• 【吸毒规则:古代世界中的葡萄酒和罂粟衍生物。六。罂粟是食物和毒品的来源。】 复制标题 收藏 收藏
    DOI:10.3109/10826089709039375 复制DOI
    作者列表:Nencini P
    BACKGROUND & AIMS: :Poppies were widely used during antiquity as a source of food, therapeutics, and poisons. It is likely that the alimentary value of poppy seeds was known in the Neolithic age, and there is some evidence that the neuropsychopharmacological effects of poppy juice were exploited during the Minoan civilization in the eastern Mediterranean basin. The Minoan civilization dates the attribution to poppies of symbolic meanings connected with rites of agricultural fertility. The persistence throughout antiquity of this symbolism is testified by literary and iconographic evidence of the attribution of poppies to goddesses of fertility, such as Demeter, Aphrodite, and Ceres.
    背景与目标: :在古代,罂粟被广泛用作食物,治疗剂和毒药的来源。罂粟种子的营养价值很可能是在新石器时代就已经知道的,并且有一些证据表明,罂粟汁的神经心理药理作用是在地中海东部的米诺斯文明期间被利用的。米诺斯文明可追溯到象征意义的罂粟的归属,这些象征意义与农业生育的仪式有关。这种象征主义在整个上古时代的持久性通过文学和肖像学证据证明,罂粟归因于狄特耳特,阿芙罗狄蒂和谷神星等生育女神。
  • 【耐药细胞提取物中癌基因依赖性细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1101/gad.11.10.1266 复制DOI
    作者列表:Fearnhead HO,McCurrach ME,O'Neill J,Zhang K,Lowe SW,Lazebnik YA
    BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

    背景与目标: 许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此,抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变,但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中,我们显示了抗药性293细胞系无法激活凋亡机制的成分(如ICE样蛋白酶(胱天蛋白酶)),随后进行了抗癌药物治疗。值得注意的是,未经处理的细胞提取物会自发激活胱天蛋白酶并在无细胞系统中诱导凋亡,这表明耐药细胞不仅具有凋亡机制,还具有其激活剂。比较具有确定的遗传差异的细胞提取物,我们表明该激活剂是由腺病毒E1A癌基因产生的,而正常细胞中却不存在。我们提供了此致癌基因产生的活性(OGA)的初步表征,并表明当添加到未转化细胞的提取物中时,部分纯化的OGA会激活胱天蛋白酶。我们建议将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞,否则它们会对常规癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性,因此这些药剂对转化细胞的作用应该是选择性的。

  • 【腺病毒对细胞蛋白质合成的抑制作用被药物2-氨基嘌呤阻止。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.87.18.7115 复制DOI
    作者列表:Huang JT,Schneider RJ
    BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.
    背景与目标: :腺病毒感染导致细胞蛋白质合成受到抑制,但该机制尚未建立。在本报告中,我们证明了通过用2-氨基嘌呤药物治疗可防止腺病毒关闭细胞蛋白质合成。已显示用2-氨基嘌呤处理可防止细胞翻译受到抑制,而不会破坏细胞mRNA从细胞核到细胞质的运输过程中的正常病毒阻滞。我们显示病毒抑制细胞蛋白质合成的发生与干扰素诱导的双链RNA激活的抑制剂(DAI),蛋白激酶和真核生物起始因子2(eIF-2 alpha)的α亚基的磷酸化的激活同时发生。 ,但可以防止2-氨基嘌呤阻止宿主细胞的关闭,而不会降低激酶活性或eIF-2α的去磷酸化。结果表明,可能需要DAI激酶的激活和eIF-2α的磷酸化,但不足以抑制腺病毒感染期间细胞蛋白质合成。我们建议其他事件,特别是其他起始因子的修饰,可能与细胞翻译的病毒抑制有关。
  • 【CHADS2评分与阵发性房颤患者抗心律失常药物治疗疗效之间的关系。】 复制标题 收藏 收藏
    DOI:10.1253/circj.cj-12-0854 复制DOI
    作者列表:Komatsu T,Sato Y,Ozawa M,Kunugita F,Ueda H,Tachibana H,Morino Y,Nakamura M
    BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  
    背景与目标: 背景:心脏衰竭,高血压,年龄,糖尿病,中风[加倍](CHADS(2))评分是对血栓栓塞患者进行风险分层的有用方案,但有关其对抗心律不齐药物(AAD)评估的有用性的信息很少) 治疗。
