BackgroundTherapeutic plasma exchange (TPE) is an important blood purification technology and most patients require multiple consecutive TPEs. Regional citrate anticoagulation (RCA) could be used for membrane therapeutic plasma exchange (mTPE). However, there is no research on the metabolic complications of the RCA for patients receiving multiple consecutive mTPEs with fresh frozen plasma (FFP) as a replacement solution.MethodsWe retrospectively included patients who used RCA for multiple consecutive mTPEs with FFP as a replacement solution in Xijing Hospital from 2020 to 2022. We collected blood gas analysis and electrolyte results before and after mTPE treatment and analysed the anticoagulation effectiveness and metabolic complications of the RCA.ResultsA total of 33 patients who underwent 131 mTPE sessions were included, and 129 (98.5%) sessions were successfully completed. Severe hypocalcemia (19.1%) and metabolic alkalosis (58.5%) were frequently observed. In single mTPE sessions, there was a significant decrease in ionized calcium levels and significant increases in serum sodium, potassium, pH, bicarbonate, and base excess (BE) levels compared to pretreatment values. When comparing the values after the last treatment to the baseline values in all 33 patients, the serum sodium, pH, bicarbonate, and BE levels increased significantly, while the ionized calcium decreased significantly. The levels of pH, bicarbonate, and BE increased with the number of mTPE sessions, and the cumulative incidence of metabolic alkalosis reached 95.2% after the fifth treatment according to the Kaplan-Meier survival analysis.ConclusionRCA is an effective anticoagulation method for patients undergoing mTPE with FFP as a replacement solution. However, the metabolic complications associated with RCA, especially hypocalcemia and metabolic alkalosis, frequently develop in patients who undergo multiple consecutive mTPEs with FFP.

BACKGROUND The opinions on the efficacy and safety of no anticoagulation versus regional citrate anticoagulation for continuous KRT (CKRT) were controversial in patients with severe liver failure with a higher bleeding risk. We performed a randomized controlled trial to assess no anticoagulation versus regional citrate anticoagulation for CKRT in these patients. METHODS Adult patients with liver failure with a higher bleeding risk who required CKRT were considered candidates. The included participants were randomized to receive regional citrate anticoagulation or no-anticoagulation CKRT. The primary end point was filter failure. RESULTS Of the included participants, 44 and 45 were randomized to receive regional citrate anticoagulation and no-anticoagulation CKRT, respectively. The no-anticoagulation group had a significantly higher filter failure rate (25 [56%] versus 12 [27%], P = 0.003), which was confirmed by cumulative incidence function analysis and sensitive analysis including only the first CKRT sessions. In the cumulative incidence function analysis, the cumulative filter failure rates at 24, 48, and 72 hours of the no-anticoagulation and regional citrate anticoagulation groups were 31%, 58%, and 76% and 11%, 23%, and 35%, respectively. Participants in the regional citrate anticoagulation group had significantly higher incidences of Ca2+tot/Ca2+ion >2.5 (7% versus 57%, P < 0.001), hypocalcemia (51% versus 82%, P = 0.002), and severe hypocalcemia (13% versus 77%, P < 0.001). However, most (73%) of the increased Ca2+tot/Ca2+ion ratios were normalized after the upregulation of the calcium substitution rate. In the regional citrate anticoagulation group, there was no significant additional increase in the systemic citrate concentration after 6 hours. CONCLUSIONS For patients with liver failure with a higher bleeding risk who required CKRT, regional citrate anticoagulation resulted in significantly longer filter lifespan than no anticoagulation. However, regional citrate anticoagulation in patients with liver failure was associated with a significantly higher risk of hypocalcemia, severe hypocalcemia, and Ca2+tot/Ca2+ion >2.5. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER RCA for CRRT in Liver Failure and High Risk Bleeding Patients, NCT03791190.

