整合应激反应( integrated stress response,ISR)广泛存在于真核细胞体内,是维护细胞内稳态和细胞生存的重要适应性机制,可被多种细胞应激和病理条件激活,如内质网应激、氧化应激、DNA损伤、营养物质缺乏等[1-2].该过程主要通过磷酸化真核生物起始因子2 ( phosphorylation of eukaryotic trans-lation initiationfactor 2,p-eIF2)α亚基中的丝氨酸-51位点,阻断鸟嘌呤核苷酸交换因子( The guanine nu-cleotide exchange factor) eIF2B 的作用,抑制细胞内翻译,减少蛋白质的总体合成,并激活下游转录因子4(activating transcription factor 4,ATF4)调控相关应激基因,如CHOP、GADD34 等的表达参与氨基酸代谢、未折叠蛋白反应、细胞凋亡等过程[3-4].

哮喘和慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是常见的呼吸系统慢性疾病,全球约3 亿人受其影响,气流受限是慢阻肺、支气管哮喘等阻塞性疾病的共同特征,急性发作时,常表现为持续气道痉挛,可能导致呼吸衰竭、甚至窒息猝死,支气管平滑肌主动收缩所致气道阻塞是患者死亡的重要因素[1] .

PURPOSE:To investigate the effect of outer membrane vesicles (OMVs) secreted by Fusobacterium nucleatum (F.n) on Claudin-4 of human oral keratinocytes (HOK) and oral epithelial barrier function.METHODS:Fusobacterium nucleatum was cultured under anaerobic conditions. The OMVs were extracted by dialysis and characterized by nanosight and transmission electron microscopy (TEM). HOK were stimulated with OMVs at different mass concentrations(0-100 μg/mL) for 12 h, and stimulated with 100 μg/mL OMVs for 6 h and 12 h respectively. The expression of Claudin-4 at gene and protein level was analyzed by RT-qPCR and Western blotting. Inverted fluorescence microscope was used to observe co-localization of HOK and OMVs and localization and distribution of Claudin-4 protein. Human oral epithelial barrier was constructed by Transwell apical chamber. Transepithelial electrical resistance(TER) of barrier was measured with a transmembrane resistance measuring instrument(EVOM2), and the permeability of the barrier was evaluated by transmittance of fluorescein isothiocyanate-dextran(FD-4). Statistical analysis was performed with GraphPad Prism 8.0 software package.RESULTS:Compared with the control group, the expression of Claudin-4 at protein and gene level in the HOK of OMVs stimulated group was significantly reduced (P＜0.05), and immunofluorescence showed that the continuity of Claudin-4 fluorescence among cells was destroyed. OMVs stimulation decreased TER value of oral epithelial barrier(P＜0.05) and increased the transmittance of FD-4(P＜0.05).CONCLUSIONS:OMVs derived from Fusobacterium nucleatum may damage oral mucosal epithelial barrier function through inhibiting the expression of Claudin-4.

Myocardial ischemia/reperfusion (I/R) injury is a pathological change that occurs during the restoration of blood supply to ischemic or occluded coronary arteries after coronary heart disease, stroke, cardiac arrest and resuscitation, organ transplantation, shock and other events. Myocardial I/R injury is often accompanied by cardiovascular adverse events, which seriously affect the prognosis of myocardial ischemia. The potential mechanism of myocardial I/R injury is complex, involving many pathological processes, such as oxygen free radical injury, calcium overload, inflammation, apoptosis, activation, immune imbalance, endoplasmic reticulum stress, autophagy, myocardial energy metabolism disorder, myocardial microvascular endothelial cell injury and so on. Ischemic preconditioning is an effective preventive and therapeutic measure to reduce ischemia-reperfusion (I/R) injury. At present, there are many experimental studies on the pathogenesis and prevention and treatment measures, but the clinical application is still limited, so the prevention and treatment of I/R injury is still a major challenge. The pathogenesis of myocardial I/R injury is not completely clear, and the treatment methods and drugs are limited, so this paper summarizes the molecular mechanism and related signal pathways involved in its injury, as well as the emerging targeted therapy, to provide strategy and theoretical basis for clinical prevention and treatment of myocardial I/R injury.

