• 【溶酶体膜向新生吞噬体的Ca2 + 和突触蛋白VII依赖性递送。】 复制标题 收藏 收藏
    DOI:10.1083/jcb.200605004 复制DOI
    作者列表:Czibener C,Sherer NM,Becker SM,Pypaert M,Hui E,Chapman ER,Mothes W,Andrews NW
    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。
  • 【在未成熟的绵羊胎儿中,与长期低氧血症相关的酸血症期间,脑氧输送减少。】 复制标题 收藏 收藏
    DOI:10.1159/000244440 复制DOI
    作者列表:McCrabb GJ,Harding R
    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。
  • 【慢性阻塞性肺疾病患者的最佳氧气滴定: 自动氧气输送的作用?】 复制标题 收藏 收藏
    DOI:10.1155/2013/376545 复制DOI
    作者列表:Lellouche F,Lipes J,L'Her E
    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。
  • 【一种靶向方法,用于递送针对副溶血性弧菌诱导的细胞毒性的聚合物微粒-抗体缀合物对人肠上皮细胞的细胞毒性。】 复制标题 收藏 收藏
    DOI:10.1080/10611860701453745 复制DOI
    作者列表:Gao F,Kodama T,Chen X,Okada K,Honda T
    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。
  • 【在存在中和抗体的情况下改变腺病毒纤维以保持基因递送功效。】 复制标题 收藏 收藏
    DOI:10.1038/gt.2008.56 复制DOI
    作者列表:Särkioja M,Pesonen S,Raki M,Hakkarainen T,Salo J,Ahonen MT,Kanerva A,Hemminki A
    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交叉阻断会影响向正常人肺外植体的基因传递,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。
  • 【靶向肌浆网Ca2 + ATPase 2a基因递送以恢复衰竭心脏的电稳定性。】 复制标题 收藏 收藏
    DOI:10.1161/CIRCULATIONAHA.111.071480 复制DOI
    作者列表:Cutler MJ,Wan X,Plummer BN,Liu H,Deschenes I,Laurita KR,Hajjar RJ,Rosenbaum DS
    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:
  • 【用于口服给药的聚 [N-vinyl-2-pyrrolidone-polyethylene二醇二丙烯酸酯]-壳聚糖互聚pH响应水凝胶的制备和体外评估。】 复制标题 收藏 收藏
    DOI:10.1016/s0378-5173(00)00533-0 复制DOI
    作者列表:Shantha KL,Harding DR
    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。
  • 【用于改善齐墩果酸口服生物利用度的自微乳化给药系统: 设计和评估。】 复制标题 收藏 收藏
    DOI:10.2147/IJN.S47510 复制DOI
    作者列表:Yang R,Huang X,Dou J,Zhai G,Su L
    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。
  • 【在先前剖宫产的妇女中同时进行铜T插入与医学终止妊娠。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Gupta I,Mahajan U,Sawhney H
    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。
  • 【开发一种纳米药物负载的水凝胶,用于将血管生成生长因子持续递送到缺血性心肌。】 复制标题 收藏 收藏
    DOI:10.1007/s13346-019-00684-5 复制DOI
    作者列表:O'Dwyer J,Murphy R,Dolan EB,Kovarova L,Pravda M,Velebny V,Heise A,Duffy GP,Cryan SA
    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。
  • 【使用通用口服霍乱疫苗交付计划和成本计算工具 (CholTool) 对口服霍乱疫苗交付进行成本计算。】 复制标题 收藏 收藏
    DOI:10.1080/21645515.2020.1747930 复制DOI
    作者列表:Morgan W,Levin A,Hutubessy RC,Mogasale V
    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: : 在许多低收入和中等收入国家,霍乱既是地方病,也是流行病。控制霍乱的策略包括改善水,卫生和个人卫生; 提供早期和有效的治疗; 并部署口服霍乱疫苗 (OCV)。这最后一种策略相对较新,考虑引入该策略的国家有兴趣不仅了解疫苗的潜在成本,而且了解引入的成本。本文介绍了使用公开可用的基于Excel的工具 (称为CholTool) 在lmic中引入OCV的成本。它包括交付成本类别的估计,这些类别不仅包括服务交付成本 (例如疫苗采购、处理、储存和运输; 疫苗接种管理、监测监督和现场支持),还包括与引入新疫苗相关的方案成本 (即微观规划,沟通和培训材料的开发、宣传/社会动员和人员培训),以确保从卫生支付者的角度提供全面的估计。CholTool带用户通过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) 的相互链接的结构化模块序列,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,以确保可考虑这两种成本。在三个国家中介绍了CholTool的四个应用示例-一个在埃塞俄比亚,两个在马拉维,一个在尼泊尔。每剂的经济交付成本估计数 (包括服务交付和方案成本) 为 (2016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。在活动之前使用该工具进行的成本预测以及在尼泊尔使用该工具进行的回顾性成本核算,导致每剂的经济交付成本之间没有显着差异。
  • 【锂在输送前后的剂量管理: 一项观察性研究。】 复制标题 收藏 收藏
    DOI:10.1111/bdi.12955 复制DOI