    方法与结果:这项研究纳入459例阵发性房颤(AF)患者(309名男性,平均年龄66±12岁,平均随访50±35个月),并根据CHADS(2)评分分析了其预防性疗效。 (1)得分为0的组在1、6、12和24个月无房颤复发的生存率分别为89%,74%,63%和47%(n = 152);得分1组(n = 158)为92%,68%,59%和48%;得分2组分别为86%,64%,56%和46%(n = 84);得分3组(n = 43)分别为81%,65%,51%和35%; ≥分数4组的患者分别为68%,50%,36%和18%(n = 22)(P <0.05;分数≥0,分数1或得分2与≥分数4组相比)。 (2)在0级评分组中,在12、36、60和90个月无进展为慢性房颤的生存率分别为95%,93%,91%和89%;得分1组分别为97%,91%,89%和88%;得分2组分别为96%,93%,88%和83%;分数3组的比例分别为91%,74%,67%和60%; ≥4分组分别为91%,82%,68%和55%(P <0.01; 0分,1分或2分与≥4分组比较)。 (3)在针对潜在混杂变量进行调整的多因素logistic回归分析中,CHADS(2)评分与房颤复发相关(优势比[OR] 1.45、95%置信区间[CI] 1.16-1.81,P <0.001)和进展到AAD治疗期间的慢性房颤(OR 1.64,95%CI 1.04-2.69,P <0.001)。
    结论:使用节律控制策略时,CHADS(2)评分是预测阵发性房颤患者AAD治疗结果的有用方案。
  • 【TeamSTEPPS创伤护士学院在1级创伤中心的影响力。】 复制标题 收藏 收藏
    DOI:10.1016/j.jen.2017.05.007 复制DOI
    作者列表:Peters VK,Harvey EM,Wright A,Bath J,Freeman D,Collier B
    BACKGROUND & AIMS: PROBLEM:Nurses are crucial members of the team caring for the acutely injured trauma patient. Until recently, nurses and physicians gained an understanding of leadership and supportive roles separately. With the advent of a multidisciplinary team approach to trauma care, formal team training and simulation has transpired. METHODS:Since 2007, our Level I trauma system has integrated TeamSTEPPS (Team Strategies & Tools to Enhance Performance & Patient Safety; Agency for Healthcare Research and Quality, Rockville, MD) into our clinical care, joint training of nurses and physicians, using simulations with participation of all health care providers. With the increased expectations of a well-orchestrated team and larger number of emergency nurses, our program created the Trauma Nurse Academy. This academy provides a core of experienced nurses with an advanced level of training while decreasing the variability of personnel in the trauma bay. Components of the academy include multidisciplinary didactic education, the Essentials of TeamSTEPPS, and interactive trauma bay learning, to include both equipment and drug use. Once completed, academy graduates participate in the orientation and training of General Surgery and Emergency Medicine residents' trauma bay experience and injury prevention activities. RESULTS:Internal and published data have demonstrated growing evidence linking trauma teamwork training to knowledge and self-confidence in clinical judgment to team performance, patient outcomes, and quality of care. IMPLICATIONS FOR PRACTICE:Although trauma resuscitations are stressful, high risk, dynamic, and a prime environment for error, new methods of teamwork training and collaboration among trauma team members have become essential.
