BACKGROUND & AIMS: :Type III protein secretion systems, which are organelles with the capacity to deliver bacterial proteins into host cells, have been adapted to deliver heterologous antigens for vaccine development. A limitation of these antigen delivery systems is that some proteins are not amenable to secretion through this pathway. We show here that proteins from the simian and human immunodeficiency viruses that are not permissive for secretion through a Salmonella enterica serovar Typhimurium type III secretion system can be modified to travel this secretion pathway by introduction of discrete mutations. Proteins optimized for secretion were presented more efficiently via the major histocompatibility complex class I pathway and were able to induce a better immune response.

背景与目标： ：III型蛋白质分泌系统具有细胞器的能力，能够将细菌蛋白质传递到宿主细胞中，已经适应于传递异源抗原用于疫苗开发。这些抗原递送系统的局限性是某些蛋白质不适合通过该途径分泌。我们在这里表明，猿猴和人类免疫缺陷病毒不允许通过沙门氏菌肠炎血清型鼠伤寒III型分泌系统分泌的蛋白质可以通过引入离散突变而被修饰为通过这种分泌途径。通过主要的组织相容性复合体I类途径可以更有效地表达针对分泌优化的蛋白质，并且能够诱导更好的免疫反应。

BACKGROUND & AIMS: :Synaptotagmin (Syt) VII is a ubiquitously expressed member of the Syt family of Ca2+ sensors. It is present on lysosomes in several cell types, where it regulates Ca2+-dependent exocytosis. Because [Ca2+]i and exocytosis have been associated with phagocytosis, we investigated the phagocytic ability of macrophages from Syt VII-/- mice. Syt VII-/- macrophages phagocytose normally at low particle/cell ratios but show a progressive inhibition in particle uptake under high load conditions. Complementation with Syt VII rescues this phenotype, but only when functional Ca2+-binding sites are retained. Reinforcing a role for Syt VII in Ca2+-dependent phagocytosis, particle uptake in Syt VII-/- macrophages is significantly less dependent on [Ca2+]i. Syt VII is concentrated on peripheral domains of lysosomal compartments, from where it is recruited to nascent phagosomes. Syt VII recruitment is rapidly followed by the delivery of Lamp1 to phagosomes, a process that is inhibited in Syt VII-/- macrophages. Thus, Syt VII regulates the Ca2+-dependent mobilization of lysosomes as a supplemental source of membrane during phagocytosis.

背景与目标： ：Synaptotagmin（Syt）VII是Syt Ca2传感器家族中一个普遍表达的成员。它存在于几种细胞类型的溶酶体中，在那里它调节依赖Ca2的胞吐作用。因为[Ca2] i和胞吐作用与吞噬作用有关，所以我们研究了Syt VII-/-小鼠巨噬细胞的吞噬能力。 Syt VII-/-巨噬细胞通常以低颗粒/细胞比例吞噬细胞，但在高负荷条件下显示出对颗粒摄取的逐步抑制作用。与Syt VII互补可挽救该表型，但仅当保留功能性Ca2结合位点时才可。为了增强Syt VII在Ca2依赖性吞噬作用中的作用，Syt VII-/-巨噬细胞中的颗粒摄取对[Ca2] i的依赖性明显降低。 Syt VII集中在溶酶体区室的外围区域，从那里募集到新生的吞噬体。 Syt VII募集后迅速将Lamp1递送至吞噬体，这一过程在Syt VII-/-巨噬细胞中受到抑制。因此，Syt VII调节溶酶体的Ca2依赖性动员，作为吞噬作用期间膜的补充来源。

BACKGROUND & AIMS: Our aim was to determine the effects of 12 h of hypoxaemia on cerebral blood flow (CBF) and cerebral O2 delivery in ovine fetuses at 0.6 gestation. During fetal hypoxaemia, induced by reduced uterine blood flow, fetal SaO2 and PaO2 were reduced (p < 0.01) from control values of 77.0 +/- 1.6% and 27.3 +/- 1.0 mm Hg, respectively, to 28.4 +/- 3.4% and 15.6 +/- 0.6 mm Hg; fetal pHa decreased from control values of 7.37 +/- 0.01 to 7.20 +/- 0.02 at 3 h, but returned to control values before 12 h. CBF (ml/min/100 g) was 2.0- to 2.6-fold higher (p < 0.01) than control values during hypoxaemia, but only 1.7-fold higher (p < 0.01) at 3 h when pHa was lowest. Cerebral O2 delivery (ml/min/100 g) was lower (p < 0.01) than control values of 3.15 +/- 0.29 at 1.5h (2.09 +/- 0.36) and 3h (1.84 +/- 0.22) of hypoxaemia and higher 1 h after hypoxaemia had ceased (3.81 +/- 0.22, p < 0.01). We conclude that the ovine fetus at 0.6 gestation is unable to sustain increased CBF and hence maintain cerebral O2 delivery during the first 6 h of hypoxaemia, a time which coincides with acidaemia; in contrast, at 6 and 12 h of hypoxaemia, when pHa was normal, cerebral O2 delivery was similar to control values. Reduced cerebral O2 delivery during the early, acidaemic, stages of hypoxaemia may lead to impaired neural development.

