芫根调节免疫功能的小肠转录组学研究

利用生物信息学技术初步探索芫根调控肠道免疫功能的分子生物学机制。方法 选择雄性SPF级BALB/c小鼠18只，随机分为3组，每组6只。SC1组小鼠每只每次灌胃芫根提取液150 μL，SC2组小鼠每只每次灌胃绞碎芫根原浆悬液150 μL，NC组小鼠每只每次灌胃生理盐水150 μL，连续7 d每日灌胃一次。分别取每组小鼠小肠组织样品提取RNA，总RNA的质检合格后，进行转录组测序。按GO功能和KEGG信号通路对差异表达基因聚类分析揭示差异表达高度富集的免疫相关通路。从免疫角度分析芫根灌胃小鼠小肠组织的基因表达变化情况。结果 转录组测序共检测到27733条 mRNA的表达，SC1组与NC组比较，显著差异表达基因1635个，其中上调差异表达基因1236个，下调差异表达基因399个；SC2组与NC组比较，显著差异表达基因2872个，其中上调差异表达基因2233个，下调差异表达基因639个（P＜0.05）。按GO功能和KEGG信号通路聚类分析显示差异表达基因在白介素分泌、干扰素反应、T细胞受体信号通路及维生素和脂肪消化吸收等途径的富集度在两个芫根组中均居于前20位（P＜0.01），肠黏膜趋化因子CCL20和巨噬细胞极化标志物CD274等免疫蛋白编码基因差异表达显著且同属于上述多个免疫通路。结论 芫根灌胃小鼠小肠的差异表达基因在白介素分泌、干扰素反应、T细胞受体信号通路、营养物质消化吸收等途径高度富集，提示芫根对肠道免疫系统及肠黏膜功能的调节，其中CD274的表达上调和CCL20的表达下调提示诱导M1型巨噬细胞极化和T细胞活化可能是芫根调控免疫和维护肠道正常结构功能的重要途径。     

基于苗药五藤膏外敷对CIA大鼠炎性骨破坏的影响探讨苗医外治就近驱邪的作用＊

目的 通过研究明确苗药五藤膏外敷缓解胶原诱导性关节炎（CIA）大鼠关节局部炎症和骨破坏的机制，证实苗医外治就近驱邪的作用。方法 将70只Wistar大鼠随机分为空白组、模型组、苗药五藤膏高、中、低剂量组、扶他林组及IL-17阻断组，每组10只。除空白组外，其余6组均构建CIA模型，并给予相应的外敷治疗。观察大鼠一般情况，HE染色进行病理学分析，TRAP染色检测OC生成，ELISA检测各炎症因子的含量，RT-PCR和WB分别检测RANKL的基因及蛋白表达。结果 苗药五藤膏能改善CIA大鼠破骨细胞浸润及关节病理性结构，并降低RANKL蛋白、基因表达以及TNF-α、IL-1、IL-6、IL-17含量。结论 苗药五藤膏外敷剂对CIA大鼠的治疗机制可能与降低致炎因子的分泌，抑制RANKL及OC的表达相关。     

Redefining “low risk”: Outcomes of surgical aortic valve replacement in low-risk patients in the transcatheter aortic valve replacement era

ObjectivesGuidelines suggest aortic valve replacement (AVR) for low-risk asymptomatic patients. Indications for transcatheter AVR now include low-risk patients, making it imperative to understand state-of-the-art surgical AVR (SAVR) in this population. Therefore, we compared SAVR outcomes in low-risk patients with those expected from Society of Thoracic Surgeons (STS) models and assessed their intermediate-term survival.MethodsFrom January 2005 to January 2017, 3493 isolated SAVRs were performed in 3474 patients with STS predicted risk of mortality <4%. Observed operative mortality and composite major morbidity or mortality were compared with STS-expected outcomes according to calendar year of surgery. Logistic regression analysis was used to identify risk factors for these outcomes. Patients were followed for time-related mortality.ResultsWith 15 observed operative deaths (0.43%) compared with 55 expected (1.6%), the observed:expected ratio was 0.27 for mortality (95% confidence interval [CI], 0.14-0.42), stroke 0.65 (95% CI, 0.41-0.89), and reoperation 0.50 (95% CI, 0.42-0.60). Major morbidity or mortality steadily declined, with probabilities of 8.6%, 6.7%, and 5.2% in 2006, 2011, and 2016, respectively, while STS-expected risk remained at approximately 12%. Mitral valve regurgitation, ventricular hypertrophy, pulmonary, renal, and hepatic failure, coronary artery disease, and earlier surgery date were residual risk factors. Survival was 98%, 91%, and 82% at 1, 5, and 9 years, respectively, superior to that predicted for the US age-race-sex–matched population.ConclusionsSTS risk models overestimate contemporary SAVR risk at a high-volume center, supporting efforts to create a more agile quality assessment program. SAVR in low-risk patients provides durable survival benefit, supporting early surgery and providing a benchmark for transcatheter AVR.     

