Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts.

AIMS: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE-/- mice with pressure overload. METHODS AND RESULTS: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE-/- background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE-/- mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE-/- mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1ß), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE-/- mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. CONCLUSION: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE-/- mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Drug-coated balloon for treatment of non-atherosclerotic renal artery stenosis-a multi-center study.

INTRODUCTION: Renal artery stenosis (RAS) is a significant reason for secondary hypertension. Impaired renal function and subsequent cardiopulmonary dysfunction could also occur. Patients of non-atherosclerotic RAS has a relatively young age and long life expectancy. Revascularization with percutaneous transluminal angioplasty (PTA) is a viable treatment option. However, restenosis is unavoidable which limits its use. Drug-coated balloon (DCB) has been proven to be effective in restenosis prevention in femoropopliteal arterial diseases and in patients with renal artery stenosis. And PTA for Renal artery fibromuscular dysplasia is safe and clinically successful. Therefore, we could speculate that DCB might have potential efficacy in non-atherosclerotic RAS treatment. METHODS AND ANALYSIS: This will be a randomized multi-center-controlled trial. Eighty-four eligible participants will be assigned randomly in a 1:1 ratio to the control group (plain old balloon, POB) and the experimental group (DCB). Subjects in the former group will receive balloon dilatation alone, and in the latter group will undergo the DCB angioplasty. The DCB used in this study will be a paclitaxel-coated balloon (Orchid, Acotec Scientific Holdings Limited, Beijing, China). Follow-up visits will be scheduled 1, 3, 6, 9, and 12 months after the intervention. Primary outcomes will include controlled blood pressure and primary patency in the 9-month follow-up. Secondary outcomes will include technical success rate, complication rate, and bail-out stenting rate. TRIAL REGISTRATION: ClinicalTrials.gov (number NCT05858190). Protocol version V.4 (3 May 2023).

Glycosylation-Engineered Platelet Membrane-Coated Interleukin 10 Nanoparticles for Targeted Inhibition of Vascular Restenosis.

Purpose: The purpose of this study was to improve the immune compatibility and targeting abilities of IL10 nanoparticles coated with platelet membrane (IL10-PNPs) by glycosylation engineering in order to effectively reduce restenosis after vascular injury. Materials and Methods: In this study, we removed sialic acids and added α (1,2)-fucose and α (1,3)-fucose to platelet membrane glycoprotein, thus engineering the glycosylation of IL10-PNPs (IL10-GE-PNPs). In vitro and in vivo experiments were conducted to evaluate the targeting and regulatory effects of IL10-GE-PNPs on macrophage polarization, as well as the influence of IL10-GE-PNPs on the phenotypic transformation, proliferation, and migration of smooth muscle cells, and its potential in promoting the repair function of endothelial cells within an inflammatory environment. In order to assess the distribution of IL10-GE-PNP in different organs, in vivo imaging experiments were conducted. Results: IL10-GE-PNPs were successfully constructed and demonstrated to effectively target and regulate macrophage polarization in both in vitro and in vivo settings. This regulation resulted in reduced proliferation and migration of smooth muscle cells and promoted the repair of endothelial cells in an inflammatory environment. Consequently, restenosis after vascular injury was reduced. Furthermore, the deposition of IL10-GE-PNPs in the liver and spleen was significantly reduced compared to IL10-PNPs. Conclusion: IL10-GE-PNPs emerged as a promising candidate for targeting vascular injury and exhibited potential as an innovative drug delivery system for suppressing vascular restenosis. The engineered glycosylation of IL10-PNPs improved their immune compatibility and targeting abilities, making them an excellent therapeutic option.

Diabetes mellitus and adverse outcomes after carotid endarterectomy: A systematic review and meta-analysis.