背景与目标： 我们的目的是确定低氧血症12 h对0.6胎的绵羊胎儿脑血流量（CBF）和脑O2输送的影响。在因子宫血流量减少而引起的胎儿低氧血症期间，胎儿的SaO2和PaO2从对照值分别从控制值77.0 /-1.6％和27.3 /-1.0 mm Hg降低（p <0.01）分别降至28.4 /-3.4％和15.6 / -0.6毫米汞柱;胎儿pHa在3 h时从7.37 /-0.01的控制值降低到7.20 /-0.02，但在12 h之前恢复到控制值。低氧血症期间的CBF（ml / min / 100 g）比对照值高2.0到2.6倍（p <0.01），但在pHa最低的3 h时，CBF仅高1.7倍（p <0.01）。低氧血症1.5小时（2.09 /-0.36）和低氧血症3小时（1.84 /-0.22）时，脑氧输送量（ml / min / 100 g）低于（3.15 /-0.29）对照值（p <0.01），高于1小时后的对照值（p <0.01）低氧血症已经停止（3.81 / 0.22，p <0.01）。我们得出的结论是，妊娠期为0.6的绵羊胎儿不能维持增加的CBF，因此在低氧血症的前6小时（与酸血症相吻合的时间）内不能维持脑氧的输送。相反，在低氧血症的6小时和12小时，当pHa正常时，脑中O2的输送与对照值相似。低氧血症早期，酸性血症阶段的大脑O2输送减少可能导致神经发育受损。

BACKGROUND & AIMS: :Oxygen therapy can be life-saving for patients with chronic obstructive pulmonary disease (COPD) and is the backbone of any acute COPD treatment strategy. Although largely considered to be a benign drug, many publications have highlighted the need to accurately adjust oxygen delivery to avoid both hypoxemia and the problem of hyperoxia-induced hypercapnia. Recent clinical data have shown that the deleterious effects of excess oxygen treatment can not only alter carbon dioxide levels (which has been known for more than 60 years) but can also lead to an increase in mortality. Nevertheless, despite the extensive literature, the risks associated with hyperoxia are often overlooked and published clinical recommendations are largely ignored. This failure in knowledge translation has become increasingly important not only because of the desire to reduce medical error, but in a society with limited health care resources, the economic burden of COPD is such that it cannot afford to make preventable medical mistakes. Recently, novel devices have been developed to automatically adjust oxygen flow rates to maintain stable oxygen saturations. These closed-loop oxygen delivery systems have the potential to reduce medical error, improve morbidity and mortality, and reduce health care costs. Preliminary data in this field are promising and will require a significant amount of research in the coming years to determine the precise indications for these systems. The importance of appropriate oxygen dosing and the current literature regarding novel oxygen delivery systems are reviewed.

背景与目标： ：氧气疗法可挽救慢性阻塞性肺疾病（COPD）患者的生命，并且是任何急性COPD治疗策略的骨干。尽管在很大程度上被认为是一种良性药物，但许多出版物都强调了准确调整氧气输送量的必要性，以避免低氧血症和高氧血症引起的高碳酸血症的问题。最近的临床数据表明，过量氧气处理的有害作用不仅会改变二氧化碳水平（已知水平已超过60年），而且还会导致死亡率增加。尽管如此，尽管有大量文献报道，但与高氧有关的风险常常被忽视，已发表的临床建议在很大程度上被忽略。知识翻译的这种失败变得越来越重要，这不仅是因为希望减少医疗错误，而且在医疗资源有限的社会中，COPD的经济负担使得它无法承担可预防的医疗错误。最近，已开发出新颖的装置来自动调节氧气流速以维持稳定的氧气饱和度。这些闭环氧气输送系统具有减少医疗错误，改善发病率和死亡率以及降低医疗保健成本的潜力。该领域的初步数据是有希望的，并且在未来几年中需要大量研究才能确定这些系统的确切适应症。适当的氧气剂量的重要性和有关新型氧气输送系统的当前文献进行了审查。