Contemporary Management of Ischemic Mitral Regurgitation at Coronary Artery Bypass Grafting

BackgroundRecent guidelines for the treatment of moderate or severe ischemic mitral regurgitation (IMR) in patients undergoing coronary artery bypass grafting (CABG) have changed. This study assessed the real-world impact of changing guidelines on the management of IMR during CABG over time. We hypothesized that the utilization of mitral valve repair for IMR would decrease over time, whereas mitral valve replacement for severe IMR would increase.MethodsPatients undergoing CABG in a statewide collaborative database (2011-2020) were stratified by severity of IMR. Trends in mitral valve repair or replacement were evaluated. To account for differences of the patients, propensity score–matched analyses were used to compare patients with and without mitral intervention.ResultsA total of 11,676 patients met inclusion criteria, including 1355 (11.6%) with moderate IMR and 390 (3.3%) with severe IMR. The proportion of patients undergoing mitral intervention for moderate IMR decreased over time (2011, 17.7%; 2020, 7.5%; P_trend = .001), whereas mitral replacement for severe IMR remained stable (2011, 11.1%; 2020, 13.3%; P_trend = .14). Major morbidity was higher for patients with moderate IMR who underwent mitral intervention (29.1% vs 19.9%; P = .005). In a propensity analysis of 249 well-matched pairs, there was no difference in major morbidity (29.3% with mitral intervention vs 23.7% without; P = .16) or operative mortality (1.2% vs 2.4%; P = .5).ConclusionsConsistent with recent guideline updates, patients with moderate IMR were less likely to undergo mitral repair. However, the rate of replacement for severe IMR did not change. Mitral intervention during CABG did not increase operative mortality or morbidity.     

慢性疼痛中枢调控网络的研究现状与思考＊

慢性疼痛是一种复杂的身心疾病，包括躯体痛觉异常、认知障碍、负性情绪等多个方面的改变，同时伴随着神经系统的功能以及结构的改变。本文将对慢性疼痛与下行疼痛调节通路、疼痛情感-认知调控网络以及中脑边缘奖赏网络的相关性，以及针刺镇痛的中枢机制相关研究文献进行综述，旨在探讨下行疼痛调节通路、疼痛情感-认知调控网络以及中脑边缘奖赏网络在慢痛发生机制中的作用，为临床治疗慢性疼痛类疾病提供更优势的治疗方案。     

Assessing the Effects of Geniculate Artery Embolization in a Nonsurgical Animal Model of Osteoarthritis

PurposeTo create a nonsurgical animal model of osteoarthritis (OA) to evaluate the effects of embolotherapy during geniculate artery embolization (GAE).Materials and MethodsFluoroscopy-guided injections of 700 mg of sodium monoiodoacetate were performed into the left stifle in 6 rams. Kinematic data were collected before and after induction. At 10 weeks after induction, Subjects 1 and 4–6 underwent magnetic resonance (MR) imaging with dynamic contrast enhancement (DCE) and Subjects 1, 3, and 4–6 underwent angiography with angiographic scoring to identify regions with greatest disease severity for superselective embolization (75–250-μm microspheres). Target vessel size was measured. At 24 weeks after angiography, DCE-MR imaging, angiography, and euthanasia were performed, and bilateral stifles were harvested. Medial/lateral tibial and femoral condylar, patellar, and synovial samples were cut, preserved, decalcified, and scored using the Osteoarthritis Research Society International criteria. The stifle and synovium Whole-Organ Magnetic Resonance Imaging Score and Multicenter Osteoarthritis Study score were determined. The volume transfer constant (K_trans) and extracellular volume fraction (v_e) were calculated from DCE-MR imaging along the lateral synovial regions of interest.ResultsThe mean gross and microscopic pathological scores were elevated at 38 and 61, respectively. Mean synovitis score was elevated at 9.2. Mean pre-embolization and postembolization angiographic scores were 5 and 3.8, respectively. Mean superior, transverse, and inferior geniculate artery diameters were 3.1 mm ± 1.21, 2.0 mm ± 0.50, and 1.6 mm ± 0.41 mm, respectively. Mean pre-embolization and postembolization cartilage and synovitis scores were elevated at 35.13 and 73.3 and 5.5 and 9.2, respectively. The K_trans/v_e values of Subjects 4, 5, and 6 were elevated at 0.049/0.38, 0.074/0.53, and 0.065/0.51, respectively. Altered gait of the hind limb was observed in all subjects after induction, with reduced joint mobility. No skin necrosis or osteonecrosis was observed.ConclusionsA nonsurgical ovine animal knee OA model was created, which allowed the collection of angiographic, histopathological, MR imaging, and kinematic data to study the effects of GAE.     