心肌缺血再灌注(ischemia/reperfusion,I/R)损伤是在冠心病、中风、心脏骤停和复苏、器官移植、休克等事件后缺血或闭塞的冠状动脉恢复供血时发生的病理改变.心肌I/R损伤常伴有心血管不良事件,严重影响心肌缺血的预后.心肌I/R损伤的潜在机制复杂,涉及氧自由基损伤、钙超载、炎症反应、细胞凋亡、补体激活、免疫失衡、内质网应激、细胞自噬、心肌能量代谢紊乱、心肌微血管内皮细胞损伤等多种病理过程.为减轻I/R损伤,缺血预处理是一种有效的防治措施.目前相关发病机制与防治措施实验性研究较多,但临床应用仍然有限,因此I/R损伤的防治仍然是一大挑战.心肌I/R损伤的发病机制不完全明确,治疗方法和药物有限,故本文对其损伤涉及的分子机制和相关信号通路以及新兴靶向治疗的研究做一总结,为心肌I/R损伤的临床防治提供治疗策略和理论依据.

BACKGROUND/PURPOSE:Oral lichenoid reactions (OLRs) are commonly characterized by the infiltration and activation of inflammatory cells at the interface of the oral mucosa. This study aimed to compare the cytokine profiles between intralesional and peripheral plasma from patients with OLRs and elucidate the cytokine profile in the OLR microenvironment. MATERIALS AND METHODS:A total of 26 paired intralesional and peripheral plasma samples were collected from patients with OLRs. A panel of 15 cytokines was measured using a Luminex assay. The reticular, erythema, and ulcerative score was used to evaluate the degree of OLR severity. RESULTS:IL-10 was detected in a fewer number of intralesional samples (19/26) compared to peripheral samples (26/26, p = 0.01). The intralesional plasma exhibited significantly elevated levels of granzyme B (median 108.94 vs. 16.00), TGF-β1 (mean 30448.92 vs. 10199.04), TGF-β2 (mean 1659.73 vs. 1308.49), and TGF-β3 (mean 914.33 vs. 573.13) compared to the peripheral plasma (p = 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively). The levels of intralesional IL-2 (median 2.84 vs. 3.45, p = 0.019) and TNF-α (median 7.66 vs. 10.34, p = 0.048) were significantly lower in the intralesional plasma compared to the peripheral plasma. CONCLUSION:The intralesional concentrations of granzyme B and TGF-β were elevated, whereas IL-2 and TNF-α were decreased in the OLR microenvironment compared to the peripheral plasma. These findings may contribute to establishing a panel of biomarkers that can be used to monitor the disease activity of OLRs in a large cohort study in future.

