Regional Citrate Anticoagulation versus No Anticoagulation for CKRT in Patients with Liver Failure with Increased Bleeding Risk.

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 Ca 2+tot /Ca 2+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 Ca 2+tot /Ca 2+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 Ca 2+tot /Ca 2+ion >2.5. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: RCA for CRRT in Liver Failure and High Risk Bleeding Patients, NCT03791190 .

Analysis of left-turn behaviors of non-motorized vehicles and vehicle-bicycle conflicts.

In order to further study the expansion characteristics of left-turning non-motorized vehicles at intersections and the relationship between expansion characteristics and vehicle-bicycle conflicts, the trajectory point data of left-turning non-motorized vehicles are extracted using video trajectory tracking technology, and construct the cubic curve expansion envelope equation with the highest fitting degree. For the purpose of quantifying the expansion degree of non-motor vehicles after starting, two intersections in Guangxi Zhuang Autonomous Region were selected for case analysis, and the numerical range of expansion degree of the intersection with a left-turn waiting area and the intersection without a left-turn waiting area was obtained. Study the mathematical relationship between the expansion degree and its influencing factors, and establish the multivariate nonlinear regression equation between the expansion degree and the left-turn non-motorized vehicle flow, the number of parallel non-motorized vehicles, and the left-turn green light time. Analyze the vehicle-bicycle conflicts caused by the expansion of left-turning non-motorized vehicles, determine the essential factors affecting the number of non-motorized vehicles, and establish the multiple linear regression equation between the number of non-motorized vehicles and the number of left-turning non-motorized vehicles, the expansion degree, and the number of parallel non-motorized vehicles, the results show that the model has high accuracy. By analyzing the expansion characteristics of left-turning non-motorized vehicles at intersections, the relationship between different influencing factors and the expansion degree is obtained. Then the vehicle-bicycle conflicts under the influence of expansion characteristics is analyzed, providing theoretical ideas for improving traffic efficiency and optimizing traffic organization at intersections.

Dissecting human placental cells heterogeneity in preeclampsia and gestational diabetes using single-cell sequencing.

Preeclampsia (PE) and gestational diabetes mellitus (GDM) are pregnancy-specific complications, which affect maternal health and fetal outcomes. Currently, clinical and pathological studies have shown that placenta homeostasis is affected by these two maternal diseases. In this study, we aimed to gain insight into the heterogeneous changes in cell types in placental tissue-isolated from cesarean section by single-cell sequencing, including those patients diagnosed with PE (n = 5), GDM (n = 5) and healthy control (n = 5). A total of 96,048 cells (PE: 31,672; GDM: 25,294; control: 39,082) were identified in six cell types, dominated by trophoblast cells and immune cells. In addition, trophoblast cells were divided into four subtypes, including cytotrophoblast cells (CTBs), villous cytotrophoblasts (VCTs), syncytiotrophoblast (STB), and extravillous trophoblasts (EVTs). Immune cells are divided into lymphocytes and macrophages, of which macrophages have 3 subtypes (decidual macrophages, Hofbauer cells and macrophages), and lymphocytes have 4 subtypes (BloodNK, T cells, plasma cells, and decidual natural killer cells). Meanwhile, we also proved the orderly differentiation sequence of CTB into VCT, then STB and EVT. By pair-wise analysis of the expression and enrichment of differentially expressed genes in trophoblast cells between PE, GDM and control, it was found that these cells were involved in immune, nutrient transfer, hormone and oxidative stress pathways. In addition, T cells and macrophages play an immune defense role in both PE and GDM. The proportion of CTB and EVT cells in placental tissue was confirmed by flow cytometry. Taken together, our results suggested that the human placenta is a dynamic heterogenous organ dominated by trophoblast and immune cells, which perform their respective roles and interact with other cells in the environment to maintain normal placental function.

Heparin anticoagulation versus regional citrate anticoagulation for membrane therapeutic plasma exchange in patients with increased bleeding risk.

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.

Long-term arteriovenous fistula prognosis for maintenance hemodialysis patients who accepted PIRRT by using arteriovenous fistula.

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.

