗法指南，尤其是关于铁的注入量和用于监测铁储存的非侵入性方法。

BACKGROUND & AIMS: :Topical application of 17 nmoles of the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, resulted in a stimulation of the incorporation of [(3)H]lysine into epidermal histones. Maximum incorporation occurred 24 hr after treatment, concurrent with maximum DNA synthesis. The effects of phorbol and two phorbol esters on histone synthesis were related to their tumor-promoting activities. Treatment with hydroxyurea partially prevented the phorbol ester-induced stimulation of both DNA and histone synthesis, although it had no effect on the stimulation of protein synthesis. These findings are consistent with the likelihood that phorbol ester-induced epidermal histone synthesis is the result of a coupling between DNA synthesis and histone synthesis.

背景与目标： ：局部应用有效的肿瘤促进剂17-noles 12-O-十四烷酰phorbol-13-乙酸盐的刺激导致[（3）H]赖氨酸掺入表皮组蛋白中的刺激。最大掺入发生在处理后24小时，同时最大DNA合成。佛波醇和两种佛波酯对组蛋白合成的影响与其促肿瘤活性有关。羟基脲的处理部分阻止了佛波酯诱导的DNA和组蛋白合成的刺激，尽管它对蛋白质合成的刺激没有影响。这些发现与佛波酯诱导的表皮组蛋白合成是DNA合成与组蛋白合成之间耦合的结果相一致。

BACKGROUND & AIMS: :The synthesis and antitumor activity in normoxic and hypoxic conditions of a series of pyrazolo[5,1-c][1,2,4]benzotriazine and its related analogues are reported. All compounds were tested on human colorectal adenocarcinoma cell line HCT-8 and for compounds 15 and 20, which show to have selective cytotoxicity in hypoxic and in normoxic conditions respectively, ROS production, cell cycle, and DNA fragmentation were measured. This preliminary study encouraged us to consider 15 and 20 as interesting leads for further optimization.

背景与目标： ：报道了一系列吡唑并[5,1-c] [1,2,4]苯并三嗪及其相关类似物在常氧和低氧条件下的合成和抗肿瘤活性。所有化合物均在人大肠腺癌细胞系HCT-8和化合物15和20上进行了测试，化合物15和20在低氧和常氧条件下分别显示出选择性细胞毒性，并测量了ROS的产生，细胞周期和DNA片段化。这项初步研究鼓励我们将15和20视为进一步优化的有趣线索。