PURPOSE To evaluate the existence of tertiary lymphoid structures(TLS) in oral lichenoid lesions and its compositional characteristics of immune cells. METHODS Tissue samples of normal oral mucosa, oral lichen planus (OLP) and oral lichenoid tissue reaction(OLTR) were collected, thirty cases in each group. Hematoxylin-eosin(H-E) staining was performed to identify the TLS-like structures, and immunohistochemistry (IHC) staining was applied to assess the structure and amount of infiltrating CD3+ T cells, CD19+, CD20+ B cells, CD21+ follicular dendritic cells (FDC), Bcl-6+ germinal centers, CD34+ PNAd+ venules and CD34+ Gp36+ micro lymphatic vessels in TLS of OLL. Histopathology and molecular markers were used to evaluate the morphological performance of TLS in OLL. Chi-square test (Fisher exact probability method) was applied to compare the proportion of TLS in each group; integral optical density (IOD) method was used to calculate the expression level of each molecular marker, nonparametric t test (Mann-Whitney U test) was employed to analyze their difference. Statistical analysis was performed with GraphPad Prism 7.0 software. RESULTS In OLP group and OLTR group, 46.7% (14/30) and 23.4% (7/30) cases had TLS-like structures, respectively. The frequency of TLS-like structures was not correlated with the type of disease(P>0.05). Compared with the control group, the molecular markers in OLP group and OLTR group were highly expressed, and the expression of CD19, CD20, and CD21 in OLP group had morphological and structural characteristics of TLS. The expression of Bcl-6(mean and standard deviation of IOD were 15 498±15 108 vs. 1 841±2 276, P<0.0001), CD20 (13 067±9 049 vs. 7 695±5 159, P<0.05), CD21 (13 968±14 560 vs. 2 552±2 584, P<0.0001), PNAd (10 328±10 383 vs. 1 756±1 570, P<0.0001) and Gp36 (12 778±12 390 vs. 2 313±2 578, P<0.0001) showed significant differences between OLP and OLTR tissues, but it could not be used as the criteria for identifying the type of diseases without morphological characters. CONCLUSIONS TLS exists in OLL lesions, mainly presented as non-classical forms. The classical forms can be occasionally found. CD20 and CD21 can be used as the biomarkers to identify the TLS in OLL. TLS can not be used as the diagnosing criteria for identifying OLP or OLTR.

目的:观测小鼠磨牙加力不同时间点脾脏CD3+、CD8+、CD4+T淋巴细胞及Th细胞亚群的比例变化,分析正畸加力对免疫系统中T淋巴细胞变化的影响.方法:4周龄雄性C57BL/6小鼠随机分为1 d、3 d、5 d和7 d加力组以及相应时间的对照组.加力组向磨牙施加25 g力;对照组安置相同加力装置,力值为0.使用流式细胞术检测小鼠脾脏单个核细胞中CD3+比例、CD4+/CD3+比例、CD8+/CD3+比例及Th1,Th2,Th17细胞占CD4+细胞比例,以及CD3,CD4,CD8,IFN-γ,IL-4,IL-17荧光强度的变化.结果:与对照组相比,7 d实验组CD8+T细胞占CD3+T细胞的比例和Th1细胞占CD4+T淋巴细胞的比例显著增高(P<0.05);CD3,CD8,IFN-γ,IL-17平均荧光强度均显著增高(P<0.05);相反,CD4+T细胞占CD3+T淋巴细胞的比例显著降低(P<0.01).而1,3,5 d实验组与对照组间未见明显差异(P>0.05).结论:正畸加力过程可引起小鼠脾脏T细胞亚群占比和及其分泌的细胞因子发生变化.

Abstract Background: Oral lichenoid reactions are intractable inflammatory diseases of oral mucosa. The cytokine profiles of intralesional blood remain unclear. We aim at revealing the intralesional cytokine profiles and providing some actual and stable intralesional cytokine biomarkers to evaluate the severity and therapeutic effects of oral lichenoid reactions.Methods: Paired intralesional and peripheral plasma from 26 patients with oral lichenoid reactions were collected. The concentration of 15 cytokines of granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL17A, TNF-α, IFN-α, IFN-β, IFN-γ, TGF-β1, TGF-β2 and TGF-β3 was measured by Luminex assays. REU score was used for evaluating the severity of the disease. Results: Eleven cytokines including IL-10, IFN-α, IL-6, IL-17A, granzyme B, TGF-β1, TGF-β2, TGF-β3, IL-2, TNF-α, IL-12p70 were detected within the reliable working range. IL-10 was detected in less intralesional samples (19/26) than peripheral samples (26/26, p=0.01). The cytokine concentrations from intralesional plasma were significantly elevated in granzyme B (median 108.94 vs. 16.00), TGF-β1 (mean 30448.92 vs. 10199.04), TGF-β2 (mean 1659.73 vs. 1308.49) and TGF-β3 (mean 914.33 vs. 573.13) than that in peripheral plasma (p=0.001, p＜0.001, p＜0.001 and p＜0.001, respectively). The concentration of IL-12p70 in peripheral plasma was positively correlated with REU score (coefficient of correlation=0.463, p=0.02).Conclusions: The concentration of granzyme B and TGF-β are more abundant in intralesional microenvironment than in peripheral plasma of oral lichenoid reactions. IL-12p70 may be a potential molecular biomarker for evaluating the severity of oral lichenoid reactions. Cohort study of large population is required.