BACKGROUND & AIMS: :A major traditional of antibacterial drugs is antibiotic which promotes more rapid release of the toxins from bacteria cells in human body, which causes severe infection. The thermostable direct hemolysin (TDH) has been proposed as a major virulence factor of Vibrio parahaemolyticus (Vp). This study covers the preparation of polymer microparticle-antibody conjugate for the development of a drug targeting approach for antibacterial drug delivery. The chemical binding of antibodies (ab) to latex bead of 0.2 mum diameter was performed by using a water-soluble carbodiimide technique. Confocal microscopy revealed that the bacteria were strongly absorbed by the latex beads with bound anti-Vp polyclonal antibody (pAb). Treatment with a latex bead bound both anti-Vp pAb and anti-TDH monoclonal antibody (mAb) significantly inhibited bacterial adherence to the Caco-2 cells (p < 0.01), and reduced TDH-induced cytotoxicity in histology. These preliminary results suggest that it may be possible to effectively protect against Vp infection by using this microparticle-antibody conjugate delivery system.

背景与目标： ：抗菌的主要传统药物是抗生素，可促进毒素从人体细菌细胞中更快释放出来，从而引起严重感染。已提出将热稳定的直接溶血素（TDH）作为副溶血性弧菌（Vp）的主要毒力因子。这项研究涵盖了聚合物微粒-抗体缀合物的制备，以开发用于抗菌药物递送的药物靶向方法。通过使用水溶性碳二亚胺技术进行抗体（ab）与0.2微米直径的乳胶珠的化学结合。共聚焦显微镜显示细菌与结合的抗Vp多克隆抗体（pAb）一起被乳胶珠强烈吸收。用结合抗Vp pAb和抗TDH单克隆抗体（mAb）的乳胶珠处理可显着抑制细菌对Caco-2细胞的粘附（p <0.01），并减少组织学中TDH诱导的细胞毒性。这些初步结果表明，通过使用这种微粒抗体结合物递送系统，可以有效地预防Vp感染。

BACKGROUND & AIMS: PURPOSE:Tear film can be altered by chronic medications that may disrupt the equilibrium responsible for the functioning of the lacrimal gland and ocular surface. The purpose of this study was to determine if antiglaucomatous chronic treatment induced alterations in the tear film and ocular surface. METHODS:After informed consent, 21 patients using antiglaucomatous eye drops for more than 8 months and 20 age- and sex-matched volunteers without eye and systemic medications (control group) were enrolled. The data of ocular discomfort, fluorescein and lisamine green staining, tear film break-up time and Schirmer test were collected and compared by Student's t test. The impression cytology data were graded and compared by chi-square test. RESULTS:Patients chronically using antiglaucomatous medications presented with significant higher fluorescein staining (p=0.003), lisamine green staining (p=0.02) and lower TFBUT (p=0.001). The other compared parameters, including impression cytology were similar between the treated and control group (p>0.05). CONCLUSIONS:The present study shows that the tear film and the ocular surface are altered in patients under antiglaucomatous medications. In common, all medications were preserved with benzalkonium chloride. Efforts to minimize the adverse effects of chronic use of antiglaucomatous drugs must be addressed.

背景与目标： 目的：长期用药可能会改变泪膜，这可能会破坏负责泪腺和眼表功能的平衡。这项研究的目的是确定抗青光眼的慢性治疗是否引起泪膜和眼表的改变。
方法：征得知情同意后，招募了21例使用抗青光眼滴眼液超过8个月的患者和20名年龄和性别相匹配的无眼和全身药物的志愿者（对照组）。收集眼部不适，荧光素和赖氨酰胺绿染色，泪膜破裂时间和Schirmer试验的数据，并通过Student's t检验进行比较。对印象细胞学数据进行分级并通过卡方检验进行比较。
结果：长期使用抗青光眼药物的患者表现出较高的荧光素染色（p = 0.003），赖氨胺绿染色（p = 0.02）和较低的TFBUT（p = 0.001）。在治疗组和对照组之间，其他比较参数（包括印象细胞学）相似（p> 0.05）。
结论：本研究表明，在接受抗青光眼治疗的患者中，泪膜和眼表发生了改变。通常，所有药物均使用苯扎氯铵保存。必须努力减少长期使用抗青光眼药物的不良影响。

