BACKGROUND & AIMS: :We have proposed a transdermal biolistic method to accelerate a powder formulation of drugs to penetrate human skin for the treatment of a range of diseases. One of the key issues for designing and evaluating transdermal biolistic system is ensuing that the powder drugs are delivered into the skin with a controllable velocity range and spatial distribution. The aerodynamics of supersonic nozzles and performance of the delivery system were initially studied, mainly analytically and experimentally. In this paper, computational fluid dynamics is utilized to characterize two existing prototype devices, in order to further investigate the transient gas and particle dynamics in their supersonic nozzles. To validate the implemented numerical approach, calculated pressure histories, two-dimensional flow structures and particle velocity distributions are made and compared with the reported experimental measurements. The key features of gas dynamics, gas-particle interaction and performance of the prototype transdermal biolistics are discussed and interpreted.

背景与目标： : 我们提出了一种经皮生物注射方法，以加速药物的粉末制剂渗透人体皮肤以治疗一系列疾病。设计和评估透皮生物成像系统的关键问题之一是，将粉末药物以可控的速度范围和空间分布输送到皮肤中。初步研究了超音速喷嘴的空气动力学和输送系统的性能，主要是通过分析和实验进行了研究。本文利用计算流体动力学来表征两个现有的原型设备，以便进一步研究其超音速喷嘴中的瞬态气体和颗粒动力学。为了验证所实施的数值方法，计算了压力历史，二维流动结构和颗粒速度分布，并与报告的实验测量值进行了比较。讨论并解释了气体动力学，气体-颗粒相互作用和原型透皮生物技术性能的关键特征。

BACKGROUND & AIMS: The in vivo effectiveness of therapeutic RNAs, like antisense molecules and ribozymes, relies on several featuresRNA molecules need to be expressed at high levels in the correct cellular compartment as stable and active molecules. The exploitation of "natural" small RNA coding genes as expressing cassettes gives high chances to fulfill these requirements. We have investigated the utilization of the adenoviral VAI RNA as a cytoplasmatic carrier for expressing ribozymes against HIV-1. The conserved 5' leader sequence of HIV was chosen as a target, because it is present in all the viral transcripts and is highly conserved. Hammerhead ribozymes were substituted to different portions of the VAI RNA and the resulting chimera were tested in the in vivo system of Xenopus laevis oocytes for their level of accumulation, cellular compartmentalization, and assembly in specific ribonucleoparticles containing the La antigen. Interesting differences in the activity of the different chimera were found in both in vitro cleavage assays and S100 extracts of injected oocytes where the catalytic activity of the ribozymes in the RNP context can be analyzed.

背景与目标： 治疗性rna的体内有效性，如反义分子和核酶，依赖于几个特征rna分子需要作为稳定和活性分子在正确的细胞区室中高水平表达。开发 “天然” 小RNA编码基因作为表达盒的机会很高，可以满足这些要求。我们已经研究了利用腺病毒VAI RNA作为表达抗HIV-1核酶的细胞质载体。HIV的保守5' 前导序列被选为靶标，因为它存在于所有病毒转录本中并且高度保守。将锤头状核酶替换为VAI RNA的不同部分，并在非洲爪蟾卵母细胞的体内系统中测试所得嵌合体的积累水平，细胞区隔和在含有La抗原的特定核糖核蛋白中的组装。在体外裂解试验和注射卵母细胞的S100提取物中均发现了不同嵌合体活性的有趣差异，其中可以分析RNP环境中核酶的催化活性。