    背景与目标: 问题:护士是护理严重受伤的创伤患者的团队的关键成员。直到最近,护士和医师还分别了解领导和支持角色。随着多学科团队创伤治疗方法的问世,正式的团队培训和模拟已经出现。
    方法:自2007年以来,我们的I级创伤系统已将TeamSTEPPS(提高绩效和患者安全的团队策略和工具;医疗研究与质量局,马里兰州罗克维尔)集成到我们的临床护理中,使用模拟对护士和医生进行联合培训在所有医疗保健提供者的参与下。随着团队的精心安排和急诊护士人数的增加,我们的计划创建了创伤护士学院。该学院为经验丰富的护士提供了高级培训,同时又减少了外伤部位人员的变异性。该学院的组成部分包括多学科的教学教育,TeamSTEPPS的基础知识以及交互式创伤海湾学习(包括设备和毒品使用)。完成后,学院的毕业生将参加普通外科和急诊科住院医师的创伤湾经验和伤害预防活动的指导和培训。
    结果:内部和公开的数据表明,越来越多的证据将创伤团队合作训练与临床判断的知识和自信心与团队绩效,患者结果和护理质量联系起来。
    实践的意义:尽管创伤复苏具有压力,高风险,动态且是错误的主要环境,但创伤团队成员之间进行团队合作培训和协作的新方法已变得至关重要。
  • 【氯苯诱导的大鼠肝中谷胱甘肽代谢异常对半胱氨酸水平的影响。】 复制标题 收藏 收藏
    DOI:10.3177/jnsv.31.69 复制DOI
    作者列表:Yoshida M,Hara I
    BACKGROUND & AIMS: :Effects of chlorobenzene-induced alteration in glutathione levels on cysteine metabolism in rat liver were investigated. Male Wistar rats were intraperitoneally injected with chlorobenzene (0.2, 0.5, 1.0 or 2.0 mmol/kg body weight). Both hepatic glutathione and cysteine levels were dose-dependently decreased by the chlorobenzene 6 h after the injection. However, at 24 h, the glutathione in the rats with chlorobenzene increased significantly as compared to that in the rats without chlorobenzene. Concomitant to the elevation in glutathione levels, hepatic glutathione synthesis activities were increased by the chlorobenzene by 68-111%. On the other hand, no significant difference between the rats with and without chlorobenzene was observed as regards cysteine levels at 24 h. Hepatic glutamate, glycine, methionine and serine levels were unaltered but hepatic taurine levels were significantly decreased by the chlorobenzene at both 6 and 24 h. Chlorobenzene administration had no effect on hepatic cystathionine synthase and cystathionase activities. These results indicate that a transient loss of hepatic glutathione, caused by the administration of chlorobenzene, resulted in an acceleration of glutathione synthesis and an increase of cysteine demand in the liver.
    背景与目标: :研究了氯苯诱导的谷胱甘肽水平改变对大鼠肝脏半胱氨酸代谢的影响。给雄性Wistar大鼠腹膜内注射氯苯(0.2、0.5、1.0或2.0mmol / kg体重)。注射后6小时,氯苯使肝谷胱甘肽和半胱氨酸水平均呈剂量依赖性降低。然而,在24小时时,与不含氯苯的大鼠相比,含氯苯的大鼠中的谷胱甘肽显着增加。伴随谷胱甘肽水平升高,氯苯使肝谷胱甘肽合成活性提高了68-111%。另一方面,在有和没有氯苯的大鼠之间,在24小时的半胱氨酸水平上没有观察到显着差异。肝谷氨酸,甘氨酸,蛋氨酸和丝氨酸水平未改变,但在6小时和24小时时,氯苯可显着降低肝牛磺酸水平。施用氯苯对肝脏胱硫醚合酶和胱硫醚酶活性没有影响。这些结果表明,由于施用氯苯而引起的肝性谷胱甘肽的瞬时损失导致了谷胱甘肽合成的加速和肝脏中半胱氨酸需求的增加。
  • 【低水平激光治疗对链脲佐菌素诱发的糖尿病大鼠骨缺损愈合的影响:组织学和形态计量学评估。】 复制标题 收藏 收藏
    DOI:10.1080/14764172.2017.1341048 复制DOI
    作者列表:Yildirimturk S,Sirin Y,Soluk Tekkesin M,Gurler G,Firat D
    BACKGROUND & AIMS: BACKGROUND:The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the healing of bone defects in rats with streptozotocin (STZ)-induced DM. METHODS:28 male Sprague-Dawley rats were used in this study. 14 animals received a single dose of STZ intraperitoneally (65 mg/kg) to induce Type I DM, whereas others were injected only with sterile saline solution. Four weeks later, standard bone defects were created in the tibiae of rats. Surgical wounds in one group from each of the diabetic and non-diabetic animals were irradiated with diode laser for every other day for 4 weeks and they were described as DM + LLLT and CONT + LLLT groups, respectively. Remaining two groups received no laser treatment. New bone formation, osteoblast and blood vessel counts were calculated in histologic sections. RESULTS:DM group had significantly smaller bone area and lower blood vessel count when compared to DM + LLLT, CONT and CONT + LLLT groups (p < 0.05 for each). CONT and CONT + LLLT groups had significantly larger bone area than DM + LLLT group (p < 0.05 for both). CONCLUSIONS:LLLT application promoted vascularization and new bone formation in animals with DM to a limited extent, since it was unable to support the healing process up to the level of non-diabetic animals.