Oral lichen planus (OLP) is a common chronic inflammatory disease in the oral cavity, and has the risk of developing into oral squamous cell carcinoma (OSCC). It is necessary to discover the role of TRIM21 in the pathogenesis of OLP and its underlying mechanism. METHODS Western bolt and qPCR assays were used to detect the effects of TRIM21 on cellular levels of ERK, p-ERK, AP-1, IL-6, TRIB2, IRF3, and IRF7, while co-immunoprecipitation was performed to verify the interaction between Trim21 and TRIB2 protein. The TRIM21 effect on TH1/TH2 balance in T cells was also evaluated using ELISA. RESULTS The results of western blot showed that TRIM21 overexpression significantly increased p-ERK, c-fos, c-jun, IL-6 and TRIB2 levels in H9 cells (P<0.01 and P<0.001), however, inhibited the IRF3 and IRF7 levels (P<0.05). On the other hand, TRIM21 did not regulate the phosphorylation of ERK and the mRNA expression of AP-1 and TRIB2. In addition, TRIM21 was in relation to the proteasome degradation in TRIB2-ERK. TRIM21 also regulated the level of TRIB2 not only by inhibiting the ubiquitination of TRIB2, but also by affecting IL-6 through the ERK pathway. CONCLUSION TRIM21 caused abnormal expression of IL-6 in OLP via regulating TRIB2-MAPK signal axis, leading to the disrupted Th1/Th2 balance in T lymphocytes.

Abstract Background: Bibliometric analysis highlights the key topics and research trends which have shaped the understanding and management of a concerned disease. The objective of this study was to identify and characterize the most-cited articles on oral lichen planus (OLP), and highlight the analysis of key topics and research trends. Methods: A comprehensive search was performed and identified in the Scopus database from 1907 to 5 March 2019 for the top-100 most-cited articles on OLP. Results: The number of citations of the 100 selected articles varied from 101 to 570, with a mean of 178.7 citations per article. Malignant potential, immunopathogenesis, and topical drug therapy were the top-3 study topics, and the majority of high-quality articles were the research of the 3 topics. Journal of Oral Pathology and Medicine (n = 19) and Oral Surgery Oral Medicine Oral Pathology Oral Radiology (n = 14) were 2 journals with the most articles published. Both van der Waal I. and Scully C. were the most frequently contributing authors (n = 9). United States (n = 27) and Academic Centre for Dentistry Amsterdam (n = 7) was the most contributing country and institution, respectively. Systematic reviews (n = 2), randomized controlled trial (n = 1), cohort studies (n = 17) were study designs with higher evidence level, but the large majority (n = 80) were considered lower level. Conclusions: The results of this first citation analysis of the 100 most cited articles on OLP provide a historical perspective on scientific evolution, and suggest further research trends and clinical practice in the field of OLP.

目的:探究干扰素(interferon,IFN)α 刺激角质形成细胞后,角质形成细胞表面共刺激分子CD40、CD80、CD86和提呈相关分子HLA-I、HLA-DR的变化以及IFN-α对角质形成细胞生存曲线的影响.方法:以人永生化口腔黏膜角质形成细胞(human immortlized oral mucosal keratinocytes,HOK)和HaCaT细胞为细胞模型,以IFN-α(实验组)、IFN-γ(阳性对照组)、PBS(阴性对照组)分别刺激细胞,以流式细胞术检测细胞表面CD40、CD80、CD86、HLA-I、HLA-DR的变化.结果:与阴性对照组相比,IFN-α实验组的角质形成细胞在刺激后24 h,HLA-I类分子、HLA-DR和CD40的阳性细胞比例及平均荧光强度明显提高.结论:IFN-α可刺激角质形成细胞表达HLA-I类分子、HLA-DR和CD40分子.