Analysis of findings of ear, nose, and throat exam of some freshmen in military college entrance examination in Shandong Province / 中国学校卫生

Objective@#To analyze the ear, nose, and throat exam of some freshmen in the military college entrance examination in Shandong Province in 2020 and to facilitate adolescent targeted health promotion.@*Methods@#The 1 411 freshmen participating in the military college entrance examination in Jinan, Zibo and Weifang of Shandong Province were included. The ear, nose, and throat exam were performed by professionals using electric otoscope, 5 meter whispering test, and front rhinoscope.@*Results@#Nasal septal deviation and hypertrophy of inferior turbinate accounted for the highest proportion. Among 489 cases of nasal septum deviation, the detection rate of Jinan (15.97%) was significantly lower than that of Weifang (43.60%) and Zibo (46.53%) ( χ 2=63.32， P <0.05). For deviation of nasal septum, the detection rate in students with urban residence (31.53%) was significantly lower than that of rural students (39.03%) ( χ 2=4.11， P <0.05). Seventy two cases of inferior turbinate hyperplasia were detected, and the detection rate in Jinan (2.99%) was significantly lower than that in Weifang (6.51%) and Zibo (6.04%) ( χ 2=6.63， P <0.05). The detection rate of tonsil hypertrophy was significantly lower in boys (4.63%), students from urban area (3.94%), compared with that of girls(9.56%) and rural students (6.70%) ( χ 2=5.35，4.86， P <0.05). In pharyngeal examination, tonsil hyperplasia was the most common condition of enlarged tonsils ( n =214), which was significantly higher in Jinan(22.36%) than that of Weifang (11.71 %) and Zibo (10.74%) ( χ 2=22.39， P <0.05), and was significantly lower in boys (14.38%) and rural students (12.40%) than that in girls (22.79%) and urban students (17.24%) ( χ 2=4.70，4.65， P <0.05).@*Conclusion@#Nasal septum deviation and tonsil hypertrophy are the most prevalent upper airway diseases among freshmen participating in the military college entrance examination. Prevention and treatment of nasopharynx diseases should be emphasized.

Organic-Inorganic High-Valence Sn18-oxo Clusters: Direct Utilization of an Inorganic Sn(IV) Source to Improve the Nuclearity and Electrocatalytic CO2 Reduction Properties.

The high-valence tin-oxo clusters are of great significance because of their structural diversity and potential applications in many fields, e.g., catalysis, extreme ultraviolet (EUV) lithography, and so on. The synthesis of high-nuclearity tin-oxo clusters remains a great challenge currently, since the key inorganic SnxOy core with Sn4+ ions could not be obtained only by the in situ Sn-C bond cleavage in organic tin sources. In this context, we synthesize three organic-inorganic hybrid Sn18-oxo clusters, [(BuSn)12Sn6(µ3-O)20(ba)12(PhPO3)4] (Bu = butyl, Hba = benzoic acid), [(BuSn)12Sn6(µ3-O)20(pmba)12(PhPO3)4]·2CH3CN·2H2O (Hpmba = p-toluic acid), and [(BuSn)12Sn6(µ3-O)20(ptba)12(PhPO3)4]·2CH3CN·2iPrOH·2H2O (Hptba = p-tert-butyl benzoic acid), as well as one Sn6-oxo cluster [(BuSn)6(µ3-O)2(µ2-OH)4(pnba)6(PhPO3)2] (Sn6) (Hpnba = p-nitrobenzoic acid) by combining an inorganic precursor (SnCl4) with an organic one (butyltin hydroxide oxide). It is shown that an inorganic dicyclo-chain-like Sn6O8 core encapsulated in a U-shaped dodecanuclear butyltin-oxo ring plays an important role in the construction of Sn18-oxo clusters and that the use of a ligand with an electron-withdrawing group reduces the nuclearity of clusters to Sn6. Moreover, electrocatalytic CO2 reduction studies confirm that the electrocatalytic activities of the Sn18 clusters are superior to those of the Sn6 cluster, probably due to the hybrid organotin-inorganotin structures. Our work not only opens a new way for constructing high-nuclearity tin-oxo clusters but also is helpful in deeply revealing the structure-properties relationship of tin-oxo clusters.