BACKGROUND & AIMS: :Prior infection has primed most adult humans for a rapid neutralizing antibody (NAb) response when re-exposed to adenovirus. NAb induction can severely limit the efficacy of systemic re-administration of adenoviral gene therapy. We hypothesized that changing the fiber knob could overcome NAb. Immune-competent mice were exposed to serotype 5 adenovirus (Ad5)(GL), Ad5/3luc1, Ad5lucRGD or Ad5pK7(GL). Mice immunized with Ad5(GL) featured reduced intravenous Ad5(GL) gene transfer to most organs, including the liver, lung and spleen. Ad5(GL) gene transfer was affected much less by exposure to capsid-modified viruses. Anti-Ad5(GL) NAb blocked intravenous Ad5(GL) gene transfer to orthotopic lung cancer xenografts, whereas capsid-modified viruses were not affected. When gene transfer to fresh cancer and normal lung explants was analyzed, we found that capsid-modified viruses allowed effective gene delivery to tumors in the presence of anti-Ad5(GL) NAb, whereas Ad5(GL) was blocked. In contrast, crossblocking by NAbs induced by different viruses affected gene delivery to normal human lung explants, suggesting the importance of non-fiber-knob-mediated infection mechanisms. We conclude that changing the adenovirus fiber knob is sufficient to allow a relative degree of escape from preexisting NAb. If confirmed in trials, this approach might improve the efficacy of re-administration of adenoviral gene therapy to humans.

背景与目标： ：先前的感染已使大多数成年人类重新暴露于腺病毒后就具有快速中和抗体（NAb）的反应。 NAb的诱导会严重限制腺病毒基因治疗的全身性重新给药的疗效。我们假设改变光纤旋钮可以克服NAb。将具有免疫能力的小鼠暴露于血清型5腺病毒（Ad5）（GL），Ad5 / 3luc1，Ad5lucRGD或Ad5pK7（GL）。用Ad5（GL）免疫的小鼠的静脉内Ad5（GL）基因转移到大多数器官，包括肝脏，肺脏和脾脏的功能降低。暴露于衣壳修饰的病毒对Ad5（GL）基因转移的影响要小得多。抗Ad5（GL）NAb阻断了静脉内Ad5（GL）基因向原位肺癌异种移植的转移，而衣壳修饰的病毒则不受影响。当分析基因转移到新鲜癌症和正常肺外植体时，我们发现衣壳修饰的病毒可以在存在抗Ad5（GL）NAb的情况下有效地将基因传递给肿瘤，而Ad5（GL）被阻断。相反，由不同病毒诱导的NAb交叉阻断影响了基因向正常人肺外植体的传递，这表明非纤维旋钮介导的感染机制的重要性。我们得出的结论是，改变腺病毒纤维瘤足以使相对存在的NAb逃逸程度。如果在试验中得到证实，这种方法可能会提高腺病毒基因疗法对人类的重新给药效果。

BACKGROUND & AIMS: BACKGROUND:Recently, we reported that sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. METHODS AND RESULTS:Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls (P<0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca(2+) release, and increased diastolic Ca(2+) (P<0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control (P<0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both V(m) alternans and Ca alternans compared with controls (P<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function (P<0.01), suppressed cardiac alternans (P<0.01), and reduced ryanodine receptor 2 P(o) secondary to reduction of ryanodine receptor 2-P(S2814) (P<0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias (P=0.05). CONCLUSIONS:These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca(2+) leak).