Backgrounds To explore the expression and functions of the tripartite motif-containing protein 21 (TRIM21) in oral lichen planus(OLP) lesions. Methods Paraffin sections of buccal mucosa samples from 15 cases of reticular oral lichen planus (OLP) patients and 10 healthy controls were used for immunohistochemistry to determine expression and distribution of TRIM21. Buccal mucosae from 11 OLP patients and seven healthy controls were analyzed by qPCR to quantify its gene expression. Peripheral blood mononuclear cells and CD3+ cells from four pairs of age- and sex-matched OLP patients and healthy controls were isolated for immunocytochemistry and culture. Following lentivirus-mediated overexpression of TRIM21 gene in CD3+ cells, CCK-8 was applied to evaluate cell proliferation. Cytokines including IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha, and IFN-gamma in the supernatants were measured by the cytometric bead array and verified by ELISA. Results A larger number of TRIM21-positive cells infiltrating the lamina propria were observed in OLP lesions by immunohistochemistry than those of healthy controls. Significantly higher transcription of TRIM21 was revealed by qPCR. TRIM21 overexpression in CD3+ cells significantly enhanced the proliferation and IL-6 secretion in CD3+ cells from 12 to 72 hours. Conclusion Overexpressed TRIM21 in OLP may be a primary proinflammatory molecule rather than a secondary and inducible regulatory factor in immunopathogenesis of OLP.

朗格汉斯细胞组织细胞增生症是一类具有独特临床特征的病变实体.其发病机制仍不明确.近年来的研究对此病的发病机制、治疗方法等有了新的认识.本文将对近5年关于朗格汉斯细胞组织细胞增生症的机制、表现、诊断、治疗和预后的文献进行一综述.

Objective. The aim of this study was to measure T helper (Th) 1/Th2 related cytokine expression in saliva from patients with oral lichen planus (OLP), compared with healthy controls (HC group) and controls with recurrent aphthous ulcers (RAU group). Study Design. Saliva was collected from 41 patients with OLP, 14 HCs, and 14 controls with RAU for Th1/Th2-related cytokines analysis with cytometric bead array. Disease activity in OLP was recorded by reticulation/keratosis, erythema, and ulceration scores. Results. Interleukin (IL)-6, IL-10, interferon-gamma (IFN-gamma), and IFN-gamma/IL-4 in saliva were significantly higher in the OLP group than in the HC group. A positive and significant correlation among IL-6, IL-10, and reticulation/keratosis, erythema, and ulceration scores in the OLP group was revealed. Significantly increased IL-4, IL-5, IL-6, IL-10, tumor necrosis factor-alpha and IFN-gamma/IL-4 were found in the RAU group. Conclusions. Salivary cytokine profiles analyzed by cytometric bead array may provide a convenient research approach to OLP. Data indicated complicated Th1/Th2-related cytokine profile changes, rather than simple dominance model, in OLP. IL-10 and especially IL-6 may provide a surrogate endpoint for monitoring OLP.

目的:探讨HRAS对人舌鳞癌CAL-27细胞增殖、迁移、侵袭及PI3K-AKT通路的影响.方法:利用Rfect将HRAS-siRNA转入人舌癌鳞癌CAL-27细胞,同时设置阴性对照组及空白对照组,检测HRAS蛋白的表达水平,CAL-27细胞增殖活性、迁移和侵袭能力,并检测PI3K-AKT及MEK-ERK通路关键蛋白PI3K、p-AKT、AKT、ERK、p-ERK表达水平.结果:实验组HRAS蛋白的表达水平明显低于阴性对照组及空白对照组;HRAS-siRNA明显抑制CAL-27细胞的增殖、迁移和侵袭能力,并且信号通路关键蛋白PI3K、p-AKT、p-ERK的表达水平明显降低.结论:HRAS-siRNA可明显抑制人舌鳞癌CAL-27细胞增殖、迁移及侵袭能力,推测其机制可能与PI3K-AKT及MEK-ERK信号通路有关.