BACKGROUND & AIMS: :Immunotherapy for tobacco addiction may offer a safe, alternative treatment if the immunogenicity of the current nicotine vaccines can be improved. We show here that intradermal (ID) immunization induces the production of antibody directed against nicotine (NicAb) at a much higher level than conventional intramuscular (IM) immunization. The magnitude and duration of NicAb production was further increased robustly by non-inflammatory laser vaccine adjuvant (LVA), slightly inflammatory monophosphoryl lipid A (MPL) or a combination of MPL and CpG adjuvants. Consequently, significantly fewer vaccination doses were required to attain a high level of NicAb production for an extended period of time and reduce nicotine entry into the brain in the presence of LVA, MPL or MPL/CpG adjuvant, respectively. Yet, the potency of these adjuvants to augment ID nicotine vaccine immunogenicity came at the expense of local skin reactogenicity, with LVA causing little skin reaction and MPL/CpG stimulating overt skin irritation. These observations underscore a necessity of a balance between optimal adjuvant potency and undesired local reactogenicity. In summary, our study presents a novel approach to significantly improve nicotine vaccine immunogenicity by a combination of safe cutaneous vaccine adjuvants with ID immunization.

背景与目标： : 如果可以改善当前尼古丁疫苗的免疫原性，则对烟草成瘾的免疫疗法可能提供安全的替代治疗。我们在这里显示，皮内 (ID) 免疫诱导针对尼古丁 (NicAb) 的抗体的产生比常规肌内 (IM) 免疫高得多。非炎症性激光疫苗佐剂 (LVA)，轻度炎症性单磷酰脂质A (MPL) 或MPL和CpG佐剂的组合进一步显着增加了NicAb产生的幅度和持续时间。因此，在存在LVA，MPL或MPL/CpG佐剂的情况下，需要较少的疫苗接种剂量才能长时间获得高水平的NicAb产生并减少尼古丁进入大脑。然而，这些佐剂增强ID尼古丁疫苗免疫原性的效力是以局部皮肤反应原性为代价的，LVA引起的皮肤反应很小，MPL/CpG刺激明显的皮肤刺激。这些观察结果强调了在最佳佐剂效力和不希望的局部反应原性之间取得平衡的必要性。总之，我们的研究提出了一种新的方法，可以通过将安全的皮肤疫苗佐剂与ID预防接种相结合来显着提高尼古丁疫苗的免疫原性。

BACKGROUND & AIMS: :Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

背景与目标： : 创伤性脑损伤 (TBI) 仍然是与伤害相关的死亡和残疾的主要原因。脑水肿是TBI的主要并发症之一，可导致颅内压升高和TBI后预后不良。神经生长因子 (NGF) 似乎是治疗脑水肿和TBI的可行策略。不幸的是，由于其血脑屏障 (BBB) 渗透性差，NGF的临床应用受到了极大的限制。我们先前证明鼻内NGF可以绕过BBB并分布在整个大脑中。在这里，我们进一步研究了鼻内NGF是否可以减轻TBI诱导的脑水肿及其推测的机制。TBI是通过改进的重量下降模型产生的。我们发现，经TBI诱导后12小时，24小时和72小时，鼻内施用NGF (5 μ g/d) 可减轻脑水肿，如半球含水量所测定。这种衰减与aquaporin-4含量的显着降低有关，这在脑水肿的形成中起着关键作用。通过rt-pcr和ELISA，我们发现鼻内NGF显着抑制促炎细胞因子 (包括IL-1β 和TNF-α) 的转录和表达。电泳迁移率变化测定 (EMSA) 显示TBI后核因子-κ b的显着激活，但是，在NGF处理的大鼠中，这一激活大大降低。此外，在鼻内补充NGF时，TBI后线粒体介导的凋亡被最小化，如Bcl-2上调和caspase-3下调所表明的。总的来说，我们的发现表明鼻内NGF可能是治疗脑水肿和TBI的有希望的策略。