    背景与目标: 背景:本研究的目的是评估低剂量激光疗法(LLLT)对链脲佐菌素(STZ)诱导的DM大鼠骨缺损愈合的作用。
    方法:采用28只雄性Sprague-Dawley大鼠。 14只动物腹膜内接受单剂STZ(65 mg / kg)诱导I型DM,而其他动物仅注射无菌盐溶液。四周后,在大鼠胫骨中形成了标准的骨缺损。每隔一天用二极管激光照射来自糖尿病和非糖尿病动物中每组的一组手术伤口,持续4周,分别称为DM LLLT组和CONT LLLT组。其余两组未接受激光治疗。在组织学切片中计算新的骨形成,成骨细胞和血管计数。
    结果:与DM LLLT,CONT和CONT LLLT组相比,DM组的骨面积显着更小,血管计数更低(每组p <0.05)。 CONT和CONT LLLT组的骨面积明显大于DM LLLT组(两者均p <0.05)。
    结论:LLLT的应用在一定程度上促进了DM动物的血管化和新骨形成,因为它不能支持非糖尿病动物的愈合过程。
  • 【手性识别多沙唑嗪对映体在3个靶标中的治疗作用以及在动物实验中的不良药物反应。】 复制标题 收藏 收藏
    DOI:10.1139/y2012-129 复制DOI
    作者列表:Zhao D,Duan LH,Wang FY,Wang M,Lu HG,Wu ZG,Wang X,Ren LM
    BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.
    背景与目标: :多沙唑嗪用于前列腺增生症具有引起低血压和心力衰竭风险的副作用。 α(1A)-肾上腺素受体(在前列腺中),α(1D)-肾上腺素受体(在主动脉中)和未知机制(在心脏中)的3个靶点分别涉及。我们假设在3个靶标中有手性识别多沙唑嗪对映体。使用分离的大鼠主动脉(α(1D)-肾上腺素受体)和兔前列腺(α(1A)-肾上腺素受体),我们检查了多沙唑嗪对映体的pA(2)和pK(B)值​​。我们观察到了多沙唑嗪对映异构体在离体大鼠和兔心脏组织中的变时性和变力作用。 (-)多沙唑嗪和()多沙唑嗪使去甲肾上腺素(主动脉)和去氧肾上腺素(前列腺平滑肌)的浓度-收缩曲线向右移动。大鼠主动脉中(-)恶唑烷的pA(2)值(8.625±0.053)小于()恶唑烷(9.503±0.051),但它们在兔前列腺中的pK(B)值​​相同。在大鼠和兔子的心脏组织中,()多沙唑嗪(3-30 µmol·L(-1))显着降低心房率,并产生负性变力作用;然而,(-)doxazosin不会影响心房率,并在心房产生正性肌力作用。因此,多沙唑嗪的手性碳原子不影响其对前列腺中α(1A)-肾上腺素受体治疗靶点的活性,但会显着改变其对主动脉中α(1D)-肾上腺素受体的阻断活性,并产生相反的正性肌力作用通过独立于α(1)-肾上腺素受体机制的心房。
  • 【药房中抗肿瘤药污染水平的常规环境监测的应用和评估-MEWIP项目。】 复制标题 收藏 收藏
    DOI:10.1093/annhyg/mes081 复制DOI
    作者列表:Kiffmeyer TK,Tuerk J,Hahn M,Stuetzer H,Hadtstein C,Heinemann A,Eickmann U
    BACKGROUND & AIMS: :A large-scale study was carried out in order to determine the contamination level of antineoplastic drugs in pharmacies and to investigate the suitability and effects of wipe sample monitoring at regular intervals. A specific study design was developed. The 130 participating pharmacies were divided into a study and a control group, carrying out five and two wipe sampling cycles, respectively. The work practice was analyzed using questionnaires to identify factors that influence the contamination level. From 1269 wipe samples, 774 (61%) were contaminated with at least one of the analyzed cytotoxic drugs: cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, and paclitaxel. A significant decrease of the contamination with cyclophosphamide and 5-fluorouracil was observed in the study group. The Monitoring-Effect Study of Wipe Sampling in Pharmacies method has proven to be a reliable and affordable tool for contamination control. Based on the 90th percentile of the contamination values, a substance-independent performance-based guidance value of 0.1ng cm(-2) has been derived.