Role of FOXO protein's abnormal activation through PI3K/AKT pathway in platinum resistance of ovarian cancer.

AIM: Platinum-based chemotherapy is the standard treatment for ovarian cancer. However, tumor cells' resistance to platinum drugs often occurs. This paper provides a review of Forkhead box O (FOXO) protein's role in platinum resistance of ovarian cancer which hopefully may provide some further guidance for the treatment of platinum-resistant ovarian cancer. METHODS: We reviewed a 128 published papers from authoritative and professional journals on FOXO and platinum-resistant ovarian cancer, and adopts qualitative analyses and interpretation based on the literature. RESULTS: Ovarian cancer often has abnormal activation of cellular pathways, the most important of which is the PI3K/AKT pathway. FOXOs act as crucial downstream factor of the PI3K/Akt pathway and are negatively regulated by it. DNA damage response and apoptosis including the relationship between FOXOs and ATM-Chk2-p53 are essential for platinum resistance of ovarian cancer. Through gene expression analysis in platinum-resistant ovarian cancer cell model, it was found that FoxO-1 is decreased in platinum-resistant ovarian cancer, so studying the role of FOXO in the pathway on platinum-induced apoptosis may further guide the treatment of platinum-resistant ovarian cancer. CONCLUSIONS: There are many drug resistance mechanisms in ovarian cancer, wherein the decrease in cancer cells apoptosis is one of the important causes. Constituted by a series of transcription factors evolving conservatively and mainly working in inhibiting cancer, FOXO proteins play various roles in cells' antitumor response. More and more evidence suggests that we need to re-understand the role that FOXOs have played in cancer development and treatment.

Prevalence and risk factors of relapse in patients with ANCA-associated vasculitis receiving cyclophosphamide induction: a systematic review and meta-analysis of large observational studies.

BACKGROUND: Clinical relapses are common in patients with ANCA-associated vasculitis (AAV). The aim of this systematic review was to estimate time-point prevalence and risk factors of relapse. METHODS: We searched PubMed, Embase, and Cochrane Library databases from their inception to March 30, 2020. Cohorts and post-hoc studies were included for the estimation of summary cumulative relapse rates (CRRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Sensitivity and meta-regression analyses were also performed. RESULTS: Of the 42 eligible studies, 24 studies with 6236 participants were used for the pooled analyses of CRRs. The summary 1-year, 3-year, and 5-year CRRs were 0.12 (95% CI, 0.10-0.14), 0.33 (0.29-0.38), and 0.47 (0.42-0.52), respectively. In meta-regressions, the baseline age was positively associated with 1-year CRR. The proportion of granulomatosis with polyangiitis was positively associated with 5-year CRR. Twenty-eight studies with 5390 participants were used for the meta-analysis of risk factors for relapse, including a lower level of baseline serum creatine, proteinase 3 (PR3)-ANCA positivity at diagnosis, an ANCA rise, extrarenal organ involvement (including lung, cardiovascular, upper respiratory, and gastrointestinal involvement), intravenous (vs oral) cyclophosphamide induction, a shorter course of immunosuppressant maintenance, and maintenance with mycophenolate mofetil (vs azathioprine). CONCLUSIONS: Our systematic review demonstrated that the 1-year, 3-year, and 5-year cumulative probabilities of relapse were ∼12%, 33%, and 47% in AAV patients receiving cyclophosphamide induction, respectively. Early identification of risk factors for relapse is helpful to the risk stratification of patients so as to achieve personalized treatment.

Transcriptomics-determined chemokine-cytokine pathway presents a common pathogenic mechanism in pregnancy loss and spontaneous preterm birth.