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型蛋白质分泌系统是具有将细菌蛋白质递送到宿主细胞中的能力的细胞器，已适应为疫苗开发提供异源抗原。这些抗原递送系统的局限性在于某些蛋白质不适合通过该途径分泌。我们在这里显示，来自猿猴和人类免疫缺陷病毒的蛋白质不允许通过沙门氏菌血清型鼠伤寒III型分泌系统分泌，可以通过引入离散突变来改变这种分泌途径。通过主要的组织相容性复合体I类途径更有效地呈现了针对分泌进行优化的蛋白质，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Ca2 + 传感器Syt家族中普遍表达的成员。它存在于几种细胞类型的溶酶体上，在其中调节Ca2依赖性胞吐作用。由于 [Ca2] i和胞吐作用与吞噬作用有关，因此我们研究了Syt VII-/-小鼠巨噬细胞的吞噬能力。Syt VII-/-巨噬细胞通常在低颗粒/细胞比率下吞噬，但在高负荷条件下显示出对颗粒吸收的逐渐抑制。与Syt VII的互补可以挽救这种表型，但只有在保留功能性Ca2结合位点的情况下。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结构域上，从那里募集到新生的吞噬体。Syt VII募集后迅速将Lamp1递送到吞噬体，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12小时低氧血症对0.6妊娠的绵羊胎儿脑血流量 (CBF) 和脑O2输送的影响。在胎儿低氧血症期间，由子宫血流量减少引起的胎儿SaO2和PaO2从77.0 +/- 1.6% 和27.3 +/-1.0毫米Hg的对照值分别降低到28.4 +/- 3.4% 和15.6 +/-0.6毫米Hg (p <0.01); 胎儿pHa在3小时从7.37 +/- 0.01的对照值降至7.20 +/- 0.02，但在12小时前恢复到对照值。在低氧血症期间，CBF (ml/min/100g) 比对照值高2.0至2.6倍 (p <0.01)，但在3小时pHa最低时仅高1.7倍 (p <0.01)。低氧血症1.5小时 (2.09 +/- 0.36) 和3小时 (1.84 +/- 0.22) 时，脑O2递送 (ml/min/100g) 低于3.15 +/- 0.29的对照值 (p <0.01)，低氧血症停止后1小时更高 (3.81 +/- 0.22，p <0.01)。我们得出的结论是，0.6妊娠的绵羊胎儿无法维持CBF的增加，因此在低氧血症的前6小时 (与酸血症相吻合) 中维持脑O2的输送; 相反，在低氧血症的6和12小时，当pHa正常时，脑O2输送与对照值相似。低氧血症的早期，酸血症阶段的脑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： : 氧疗可以挽救慢性阻塞性肺疾病 (COPD) 患者的生命，并且是任何急性COPD治疗策略的支柱。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需要准确调整氧气输送以避免低氧血症和高氧诱导的高碳酸血症的问题。最近的临床数据表明，过量氧气治疗的有害影响不仅会改变二氧化碳水平 (已知已有60多年的历史)，还会导致死亡率增加。然而，尽管有大量文献，但与高氧相关的风险经常被忽视，发表的临床建议在很大程度上被忽视。这种知识翻译的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的经济负担使它无法承受可预防的医疗错误。最近，已经开发了新颖的设备来自动调节氧气流速以保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，提高发病率和死亡率以及降低医疗保健成本的潜力。该领域的初步数据很有希望，并且在未来几年中将需要大量研究以确定这些系统的确切指示。回顾了适当的氧气剂量的重要性以及有关新型氧气输送系统的当前文献。

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： 抗菌药物的主要传统是抗生素，它促进人体细菌细胞中毒素的更快释放，从而引起严重的感染。已提出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-抗体偶联物的制备，用于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) 与直径为0.2的乳胶珠的化学结合。共聚焦显微镜显示，细菌被结合了抗Vp多克隆抗体 (pAb) 的乳胶珠强烈吸收。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)，并降低组织学中TDH诱导的细胞毒性。这些初步结果表明，通过使用这种微粒-抗体缀合物递送系统，有可能有效地预防Vp感染。