    背景与目标: :进行了一项大规模研究,以确定药房中抗肿瘤药的污染水平,并定期调查擦拭样品监测的适用性和效果。开发了具体的研究设计。将130家参与活动的药店分为研究组和对照组,分别进行了5次和2次擦拭采样。使用调查表对工作实践进行了分析,以找出影响污染水平的因素。从1269个擦拭样品中,有774个(61%)被至少一种分析的细胞毒性药物污染:环磷酰胺,多西他赛,依托泊苷,5-氟尿嘧啶,吉西他滨,异环磷酰胺,甲氨蝶呤和紫杉醇。在研究组中观察到环磷酰胺和5-氟尿嘧啶的污染显着降低。药房擦拭采样的监测效果研究方法被证明是一种可靠且负担得起的污染控制工具。基于污染值的第90个百分位数,得出了与物质无关的基于性能的指导值0.1ng cm(-2)。
  • 【基于多孔二氧化硅纳米粒子的难溶性水飞蓟宾的72小时释放制剂:比格犬的体外释放动力学和体内/体外相关性。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejps.2012.10.012 复制DOI
    作者列表:Cao X,Deng W,Fu M,Zhu Y,Liu H,Wang L,Zeng J,Wei Y,Xu X,Yu J
    BACKGROUND & AIMS: :The objective of this study was to prepare a 72 h-release formulation of silybin (72 h-SLB) using a combination of solid dispersion, gel matrix and porous silica nanoparticles (PSNs) and to investigate the in vitro/in vivo correlations (IVIVCs). The results of scanning electron microscopy and N(2) adsorption demonstrated that empty PSNs possessed a spherical shape, a highly porous structure, a large specific surface area (385.89 ± 1.12 m(2)/g) and a small pore size (2.74 nm on average). The in vitro dissolution profiles of both 72 h-SLB and silybin-loaded PSNs in different concentrations (0.01, 0.06 and 0.08M) of Na(2)CO(3) solutions revealed that 0.06 M Na(2)CO(3) solution was the optimal medium in which silybin could be released from 72 h-SLB with first-order release kinetics and from PSNs with Higuchi kinetics. Furthermore, the IVIVCs of 72 h-SLB and silybin-loaded PSNs in beagle dogs were also established. Using 0.06 M Na(2)CO(3) solution as the in vitro dissolution medium, a good linear relationship could be achieved for both 72 h-SLB and silybin-loaded PSNs. The findings support the fact that the 72 h-SLB (consisting of solid dispersion, regular gel matrix and PSNs) together with Na(2)CO(3) solution as an in vitro dissolution medium can be developed into a promising formulation for poorly soluble drugs, which enjoys a good IVIVC.
