BACKGROUND & AIMS: AIM:To report the patterns and sites of 18-FDG uptake in patients of presumed ocular tuberculosis. MATERIALS AND METHODS:The clinical and investigational findings of 11 patients were reviewed retrospectively. These included 6 males and 5 females with a mean age of 46.2 years. 21 eyes were included in the data analysis. Clinical presentations include 15 eyes with anterior uveitis, 2 eyes with retinal vasculitis, 2 eyes with panuveitis and 2 eyes with multifocal choroidopathy. RESULTS:Two distinct patterns of systemic uptake emerged. Pattern 1: No detectable systemic uptake (4 patients). Pattern 2: Detectable systemic uptake. a. Chest disease only (2 patients). b. Disseminated pattern, uptake seen at multiple sites (4 patients). c. Extrapulmonary only (1 patient). CONCLUSIONS:Ocular tuberculosis may often be part of a wider disseminated disease.

背景与目标： 目的：报告推测的眼结核患者摄取18-FDG的方式和部位。
材料与方法：回顾性分析11例患者的临床和研究结果。其中包括6名男性和5名女性，平均年龄为46.2岁。数据分析包括21只眼睛。临床表现包括前葡萄膜炎15眼，视网膜血管炎2眼，胰腺炎2眼和多灶性脉络膜病变2眼。
结果：出现了两种不同的全身吸收模式。模式1：未检测到全身吸收（4例患者）。模式2：可检测到的全身吸收。一种。仅胸部疾病（2例）。 b。分布模式，在多个部位可见吸收（4例）。 C。仅肺外（1例患者）。
结论：眼结核通常可能是更广泛传播的疾病的一部分。

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会提供一种安全的替代疗法。我们在这里显示皮内（ID）免疫诱导产生比常规肌内（IM）免疫高得多的针对尼古丁（NicAb）的抗体。通过非炎性激光疫苗佐剂（LVA），轻度炎性单磷酰脂质A（MPL）或MPL和CpG佐剂的组合，NicAb产生的强度和持续时间进一步提高。因此，分别在LVA，MPL或MPL / CpG佐剂的存在下，要长时间获得高水平的NicAb产量并减少尼古丁进入大脑所需的疫苗接种剂量就大大减少了。但是，这些佐剂增强ID尼古丁疫苗免疫原性的能力是以牺牲局部皮肤反应原性为代价的，LVA引起的皮肤反应很小，而MPL / CpG刺激了明显的皮肤刺激性。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。总而言之，我们的研究提出了一种通过安全的皮肤疫苗佐剂与ID免疫相结合来显着提高尼古丁疫苗免疫原性的新方法。

BACKGROUND & AIMS: PURPOSE:To investigate the epidemiology and clinicopathological management for ocular sebaceous carcinoma (OSC) in the UK. METHODS:Observational prospective cohort study of patients with newly-diagnosed OSC. The British Ophthalmological Surveillance Unit captured incident cases of OSC between 2008 and 2010. Incident and 6-month follow-up questionnaires from reporting ophthalmologists captured OSC demographic and clinical data. RESULTS:Data were available on 51 patients with unilateral OSC (response rate 85%). The UK estimated annual incidence was 0.41 cases per million population (95% CI 0.31 to 0.54). Median age was 70 years (SD 14, range 28-98) with 57% women. OSC location was upper lid (54%), lower lid (20%), multicentric (14%) and caruncle (12%). Most common misdiagnoses included chalazion (42%), basal cell carcinoma (30%) and blepharoconjunctivitis (16%), with median delay in diagnosis of 10 months (SD 9, range 0.5-36). Specialist ophthalmic pathologists performed diagnostics in 62%, with pagetoid/intraepithelial spread present in 39%. Misdiagnosis of chalazion (p=0.019) and pagetoid tumour spread (p=0.016) was associated with a significant diagnostic delay (one-way ANOVA/R(2)). Primary surgical management involved excision with reconstruction (49%), primary exenteration (10%) and Mohs surgery (8%). There were three deaths (out of 51) during the study period; one patient died of OSC-related disease and the other two due to other causes. CONCLUSIONS:This population-based prospective study confirms OSC as a rare cancer in the UK. Masquerade syndromes result in significant diagnostic delays and increase the risk of pagetoid tumour spread. There is considerable UK variation in pathological and surgical management, and ocular reconstruction and radical surgery is often required for OSC due to delayed presentation.