Outcomes of Incidental Lung Nodules With Structured Recommendations and Electronic Tracking

ObjectiveTo evaluate the impact of structured recommendations on follow-up completion for incidental lung nodules (ILNs).MethodsPatients with ILNs before and after implementation of structured Fleischner recommendations and electronic tracking were sampled randomly. The cohorts were compared for imaging follow-up. Multivariable logistic regression was used to assess appropriate follow-up and loss to follow-up, with independent variables including use of structured recommendations or tracking, age, sex, race, ethnicity, setting of the index test (inpatient, outpatient, emergency department), smoking history, and nodule features.ResultsIn all, 1,301 patients met final inclusion criteria, including 255 patients before and 1,046 patients after structured recommendations or tracking. Baseline differences were found in the pre- and postintervention groups, with smaller ILNs and younger age after implementing structured recommendations. Comparing pre- versus postintervention outcomes, 40.0% (100 of 250) versus 29.5% (309 of 1,046) of patients had no follow-up despite Fleischner indications for imaging (P = .002), and among the remaining patients, 56.6% (82 of 145) versus 75.0% (553 of 737) followed up on time (P < .001). Delayed follow-up was more frequent before intervention. Differences postintervention were mostly accounted for by nodules ≤8 mm in the outpatient setting (P < .001). In multivariable analysis, younger age, White race, outpatient setting, and larger nodule size showed significant association with appropriate follow-up completion (P < .015), but structured recommendations did not. Similar results applied for loss to follow-up.DiscussionConsistent use of structured reporting is likely key to mitigate selection bias when benchmarking rates of appropriate follow-up of ILN. Emergency department patients and inpatients are at high risk of missed or delayed follow-up despite structured recommendations.     

Transhiatal lower mediastinal lymph node dissection for esophagogastric junction carcinoma by interconnecting four body cavities

BackgroundDue to the limited number of landmark structures, it is difficult to standardize the surgical procedures for advanced esophagogastric junction cancer such as Ivor Lewis esophagectomy that require transhiatal lower mediastinal lymph node dissection (TH-LMND). We demonstrate an easily reproducible procedure for TH-LMND, wherein four body cavities, namely, the abdominal cavity, infracardiac bursa (ICB), and left and right thoracic cavities are interconnected.MethodsFirst, the dissection between the right crus and the esophagus was used to connect the abdominal cavity to the ICB — a lower mediastinal cavity separated from the omental bursa during embryonic development [1,2]. Second, the right thoracic cavity was opened with the shortest distance by dissecting the cranial side of the ICB. The right pulmonary ligament was dissected from the right lung. Third, the dissection to the contralateral side while exposing the aorta and the pericardium connected the left and right thoracic cavities. Then, the left pulmonary ligament was dissected from the left lung. The dissected tissues, including the lymph nodes, were subsequently peeled from the esophagus.ResultsBetween April 2018 and August 2021, 14 patients underwent laparoscopic or robotic TH-LMND via the procedure above. The median time required to complete the dissection was 75 min. None of the procedures were converted to open surgery, and none of the patients experienced intraoperative complications such as pericardial injury, lung injury, or massive bleeding.ConclusionThe surgical concept of interconnecting four body cavities made the procedure more accessible and reproducible while achieving en bloc TH-LMND.     

Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults

ObjectivesDonor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients.MethodsPediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated.ResultsA total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively).ConclusionsDonor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.