    背景与目标: :这项研究的目的是使用固体分散体,凝胶基质和多孔二氧化硅纳米粒子(PSN)的组合制备水飞蓟宾(72 h-SLB)的72 h释放制剂,并研究体内/体外相关性( IVIVC)。扫描电子显微镜和N(2)吸附的结果表明,空的PSN具有球形,高度多孔的结构,较大的比表面积(385.89±1.12 m(2)/ g)和较小的孔径(2.74 nm)一般)。 Nah(2)CO(3)解决方案中不同浓度(0.01、0.06和0.08M)的72 h-SLB和水飞蓟宾加载的PSNs的体外溶出曲线显示0.06 M Na(2)CO(3)解决方案是最佳的培养基,其中水飞蓟宾可以从72 h-SLB中以一级释放动力学释放,而从PSN中以Higuchi动力学释放。此外,还建立了比格犬中72 h-SLB和水飞蓟宾的PSN的IVIVC。使用0.06 M Na(2)CO(3)解决方案作为体外溶出介质,可以为72 h-SLB和水飞蓟宾加载的PSNs都实现良好的线性关系。这些发现支持以下事实:72 h-SLB(由固体分散体,规则的凝胶基质和PSN组成)与Na(2)CO(3)解决方案一起作为体外溶出介质,可以开发为溶解性较差的有前途的制剂药物,享有良好的IVIVC。
  • 【包容性学前班教室在活动水平上的感官加工策略的有效性。】 复制标题 收藏 收藏
    DOI:10.2147/NDT.S37146 复制DOI
    作者列表:Lin CL,Min YF,Chou LW,Lin CK
    BACKGROUND & AIMS: BACKGROUND:The purpose of this study was to investigate the effectiveness of sensory processing strategies in improving the activity level of children with sensory integration dysfunction. METHODS:The study used a matching-only pretest-posttest control group design, which requires random matching of sensory integration dysfunction to the corresponding intervention group (n = 18) and control group (n = 18). The intervention group comprised 3-6-year-old children who received an 8-week school-day intervention during implementation of the theme curriculum. RESULTS:The 8-week treatment significantly reduced the activity level and foot-swinging episodes in children with sensory integration dysfunction, and obtained a medium-effect size. However, the level of improvement in the control group did not show any statistically significant change. CONCLUSION:Sensory processing strategies could improve activity levels in children with sensory integration dysfunction. However, this study was unable to exclude a developmental effect. The social validity results show that sensory processing strategies can be integrated into the theme curriculum and improve activity levels in children.
    背景与目标: 摘要背景:本研究的目的是探讨感觉处理策略在改善感觉统合功能障碍儿童活动水平方面的有效性。
    方法:本研究使用仅匹配的前测-后测对照组设计,该设计要求将感觉统合功能障碍随机匹配至相应的干预组(n = 18)和对照组(n = 18)。干预小组由3-6岁的儿童组成,他们在实施主题课程期间接受了为期8周的上学日干预。
    结果:为期8周的治疗显着降低了感觉统合功能障碍儿童的活动水平和摆动脚步发作,并获得了中等程度的效果。但是,对照组的改善水平没有显示任何统计学上的显着变化。
    结论:感觉处理策略可以提高感觉统合功能障碍儿童的活动水平。但是,这项研究无法排除发育的影响。社会有效性的结果表明,可以将感官加工策略整合到主题课程中,并提高儿童的活动水平。
  • 【在晚期前列腺癌的早期药物开发中测试生物学假设的新策略。】 复制标题 收藏 收藏
    DOI:10.1373/clinchem.2012.185157 复制DOI
    作者列表:Ferraldeschi R,Attard G,de Bono JS
    BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.
    背景与目标: 背景:我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌(CRPC)治疗的新时代,最近5年中有5种新药显示出生存优势,并且数量惊人的有希望的新型药物进入临床。
    内容:我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略,不仅着眼于预测性和中间终点生物标志物的开发,还着重于新的假设检验,生物标志物驱动的临床试验设计。
    简介:随着一些有前途的药物进入临床,对CRPC进行药物开发的重新思考的压力越来越大,以确保对新型药物进行适当评估,并适当分配患者和资源。我们设想,通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试,生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。
  • 【肌萎缩性侧索硬化症:从板凳到床边的药物治疗。】 复制标题 收藏 收藏
    DOI:10.1055/s-0032-1329193 复制DOI
    作者列表:Gibson SB,Bromberg MB
    BACKGROUND & AIMS: :Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.