Background Heparin anticoagulation (HA) is commonly employed for membrane therapeutic plasma exchange (mTPE). However, for patients with increased bleeding risk, there were controversial opinions on the use of HA versus regional citrate anticoagulation (RCA) for mTPE. Our present study aimed to evaluate the efficacy and safety of HA vs. RCA for mTPE in patients with increased bleeding risk.Methods Patients with increased bleeding risk who underwent mTPE between 2014 and 2021 in our center were screened. Observations of anticoagulation efficacy and safety were used as the study endpoints.Results A total of 108 patients with 368 mTPE sessions were included. Of the included patients, 38 and 70 received HA and RCA mTPE, respectively. There was no significant difference in the clotting of extracorporeal circuits between the HA and RCA groups (4.1% vs. 4.4%, p = 0.605). More bleeding episodes were observed in the HA group compared to the RCA group (16.4% vs. 4.4% mTPE sessions, p < 0.001). The frequency of postoperative transfusion within 24 h (11% vs. 3.4%, p = 0.007) was significantly different in the HA and RCA group. Anticoagulation strategy (HA vs. RCA; OR 5.659, 95%CI 2.266-14.129; p < 0.001), and mean arterial pressure (prior treatment, OR 1.052, 95%CI 1.019-1.086; p = 0.002) were independent risk factors of bleeding episodes. At the end of mTPE treatment, the incidence of metabolic alkalosis (16.7% vs. 54.1%, p = 0.027) and hypocalcemia (41.7% vs. 89.2%, p = 0.001) was significantly different in the HA (n = 5, 12 sessions) and RCA (n = 22, 74 sessions) groups, respectively.Conclusion RCA is as effective as HA for mTPE. However, for patients with increased bleeding risk, RCA is associated with a lower risk of bleeding, compared with HA. With careful monitoring and timely adjustment, RCA most likely is a safe and effective anticoagulation option for mTPE in patients with increased bleeding risk.

Introduction: Culturing cerebrovascular smooth muscle cells (CVSMCs) in vitro can provide a model for studying many cerebrovascular diseases. This study describes a convenient and efficient method to obtain mouse CVSMCs by enzyme digestion. Methods: Mouse circle of Willis was isolated, digested, and cultured with platelet-derived growth factor-BB (PDGF-BB) to promote CVSMC growth, and CVSMCs were identified by morphology, immunofluorescence analysis, and flow cytometry. The effect of PDGF-BB on vascular smooth muscle cell (VSMC) proliferation was evaluated by cell counting kit (CCK)-8 assay, morphological observations, Western blotting, and flow cytometry. Results: CVSMCs cultured in a PDGF-BB-free culture medium had a typical peak-to-valley growth pattern after approximately 14 days. Immunofluorescence staining and flow cytometry detected strong positive expression of the cell type-specific markers alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain 11 (SMMHC), smooth muscle protein 22 (SM22), calponin, and desmin. In the CCK-8 assay and Western blotting, cells incubated with PDGF-BB had significantly enhanced proliferation compared to those without PDGF-BB. Conclusion: We obtained highly purified VSMCs from the mouse circle of Willis using simple methods, providing experimental materials for studying the pathogenesis and treatment of neurovascular diseases in vitro. Moreover, the experimental efficiency improved with PDGF-BB, shortening the cell cultivation period.

We evaluated the effect of acute hypobaric hypoxia (AHH) on the hippocampal region of the brain in early-stage spontaneously hypertensive male rats. The rats were classified into a control (ground level; ~ 400 m altitude) group and an AHH experimental group placed in an animal hypobaric chamber at a simulated altitude of 5500 m for 24 h. RNA-Seq analysis of the brains and hippocampi showed that differentially expressed genes (DEGs) were primarily associated with ossification, fibrillar collagen trimer, and platelet-derived growth factor binding. The DEGs were classified into functional categories including general function prediction, translation, ribosomal structure and biogenesis, replication, recombination, and repair. Pathway enrichment analysis revealed that the DEGs were primarily associated with relaxin signaling, PI3K-Akt signaling, and amoebiasis pathways. Protein–protein interaction network analysis indicated that 48 DEGs were involved in both inflammation and energy metabolism. Further, we performed validation experiments to show that nine DEGs were closely associated with inflammation and energy metabolism, of which two ( Vegfa and Angpt2 ) and seven ( Acta2, Nfkbia, Col1a1, Edn1, Itga1, Ngfr , and Sgk1 ) genes showed up and downregulated expression, respectively. Collectively, these results indicated that inflammation and energy metabolism-associated gene expression in the hippocampus was altered in early-stage hypertension upon AHH exposure.