PROBLEM: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear. We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic-environmental factors. The specific objective of the current study is to uncover the common molecular mechanism(s) by identifying the specific transcripts that are present in variant subtypes of pregnancy loss and preterm birth. METHOD OF STUDY: Transcriptomic profiling was performed with RNA expression microarray or RNA sequencing of placentas derived from pregnancy loss (which includes spontaneous miscarriage, recurrent miscarriage, and stillbirth) and spontaneous preterm birth, followed by bioinformatic analysis of multi-omic integration to identify pathogenic molecules and pathways involved in pathological pregnancies. RESULTS: The enrichment of common differentially expressed genes between full-term birth and preterm birth and pregnancy loss of miscarriage and stillbirth revealed different pathophysiological pathway(s), including cytokine signaling dysregulated in spontaneous preterm birth, defense response, graft-versus-host disease, antigen processing and presentation, and T help cell differentiation in spontaneous miscarriage. Thirty-three genes shared between spontaneous preterm birth and spontaneous miscarriage were engaged in pathways of interferon gamma-mediated signaling and of antigen processing and presentation. For spontaneous miscarriage, immune response was enriched in the fetal tissue of chorionic villi and in the maternal facet of the placental sac. The transcript of nerve growth factor receptor was identified as the common molecule that is differentially expressed in all adverse pregnancies: spontaneous preterm birth, stillbirth, spontaneous miscarriage, and recurrent miscarriage. Superoxide dismutase 2 was up-regulated in all adverse outcomes of pregnancy except for recurrent miscarriage. Cytokine-cytokine receptor interaction was the common pathway in spontaneous preterm birth and spontaneous miscarriage. Defense response was enriched in the fetal tissue of miscarriage and in the maternal tissue in spontaneous miscarriage. CONCLUSIONS: Our results indicated that the chemokine-cytokine pathway may play important roles in and function as a common pathogenic mechanism associated with, the different adverse outcomes of pregnancy, which demonstrated that differentially expressed transcripts could result from a common pathogenic mechanism associated with pregnancy loss and spontaneous preterm birth, although individual pregnancy outcomes may differ from each other phenotypically.

(Epi)genetic variants of the sarcomere-desmosome are associated with premature utero-contraction in spontaneous preterm labor.

Spontaneous preterm birth is a syndrome with clinical and genetic heterogeneity. Few studies have focused on the genetic and epigenetic defects and pathogenic mechanisms associated with premature uterine contraction in spontaneous preterm birth. The objective of this study was to investigate the (epi)genetic variations associated with premature uterine contraction of spontaneous preterm birth. A systems biology approach with an integrated multiomic study was employed. Biobanked pregnancy tissues selected from a pregnancy cohort were subjected to genomic, transcriptomic, methylomic, and proteomic studies, with a focus on genetic loci/genes related to uterine muscle contraction, specifically, genes associated with sarcomeres and desmosomes. Thirteen single nucleotide variations and pathogenic variants were identified in the sarcomere gene, TTN, which encodes the protein Titin, from 146 women with spontaneous preterm labor. Differential expression profiles of five long non-coding RNAs were identified from loci that overlap with four sarcomeric genes. Longitudinally, the long non-coding RNA of gene TPM3 that encodes the protein tropomysin 3 was found to significantly regulate the mRNA of TPM3 in the placenta, compared to maternal blood. The majority of genome methylation profiles related to premature uterine contraction were also identified in the CpG promoters of sarcomeric genes/loci. Differential expression profiles of mRNAs associated with premature uterine contraction showed 22 genes associated with sarcomeres and three with desmosomes. The results demonstrated that premature uterine contraction was associated mainly with pathogenic variants of the TTN gene and with transcriptomic variations of sarcomeric premature uterine contraction genes. This association is likely regulated by epigenetic factors, including methylation and long non-coding RNAs.

Proteomic Study of Fetal Membrane: Inflammation-Triggered Proteolysis of Extracellular Matrix May Present a Pathogenic Pathway for Spontaneous Preterm Birth.