BACKGROUND: There is still uncertainty regarding whether diabetes mellitus (DM) can adversely affect patients undergoing carotid endarterectomy (CEA) for carotid stenosis. The aim of the study was to assess the adverse impact of DM on patients with carotid stenosis treated by CEA. METHODS: Eligible studies published between 1 January 2000 and 30 March 2023 were selected from the PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials databases. The short-term and long-term outcomes of major adverse events (MAEs), death, stroke, the composite outcomes of death/stroke, and myocardial infarction (MI) were collected to calculate the pooled effect sizes (ESs), 95% confidence intervals (CIs), and prevalence of adverse outcomes. Subgroup analysis by asymptomatic/symptomatic carotid stenosis and insulin/noninsulin-dependent DM was performed. RESULTS: A total of 19 studies (n = 122,003) were included. Regarding the short-term outcomes, DM was associated with increased risks of MAEs (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 5.1%), death/stroke (ES = 1.61, 95% CI: [1.13-2.28], prevalence = 2.3%), stroke (ES = 1.55, 95% CI: [1.16-1.55], prevalence = 3.5%), death (ES = 1.70, 95% CI: [1.25-2.31], prevalence =1.2%), and MI (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 1.4%). DM was associated with increased risks of long-term MAEs (ES = 1.24, 95% CI: [1.04-1.49], prevalence = 12.2%). In the subgroup analysis, DM was associated with an increased risk of short-term MAEs, death/stroke, stroke, and MI in asymptomatic patients undergoing CEA and with only short-term MAEs in the symptomatic patients. Both insulin- and noninsulin-dependent DM patients had an increased risk of short-term and long-term MAEs, and insulin-dependent DM was also associated with the short-term risk of death/stroke, death, and MI. CONCLUSIONS: In patients with carotid stenosis treated by CEA, DM is associated with short-term and long-term MAEs. DM may have a greater impact on adverse outcomes in asymptomatic patients after CEA. Insulin-dependent DM may have a more significant impact on post-CEA adverse outcomes than noninsulin-dependent DM. Whether DM management could reduce the risk of adverse outcomes after CEA requires further investigation.

Endothelial KCa3.1 and KCa2.3 Mediate S1P (Sphingosine-1-Phosphate)-Dependent Vasodilation and Blood Pressure Homeostasis.

BACKGROUND: S1P (sphingosine-1-phosphate) has been reported to possess vasodilatory properties, but the underlying pathways are largely unknown. METHODS: Isolated mouse mesenteric artery and endothelial cell models were used to determine S1P-induced vasodilation, intracellular calcium, membrane potentials, and calcium-activated potassium channels (KCa2.3 and KCa3.1 [endothelial small- and intermediate-conductance calcium-activated potassium channels]). Effect of deletion of endothelial S1PR1 (type 1 S1P receptor) on vasodilation and blood pressure was evaluated. RESULTS: Mesenteric arteries subjected to acute S1P stimulation displayed a dose-dependent vasodilation response, which was attenuated by blocking endothelial KCa2.3 or KCa3.1 channels. In cultured human umbilical vein endothelial cells, S1P stimulated immediate membrane potential hyperpolarization following activation of KCa2.3/KCa3.1 with elevated cytosolic Ca2+. Further, chronic S1P stimulation enhanced expression of KCa2.3 and KCa3.1 in human umbilical vein endothelial cells in dose- and time-dependent manners, which was abolished by disrupting either S1PR1-Ca2+ signaling or downstream Ca2+-activated calcineurin/NFAT (nuclear factor of activated T-cells) signaling. By combination of bioinformatics-based binding site prediction and chromatin immunoprecipitation assay, we revealed in human umbilical vein endothelial cells that chronic activation of S1P/S1PR1 promoted NFATc2 nuclear translocation and binding to promoter regions of KCa2.3 and KCa3.1 genes thus to upregulate transcription of these channels. Deletion of endothelial S1PR1 reduced expression of KCa2.3 and KCa3.1 in mesenteric arteries and exacerbated hypertension in mice with angiotensin II infusion. CONCLUSIONS: This study provides evidence for the mechanistic role of KCa2.3/KCa3.1-activated endothelium-dependent hyperpolarization in vasodilation and blood pressure homeostasis in response to S1P. This mechanistic demonstration would facilitate the development of new therapies for cardiovascular diseases associated with hypertension.

