肝细胞损伤的分子生物学机制

随着医学研究的不断进展,我们对各种肝脏疾病的病因有了更加深入的了解,对疾病的治疗也渐渐从对症治疗转移到病因治疗,但是,在强调病因学治疗的同时,不应忽略对肝细胞的保护,因为肝细胞损伤是各型肝病共同的病理基础,是各种原因引起肝脏疾病的共同的表现.     

Potential Mechanisms of Interferon-α Induced Autoimmunity

The type I interferons (IFN) are cytokines encoded by a multigene family comprising 13 closely related IFN-A genes, and a single IFN-B gene. These factors are rapidly induced upon viral infection, and have pleiotropic effects. Historically, the induction of a cell-autonomous state of antiviral resistance, the inhibition of cell growth, and the regulation of apoptosis were appreciated first. More recently, it became generally accepted that they can regulate immune effector functions. This latter feature led them to be reconsidered as signals linking innate and adaptive immunity, and potentially orchestrating autoimmunity associated with viral infection and IFN-α therapy. Common to almost all autoimmune diseases is their polygenic inheritance, incomplete penetrance, and evidence for the role of environmental factors, particularly viral infection. In addition, they are characterized by increased numbers of circulating autoreactive T- and B-cells. Endogenously produced or therapeutically applied IFN-α can tilt the usually tightly controlled balance towards activation of these autoreactive cells via a vast array of mechanisms. The genetic susceptibility factors determine which type of autoimmunity will develop. IFN-α induces numerous target genes in antigen presenting cells (APC), such that APC are stimulated and enhance humoral autoimmunity, promote isotype switching, and potently activate autoreactive T cells. Moreover, IFN-α can synergistically amplify T cell autoreactivity by directly promoting T cell activation and keeping activated T cells alive. In essence, type I IFNs may constitute one example of genes that have been conserved because they confer dominant disease resistance, but at the same time they can trigger autoimmunity in genetically susceptible individuals.     

Musculoskeletal regeneration and its implications for the treatment of tendinopathy

Tendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non‐mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non‐mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration.     

Grafting of Chitosan with Styrene and Maleic Anhydride via Nitroxide‐Mediated Radical Polymerization in Supercritical Carbon Dioxide

A novel synthesis route is used to produce chitosan‐graft‐poly(styrene‐maleic anhydride)‐OH‐TEMPO (CTS‐g‐PSMA‐T). A three‐step reaction scheme is proposed: 1) bromine 4‐OH‐TEMPO oxoammonium salt is synthesized. 2) Hydroxyl‐targeted groups in the CTS molecule are reacted with the synthesized salt in aqueous acid solution. A functionalization of 18.9% is achieved. 3) Graft copolymerization of styrene and maleic anhydride is done via NMRP by a unimolecular initiation system. The reaction is run in a dispersion in supercritical carbon dioxide (scCO₂) in the presence of camphorsulfonic acid (CSA) to avoid autopolymerization. A modified CTS with a graft content of 68% in weight is obtained.

     

降尿酸治疗对脑梗死患者血管内皮功能的影响

目的:研究高尿酸血症的急性脑梗死患者降尿酸治疗对血管内皮功能及血压的影响。方法:搜集同一中心共138例患者入选该研究。高尿酸血症并急性脑梗死者入选92例,随机（随机数字法）分为实验组46例,对照组46例,同时入选同期血尿酸正常的急性脑梗死患者46例,实验组口服别嘌醇3个月治疗高尿酸血症。对这些人群进行抽血化验,记录治疗前后血尿酸、血脂及hs-CRP,同时检测患者血压、体质量指数（BMI）,并采用超声无创血流介导的血管舒张功能（FMD）进行血管内皮功能评估,治疗前后各组之间比较并进行统计学分析。结果:别嘌醇治疗3个月后实验组血尿酸[(479.7±49.0) μmol/L vs. (381.2±76.7)μmol/L]、hs-CRP[(8.1±6.7) mg/L vs. (5.1±4.6) mg/L]、收缩压[(124.7±26.3) mmHg vs. (97.4±13.5) mmHg]明显降低( P<0.05),FMD[(7.6±3.5%) vs. (11.2±3.9%)]明显升高( P<0.05),FMD升高的程度与血尿酸降低的程度呈正相关( r=0.463, P<0.01),多元回归分析显示血尿酸是FMD的独立影响因子（ β=-0.229, P=0.035)。 结论:高尿酸血症的急性脑梗死患者中降尿酸治疗可明显改善患者的血管内皮功能,改善炎症状态,降低患者血压,进一步印证了高尿酸血症导致血管内皮功能紊乱,促进动脉粥样硬化的发生与发展。     

The significance of histological diagnosis in renal allograft biopsies in 2014

In 2014, the renal allograft biopsy still represents the best available diagnostic ‘gold’ standard to assess reasons for allograft dysfunction. However, it is well recognized that histological lesion observed in the biopsy is of limited diagnostic specificity and that the Banff classification as the international diagnostic standard represents mere expert consensus. Here, we review the role of the renal allograft biopsy in different clinical and diagnostic settings. To increase diagnostic accuracy and to compensate for lack of specificity, the interpretation of biopsy pathology needs to be within the clinical context, primarily defined by time post‐transplantation and patient‐specific risk profile. With this in mind, similar histopathological patterns will lead to different conclusions with regard to diagnosis, disease grading and staging and thus to patient‐specific clinical decision‐making. Consensus generation for such integrated diagnostic approach, preferably including new molecular tools, represents the next challenge to the transplant community on its way to precision medicine in transplantation.     

Difference in outcomes after antibody‐mediated rejection between abo‐incompatible and positive cross‐match transplantations

Graft survival seems to be worse in positive cross‐match (HLAi) than in ABO‐incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty‐nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody‐mediated rejection (AMR) were different. Five‐year death‐censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti‐A/B and anti‐HLA antibodies.     

Th‐17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell–mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell–mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il‐17 and T‐bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell–mediated rejection reversal (p = 0.03). The presence of IL‐17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell–mediated rejection in recipients of expanded criteria allograft.