Background: Maintenance hemodialysis (MHD) patients are often admitted to the hospital for severe morbidities. Prolonged intermittent renal replacement therapy (PIRRT) is required during the hospital staying. There are controversial opinions on the use of arteriovenous fistula (AVF) as vascular access for PIRRT in MHD patients. Methods: Patients with AVF who accepted PIRRT in our center between January 2014 and June 2021 were retrospectively screened. AVF dysfunction and patient mortality were assessed as endpoints. Univariate and multivariate regression models were employed to identify the risk factors of AVF dysfunction. Results: About 162 patients were included in our present study. Twenty-six experienced AVF dysfunction, of whom 53.8%, 19.2%, and 27.0% had percutaneous transluminal balloon angioplasty, surgical revision, and AVF reconstruction, respectively. The accumulated AVF dysfunction rates were 11.8%, 16.2%, and 21.0% in 1, 2, and 3 years, respectively. Multivariate analysis revealed that smoking (HR 2.750, 95% CI 1.181–6.402, p = 0.019), higher platelet (PLT, HR 1.009, 95% CI 1.000–1.017, p = 0.047), higher prothrombin activity (PTA, HR 1.039, 95% CI 1.012–1.066, p = 0.004), and lower diastolic blood pressure (DBP, HR 0.963, 95% CI 0.932–0.996, p = 0.026) were independent risk factors for AVF dysfunction. During the follow-up period, 37 patients died. Conclusions: Overall, the use of AVF for PIRRT might not dramatically increase the incidence of AVF dysfunction. And, Smoking, lower DBP, higher PLT, and higher PTA were associated with increased AVF dysfunction.

BACKGROUND:Myocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms.METHODS:To examine the role of endothelial MICU1 in diabetic cardiomyopathy (DCM), we used endothelial-specific MICU1ecKO mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome sequencing technology was used to explore underlying molecular mechanisms.RESULTS:Here, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression.CONCLUSIONS:Our findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.

哌托生特作为一种组胺H3受体拮抗剂/反向激动剂,其明确的促觉醒作用以及低药物依赖性使其迅速成为欧美治疗成人发作性睡病的一线用药.本文通过总结组胺H3受体分布及作用特点,阐明了哌托生特的作用靶点及其产生的相关效应;并通过总结哌托生特的药物化学特点以及将其与常见抗疲劳药物成瘾性之间进行对比,展望了哌托生特在特殊环境/条件下的应用潜能.本文为哌托生特在我国特殊环境/条件下,如军事、轮班、紧急任务等方面的合理化应用提供了理论依据.

Background: Continue renal replacement therapy (CRRT) is commonly employed for rhabdomyolysis (RM) patients. However, the optimal initiation timing of CRRT and prognostic factors were not well evaluated for patients with RM. We aimed to investigate the efficacy of CRRT timing on mortality and the risk factors of death in RM patients who accepted CRRT. Methods: RM patients who received CRRT between May 2010 and May 2021 in our center were retrospectively included. The primarily endpoint was 90-day mortality. Univariate and multivariate logistic analyses were performed to identify the risk factors of 90-day mortality. Results: A total of 134 patients were included in our present study. The 90-day mortality rate was 38.06%. Most of the patients (88.81%) reached peak creatine kinase (CK) within 72 hours after admission, and 58 (43.28%) patients received CRRT before the peak CK occurrence (earlier CRRT) and 76 (56.72%) of patients had CRRT after the peak CK occurrence (later CRRT). Multivariate logistic regression analysis showed that CRRT initiation after the peak CK occurrence (OR = 3.74, 95%CI 1.17-11.95, p = 0.026), the elevated serum cTnI (OR = 1.23, 95%CI 1.02-1.49, p = 0.032), and the need of mechanical ventilation support (OR = 7.18, 95%CI 1.67-30.83, p = 0.008) were independent risk factors of 90-day mortality. Similar results were obtained in a subgroup analysis of patients with acute kidney injury (AKI). Conclusions : Earlier CRRT initiation before the peak CK occurrence was associated with lower 90-day patient mortality.

目的 探究服用10 mg扎来普隆对主观视觉功能的影响,评估服药后的安全放飞时间.方法 15名健康男性被试者,采用双盲、单模拟和自身交叉对照研究方法,交叉服用10 mg扎来普隆和安慰剂(前后相隔3 d),服药后被试者均给予了 2.5 h的睡眠时间,于服药3、4、5 h后分别进行一次主观视觉功能评估.评估内容包括视力、主观快速暗适应、夜间视力、对比敏感度、立体视觉以及临界闪光融合频率.结果 服药3 h后扎来普隆组和安慰剂组0.6 c/d空间频率下对比敏感度为(15.49±2.92)dB vs(16.51±2.03)dB(P=0.035),差异虽有统计学意义,但其结果仍在正常范围内,扎来普隆并未导致该服药时段对比敏感度异常.服药5h后主观暗适应时间为(3.63±0.85)s vs(4.37±1.14)s(P=0.038),服用扎来普隆缩短了暗适应时间;服药后3、4、5 h扎来普隆组和安慰剂组的左、右眼视力,主观暗适应、夜间视力,对比敏感度、立体视觉以及临界闪光融合频率指标均无统计学差异(P＞0.05).结论 服用10 mg扎来普隆自服药3 h起对主观视觉功能无不良影响.