背景与目标： 目的：探讨英国眼皮脂腺癌（OSC）的流行病学和临床病理管理。
方法：对新诊断为OSC的患者进行观察性前瞻性队列研究。英国眼科监视部门捕获了2008年至2010年之间发生OSC的事件。来自报告眼科医师的事件和6个月的后续调查表捕获了OSC的人口统计和临床数据。
结果：有51例单侧OSC患者的数据（有效率85％）。英国估计的年发病率为每百万人口0.41例（95％CI为0.31至0.54）。中位年龄为70岁（SD 14，范围28-98），其中女性占57％。 OSC位置是上盖（54％），下盖（20％），多中心（14％）和and形（12％）。最常见的误诊包括睑板裂（42％），基底细胞癌（30％）和睑结膜炎（16％），中位诊断时间延迟10个月（SD 9，范围0.5-36）。专门的眼科病理学家对62％的患者进行了诊断，其中39％的患者出现了页面状/上皮内扩散。龟头孢子虫（p = 0.019）和页面状肿瘤扩散（p = 0.016）的误诊与显着的诊断延迟有关（单向ANOVA / R（2））。主要的外科手术管理包括切除术，重建术（49％），初次切除术（10％）和莫氏手术（8％）。在研究期间，有3例死亡（共51例）。一名患者死于OSC相关疾病，另一例死于其他原因。
结论：这项基于人群的前瞻性研究证实了OSC在英国是一种罕见的癌症。假面舞会综合症会导致严重的诊断延迟，并增加页面状肿瘤扩散的风险。英国在病理和手术管理上存在很大差异，由于延迟出现，OSC经常需要眼球重建和根治性手术。

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： ：脑外伤（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最主要的并发症之一，导致颅内压升高，TBI后预后较差。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，由于其不良的血脑屏障（BBB）通透性，NGF的临床应用受到了极大的限制。我们先前证明了鼻内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诱导的脑水肿及其可能的机制。 TBI是通过修改后的体重减轻模型产生的。我们发现，鼻腔注射NGF（5μg/ d）可以减轻脑水肿，通过​​TBI诱导后12h，24h和72h的半球水含量测定。这种衰减与aquaporin-4含量的显着下降有关，aquaporin-4的含量在脑水肿的形成中起着关键作用。通过使用RT-PCR和ELISA，我们显示鼻内NGF明显抑制促炎细胞因子包括IL-1β和TNF-α的转录和表达。电泳迁移率迁移分析（EMSA）显示TBI后核因子-κB的显着激活，但是在NGF治疗的大鼠中其活性大大降低。此外，鼻内补充NGF后，TBI后线粒体介导的凋亡得以最小化，如Bcl-2的上调和caspase-3的下调所表明的。总体而言，我们的研究结果表明，鼻内NGF可能是治疗脑水肿和TBI的一种有前途的策略。

BACKGROUND & AIMS: PURPOSE:Amniotic membrane (AM) transplantation is an accepted procedure in ocular surgery. However, little is known of the interdonor and intradonor variability within the membrane. In addition, the effects of the methods of processing, storage, and preoperative preparation on the membrane are not fully elucidated. The purpose of this study was to use TGF-beta as an example to investigate interdonor and intradonor variability and to determine the effect of "handling " on TGF-beta1 within fresh, processed and stored, and transplantation-ready AM (TRAM). METHODS:Seventeen human AMs, both fresh and handled, were analyzed for TGF-beta1 by real-time polymerase chain reaction, immunohistochemistry, SDS-PAGE, and Western blotting. RESULTS:TGF-beta1 was the highest normalized expressed isoform of TGF-beta in all samples, but it varied between membranes of different donors and at different sites within the same membrane. The highest concentration was noted in the spongy layer. Removal of the spongy layer successfully removed the bulk of TGF-beta1 from TRAM. Latency-associated protein (LAP) and a latent TGF-beta-binding protein (LTBP) were also detected. CONCLUSION:TGF-beta1 is present in various regulatory forms in the AM. A degree of intermembrane and intramembrane variation is modified by handling. Unless a standardized protocol is adopted that delivers a membrane with consistent constituents, clinical outcomes may vary and comparisons may be invalid.

背景与目标： 目的：羊膜移植术是眼科手术中公认的手术方法。然而，对于膜内的供体间和供体内变异性知之甚少。另外，尚未完全阐明处理，储存和术前准备方法对膜的影响。这项研究的目的是以TGF-β为例，研究供体间和供体内的变异性，并确定“处理”对新鲜，加工和储存以及准备好移植的AM（TRAM）中TGF-beta1的影响。
方法：通过实时聚合酶链反应，免疫组织化学，SDS-PAGE和Western印迹分析了17例新鲜和处理过的人类AMs的TGF-beta1。
结果：TGF-β1是所有样品中TGF-β的最高标准化表达同工型，但在不同供体的膜之间以及同一膜内的不同位置上，TGF-β1均存在差异。在海绵层中观察到最高浓度。去除海绵层成功地从TRAM中去除了大部分TGF-beta1。还检测到潜伏期相关蛋白（LAP）和潜在的TGF-β结合蛋白（LTBP）。
结论：TGF-beta1以各种调控形式存在于增材制造中。膜间和膜内的变化程度通过处理而改变。除非采用标准化的方案来递送具有一致成分的膜，否则临床结果可能会有所不同，并且比较可能无效。

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。