Janus激酶/信号转导子与转录激活子阻断剂AG490对类风湿关节炎大鼠滑膜组织Caspase-3表达的影响

目的 探讨Janus激酶信号转导子与转录激活子(JAK/STAT)信号通路阻断剂AG490对类风湿关节炎(RA)大鼠滑膜组织天冬氨酸特异性半胱氨酸蛋白酶-3(Caspase-3)表达的影响.方法 雄性Wistar大鼠50只,除对照组6只外,其余均建立胶原诱导的关节炎(CIA)模型,关节炎指数＞2分的大鼠再随机分为CIA模型组,JAK/STAT阻断剂低、中、高剂量组,每组6只.在关节炎开始后,阻断剂组分别予以AG490 1、5、10 mg,kg-1·1d-1腹腔注射,对照组及模型组予以0.9％氯化钠注射液1ml/d腹腔注射.观察应用AG490前后大鼠足趾容积、关节组织病理学评分及滑膜组织Caspase-3表达情况.应用单因素方差分析对结果进行统计.结果 CIA模型组足趾容积及病理评分明显高于对照组,同时在对照组未见可探测到水平的Caspase-3阳性表达条带,而模型组其表达水平略有升高;经过应用不同剂量AG490后,大鼠关节肿胀较模型组明显改善,组织病理评分AG490中、高剂量组(分另为2.7±0.8,1.8±0.9)较模型组(4.3±1.2)明显降低,差异均有统计学意义(P＜0.01),而Caspase-3表达AG490低、中、高剂量组(分别为1.90±0.15,3.13±0.33,3.56±0.34)较模型组(1.48±0.18)明显增高,差异均有统计学意义(P＜0.05或P＜0.01).结论 JAK/STAT信号通路阻断剂AG490可上调Caspase-3的表达,明显改善RA的病理过程.     

血管内皮生长因子在大鼠实验性关节炎模型中表达的动态观察

目的：观察血管内皮生长因子（VEGF）在大鼠实验性关节炎模型中的表达，探讨VEGF在类风湿关节炎（RA）发病机制中的作用。方法：30只雄性Wistar大鼠采用皮下注射Ⅱ型胶原的方法诱导实验性关节炎模型，并随机分为6组，每组5只。致敏1、2、3、4、5、6周后分别将各组动物处死，采用免疫组织化学方法对组织中表达的VEGF进行观察，并采用计算机图像分析的方法对各时期VEGF的表达量进行定量分析。结果：大鼠在接受胶原致敏后2周左右发病，滑膜组织中的VEGF蛋白的分泌与炎症发展密切相关。结论：VEGF参与了实验性关节炎滑膜血管翳的形成过程，在RA的发病机制中具有重要意义。     

缺氧诱导因子-1α血管内皮生长因子在胶原诱导性关节炎滑膜中的表达及其与血管生成的关系

目的 探讨缺氧诱导因子(HIF)-1α和血管内皮生长因子(VEGF)在类风湿关节炎(RA)血管生成中的作用.方法 建立大鼠胶原诱导性关节炎(CIA)模型,采用苏木素-伊红(HE)染色评估滑膜病理血管生成、SP法免疫组织化学染色检测HIF-1α和VEGF的表达,动态观察HIF-1α表达与VEGF表达及血管生成之间的关系.结果 CIA大鼠滑膜HIF-1α及VEGF表达增加,且随发病时间的延长而逐渐增加,两者均与滑膜病理血管生成评分呈显著正相关,同时滑膜衬里层和衬里下层HIF-1α表达又与相应部位的VEGF表达呈显著正相关.结论 HIF-1α可能参与上调VEGF表达促进血管生成,从而在RA关节破坏中起一定作用.     