背景与目标： 背景：最近，我们报告肌浆网Ca（2）ATPase 2a（SERCA2a），负责舒张期期间细胞内钙的再摄取的泵，在心脏交替分子的分子机制中起着核心作用。心力衰竭（HF）与心肌钙处理受损，SERCA2a不足以及对心脏交替素的敏感性增加有关。因此，我们假设通过基因转移恢复有缺陷的SERCA2a将显着减少衰竭心脏中的致心律失常性心脏交替链。
方法与结果：成年豚鼠分为3组：对照组，HF和HF AAV9.SERCA2a基因转移。与对照组相比，HF导致左心室缩短缩短的减少（P <0.001）。如预期的那样，与对照组相比，孤立的HF心肌细胞显示出较慢的肌质网钙摄取，减少的Ca（2）释放和增加的舒张期Ca（2）（P <0.05）。此外，与对照组相比，HF患者的SERCA2a，心脏ryanodine受体2和钠钙交换蛋白表达降低（P <0.05）。正如预测的那样，HF对心脏交替素的敏感性增加，与对照组相比，V（m）交替素和Ca交替素的心率阈值降低证明了这一点（P <0.01）。有趣的是，在衰竭心脏中，AAV9.SERCA2a的体内基因转移改善了左心室收缩功能（P <0.01），抑制了心脏交替素（P <0.01），并降低了瑞丹碱受体2继而降低了瑞丹碱受体2 P（o）。 -P（S2814）（P ＜0.01）。这最终导致可诱发的室性心律失常的发生率降低（P = 0.05）。
结论：这些数据表明，SERCA2a基因在衰竭心脏中的转移不仅改善了收缩功能，而且还通过改善关键的心律失常性底物（即心脏交替神经）和触发因素（即肌浆网Ca（2）泄漏）直接恢复了电稳定性。 。

BACKGROUND & AIMS: PURPOSE:To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y-27632, in animal eyes. METHODS:Y-39983 was compared with Y-27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y-39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y-39983 were observed in albino rabbits and cynomolgus monkeys. RESULTS:A biochemical assay showed that Y-39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y-39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg (mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y-39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals). CONCLUSIONS:Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.

背景与目标： 目的：为了阐明动物眼中Y-39983（一种选自R-27632的选择性Rho相关的卷曲螺旋形成蛋白激酶（ROCK）抑制剂）Y-39983的降低眼内压（IOP）的作用和相关特征。
方法：通过生化分析比较Y-39983和Y-27632对ROCK的选择性。通过肺气量计在局部给予Y-39983的白化兔和食蟹猴中监测IOP。在白化兔中局部施用Y-39983后2小时，分别通过两级恒压灌注和灌注技术使用异硫氰酸荧光素-右旋糖酐测量总流出设施和葡萄膜巩膜流出。在白化病兔和食蟹猴中观察到局部施用Y-39983的眼部毒理作用。
结果：生化分析表明，Y-39983比ROCK-Y-27632对ROCK的抑制作用更强。在兔子中，局部施用Y-39983可将常规流出量显着增加65.5％，然后是IOP的剂量依赖性显着降低。在0.1％的Y-39983中，兔子的最大IOP降低为13.2 /-0.6毫米汞柱（平均/-SE）。在猴子中，局部给药0.05％Y-39983后3小时，IOP的最大降低为2.5±0.8 mm Hg。在兔子或猴子中，一天四次（以2小时为间隔）每天四次Y-39983长期局部给药期间，偶发性点状结膜下出血除外，在眼组织中未观察到严重的副作用。但是，每日两次（每隔6小时）或每天三次（每隔5小时）给药未观察到点状结膜下出血。
结论：Y-39983引起流出设施增加，随后IOP降低。 Y-39983眼用溶液剂可能是降低IOP的候选药物，因为它增加了常规流出量并且产生了相对较少的副作用。

BACKGROUND & AIMS: :Biocompatible and biodegradable pH-responsive hydrogels based on N-vinyl pyrrolidone (NVP), polyethylene glycol diacrylate (PAC) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a free radical polymerization technique using azobisisobutyronitrile (AIBN) as initiator and N,N'-methylenebisacrylamide (BIS) as crosslinker. These hydrogels were subjected to equilibrium swelling studies in enzyme-free simulated gastric and intestinal fluids (SGF and SIF). These swelling studies clearly indicated that these hydrogels were swollen more in SGF when compared to SIF. Theophylline and 5-fluorouracil (5-FU) were entrapped into these hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels in enzyme-free SGF and SIF. The in-vitro release profiles of the drugs were established in enzyme-free SGF. More than 50% of the entrapped drugs were released in the first 2 h at gastric pH and the rest of the drug release was slower.