Background: Anticoagulation-free continuous renal replacement therapy (CRRT) was recommended by the current clinical guideline for patients with increased bleeding risk and contraindications of citrate. Nevertheless, anticoagulation-free CRRT yielded heterogeneous filter lifespan. Furthermore, the specific cutoff values for traditional coagulation parameters to predict sufficient filter lifespan of anticoagulation-free CRRT have not yet been determined. The purpose of our present study was to develop and validate a model for predicting sufficient filter lifespan in anticoagulation-free CRRT patients. Methods: Patients who underwent anticoagulation-free CRRT in our center between June 2013 and June 2019 were retrospectively included. The primary outcome was sufficient filter lifespan (≥24 h). Thirty-seven predictors were included for modeling based on their clinical significance and previous reports. The final model was developed by using multivariable logistic regression analysis and was validated in a separate external cohort. Results: The development cohort included 170 patients. Sufficient filter lifespan was observed in 80 patients. Thirteen variables were independent predictors for sufficient filter lifespan by logistic regression: body temperature, mean arterial pressure, activated partial thromboplastin time, direct bilirubin, alkaline phosphatase, blood urea nitrogen, vasopressor use, body mass index, white blood cell, platelet count, D-dimer, uric acid, and pH. The area under the curve (AUC) of the stepwise model and internal validation model was 0.82 (95% confidence interval [CI] [0.76–0.88]) and 0.8 (95% CI [0.74–0.87]), respectively. The positive predictive value and the negative predictive value of the stepwise model were 0.77 and 0.79, respectively. The validation cohort included 44 eligible patients and the AUC of the external validation model was 0.82 (95% CI [0.69–0.96]). Conclusions: The use of a prediction model instead of an assessment based only on coagulation parameters could facilitate the identification of the patients with filter lifespan of ≥24 h when they accepted anticoagulation-free CRRT.

Background: Anticoagulation-free continuous renal replacement therapy (CRRT) was recommended by the current clinical guideline for patients with increased bleeding risk and contraindications of citrate and resulted in heterogeneous filter lifespan. There was no prediction model to identify the patients would have sufficient filter lifespan when they have to accept CRRT without the use of any anticoagulation. The purpose of our present study is to develop a clinical prediction model of sufficient filter lifespan in anticoagulation-free CRRT patients. Method: Patients who underwent anticoagulation-free CRRT in our center between June 2013 and June 2019 were retrospectively included. The primary outcome was sufficient filter lifespan (≥ 24 hours). The final model was established by using multivariable logistic regression analysis. And, the prediction model was validated in an external cohort. Results: A total of 170 patients were included in the development cohort. Sufficient filter lifespan were observed in 80 patients. The probability of sufficient filter lifespan could be calculated using the following regression formula: P (%) = exp (Z)/1 + exp (Z), where Z = 0.49896-(0.08552*BMI)+(0.44107*T)+(0.03373*MAP)-(0.03389*WBC)+(1.51579*[vasopressor=1])-(0.01132*PLT)+(0.00422*ALP)-(2.66910*pH)-(0.00214*UA)+(0.05992*BUN)+(0.00400*Db)–(0.00014*D-dimer)+(0.02818*APTT). The area under the curve (AUC) of the stepwise model and internal validation model was 0.82 (95%CI [0.76-0.88]) and 0.8 (95%CI [0.74-0.87]), respectively. At the optimal cut-off value of -0.1052, the positive predictive value and the negative predictive value of the stepwise model was 0.77 and 0.79, respectively. The AUC of the external model was 0.82 (95%CI [0.69-0.96]). Conclusion: The use of a prediction model instead of an assessment based only on coagulation parameters could facilitate the identification of the patients with filter lifespan of ≥ 24 hours when they accepted anticoagulation-free CRRT.

Objective To explore effects of programming puncture method on success rate and complication inpatients with hemodialysis. Methods According to inclusion and exclusion criteria, 100 cases with hemodialysis were collected and were divided into two groups: the study group and the control group with 50 patients in each group. The study group performed programming puncture method while the control group conducted conventional puncture method. Success rate of puncture, incidence of fistula thrombosis and complications were compared between two groups. Results One-time success rate of puncture in study group was 99.98% higher than 95.99% in control group. Furthermore, no patient occurred fistula thrombosis and pseudoaneurysm in study group. In addition, in bleeding of puncture site, the study group was better than the control group too. Conclusions Programming puncture method can improve the success rate of fistula puncture, reduce the fistula thrombosis rate and other complications in patients with hemodialysis.