肝复康对肝纤维化大鼠肝组织JAK2和STAT3表达的影响

目的观察中药肝复康对肝纤维化大鼠肝组织Janus激酶2（JAK2）及信号转导子和转录激活子3（STAT3）表达的影响,并对其在JAK2/STAT3信号通路上治疗肝纤维化的作用机制进行初步探讨。方法采用10%四氯化碳皮下注射制备肝纤维化模型,于造模第9周给予肝复康治疗12周。通过测定血清中ALT、AST活性及白蛋白和总蛋白的含量来反映肝脏功能,HE染色法观察肝组织病理学变化,RT-PCR观察JAK2和STAT3 mR-NA的表达。结果经肝复康治疗后,中剂量治疗组与模型组相比较,肝脏的组织学和血清学指标均明显改善,肝组织JAK2、STAT3 mRNA的表达显著减少（P〈0.01）。结论 （1）JAK2/STAT3信号通路在肝纤维化的形成过程中起重要作用;（2）肝复康对肝纤维化有疗效,其作用机制可能与降低肝组织JAK2和STAT3的表达,阻断JAK2/STAT3信号通路有关。     

抑制JAK／STAT信号通路对实验性急性胰腺炎大鼠肝损伤的保护作用

背景：JAK／STAT细胞内信号通路广泛参与细胞的增殖、分化、凋亡以及炎症、肿瘤的发生等多种生理、病理生理过程，然而关于其在重症急性胰腺炎（SAP）急性肝损伤中作用的研究尚少。目的：观察抑制JAK〈STAT通路对实验性急性胰腺炎（AP）大鼠肝损伤的保护作用。方法：56只Sprague-Dawley大鼠随机分为正常对照组、3组AP模型组和3组JAK特异性抑制剂AG490干预组。以4％牛磺胆酸钠胰胆管逆行注射诱导AP模型。分批处死各组大鼠，动态测定血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）水平，观察肝脏大体和组织学表现，以免疫组化染色和蛋白质印迹法检测肝组织中JAK2的定位和表达。结果：与正常对照组相比，AP模型组各时间点血清ALT、AST水平均显著升高；肝组织大体和组织学损伤随病情进展而逐渐加重；肝组织JAK2表达逐渐增强，于18h时达高峰。经AG490预处理的大鼠，上述各项指标均较同时间点AP模型组显著改善。结论：JAK2参与了大鼠实验性AP肝损伤的病理过程，抑制肝组织JAK／STAT通路活化有助于SAP急性肝损伤的防治。     

低氧诱导因子-1α在大鼠胶原诱导性关节炎中的表达及与血管生成的关系

目的制备牛Ⅱ型胶原诱导性大鼠关节炎(CIA)模型,探讨低氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)在类风湿关节炎(RA)组织中的动态表达及其相关性作用。方法 50只SD大鼠,随机分为对照组与模型组。建立CIA模型,动态观察各项关节炎活动指标,于造模21、28、35、42d取踝关节行HE染色及HIF-1α、VEGF免疫组化染色,分析两者在CIA中的相关性及与关节炎活动指标、滑膜病理学评分之间的关系。结果 CIA大鼠关节滑膜层和滑膜下层均表达HIF-1α、VEGF,第21天阳性表达量最高,随病程进展,表达逐渐下降,与滑膜病理学评分、滑膜增生评分及血管生成评分呈显著正相关,与炎症浸润评分无明显相关。结论Ⅱ型胶原可成功诱导大鼠关节炎模型。HIF-1α、VEGF在RA组织中的表达,与炎症严重程度呈明显正相关。HIF-1α可能通过调控一系列下游靶基因,如VEGF等,促进滑膜增生及血管生成,影响RA的发生、发展。     