背景与目标： ：制备了基于N-乙烯基吡咯烷酮（NVP），聚乙二醇二丙烯酸酯（PAC）和壳聚糖的生物相容性和可生物降解的pH响应水凝胶，以控制药物的递送。这些共聚水凝胶是通过自由基聚合技术使用偶氮二异丁腈（AIBN）作为引发剂和N，N'-亚甲基双丙烯酰胺（BIS）作为交联剂合成的。这些水凝胶在不含酶的模拟胃液和肠液（SGF和SIF）中进行了平衡溶胀研究。这些溶胀研究清楚地表明，与SIF相比，这些水凝胶在SGF中的溶胀程度更高。将茶碱和5-氟尿嘧啶（5-FU）截留在这些水凝胶中，并在无酶的SGF和SIF中对截留药物的凝胶进行了平衡溶胀研究。在无酶的SGF中建立了药物的体外释放曲线。在头2小时内，在胃液pH值下，超过50％的截留药物被释放，而其余药物的释放则较慢。

BACKGROUND & AIMS: PURPOSE:To report a new ocular manifestation of the dup22q11 syndrome and explore involved genes that may offer insight to mechanisms of pathogenesis. DESIGN:Case series. PARTICIPANTS:Two male patients with this syndrome diagnosed with dup22q11.2. METHODS:Medical records were reviewed. Duplication was detected in the oligo-single nucleotide polymorphism chromosomal microarray and duplicated genes within the segment where determined by literature and database review. Potential associations between the ophthalmologic manifestations and their physiopathology were investigated. MAIN OUTCOME MEASURES:Microarray results and identification of candidate genes within the duplicated segment. RESULTS:Our patients demonstrate previously unreported findings of dup22q11.2, including Marcus Gunn jaw winking, Duane's retraction syndrome, and other abnormal eye movements consistent with a congenital cranial dysinnervation disorder (CCDD), retinal vascular tortuosity, and primary infantile glaucoma. The duplicated segment in case 1 includes SNAP29, which could be linked with the development of retinal vascular tortuosity, and MAPK1, which seems to play a role in axonal development through the semaphorin pathway, which may serve as a candidate gene for CCDD. In case 2, the CLDN5 gene is within the duplicated segment. CLDN5 could be involved in the pathophysiology of glaucoma. CONCLUSIONS:Our cases expand the ocular phenotype for duplication of 22q11 and serve to identify potential candidate genes for the development of CCDD, retinal vascular tortuosity, and glaucoma.

背景与目标： 目的：报告dup22q11综合征的一种新的眼部表现，并探索可能为发病机理提供洞察力的相关基因。
设计：案例系列。
对象：两名患有此综合征的男性患者，被诊断出患有dup22q11.2。
方法：对病历进行回顾。在寡-单核苷酸多态性染色体微阵列中检测到重复，并通过文献和数据库综述确定了该片段内的重复基因。研究了眼科表现与其生理病理之间的潜在关联。
主要观察指标：芯片结果和重复片段内候选基因的鉴定。
结果：我们的患者证明了dup22q11.2以前未报告的发现，包括Marcus Gunn下颌眨眼，Duane的回缩综合征以及其他与先天性颅神经失调症（CCDD），视网膜血管曲折和原发性婴儿青光眼一致的异常眼球运动。案例1中的重复片段包括SNAP29（可能与视网膜血管曲折的发展有关）和MAPK1（似乎通过信号灯途径在轴突发育中起作用），它可能是CCDD的候选基因。在情况2中，CLDN5基因在重复的片段内。 CLDN5可能与青光眼的病理生理有关。
结论：我们的病例扩大了眼表型以重复22q11，并有助于确定潜在的候选基因，以发展CCDD，视网膜血管曲折和青光眼。

BACKGROUND & AIMS: :Oleanolic acid is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance the solubility and oral bioavailability of oleanolic acid. The formulation design was optimized by solubility assay, compatibility tests, and pseudoternary phase diagrams. The morphology, droplet size distribution, zeta potential, viscosity, electrical conductivity, and refractive index of a SMEDDS loaded with oleanolic acid were studied in detail. Compared with oleanolic acid solution, the in vitro release of oleanolic acid from SMEDDS showed that the drug could be released in a sustained manner. A highly selective and sensitive high-performance liquid chromatographymass spectrometry method was developed for determination of oleanolic acid in rat plasma. This method was used for a pharmacokinetic study of an oleanolic acid-loaded SMEDDS compared with the conventional tablet in rats. Promisingly, a 5.07-fold increase in oral bioavailability of oleanolic acid was achieved for the SMEDDS compared with the marketed product in tablet form. Our studies illustrate the potential use of a SMEDDS for delivery of oleanolic acid via the oral route.