INTRODUCTION: Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5-10% of live births annually. The long-term morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood. Human placenta, the maternal and fetal interface, is an environmental core of fetal intrauterine life, mediates fetal oxygen exchange, nutrient uptake, and waste elimination and functions as an immune-defense organ. In this study, the molecular signature of preterm birth placenta was assessed and compared to full-term placenta by proteomic profiling. MATERIALS AND METHODS: Four groups of fetal membranes (the amniochorionic membranes), with five cases in each group in the discovery study and 30 cases in each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal membranes were dissected and used for proteome quantification study. Maxquant and Perseus were used for protein quantitation and statistical analysis. Both fetal membranes and placental villi samples were used to validate proteomic discovery. RESULTS: Proteomics analysis of fetal membranes identified 2,800 proteins across four groups. Sixty-two proteins show statistical differences between the preterm and full-term groups. Among these differentially expressed proteins are (1) proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and (6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and ACSL3), and energy biosynthesis (ATP6AP1 and CYBB). CONCLUSION: Our molecular signature study of preterm fetal membranes revealed inflammation as a major event, which is inconsistent with previous findings. Proteolysis may play an important role in fetal membrane rupture. Extracellular matrix s have been altered in preterm fetal membranes due to proteolysis. Metabolism was also altered in preterm fetal membranes. The molecular changes in the fetal membranes provided a significant molecular signature for PPROM in preterm syndrome.

Red blood cell distribution width and peritoneal dialysis-associated peritonitis prognosis.

Objective: Red blood cell distribution width (RDW) is a parameter of the heterogeneity of circulating erythrocyte size. Recent researches have pointed out a link among RDW, chronic kidney disease, and inflammation. We sought to investigate the prognostic value of baseline RDW in patients with peritoneal dialysis-associated peritonitis (PDAP).Methods: Our study included 337 peritonitis episodes experienced by 202 patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD) at a single center from 2013 to 2018. Episodes were categorized according to the tertiles of baseline RDW levels (T1, <13.2%; T2, 13.2-14.3%; T3, >14.3%). Routine logistic regression and generalized estimating equation (GEE) were used to estimate the association between RDW and treatment failure, which was defined as relapse/recurrent episodes, catheter removal, or death during therapy.Results: After adjusting for other potential predictors, RDW exhibited an incremental relationship with the risk of treatment failure. The baseline RDW of T3 indicated a 43% and 52% increased venture of treatment failure in logistic and GEE analyses, respectively, compared with T1. As a continuous variable, the fitting curve based on restricted cubic spiline showed that the relationship was nonlinearly but positively correlated. The multivariate model A (combined RDW with baseline age, albumin, serum ferritin, and duration on CAPD) showed an area under the curve of 0.671 (95% confidence interval, 0.5920.749) for the prediction of treatment failure.Conclusions: A Higher baseline level of RDW was significantly associated with a greater rate of treatment failure among PDAP episodes independent of other potential predictors.

Micro-vesicles from mesenchymal stem cells over-expressing miR-34a inhibit transforming growth factor-ß1-induced epithelial-mesenchymal transition in renal tubular epithelial cells in vitro.

BACKGROUND: The use of microRNAs in the therapy of kidney disease is hampered by the difficulties in their effective delivery. Micro-vesicles (MVs) are known as natural carriers of small RNAs. Our prior research has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) are capable of attenuating kidney injuries induced by unilateral ureteral obstruction and 5/6 sub-total nephrectomy in mice. The present study aimed to evaluate the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-ß1-induced fibrosis and apoptosis in vitro. METHODS: Bone marrow MSCs were modified by lentiviruses over-expressing miR-34a, from which MVs were collected for the treatment of human Kidney-2 (HK-2) renal tubular cells exposed to TGF-ß1 (6 ng/mL). The survival of HK-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and Annexin V-Light 650/propidium iodide (PI) assays. The expression levels of epithelial markers (tight junction protein 1 [TJP1] and E-cadherin) and mesenchymal markers (smooth muscle actin alpha (α-SMA) and fibronectin) in HK-2 cells were measured using Western blot analysis and an immunofluorescence assay. In addition, changes in Notch-1/Jagged-1 signaling were analyzed using Western blotting. Data were analyzed using a Student's t test or one-way analysis of variance. RESULTS: MiR-34a expression increased three-fold in MVs generated by miR-34a-modified MSCs compared with that expressed in control MVs (P < 0.01, t = 16.55). In HK-2 cells, TJP1 and E-cadherin levels decreased to 31% and 37% after treatment with TGF-ß1, respectively, and were restored to 62% and 70% by miR-34a-enriched MSC-MVs, respectively. The expression of α-SMA and fibronectin increased by 3.9- and 5.0-fold following TGF-ß1 treatment, and decreased to 2.0- and 1.7-fold after treatment of HK-2 cells with miR-34a-enriched MSC-MVs. The effects of miR-34a-enriched MSC-MVs on epithelial-mesenchymal transition (EMT) markers were stronger than control MSC-MVs. The effects of miR-34a-enriched MSC-MVs on these EMT markers were stronger than control MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. It was further observed that elevation of Notch-1 and Jagged-1 induced by TGF-ß1 was inhibited by miR-34a-enriched MSC-MVs. In addition, TGF-ß1 exposure also induced apoptosis in HK-2 cells. Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-ß1-triggered apoptosis in HK-2 cells, the effects were less significant than control MSC-MVs (control:TGF-ß1: miR-nc-MV:miR-34a-MV = 1.3:0.6:1.1:0.9 for MTT assay, 1.8%:23.3%:9.4%:17.4% for apoptosis assay). This phenomenon may be the result of the pro-apoptotic effects of miR-34a. CONCLUSIONS: The present study demonstrated that miR-34a-over-expressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-ß1 in renal tubular epithelial cells, possibly through inhibition of the Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with an anti-fibrotic molecule may represent a novel strategy for the treatment of renal injuries.