Janus激酶/信号转导子与转录激活子通路对类风湿关节炎大鼠滑膜细胞凋亡相关基因表达的影响

目的 探讨Janus激酶/信号转导子与转录激活子(JAK/STAT)信号通路对类风湿关节炎(RA)大鼠滑膜细胞凋亡相关基因表达的影响.方法 雄性Wistar大鼠50只,除对照组6只外,其余均建立胶原诱导的关节炎(CIA)模型,关节炎指数＞2分的大鼠再随机分为CIA模型组,JAK/STAT阻断剂低、中、高剂量组,每组6只.在关节炎开始后,阻断剂组分别予以AG490 1、5、10 mg·kg-1·d-1腹腔注射,对照组及模型组于以生理盐水1 ml/腹腔注射.应用单因素方差分析观察应用JAK/STAT阻断剂前后滑膜细胞Bcl-2、Bcl-xl、Bax mRNA及蛋白表达情况.结果 CIA模型组Bcl-2、Bcl-xl mRNA及蛋白表达水平较对照组明显增高(0.931±0.035与0.351±0.024,0.920±0.037与0.271±0.029,0.322±0.047与0.230±0.031),Bax表达轻微上调;应用JAK/STAT阻断剂后Bcl-2、Bcl-xl基因及蛋白质表达水平明显下降,而 Bax的基因及蛋白质水平明显升高.结论 在RA发病过程抗凋亡因子呈明显高表达状态,而JAK/STAT通路对凋亡调控基因具有直接的调节作用.

Abstract：

Objective To explore the effect of the JAK/STAT signal pathway on the apoptosis-related gene in the synovial tissue of rat rheumatoid arthritis (RA).Methods Fifty rat models of collagen-induced arthritis,whose arthritis index was more than 2,were divided into the model group,the low dose of AG490 group,the medium dose of AG490 group and the high dose of AG490 group.In addition,6 rats were treated intraperitoneal injection.Then,the arthritis index and the change of apoptosis-related genes were compared.Multiple-sample average was analyzed by single-factor x2 test and LSD-t or Tamhane's T 2 test were used for two-two comparison.Results The arthritis index of the model group increased evidently,and the apoptosis inhibitor Bcl-2,Bcl-xl gene and protein expression was up-regulated,which was significantly different when compared with that of the control group(0.931±0.035 vs 0.351±0.024,0.920±0.037 vs 0.271±0.029,0.322±0.047 vs 0.230±0.031 ).The expression of apoptosis promoting factor Bax wasslightly up-regulated.The blockage of JAK/STAT pathway cotld down-regulate the expression levels of the gene and protein of survivins Bcl-2 and Bcl-xl,and up-regulate the gene and protein expressions of Bax.Conclusion In the process of RA development,apoptosis inhibitor Bcl-2,Bcl-xl gene and protein expression is up-regulated.JAK/STAT signal transduction pathway regulates the apoptosis process.     

胶原诱导关节炎大鼠滑膜中血管内皮生长因子和内皮抑素的表达及意义

目的观察血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、内皮抑素（endostatin）在胶原诱导关节炎（CIA）大鼠不同时期滑膜中的蛋白表达，通过CD34给血管密度计数．明确生长因子在血管翳形成中的作用机制。方法建立CIA大鼠模型，测量关节体积，计算关节病理积分，并用免疫组织化学染色检测VEGF、bFGF、endostatin和CD34的蛋白表达。结果模型组大鼠滑膜VEGF和bFGF表达明显高于正常组大鼠（P〈0．01），并且二者表达存在相关性（P〈0．01），内皮抑素表达模型组与正常组比较差异无统计学意义（P〉0．05）。结论滑膜中生长因子表达失衡在关节炎的形成及发展过程中起重要作用，促血管生长因子表达升高是导致滑膜新生血管形成的主要原因。     

缺氧诱导因子-1α及血管内皮生长因子在Ⅱ型胶原诱导性关节炎模型中的致病作用

目的 探讨低氧诱导因子-1α(HIF-1α)及血管内皮生长因子(VEGF)在Ⅱ型胶原诱导性关节炎(CIA)模型中的致病作用.方法 选用50只SD大鼠(雌雄各半),建立CIA模型,分别于造模第21、28、35、42天取踝关节作HE染色及HIF-1α免疫组化染色,分析其在CIA中与关节炎活动指标,滑膜病理学评分之间的关系.结果 CIA大鼠关节滑膜层和滑膜下层均表达HIF-1α,第21天阳性表达量最高,随病程进展,表达逐渐下降,与滑膜病理学评分、滑膜增生评分及血管生成评分呈显著正相关.结论 HIF-1α在RA致病机制中发挥关键作用,可能是重要的治疗靶点.     