    作者列表:Molenaar NM,Poels EMP,Robakis T,Wesseloo R,Bergink V
    BACKGROUND & AIMS: OBJECTIVES:Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. METHODS:In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. RESULTS:There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. CONCLUSION:Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
    背景与目标:
  • 【合成mRNA向阴道粘膜的气溶胶递送可导致针对HIV的广泛中和抗体的持久表达。】 复制标题 收藏 收藏
    DOI:10.1016/j.ymthe.2020.01.002 复制DOI
    作者列表:Lindsay KE,Vanover D,Thoresen M,King H,Xiao P,Badial P,Araínga M,Park SB,Tiwari PM,Peck HE,Blanchard EL,Feugang JM,Olivier AK,Zurla C,Villinger F,Woolums AR,Santangelo PJ
    BACKGROUND & AIMS: :There is a clear need for low-cost, self-applied, long-lasting approaches to prevent human immunodeficiency virus (HIV) infection in both men and women, even with the advent of pre-exposure prophylaxis (PrEP). Broadly neutralizing antibodies represent an option to improve HIV prophylaxis, but intravenous delivery, cold-chain stability requirements, low cervicovaginal concentrations, and cost may preclude their use. Here, we present an approach to express the anti-GP120 broadly neutralizing antibody PGT121 in the primary site of inoculation, the female reproductive tract, using synthetic mRNA. Expression is achieved through aerosol delivery of unformulated mRNA in water. We demonstrated high levels of antibody expression for over 28 days with a single mRNA administration in the reproductive tract of sheep. In rhesus macaques, neutralizing antibody titers in secretions developed within 4 h and simian-HIV (SHIV) infection of ex vivo explants was prevented. Persistence of PGT121 in vaginal secretions and epithelium was achieved through the incorporation of a glycosylphosphatidylinositol (GPI) anchor into the heavy chain of the antibody. Overall, we present a new paradigm to deliver neutralizing antibodies to the female reproductive tract for the prevention of HIV infections.
    背景与目标: : 显然需要低成本,自我应用,持久的方法来预防男性和女性的人类免疫缺陷病病毒 (HIV) 感染,即使出现了接触前预防 (PrEP)。广泛中和抗体是改善HIV预防的一种选择,但是静脉内给药,冷链稳定性要求,低宫颈阴道浓度和成本可能会阻止其使用。在这里,我们提出了一种使用合成mRNA在接种的主要部位女性生殖道中表达anti-GP120的广泛中和抗体PGT121的方法。通过在水中气溶胶递送未配制的mRNA来实现表达。我们在绵羊的生殖道中单次施用mRNA证明了超过28天的高水平抗体表达。在恒河猴中,分泌物中的中和抗体滴度在4小时内产生,并防止了离体外植体的猿猴HIV (SHIV) 感染。PGT121在阴道分泌物和上皮中的持久性是通过将糖基磷脂酰肌醇 (GPI) 锚入抗体的重链中实现的。总体而言,我们提出了一种向女性生殖道提供中和抗体以预防HIV感染的新范式。
  • 【氧气输送到家用呼吸机的位置会影响记录的体积。】 复制标题 收藏 收藏
    DOI:10.4187/respcare.06829 复制DOI
    作者列表:d'Aranda E,Cungi PJ,Mathais Q,Cardinal M,Esnault P,Nguyen C,Bordes J,Meaudre E,Goutorbe P
    BACKGROUND & AIMS: BACKGROUND:Long-term home mechanical ventilation is increasingly used by patients with chronic respiratory failure. Storage of medical data in the cloud is expanding, and ventilation can be monitored remotely. The aim of this bench study was to determine whether tidal volume (VT) can be affected by the location of supplemental oxygen placement. METHODS:We tested 4 home ventilators in a bench test using a dual-chamber test lung to test the addition of supplemental oxygen placement via a connector in the circuit (ie, front intake port) versus via the manufacturer's