    背景与目标: 肌萎缩性侧索硬化症(ALS)是一种持续不断的进行性神经退行性疾病,会导致进行性无力,最终导致死亡。尽管进行了积极的研究,导致神经元死亡的途径仍未完全了解。利鲁唑是临床上唯一被证明可提高ALS患者生存率的药物,但其作用机理尚不清楚。在本文中,对ALS的拟议病理生理进行了综述,包括谷氨酸兴奋性毒性,氧化应激,线粒体功能障碍,自身免疫机制,蛋白质聚集,SOD1积累和神经元死亡。基于这些机制,将回顾过去的主要ALS药物研究以及有前途的当前ALS药物研究,重点是这些研究从实验台到患者床边的进展。
  • 【重复基因家族成员的高水平转录赋予了植物油菜的愈伤组织脱水耐受性。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.12.3599 复制DOI
    作者列表:Furini A,Koncz C,Salamini F,Bartels D
    BACKGROUND & AIMS: An experimental system has been developed which allows the identification of intermediates in the abscisic acid (ABA) signal transduction pathway leading to desiccation tolerance in plants. Desiccation tolerance in callus of the resurrection plant Craterostigma plantagineum is mediated via the plant hormone ABA, which induces the expression of gene products related to desiccation tolerance. Based on T-DNA activation tagging, a gene (CDT-1) was isolated which encodes a signalling molecule in the ABA transduction pathway. Constitutive overexpression of CDT-1 leads to desiccation tolerance in the absence of ABA and to the constitutive expression of characteristic transcripts. CDT-1 represents a novel gene with unusual features in its primary sequence. The CDT-1 gene resembles in several features SINE retrotransposons. Mechanisms by which CDT-1 activates the pathway could be via a regulatory RNA or via a short polypeptide.

    背景与目标: 已经开发了一种实验系统,该系统允许鉴定脱落酸(ABA)信号转导途径中的中间体,导致植物中的脱水耐受性。复活植物Craterostigma plantagineum愈伤组织中的干燥耐性是通过植物激素ABA介导的,ABA诱导了与干燥耐性有关的基因产物的表达。基于T-DNA激活标记,分离了一个基因(CDT-1),该基因在ABA转导途径中编码一个信号分子。 CDT-1的组成型过表达会导致在不存在ABA的情况下产生脱水耐受性,并导致特征性转录本的组成型表达。 CDT-1代表一个在其主要序列中具有异常特征的新基因。 CDT-1基因在几个特征上类似于SINE逆转座子。 CDT-1激活该途径的机制可能是通过调控RNA或通过短多肽。

  • 【HBV药物恩替卡韦-对HIV-1复制和耐药性有影响。】 复制标题 收藏 收藏
    DOI:10.1056/NEJMoa067710 复制DOI
    作者列表:McMahon MA,Jilek BL,Brennan TP,Shen L,Zhou Y,Wind-Rotolo M,Xing S,Bhat S,Hale B,Hegarty R,Chong CR,Liu JO,Siliciano RF,Thio CL
    BACKGROUND & AIMS: :Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.
    背景与目标: :恩替卡韦是食品和药物管理局批准用于治疗慢性乙型肝炎病毒(HBV)感染的药物,但据信在临床相关剂量下它不会抑制1型人类免疫缺陷病毒(HIV-1)的复制。我们观察到恩替卡韦导致三名患有HIV-1和HBV合并感染的人的HIV-1 RNA持续1-log(10)降低,并且我们获得了支持性的体外证据,证明恩替卡韦是HIV-1复制的有效部分抑制剂。详细的分析表明,在其中一名患者中,恩替卡韦单药治疗导致带有拉米夫定耐药突变M184V的HIV-1变异的积累。体外实验表明,M184V赋予了对恩替卡韦的抗药性。直到人们对恩替卡韦对HIV-1耐药性的模式及其选择有了更多的了解之前,在尚未接受完全抑制性抗逆转录病毒疗法的HIV-1和HBV合并感染者中使用恩替卡韦是需要谨慎的。

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