Control of intraabdominal hemorrhage and shock: a comparison of fluid resuscitation, MAST, and balloon occlusion

Our study examined the efficacy of four treatment modalities in controlling hemorrhage and achieving hemodynamic stabilization in hemorrhagic shock: intravenous fluid replacement (IV); military antishock trousers used concomitantly with fluids (MAST); balloon occlusion at the level of the diaphragm with concomitant fluid replacement (balloon); and a combination of MAST inflation, balloon occlusion, and fluid resuscitation (MAST and balloon). Twenty-eight mongrel dogs were anesthetized, and the spleen was exposed and completely crushed. The abdomen was closed, and treatment was initiated and continued for four hours or until the dog died. For all conditions the hematocrit dropped during the course of the experiment; balloon occlusion was effective at slowing this drop (P less than .0001), but MAST had no statistically significant effect. Animals with balloons bled more slowly into the abdominal cavity than did animals in the other two groups (P less than .0001). MAST also were effective at slowing the bleeding (P less than .05). Of the balloon and the MAST and balloon dogs, all except one survived the entire four hours; this difference between balloon and nonballoon dogs is significant (P = .002). MAST did not have a statistically significant effect on survival. Perfusion pressure (PP) declined during the course of the experiment, and the balloon was effective at slowing this decline (P less than .0001); none of the other comparisons was statistically significant.     

Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus

Innate immunity is the first line of defense against viral infection, and in turn, viruses have evolved to evade host immune surveillance. As a result, viruses may persist in host and develop chronic infections. Type I interferons (IFN-α/β) are among the most potent antiviral cytokines triggered by viral infections. Porcine reproductive and respiratory syndrome (PRRS) is a disease of pigs that is characterized by negligible induction of type I IFNs and viral persistence for an extended period. For IFN production, RIG-I/MDA5 and JAK-STAT pathways are two major signaling pathways, and recent studies indicate that PRRS virus is armed to modulate type I IFN responses during infection. This review describes the viral strategies for modulation of type I IFN responses. At least three non-structural proteins (Nsp1, Nsp2, and Nsp11) and a structural protein (N nucleocapsid protein) have been identified and characterized to play roles in the IFN suppression and NF-κB pathways. Nsp's are early proteins while N is a late protein, suggesting that additional signaling pathways may be involved in addition to the IFN pathway. The understanding of molecular bases for virus-mediated modulation of host innate immune signaling will help us design new generation vaccines and control PRRS.     

A Call to Action to Enhance Filovirus Disease Outbreak Preparedness and Response

The frequency and magnitude of recognized and declared filovirus-disease outbreaks have increased in recent years, while pathogenic filoviruses are potentially ubiquitous throughout sub-Saharan Africa. Meanwhile, the efficiency and effectiveness of filovirus-disease outbreak preparedness and response efforts are currently limited by inherent challenges and persistent shortcomings. This paper delineates some of these challenges and shortcomings and provides a proposal for enhancing future filovirus-disease outbreak preparedness and response. The proposal serves as a call for prompt action by the organizations that comprise filovirus-disease outbreak response teams, namely, Ministries of Health of outbreak-prone countries, the World Health Organization, Médecins Sans Frontières, the Centers for Disease Control and Prevention—Atlanta, and others.     