Ant-Neointimal Formation Effects of SLC6A6 in Preventing Vascular Smooth Muscle Cell Proliferation and Migration via Wnt/ß-Catenin Signaling.

Vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of vascular remolding, such as atherosclerosis and restenosis. Solute carrier family 6 member 6 (SLC6A6) is a transmembrane transporter that maintains a variety of physiological functions and is highly expressed in VSMCs. However, its role on VSMCs during neointimal formation remains unknown. In this study, mRNA and protein levels of SLC6A6 were examined using models of VSMC phenotype switching in vivo and in vitro and human artery samples with or without atherosclerosis. SLC6A6 gain- and loss-of-function approaches were performed by adenovirus infection or small interfering RNA (siRNA) transfection, respectively. Reactive oxygen species (ROS), proliferation, migration, and phenotype-related proteins of VSMCs were measured. Vascular stenosis rate and related genes were assessed in a rat vascular balloon injury model overexpressing SLC6A6. SLC6A6 was downregulated in dedifferentiated VSMCs, atherosclerotic vascular tissues, and injured vascular tissues. SLC6A6 suppressed VSMC proliferation and migration, while increasing contractile VSMC proteins. Mechanistically, SLC6A6 overexpression reduced ROS production and inhibited the Wnt/ß-catenin pathway. Furthermore, SLC6A6 overexpression suppressed neointimal formation in vivo. Collectively, overexpression of SLC6A6 suppresses neointimal formation by inhibiting VSMC proliferation and migration via Wnt/ß-catenin signaling and maintaining the VSMC contractile phenotype.

Inhibition of tiRNA-Gly-GCC ameliorates neointimal formation via CBX3-mediated VSMCs phenotypic switching.

Background and aim: tRNA-derived fragments (tRFs) are a new class of non-coding RNAs involved in a variety of pathological processes, but their biological functions and mechanisms in human aortic smooth muscle cells (HASMCs) phenotype transition and vascular intimal hyperplasia are unclear. Methods/results: tiRNA-Gly-GCC is upregulated in synthetic HASMCs, atherosclerotic arteries, plasma, and the balloon injured carotid artery of rats. Functionally, the inhibition of tiRNA-Gly-GCC represses HASMCs proliferation, migration, and reversed dedifferentiation, whereas the overexpression of tiRNA- Gly-GCC have contrary effects. Mechanistically, tiRNA-Gly-GCC performs these functions on HASMCs via downregulating chromobox protein homolog 3 (CBX3). Finally, the inhibition of tiRNA-Gly-GCC could ameliorate neointimal formation after vascular injury in vivo. Conclusions: tiRNA-Gly-GCC is a mediator of HASMCs phenotypic switching by targeting CBX3 and inhibition of tiRNA-Gly-GCC suppresses neointimal formation.

Conception and features of bacillary layer detachment / 中华实验眼科杂志

The separation of outer retinal photoreceptors in patients with toxoplasmosis chorioretinitis was first named bacillary layer detachment (BALAD), which was manifested as a split at the level of the photoreceptor inner segment myoid creating a distinctive intraretinal cavity in optical coherence tomography.Subsequently BALAD has been reported by many researchers in different diseases.In the outer retina, the myoid is a relatively weak structure in photoreceptor inner segment.When the outward force that promotes the attachment of the photoreceptor outer segment to the retinal pigment epithelium exceeds the tensile strength of the photoreceptor inner segment myoid, the myoid zone splits and BALAD occurs.BALAD has its unique multimodal imaging characteristics, and the identification of it can provide a new idea for the diagnosis, detection and treatment of ocular diseases.This paper reviewed the development of BALAD nomenclature, its anatomical structure, pathophysiological mechanism and multimodal image features.

Vascular restenosis reduction with platelet membrane coated nanoparticle directed M2 macrophage polarization.

Vascular restenosis is the main factor affecting the prognosis of angioplasty in cardiovascular diseases, and inflammation is a central link in the progression of restenosis. Previous research that applies interleukin 10 (IL10) nanoparticles can effectively regulate local inflammation, but their targeted delivery efficacy remains to be improved. In this study, IL10 nanoparticles were successfully prepared and then coated by a preactive platelet membrane. The ability to target and regulate macrophage polarization has been demonstrated, thereby regulating smooth muscle cell and endothelial cell functions. In vivo experiments were carried out in a carotid artery injury model and verified the above functions and the effect on inhibiting vascular restenosis. Immune regulation-based platelet membrane coated nanoparticle loaded with IL10 proved to be an excellent candidate for targeting vascular injury and holds promise as an innovative drug delivery system for suppressing vascular restenosis.

Rationale and design for the study of recombinant human hepatocyte growth factor plasmid in the treatment of patients with chronic limb-threatening ischemia (HOPE CLTI): Randomized, placebo-controlled, double-blind, phase III clinical trials.

BACKGROUND: Although patients with CLTI have benefited from the rapid development of endovascular techniques, many patients are considered unsuitable for revascularization procedures. A previous phase II clinical trial has suggested that recombinant human hepatocyte growth factor plasmid (NL003) can salvage limbs during the treatment of patients with CLTI. However, the safety and efficacy of this drug need to be evaluated in a larger cohort. STUDY DESIGN: HOPE CLTI is a multicenter, randomized, double-blind, placebo-controlled phase III clinical study to evaluate the efficacy and safety of intramuscular injection of NL003 in CLTI patients. This study consisted of 22 trials: HOPE CLTI-1, which includes patients with rest pain (Rutherford stage 4), and HOPE CLTI-2, which includes patients with limb ulcers (Rutherford stage 5). In both trials, patients are randomized with a 2:1 ratio of intramuscular injection of NL003 to placebo. The primary endpoint of HOPE CLTI-1 is the complete pain relief rate. The primary endpoint of HOPE CLTI-2 is the complete ulcer healing rate. The safety endpoint was assessed based on adverse events after injection of NL003. Enrollment began in July 2019. The HOPE CLTI-1 trial aims to complete the randomization of at least 300 patients, while the HOPE CLTI-2 trial aims to enroll at least 240 patients. Both trials are organized such that patients will be followed for 6 months after the first intramuscular injection. CONCLUSIONS: HITOP CLTI, which is comprised of 2 multicenter, double-blind, placebo-controlled phase III clinical trials, aims to evaluate the efficacy and safety of the intramuscular administration of NL003 in patients with CLTI.

Quantitative interactome proteomics identifies a proteostasis network for GABAA receptors.

Gamma-aminobutyric acid type A (GABAA) receptors are the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous system. Maintenance of GABAA receptor protein homeostasis (proteostasis) in cells utilizing its interacting proteins is essential for the function of GABAA receptors. However, how the proteostasis network orchestrates GABAA receptor biogenesis in the endoplasmic reticulum is not well understood. Here, we employed a proteomics-based approach to systematically identify the interactomes of GABAA receptors. We carried out a quantitative immunoprecipitation-tandem mass spectrometry analysis utilizing stable isotope labeling by amino acids in cell culture. Furthermore, we performed comparative proteomics by using both WT α1 subunit and a misfolding-prone α1 subunit carrying the A322D variant as the bait proteins. We identified 125 interactors for WT α1-containing receptors, 105 proteins for α1(A322D)-containing receptors, and 54 overlapping proteins within these two interactomes. Our bioinformatics analysis identified potential GABAA receptor proteostasis network components, including chaperones, folding enzymes, trafficking factors, and degradation factors, and we assembled a model of their potential involvement in the cellular folding, degradation, and trafficking pathways for GABAA receptors. In addition, we verified endogenous interactions between α1 subunits and selected interactors by using coimmunoprecipitation in mouse brain homogenates. Moreover, we showed that TRIM21 (tripartite motif containing-21), an E3 ubiquitin ligase, positively regulated the degradation of misfolding-prone α1(A322D) subunits selectively. This study paves the way for understanding the molecular mechanisms as well as fine-tuning of GABAA receptor proteostasis to ameliorate related neurological diseases such as epilepsy.

A Potential Target for Diabetic Vascular Damage: High Glucose-Induced Monocyte Extracellular Vesicles Impair Endothelial Cells by Delivering miR-142-5p.

Endothelial dysfunction is a key accessory to diabetic cardiovascular complications, and the regulatory role of the extracellular vesicles (EVs) from the innate immune system is growing. We tested whether EVs derived from high glucose-induced monocytes could shuttle microRNAs and impair endothelial cells. EVs from high glucose- and basal glucose-treated THP-1 cells (HG-THP-1 EVs and BG-THP-1 EVs) were isolated and identified. After coculture with THP-1 EVs, human umbilical vein endothelial cells (HUVECs) were tested by proliferation, migration, reactive oxygen species (ROS) detection assays, and western blot for Nrf2/NLRP3 signaling. MiR-142-5p was predicted by miRNAs databases and further verified by RT-qPCR and dual-luciferase reporter gene assays that inhibit Nrf2 expression. The regulation of miR-142-5p in HUVECs was further evaluated. A type 1 diabetes mellitus (T1DM) mouse model was developed for miR-142-5p inhibition. Aorta tissue was harvested for hematoxylin-eosin staining and immunohistochemistry of interleukin-1ß (IL-1ß). Compared to BG-THP-1 EVs, HG-THP-1 EVs significantly reduced migration and increased ROS production in HUVECs but did not affect proliferation. HG-THP-1 EVs induced suppression of Nrf2 signaling and NLRP3 signaling activation. RT-qPCR results showed that HG-THP-1 EVs overexpressed miR-142-5p in HUVECs. The transfection of miR-142-5p mimics into HUVECs exhibited consistent regulatory effects on HG-THP-1 EVs, whereas miR-142-5p inhibitors demonstrated protective effects. The miR-142-5p antagomir significantly reduced the IL-1ß level in T1DM aortas despite morphological changes. To conclude, miR-142-5p transferred by high glucose-induced monocyte EVs participates in diabetic endothelial damage. The inhibition of miR-142-5p could be a potential adjuvant to diabetic cardiovascular protection.

[Clinical Efficacy of Haplo-HSCT of ATG Combined with PTCy for Children with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in combination of ATG and post-transplant cyclophosphamide (PTCy) -induced immune tolerance after transplantation in treatment of childhood myelodysplastic syndromes(MDS）. METHODS: From July 2016 to November 2020, a total of 8 children with MDS receiving the haploidentical allo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation in our hospital were enrolled, whose clinical data were retrospected and analyzed. RESULTS: Median age at diagnosis of the 8 children (1 male and 7 females) was 6.4 (range, 10 months to 15 years) years old. The median medical history of MDS was 2.7 years (range, 3 months to 8 years). Among the 8 patients, 7 cases were diagnosed with refractory cytopenia of childhood and one with refractory anemia with excess of blasts. The HSC donors were father, mother or brother of patients and HLA matching in 6-9/12 loci were identical. All the donors were healthy and didn't carry the same pathogenic genes as the recipients. The median age of donors was 36.4 (range, 25 to 49) years old. The median mononuclear cell (MNC) number of the graft was 19.8, ranging in (13.2-47.3)×108/kg, and the median CD34+ cell number was 11.8×106/kg, ranging in (5.0-18.3)×106/kg. Graft-versus-host disease prophylactic regimen was started on day 3 and 4 after transplantation, in which cyclophosphamide (50 mg/kg·d) was administered by intravenous infusion. From day 5 after transplantation, low-dose tacrolimus was administered by intravenous infusion and mycophenolate mofetil was administered orally. The median time of neutrophil and platelet engraftment was 12.6 (rang, 11 to 15) days and 13.3 (rang, 11 to 18) days, respectively. All the patients achieved full donor chimerism on neutrophil engraftment after transplantation. The median follow-up time was 1 032 (rang, 747 to 1 536) days. Both overall survival rate and disease-free survival rate were 100%. CONCLUSION: Haplo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation is a safe and effective treatment for children with MDS.

Clinical outcomes of individualized busulfan-dosing in hematopoietic stem cell transplantation in Chinese children undergoing with therapeutic drug monitoring.

To identify relationships between busulfan (Bu) exposure and outcomes of a cohort pediatric patients receiving hematopoietic stem cell transplantation (HSCT), along with a targeted busulfan-based conditioning regimen. We retrospectively evaluated targeted busulfan concentrations in 53 pediatric patients (age 0.4-16 years) who received busulfan 4 times daily according to recommended weight-based doses in a single-center analysis between 2018 and 2020. In this trial, individual busulfan pharmacokinetics were performed following dose 5 of the conditioning regimen. Twenty four of 53 patients (45.3%) studies did not require dose adjustments. Equal number of patients (24/53) required one dose adjustments while two-dose adjustment applied for 5 of 53 (9.4%). Twenty-one percent of the patients exhibited ll-lV aGVHD. The incidence of veno-occlusive disease (VOD) was in 3.8% of the 53 patients, while incidence of hemorrhagic cystitis (II-III) reached to 9.7%. Engraftment was successful in 98% of the 53 patients with relapse in 2% of cases. The probability of overall survival and disease-free survival at day 100 was 96% and 94%, respectively. In conclusion, therapeutic drug monitoring (TDM) and individualization of Bu dosage are essential to improve the efficacy and safety of busulfan-based regimen in Chinese pediatric HSCT recipients.

C-reactive Protein, Free Fatty Acid, and Uric Acid as Predictors of Adverse Events after Endovascular Revascularization of Arterial Femoropopliteal Occlusion Lesions.

OBJECTIVES: This study aimed to investigate the relationship between pre-procedure high-sensitivity C-reactive protein (hsCRP), free fatty acid (FFA), and uric acid (UA) levels and post-procedure mortality and morbidity of endovascular revascularization of arterial femoropopliteal occlusion lesions. METHODS: This was a retrospective review of clinical data retrieved from a prospectively held database in Peking Union Medical College Hospital. A total of 71 Patients who underwent endovascular treatment (EVT) for femoropopliteal occlusive disease between January 1, 2014 and November 1, 2017, were included in this study. Endpoints were defined as major adverse limb events (MALE; target vessel revascularization, amputation, or disease progression) and major adverse cardiovascular events (MACE; stroke, myocardial infarction, or all-cause death) during the entire follow-up period. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the relationship of elevated biomarker levels (hsCRP, FFA and UA, measured by immunoturbidimetry assay, enzymatic assay and enzymatic assay, respectively) to MALE and MACE outcomes. RESULTS: Seventy-one patients (72 limbs) with sufficient follow-up information were included in the analysis. The mean age was 69.7 ± 8.6 years; 21.1% were female. The Rutherford class of target limbs were ≥ 3. The median follow-up was 36 (range 18-59 months). Univariate analyses revealed that patients with elevated hsCRP levels had an increased risk of MALE (hazard ratio [HR], 2.682; 95% confidence interval [CI], 1.281-5.617, P = 0.009). High FFA levels were associated with an increased risk of MALE (HR, 2.658; 95% CI, 1.075-6.573; P = 0.034). Multivariate analyses demonstrated that elevated hsCRP values (HR, 4.015; 95% CI, 1.628-10.551; P = 0.003) and FFA value (HR, 3.034; 95% CI, 1.102-8.354; P = 0.032) were both significantly associated with increased MALE. Elevated UA levels predicted MACE in the presence of confounders (HR, 11.446; 95% CI, 1.367-95.801 P = 0.023). CONCLUSION: Pre-procedure hsCRP and FFA levels could serve as predictors of adverse events after EVT in patients with arterial femoropopliteal occlusive disease. The role of UA in MACE may warrant further investigation, because the correlation is not as powerful as the other two in the study.

Clinical Efficacy of Haplo-HSCT of ATG Combined with PTCy for Children with Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in combination of ATG and post-transplant cyclophosphamide (PTCy) -induced immune tolerance after transplantation in treatment of childhood myelodysplastic syndromes(MDS）.@*METHODS@#From July 2016 to November 2020, a total of 8 children with MDS receiving the haploidentical allo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation in our hospital were enrolled, whose clinical data were retrospected and analyzed.@*RESULTS@#Median age at diagnosis of the 8 children (1 male and 7 females) was 6.4 (range, 10 months to 15 years) years old. The median medical history of MDS was 2.7 years (range, 3 months to 8 years). Among the 8 patients, 7 cases were diagnosed with refractory cytopenia of childhood and one with refractory anemia with excess of blasts. The HSC donors were father, mother or brother of patients and HLA matching in 6-9/12 loci were identical. All the donors were healthy and didn't carry the same pathogenic genes as the recipients. The median age of donors was 36.4 (range, 25 to 49) years old. The median mononuclear cell (MNC) number of the graft was 19.8, ranging in (13.2-47.3)×108/kg, and the median CD34+ cell number was 11.8×106/kg, ranging in (5.0-18.3)×106/kg. Graft-versus-host disease prophylactic regimen was started on day 3 and 4 after transplantation, in which cyclophosphamide (50 mg/kg·d) was administered by intravenous infusion. From day 5 after transplantation, low-dose tacrolimus was administered by intravenous infusion and mycophenolate mofetil was administered orally. The median time of neutrophil and platelet engraftment was 12.6 (rang, 11 to 15) days and 13.3 (rang, 11 to 18) days, respectively. All the patients achieved full donor chimerism on neutrophil engraftment after transplantation. The median follow-up time was 1 032 (rang, 747 to 1 536) days. Both overall survival rate and disease-free survival rate were 100%.@*CONCLUSION@#Haplo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation is a safe and effective treatment for children with MDS.

Nano-Silver Medical Antibacterial Dressing Combined with High-Flow Oxygen Therapy Facilitates Ulcer Wound Healing of Superficial Malignant Tumors.

BACKGROUND: Due to the poor healing of superficial malignant tumor ulcer wounds, patients suffer great pain and significantly reduced quality of life. Related research shows that oxygen therapy can reduce wound bleeding and promote wound healing. OBJECTIVE: This study aims to explore the therapeutic effect of nano-silver antibacterial dressing combined with high-flow oxygen therapy on surface malignant tumor ulcers. METHODS: In this retrospective analysis, 64 patients with superficial malignant tumors and ulcer infection were included and divided into the research group and the control group, with 32 cases in each group. After conventional debridement, the control group was treated with vaseline dressing, while the research group was treated with nano-silver medical antibacterial dressing combined with high-flow oxygen therapy. Both groups were treated for 7 days. The frequency of dressing change and the number of times of blood oozing between the two groups after treatment were recorded. The pain, clinical efficacy, and levels of procalcitonin (PCT) and C-reactive protein (CRP) were compared between the two groups before and after treatment. RESULTS: The dressing changes and blood oozing were less frequent in the research group compared with the control group. The pain score and the levels of PCT and CRP in the research group were lower than those in the control group. The overall response rate was significantly higher in the research group as compared to the control group. All the above differences were statistically significant (P<0.05). CONCLUSION: Nano-silver medical antibacterial dressing combined with high-flow oxygen therapy can reduce the frequency of dressing changes in patients, relieve pain, reduce inflammation, and accelerate the healing of superficial malignant tumor ulcer wounds.

Human urinary kallidinogenase combined with edaravone in treating acute ischemic stroke patients: A meta-analysis.

INTRODUCTION: Several studies have investigated the efficacy of human urinary kallidinogenase (HUK) combined with edaravone (Eda) in acute ischemic stroke (AIS) patients. Our aim was to provide the best available evidence for clinical practice and further research programs for stroke treatment. METHODS: We searched the online database for paper published between January 2015 and April 2021. We calculated weighted mean difference (WMD) or odds risk (OR) and their corresponding 95% confidence interval (95% CI) of reported outcomes between HUK plus Eda and Eda groups for each study. The random-effect models or fixed-effect models were used to pool the analysis. RESULTS: Thirteen studies with 1242 patients were included. In the pooled analysis, the scores of NIHSS in the HUK plus Eda group were significantly lower than that in patients receiving Eda (WMD = -3.92, 95% CI (-4.82, -3.02), p < .0001). The ADL scores in the HUK plus Eda group were significantly greater than that in patients receiving Eda (WMD = 14.13, 95% CI (10.67, 17.60), p < .0001). Furthermore, HUK plus Eda was associated with a higher rate of total efficacy (OR = 3.97, 95% CI (2.81, 5.59), p < .0001). CONCLUSIONS: HUK combined with Eda provides potential clinical benefits as a treatment for AIS. Further high-quality, large-scale randomized trials are needed to confirm these results.

A novel strategy for the detection of SARS-CoV-2 variants based on multiplex PCR-MALDI-TOF MS

BackgroundThe second wave of coronavirus disease 2019 (COVID-19) has been incessantly causing catastrophe worldwide, and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants causes further uncertainty regarding epidemic risk. Here, a novel strategy for the detection of SARS-CoV-2 variants using multiplex PCR coupled with MALDI-TOF MS was developed. MethodsPlasmids carrying gene sequences containing 9 mutation types in 7 mutated sites (HV6970del, N501Y, K417N, P681H, D614G, E484K, L452R, E484Q and P681R) in the receptor-binding domain of the spike protein of SARS-CoV-2 variants were synthesized. Using the nucleic acid sequence of SARS-CoV-2 nonvariant and a synthetic SARS-CoV-2-variant-carrying plasmid, a MALDI-TOF MS method based on the single-base mass probe extension of multiplex PCR amplification products was established to detect the above nine mutation types. The detection limit of this method was determined via the concentration gradient method. Twenty-one respiratory tract pathogens (9 bacteria, 11 respiratory viruses) and pharyngeal swab nucleic acid samples from healthy people were selected for specific validation. Sixteen samples from COVID-19 patients were used to verify the accuracy of this method. ResultsThe 9 mutation types could be detected simultaneously by triple PCR amplification coupled with MALDI-TOF MS. SARS-CoV-2 and all six variants (B.1.1.7, B.1.351, B.1.429, B.1.526, P.1 and B.1.617) could be identified. The detection limit for all 9 sites was 1.5x103 copies. The specificity of this method was 100%, and the accuracy of real-time PCR CT values less than 30 among positive samples was 100%. This method is open and extensible, and can be used in a high-throughput manner, easily allowing the addition of new mutation sites as needed to identify and track new SARS-CoV-2 variants as they emerge. ConclusionsMultiplex PCR-MALDI-TOF MS provides a new detection option with practical application value for SARS-CoV-2 and its variant infection. Key pointAn all-in-one SARS-CoV-2 variant identification method based on a multiplex PCR-MALDI-TOF MS system was developed. All of the SARS-CoV-2 variants can be identified based on 9 types of 7 mutated sites of RBD of spike protein using this method.