背景与目标： ：齐墩果酸是水溶性差的药物，口服生物利用度低。为了增强齐墩果酸的溶解度和口服生物利用度，已经开发了一种自微乳化药物递送系统（SMEDDS）。通过溶解度测定，相容性测试和拟三元相图对制剂设计进行了优化。详细研究了负载齐墩果酸的SMEDDS的形貌，液滴尺寸分布，ζ电位，粘度，电导率和折射率。与齐墩果酸溶液相比，体外从SMEDDS释放齐墩果酸表明该药物可以持续释放。建立了一种高选择性，灵敏的高效液相色谱质谱法，用于测定大鼠血浆中的齐墩果酸。与常规片剂相比，该方法用于大鼠中富含齐墩果酸的SMEDDS的药代动力学研究。令人信服的是，与市售的片剂形式相比，SMEDDS的齐墩果酸口服生物利用度提高了5.07倍。我们的研究说明了SMEDDS通过口服途径输送齐墩果酸的潜在用途。

BACKGROUND & AIMS: :The event rates up to 1 year after insertion of a Copper-T IUD were compared in 76 women who had 1 or more cesarean sections, and were given their IUD immediately after medical termination of pregnancy, and in 76 women matched for age and parity but normal vaginal deliveries. The cesarean group had abortion performed under general anesthesia; the vaginal group had iv diazepam and paracervical block. All subjects were less than 11 weeks gestation. They were followed up at 7 days, 6 weeks, and 3 monthly intervals for 1 year. No perforations or pregnancies occurred. Incomplete abortion caused expulsion in 2.6% of women in both groups, and removal in 6.5 and 5.3%, in the cesarean and control groups respectively, and was responsible for most discontinuations. It was concluded that IUD insertion is safe after medical termination of pregnancy in women with a history of cesarean section, depending on the skill of the surgeon.

背景与目标： ：比较了76例剖宫产为1例或以上并在妊娠医学终止后立即给予宫内节育器的女性以及76例年龄和均等的女性，比较了插入Copper-T宫内节育器后一年的事件发生率但正常的阴道分娩。剖宫产组在全身麻醉下进行了流产。阴道组有静脉地西epa和宫颈旁阻滞。所有受试者的妊娠均少于11周。他们以7天，6周和3个月的间隔进行随访，为期1年。没有发生穿孔或怀孕。不完全流产导致剖宫产组和对照组分别有2.6％的女性被驱逐，剖宫产和对照组的女性分别被驱逐出6.5％和5.3％，这是大多数中断治疗的原因。结论是，对有剖宫产史的妇女，在医学上终止妊娠后，宫内节育器的插入是安全的，这取决于外科医生的技能。

BACKGROUND & AIMS: :The 5-year mortality rate for heart failure borders on 50%. The main cause is an ischaemic cardiac event where blood supply to the tissue is lost and cell death occurs. Over time, this damage spreads and the heart is no longer able to pump efficiently. Increasing vascularisation of the affected area has been shown to reduce patient symptoms. The growth factors required to do this have short half-lives making development of an efficacious therapy difficult. Herein, the angiogenic growth factor Vascular Endothelial Growth Factor (VEGF) is complexed electrostatically with star-shaped or linear polyglutamic acid (PGA) polypeptides. Optimised PGA-VEGF nanomedicines provide VEGF encapsulation of > 99% and facilitate sustained release of VEGF for up to 28 days in vitro. The star-PGA-VEGF nanomedicines are loaded into a percutaneous delivery compliant hyaluronic acid hydrogel. Sustained release of VEGF from the composite nano-in-gel system is evident for up to 35 days and the released VEGF has comparable bioactivity to free, fresh VEGF when tested on both Matrigel® and scratch assays. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. Therefore, we report the development of novel, self-assembling PGA-VEGF nanomedicines and their incorporation into a hyaluronic acid hydrogel that is compatible with medical devices to enable minimally invasive delivery to the heart. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. This formulation provides the basis for optimal spatiotemporal delivery of an angiogenic growth factor to the ischaemic myocardium.