Disease Pandemics and Major Epidemics Arising From New Encounters between Indigenous Viruses and Introduced Crops

Virus disease pandemics and epidemics that occur in the world’s staple food crops pose a major threat to global food security, especially in developing countries with tropical or subtropical climates. Moreover, this threat is escalating rapidly due to increasing difficulties in controlling virus diseases as climate change accelerates and the need to feed the burgeoning global population escalates. One of the main causes of these pandemics and epidemics is the introduction to a new continent of food crops domesticated elsewhere, and their subsequent invasion by damaging virus diseases they never encountered before. This review focusses on providing historical and up-to-date information about pandemics and major epidemics initiated by spillover of indigenous viruses from infected alternative hosts into introduced crops. This spillover requires new encounters at the managed and natural vegetation interface. The principal virus disease pandemic examples described are two (cassava mosaic, cassava brown streak) that threaten food security in sub-Saharan Africa (SSA), and one (tomato yellow leaf curl) doing so globally. A further example describes a virus disease pandemic threatening a major plantation crop producing a vital food export for West Africa (cacao swollen shoot). Also described are two examples of major virus disease epidemics that threaten SSA’s food security (rice yellow mottle, groundnut rosette). In addition, brief accounts are provided of two major maize virus disease epidemics (maize streak in SSA, maize rough dwarf in Mediterranean and Middle Eastern regions), a major rice disease epidemic (rice hoja blanca in the Americas), and damaging tomato tospovirus and begomovirus disease epidemics of tomato that impair food security in different world regions. For each pandemic or major epidemic, the factors involved in driving its initial emergence, and its subsequent increase in importance and geographical distribution, are explained. Finally, clarification is provided over what needs to be done globally to achieve effective management of severe virus disease pandemics and epidemics initiated by spillover events.     

Barrett's Esophagus: Where Do We Stand?

Barrett''s esophagus (BE) is a precursor for esophageal adenocarcinoma, which has an increased incidence rate over the last few decades. Its importance stems from the poor five-year survival of esophageal adenocarcinoma and current data that suggest a survival benefit when surveillance programs are implemented. In this review, we will cover the pathophysiology and natural history of BE and the different endoscopic findings. The prevalence of BE in different geographic areas and the incidence of high-grade dysplasia and adenocarcinoma in this patient population is reviewed. Recent recommendation for screening and surveillance of BE has been covered in this review as well as the efficacy of nonconventional imaging modalities and endoscopic ablation therapies.     

The Technology Transfer from Europe to China in the 17th–18th Centuries: Non-Invasive On-Site XRF and Raman Analyses of Chinese Qing Dynasty Enameled Masterpieces Made Using European Ingredients/Recipes

Two masterpieces of the Qing Dynasty (1644–1912 CE), one in gilded brass (incense burner) decorated with cloisonné enamels stylistically attributed to the end of the Kangxi Emperor’s reign, the other in gold (ewer offered by Napoleon III to the Empress as a birthday present), decorated with both cloisonné and painted enamels bearing the mark of the Qianlong Emperor, were non-invasively studied by optical microscopy, Raman microspectroscopy and X-ray microfluorescence spectroscopy (point measurements and mapping) implemented on-site with mobile instruments. The elemental compositions of the metal substrates and enamels are compared. XRF point measurements and mappings support the identification of the coloring phases and elements obtained by Raman microspectroscopy. Attention was paid to the white (opacifier), blue, yellow, green, and red areas. The demonstration of arsenic-based phases (e.g., lead arsenate apatite) in the blue areas of the ewer, free of manganese, proves the use of cobalt imported from Europe. The high level of potassium confirms the use of smalt as the cobalt source. On the other hand, the significant manganese level indicates the use of Asian cobalt ores for the enamels of the incense burner. The very limited use of the lead pyrochlore pigment (European Naples yellow recipes) in the yellow and soft green cloisonné enamels of the Kangxi incense burner, as well as the use of traditional Chinese recipes for other colors (white, turquoise, dark green, red), reinforces the pioneering character of this object in technical terms at the 17th–18th century turn. The low level of lead in the cloisonné enamels of the incense burner may also be related to the use of European recipes. On the contrary, the Qianlong ewer displays all the enameling techniques imported from Europe to obtain a painted decoration of exceptional quality with the use of complex lead pyrochlore pigments, with or without addition of zinc, as well as cassiterite opacifier.