rear intake port, with different oxygen supply flows of 2, 4, 6, and 8 L/min. We compared the effectively delivered VT as measured with a pneumotachograph (ie, measured VT) versus the VT reported by each home ventilator (ie, monitored VT). RESULTS:For all of the home ventilators, the monitored VT and measured VT were comparable when the rear oxygen intake was used, regardless of oxygen flow. However, when the front oxygen intake was used, the monitored VT as measured by the ventilators was significantly lower than the measured VT, with the greatest difference reaching 29% for the highest oxygen flow tested (8 L/min). CONCLUSIONS:The monitored VT may be inaccurate if oxygen is added with a connector in the circuit, which may have consequences on both the individual level and collective level (ie, big data analysis). Physicians who analyze data from home ventilators should be aware of the site of oxygen supplementation and promote use of only the rear oxygen intake.
    背景与目标:
  • 【具有pH响应特性的多离子交联纳米颗粒用于口服蛋白质药物。】 复制标题 收藏 收藏
    DOI:10.1016/j.jconrel.2008.08.020 复制DOI
    作者列表:Lin YH,Sonaje K,Lin KM,Juang JH,Mi FL,Yang HW,Sung HW
    BACKGROUND & AIMS: :pH-Responsive nanoparticles composed of chitosan (CS) and poly-gamma-glutamic acid (gamma-PGA) blended with tripolyphosphate (TPP) and MgSO(4) (multi-ion-crosslinked NPs) were prepared and characterized to determine their effectiveness in the oral delivery of insulin. Their counterparts without TPP and MgSO(4) (NPs) were used as a control. FT-IR and XRD results indicated that the spontaneous interaction between CS, insulin, gamma-PGA, MgSO(4) and TPP can form an ionically crosslinked network-structure, leading to the formation of nanoparticles. Multi-ion-crosslinked NPs were more compact than NPs, while their zeta potential values were comparable. During storage, multi-ion-crosslinked NPs suspended in deionized water were stable for at least 10 weeks. Multi-ion-crosslinked NPs had a superior stability over a broader pH range than NPs. In the in vitro release study, NPs failed to provide an adequate retention of loaded insulin in dissolution media compared to multi-ion-crosslinked NPs. Transepithelial-electrical-resistance and transport experiments demonstrated that multi-ion-crosslinked NPs significantly more effectively transported insulin than NPs; confocal visualization further validated the enhanced permeation of insulin via the paracellular pathway. The aforementioned results suggest that multi-ion-crosslinked NPs are a promising carrier for improved transmucosal delivery of insulin in the small intestine.
    背景与目标: : 制备了由壳聚糖 (CS) 和聚 γ-谷氨酸 (γ-PGA) 与三聚磷酸盐 (TPP) 和MgSO(4) (多离子交联np) 混合组成的pH响应纳米颗粒,并对其进行了表征,以确定其在胰岛素口服递送中的有效性。没有TPP和MgSO(4) (NPs) 的同类产品被用作对照。Ft-ir和XRD结果表明,CS,胰岛素,γ-PGA,MgSO(4) 和TPP之间的自发相互作用可以形成离子交联的网络结构,从而导致纳米颗粒的形成。多离子交联的np比np更紧凑,而其zeta电位值可比。在储存过程中,悬浮在去离子水中的多离子交联np稳定至少10周。与NPs相比,多离子交联的NPs在更宽的pH范围内具有优异的稳定性。在体外释放研究中,与多离子交联的np相比,NPs未能在溶解介质中充分保留负载的胰岛素。跨上皮电阻和转运实验表明,多离子交联的NPs比NPs更有效地转运胰岛素; 共聚焦可视化进一步验证了通过细胞旁途径增强的胰岛素渗透。上述结果表明,多离子交联的np是改善小肠中胰岛素经粘膜递送的有前途的载体。

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