背景与目标： ：心力衰竭的5年死亡率接近50％。主要原因是缺血性心脏事件，其中组织的血液供应丢失并发生细胞死亡。随着时间的流逝，这种损害会蔓延开来，心脏将不再能够有效地进行抽动。已显示增加患处的血管形成可减轻患者症状。为此所需的生长因子具有短的半衰期，使得难以开发有效的疗法。在本文中，血管生成生长因子血管内皮生长因子（VEGF）与星形或线性聚谷氨酸（PGA）多肽静电复合。优化的PGA-VEGF纳米药物可提供> 99％的VEGF封装，并促进VEGF在体外长达28天的持续释放。将星形-PGA-VEGF纳米药物加载到经皮递送顺应性透明质酸水凝胶中。 VEGF在复合纳米凝胶系统中的持续释放长达35天是明显的，并且在Matrigel®和刮擦试验中进行测试时，所释放的VEGF具有与游离的新鲜VEGF相当的生物活性。最终的星形-PGA-VEGF纳米药物负载水凝胶具有生物相容性，并提供生物活性VEGF的持续释放。因此，我们报告了新型的，自组装的PGA-VEGF纳米药物的发展及其与医疗设备兼容的透明质酸水凝胶的掺入，从而能够以最小的侵入性输送到心脏。最终的星形-PGA-VEGF纳米药物负载水凝胶具有生物相容性，并提供生物活性VEGF的持续释放。该制剂为将血管生成生长因子最佳时空递送至缺血心肌提供了基础。

BACKGROUND & AIMS: :Cholera is both an endemic and epidemic disease in many low and middle-income countries (LMICs). Strategies for cholera control include improving water, sanitation, and hygiene; providing early and effective treatment; and deploying oral cholera vaccine (OCV). This last strategy is relatively new, and countries considering its introduction are interested in knowing the potential cost not only of the vaccine, but also the cost of introduction. This paper describes the costing of OCV introduction in LMICs using a publicly available Excel-based tool known as the CholTool. It includes estimates of delivery cost categories which cover not only the service delivery costs (e.g. vaccine procurement, handling, storage, and transport; vaccination administration, monitoring supervision, and field support), but also the programmatic costs associated with introducing a new vaccine (i.e. microplanning, communication and training materials development, sensitization/social mobilization, and personnel training) to ensure that a comprehensive estimate is provided with health payer perspective. CholTool takes the user through a structured sequence of interlinked modules containing input parameter cells (assumptions), decision cells (variable selections), and formulas (calculations) to produce customized cost estimates based on standardized methods. The tool provides both financial and economic cost estimates, to ensure that both costs are available for consideration. Four examples of applications of CholTool are presented in three countries- one in Ethiopia, two in Malawi and one in Nepal. The estimates of economic delivery cost per dose (including service delivery and programmatic costs) were (in USD 2016): $2.89 in Ethiopia, $3.04 in Malawi1, $3.35 in Malawi2 and $3.06 in Nepal. A cost projection conducted before the campaign using the tool and a retrospective costing using the tool in Nepal resulted in no significant difference between economic delivery costs per dose.

背景与目标： 在许多中低收入国家（LMIC），霍乱既是地方病又是流行病。霍乱控制策略包括改善水，环境卫生和个人卫生；提供早期有效的治疗；并部署口服霍乱疫苗（OCV）。最后一种策略是相对较新的，考虑引入该疫苗的国家不仅对疫苗的潜在成本感兴趣，而且也对引入疫苗的成本感兴趣。本文介绍了使用称为CholTool的基于Excel的公开可用工具，在LMIC中引入OCV的成本。它包括交付成本类别的估计值，这些估计不仅涵盖服务交付成本（例如，疫苗的采购，处理，存储和运输；疫苗管理，监测监督和现场支持），还包括与引入新疫苗相关的计划成本（例如，微计划，沟通和培训材料的开发，宣传/社会动员和人员培训），以确保从卫生保健付款人的角度提供全面的估计。 CholTool引导用户完成一系列互连模块的结构化序列，这些模块包含输入参数单元格（假设），决策单元格（变量选择）和公式（计算），以基于标准化方法生成定制的成本估算。该工具提供财务和经济成本估算，以确保可以同时考虑这两种成本。在三个国家/地区介绍了CholTool应用程序的四个示例-一个在埃塞俄比亚，两个在马拉维和一个在尼泊尔。估计每剂经济交付费用（包括服务交付和计划费用）为（2016年美元）：埃塞俄比亚为2.89美元，马拉维1为3.04美元，马拉维2为3.35美元，尼泊尔为3.06美元。在运动前使用该工具进行的费用预测以及在尼泊尔使用该工具进行的追溯性费用计算得出，每剂药的经济交付成本之间没有显着差异。