Tetrahedral µ4-chloride and in situ generated octahedral µ6-sulfide templating Co8 complexes with different distortions of the cube.

Herein two unprecedented octanuclear Co8 clusters are presented, [Cl@Co8 (TEOA)4(CH3CN)Cl3] (1) and [S@Co8(DEOA)6(NCS)2] (2) (H3TEOA = triethanolamine, H2DEOA = diethanolamine), in which tetrahedral µ4-chloride and in situ generated octahedral µ6-sulfide are used as templates. In spite of them being derivatives of cubes, eight Co atoms in 1 consist of two co-centered tetrahedra of different sizes, whereas in 2 they appear as a rhombohedron formed via elongating a cube along the C3-axis direction. Strong intra-cluster antiferromagnetic interactions were found.

Regional Citrate Anticoagulation versus No-Anticoagulation for Continuous Venovenous Hemofiltration in Acute Severe Hypernatremia Patients with Increased Bleeding Risk: A Retrospective Cohort Study.

PURPOSE: This study was aimed at evaluating the efficacy and safety of regional citrate anticoagulation (RCA) versus no-anticoagulation continuous venovenous hemofiltration (CVVH) in acute severe hypernatremia patients with increased bleeding risk. MATERIALS AND METHODS: Acute severe hypernatremia patients with high bleeding risk who underwent CVVH in our center between January 2011 and October 2017 were considered as candidates. Patients who were <18 years old, with hypovolemic hypernatremia, and had systemic anticoagulation were excluded. The included patients were divided into RCA and no-anticoagulation groups according to their anticoagulation strategy during CVVH and matched by age, sequential organ failure assessment scores, and vasopressor dependency. RESULTS: Of the 64 included patients, no-anticoagulation and RCA were employed for CVVH in 23 and 41 patients, respectively. The serum sodium reduction rate (RRSeNa) was not significantly different between the no-anticoagulation and RCA groups (p = 0.729). Compared to no-anticoagulation, RCA significantly prolonged the circuit survival time (15 h [4.1-23.9] vs. 51 h [21.3-80.7], p = 0.001). The incidence of filter failure was 65.2% (15/23) in the no-anticoagulation group and 2.4% (1/41) in the RCA group (p < 0.001), respectively. In the matched cohort, the RRSeNas were not different between the 2 groups (p = 0.569), and the filter lifespan was significantly longer in the RCA group as well (p < 0.001). CONCLUSION: RCA might be safe and effective for acute severe hypernatremia patients who underwent CVVH treatment. Further prospective, randomized, control trials are warranted to obtain robust evidences.

Efficacy and tolerability of fluvoxamine in adults with social anxiety disorder: A meta-analysis.