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在再次暴露于腺病毒时具有快速中和抗体 (NAb) 反应。NAb诱导会严重限制腺病毒基因治疗的全身性再给药的疗效。我们假设更换光纤旋钮可以克服NAb。免疫能力的小鼠暴露于血清型5腺病毒 (Ad5)(GL) 、Ad5/3lug1、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，肺和脾脏。暴露于衣壳修饰的病毒对Ad5(GL) 基因转移的影响要小得多。Anti-Ad5(GL) NAb阻断了静脉内Ad5(GL) 基因转移至原位肺癌异种移植物，而衣壳修饰的病毒不受影响。当分析基因转移到新鲜癌症和正常肺脏外植体时，我们发现衣壳修饰的病毒在存在anti-Ad5(GL) NAb的情况下允许有效的基因递送到肿瘤，而Ad5(GL) 被阻断。相反，由不同病毒诱导的NAbs交叉阻断会影响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，改变腺病毒光纤旋钮足以允许从先前存在的NAb中逸出相对程度。如果在试验中得到证实，这种方法可能会提高对人类重新施用腺病毒基因疗法的疗效。

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：

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，用于控制药物递送。这些共聚水凝胶是通过自由基聚合技术合成的，使用偶氮二异丁腈 (AIBN) 作为引发剂，N，N'-亚甲基双丙烯酰胺 (BIS) 作为交联剂。这些水凝胶在无酶的模拟胃液和肠液 (SGF和SIF) 中进行了平衡肿胀研究。这些溶胀研究清楚地表明，与SIF相比，这些水凝胶在SGF中的溶胀更多。将茶碱和5-氟尿嘧啶 (5-FU) 包埋到这些水凝胶中，并对无酶SGF和SIF中的药物包埋凝胶进行了平衡溶胀研究。在无酶SGF中建立了药物的体外释放曲线。在胃pH下的前2小时内释放了超过50% 的截留药物，其余的药物释放较慢。

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： : 齐墩果酸是一种水溶性差的药物，口服生物利用度低。已开发出一种自微乳化药物递送系统 (SMEDDS)，以增强齐墩果酸的溶解度和口服生物利用度。通过溶解度测定，相容性测试和假三元相图优化了配方设计。详细研究了装有齐墩果酸的SMEDDS的形态，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，齐墩果酸从SMEDDS的体外释放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测定大鼠血浆中齐墩果酸的方法。与传统片剂相比，该方法用于齐墩果酸负载的SMEDDS的药代动力学研究。令人鼓舞的是，与片剂形式的市售产品相比，SMEDDS的齐墩果酸的口服生物利用度提高了5.07倍。我们的研究说明了SMEDDS通过口服途径递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名剖宫产1次或更多次，并在医学终止妊娠后立即给予宫内节育器的妇女和76名年龄和胎次匹配但阴道分娩正常的妇女插入铜-T宫内节育器后1年的事件发生率。剖宫产组在全麻下进行人工流产术; 阴道组静脉注射安定和宫颈旁阻滞。所有受试者妊娠均少于11周。对他们进行了7天，6周和3个月的随访，为期1年。没有发生穿孔或怀孕。不完全流产导致两组2.6% 的妇女被驱逐，剖宫产组和对照组分别在6.5和5.3% 中被驱逐，这是大多数中止的原因。结论是，根据外科医生的技能，有剖宫产史的妇女在医学终止妊娠后插入宫内节育器是安全的。

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年死亡率与50% 年接壤。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，这种伤害会扩散，心脏不再能够有效地泵送。疫区血管化的增加已被证明可以减轻患者的症状。这样做所需的生长因子半衰期短，因此很难开发有效的疗法。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纳米药物提供> 99% 的VEGF包封并促进VEGF在体外持续释放达28天。将star-PGA-VEGF纳米药物加载到经皮递送顺应性透明质酸水凝胶中。从复合纳米凝胶系统中持续释放VEGF长达35天，并且在两种Matrigel上测试时，释放的VEGF具有与游离的新鲜VEGF相当的生物活性®和划痕分析。最终的star-pga-vegf纳米药物负载的水凝胶是生物相容性的，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PGA-VEGF纳米药物的开发，并将其掺入透明质酸水凝胶中，该水凝胶与医疗设备兼容，从而能够微创地输送到心脏。最终的star-pga-vegf纳米药物负载的水凝胶是生物相容性的，并提供生物活性VEGF的持续释放。该配方为将血管生成生长因子最佳时空传递到缺血性心肌提供了基础。