Objective To discuss the application effect of "happy ward"work model in department of pediatric orthopedics.Methods By convenience sampling,100 parents from January 2014 to September 2014 were selected as control group,and 96 cases from October 2014 to Jun 2014 were selected as observation group.Patients in control group received routine nursing procedure from parents,while the observation group was applied with "happy ward"work model.The symp-tom check list-90 (SCL-90 )was used to evaluate parents before and after the intervention.Results Before intervention,there was no statistical significance of the score of SCL-90 between two groups (all P>0 .05 ).After intervention the SCL-90 score in control group was higher than which in observation group.There were significant differences in "somatization","obsessive-compulsive symptoms","anxiety",and "hostility"found in two groups(all P < 0.01 ).Conclusions The"happy ward"work model relieves patients and parents'negative mood,raises medical workers' self-efficiency,and promotes patients'recovery.

目的 编制《运输飞行员安全能力问卷》,为评估飞行员安全能力情况提供工具.方法 结合相关文献,在半开放式问卷和访谈的基础上,自编初测问卷,经过修订形成正式问卷,并对其信效度进行检验.结果 运输飞行员安全能力正式问卷,共13个题项,包括认知能力、安全观念、社会能力三个因子,三个因子的累积方差贡献率为56.857％.总问卷及三个因子的内部一致性系数分别是总问卷为0.884,认知能力为0.575,安全观念为0.722,社会能力为0.834.因素理论模型拟合较好(GFI=0.827,CFI=0.876,RMSEA=0.074).结论 编制的问卷可以为相关研究提供测评工具.

近年来，我国的研究表明，伤害是我国0～14岁儿童的首位死亡原因，导致儿童、青少年的早死或残疾，给个人、家庭和社会造成巨大的负担和损失。伤害已成为国内外关注的重要公共卫生问题［1－2］。每年平均约有25％的儿童发生外伤，其中10％～25％为骨折［3］。笔者就儿童骨折发生原因及骨折部位的研究进展作一综述。

目的：探讨骨折患儿背景对父母的心理状况的影响，为临床干预提供依据。方法对100例骨折患儿父母心理状况进行一般资料问卷和症状自评量表（SCL－90）调查。分析不同性别患儿 SCL－90的躯体化、强迫症状、人际关系、敌对性及精神病性的得分差异；主要分析不同部位骨折及是否是独生子女患儿家长 SCL－90的躯体化、强迫症状、人际关系、敌对性及精神病性的得分差异。结果男性患儿父母除强迫症状、恐怖、偏执、精神病性四个因子得分高于女性患儿父母外（ P ＜0．05），而恐怖、敌对性及抑郁得分均低于女性父母（ P ＜0．05）。25例下肢骨折患儿的 SCL－90的强迫、偏执、躯体化、人际关系敏感、焦虑、敌对性因子得分显著高于75例上肢骨折患儿（ P ＜0．01）。独生子女患儿父母 SCL－90的强迫、敌对性、恐怖、偏执、人际关系、抑郁及焦虑得分高于非独生子女（ P ＜0．05或 P ＜0．01）。结论骨折患儿有不同程度的心理问题，直接影响其父母的心理状况，故医务人员应针对患儿的不同性别、骨折不同部位及是否是独生子女家长的心理状态制定个性化措施进行干预，引导家长关心骨折患儿疾苦，避免性别歧视，使患儿及家属有归属感，提高治疗的依从性，利于骨折的愈合和心理上的康复。