BACKGROUND: No meta-analysis for estimating the comprehensive efficacy and tolerability of fluvoxamine in patients with social anxiety disorder (SAD) has been published. OBJECTIVE: To investigate the efficacy and tolerability of fluvoxamine in adults with SAD, trials meeting the following criteria were identified: population: ≥18 years of age with a diagnosis of SAD; intervention: fluvoxamine; study design: placebo-controlled randomized controlled trials (RCTs); outcomes: efficacy and tolerability outcomes. METHODS: We conducted a comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for RCTs on January 3, 2018. Review Manager 5.3 and Stata Version 12.0 software were used for all statistical analyses. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous variables, and odds ratios (ORs) with 95% CIs were calculated for dichotomous variables. Cochrane Collaboration's risk of bias tool was used to assess the likelihood of risk of bias. Efficacy was assessed by mean changes in the Liebowitz Social Anxiety scale (LSAS) total score and the Clinical Global Impression Severity of Illness (CGI-S) score as well as the response rate. Tolerability was mainly assessed by the discontinuation rate due to adverse events (AEs) and the incidence of most frequent treatment-emergent AEs (TEAEs). RESULTS: This meta-analysis included 5 RCTs. Mean changes in LSAS total and CGI-S scores were both significantly greater in patients treated with fluvoxamine than those treated with placebo (LSAS: MD = 11.90, 95% CI = 8.09-15.71, P < .001; CGI-S: MD = 0.52, 95% CI = 0.33-0.72, P < .001). Response rate was higher in fluvoxamine group as compared with placebo (OR = 1.71, 95% CI = 1.30-2.24, P < .001). Additionally, mean change in the Sheehan disability scale score was significantly greater in fluvoxamine group than placebo group (OR = 2.11, 95% CI = 1.03-3.18, P < .001). The discontinuation rate due to AEs was higher in patients that received fluvoxamine compared to those received placebo (OR = 5.99, 95% CI = 2.24-15.99, P < .001), as was the incidence of overall TEAEs (any AE) (OR = 2.66, 95% CI = 1.77-4.02, P < .001). However, the incidence of serious AEs was not significantly different between the 2 groups (OR = 0.99, 95% CI = 0.25-3.89, P = .99). CONCLUSION: Fluvoxamine was found to be effective in adult patients with SAD, with acceptable tolerability.

Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1hibreast cancer via enhancing immune cells activity.

MuS110 and MT110 are BiTE antibodies bispecific for CD3 and EpCAM, which is the most frequently and highly expressed tumor-associated antigen on breast cancer. And pronounced expression of IDO1 has also been reported in breast cancer. Our study aimed to investigate whether IDO1 inhibitor D-1MT combing with MuS110/MT110 had synergistic antitumor effects on IDO expressing EpCAM-positive breast cancer cells in vitro and in vivo. Data suggested that the expression of IDO1 on Epcam-positive breast cancer 4T1 and MCF-7 decreased MuS110/MT110 antitumor efficacy by the suppression of T cells activation in vitro. Combining D-1MT with MT110 in IDO+MCF-7 cells, or with MuS110 in IDO+4T1 cells, significantly improved the antitumor efficacy of BiTE antibodies via increasing T cell cytotoxicity and contributing to cytokines releasing. In vivo assay, combination of D-1MT with MT110 in NOD/SCID mice bearing IDOhi MCF-7 xenografts or MuS110 in immune competent BALB/c mice bearing IDOhi 4T1 xenografts suggested the similar synergistic effect. Together, IDO inhibition could reverse the suppression of T cells due to IDO expressing on breast cancer, and improve the antitumor efficacy of EpCAM/CD3-bispecific BiTE antibody.

A Ratiomeric Fluorescent Sensor for Zn2+ Based on N,N'-Di(quinolin-8-yl)oxalamide.

A new ratiometric fluorescent sensor (DQO) based on N,N'-Di(quinolin-8-yl) oxalamide has been designed and synthesized for selective detection of Zn2+. The fluorescence ratio (I 536 nm/I 450 nm) of DQO was enhanced 10-fold when Zn2+ was present in a buffer aqueous solution at pH 8.66. The sensor showed linear response toward Zn2+ in the concentration range 0-15 µM, and the detection limit was calculated to be 2.4 µM. A Job's plot implied the formation of a DQO/Zn2+ complex with 1:1 stoichiometry, and the apparent association constant of DQO/Zn2+ complex was computed to be 1.5 × 104 M-1.