Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation

In several murine models of transplantation, the “cross-dressing” of recipient antigen presenting cells (APCs) with intact donor major histocompatibility complex (MHC) derived from allograft-released small extracellular vesicles (sEVs) has been recently described as a key mechanism in eliciting and sustaining alloimmune responses. Investigation of these processes in clinical organ transplantation has, however, been hampered by the lack of sensitivity of conventional instruments and assays. We have employed advanced imaging flow cytometry (iFCM) to explore the kinetics of allograft sEV release and the extent to which donor sEVs might induce cross-dressing following liver and kidney transplantation. We report for the first time that recipient APC cross-dressing can be transiently detected in the circulation shortly after liver, but not kidney, transplantation in association with the release of HLA-bearing allograft-derived sEVs. In liver transplant recipients the majority of circulating cells exhibiting donor HLA are indeed cross-dressed cells and not passenger leukocytes. In keeping with experimental animal data, the downstream functional consequences of the transfer of circulating sEVs harvested from human transplant recipients varies depending on the type of transplant and time posttransplant. sEVs released shortly after liver, but not kidney, transplantation exhibit immunoinhibitory effects that could influence liver allograft immunogenicity.     

Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.     

Sleeve gastrectomy prior to liver transplantation is superior to medical weight loss in reducing posttransplant metabolic complications

Strategies to optimize the management of obesity-related metabolic complications after liver transplantation (LT) are needed. We examined the effect of pre-LT sleeve gastrectomy (SG), as compared to medical weight loss (MWL), on post-LT outcomes. This is a cohort study of adults (≥18 years) with medically complicated obesity who were eligible for pre-LT SG and underwent LT from January 1, 2006 to June 1, 2016. Logistic regression models evaluated the association of SG on post-LT diabetes and hypertension, defined as new-onset or progressive disease post-LT. Cox regression models evaluated the association of SG on recurrent and de novo nonalcoholic fatty liver disease (NAFLD). Among 70 LT recipients who were eligible for pre-LT SG, 14 (20%) underwent SG and 56 (80%) underwent MWL only. Mean follow-up was 5.2 years post-LT. The SG cohort sustained higher % total body weight loss at 3 years post-LT (28.9% vs. 5.4%, p < .001). In multivariable analyses, SG was associated with significantly lower risk of post-LT diabetes (OR 0.04, 95% CI 0.00–0.41, p = .01), hypertension (OR 0.15, 95% CI 0.04–0.67, p = .01), and recurrent and de novo NAFLD (HR 0.19, 95% CI 0.04–0.91, p = .04). When compared to MWL, SG resulted in sustained weight loss and significantly lower risk of diabetes, hypertension, and recurrent and de novo NAFLD post-LT.     

参连合用对代谢综合征患者“肠道菌群-免疫反应”的影响

目的　观察参连联合常规西药治疗对代谢综合征（metabolic syndrome, MS）患者糖脂代谢及肠道菌群-免疫反应的影响。方法　选取 2019年 1月—2020年 8月上海交通大学医学院附属同仁医院收治的54例湿热中阻兼气虚型的MS患者作为研究对象,按照随机数字表法分为对照组（常规西药治疗）与治疗组（常规西药+参连联合治疗）,每组各27例。观察2组治疗前后的血糖、血脂、CRP、IL-6、IL-10水平;采用荧光定量PCR法测定肠道细菌DNA,定量分析肠道主要菌群结构变化。结果　与治疗前相比,2组治疗后肠杆菌含量及空腹血糖、TC、TG、LDL-C、CRP、IL-6水平均下降,乳酸杆菌含量、双歧杆菌含量、HDL-C、IL-10水平均升高,其中2组TG、IL-6水平下降及IL-10水平上升差异均有统计学意义,治疗组乳酸杆菌含量升高差异有统计学意义（P均＜0.05）;治疗组IL-10上升幅度及IL-6下降幅度均大于对照组（P均＜0.05）。结论　参连联合常规西药治疗MS患者可提高其外周血免疫炎性因子IL-10水平,降低IL-6水平,明显升高肠道乳酸杆菌含量,对于探索参连联合常规西医治疗的MS患者“肠道菌群-免疫反应”机制研究具有重要意义。     

基于关联规则的脂肪肝与5种慢性代谢性疾病的关联性分析

目的 探讨体检人群中高血压、超重肥胖、血脂异常、高尿酸、糖尿病等5种慢性代谢性疾病与脂肪肝的关系,为脂肪肝和慢性代谢性共患病的防治提供依据。方法 采用二分类logistic回归分析脂肪肝患病的危险因素;运用Apriori算法进行年龄别和性别分组的5种慢性代谢性疾病与脂肪肝关联规则挖掘。结果 研究人群中,高血压、超重肥胖、血脂异常、高尿酸、糖尿病、脂肪肝的患病率分别为32.0%、52.0%、34.7%、31.8%、9.9% 和43.4% ;高血压、超重肥胖、血脂异常、高尿酸、糖尿病均是脂肪肝患病的危险因素 (P<0.001,OR值>1);5种慢性代谢性疾病单独患病对脂肪肝患病的提升度均大于1 (1.42~1.66);年龄、性别分组后按置信度排名第1的强关联规则均为{高血压,超重肥胖,血脂异常,高尿酸}→{脂肪肝};不同年龄组和不同性别组在强关联规则个数、关联强度等方面存在差异。结论 高血压、超重肥胖、血脂异常、高尿酸、糖尿病等5种慢性代谢性疾病均可单独对脂肪肝患病起到提升作用,多种疾病共患可增加脂肪肝患病的风险。     

健康素养在脑卒中患者积极度与自我管理行为间的中介效应

目的 探讨脑卒中患者健康素养、患者积极度和自我管理行为的现状,明确三个变量间关系,并探讨健康素养在患者积极度与自我管理行为间的中介效应。方法 采用一般资料问卷、慢性病健康素养调查量表、患者积极度量表、脑卒中自我管理行为调查问卷对河南省4所三级甲等医院就诊的223名脑卒中患者进行调查。结果 脑卒中患者健康素养得分为（82.30±15.28）分,自我管理行为得分为（40.89±9.74）分,患者积极度得分为（45.21±11.30）分。脑卒中患者健康素养、自我管理行为与患者积极度三个变量间呈正相关（r值分别为0.622、0.479、0.457,且均P<0.01）;且健康素养在患者积极度与自我管理行为间起显著部分中介效应,中介效应占总效应的53.79%。结论 脑卒中患者健康素养、患者积极度可预测其自我管理行为,且患者积极度既可直接影响自我管理行为,也可通过健康素养间接影响自我管理行为。     

Practice improves even the simplest movements

Summary Three subjects practiced accurate, fast elbow flexions of 54° to a 3° wide target. Movements of 36°, 54° and 72° were then tested. Comparison over the three distances showed that the normally monotonic relationship between movement distance and movement time is alterable by specific training. Subjects learn to go faster over the practiced distance by refining their neural commands to the muscles. The benefits of practice only partially transfer to other distances. We conclude that many of the relationships seen among movement variables in simple tasks are plastic in nature and affected by prior experience.     

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases.