Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.

BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear. METHODS: Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed. RESULTS: We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a ß-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in ß-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency. CONCLUSIONS: This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.

Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection.

AIMS: Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. METHODS AND RESULTS: Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a ß-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. CONCLUSION: The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.

[Correlation analysis between combined deflection angle and osteonecrosis of femoral head after femoral neck fracture].

Objective: To evaluate the correlation between pelvic incidence (PI) angle, hip deflection angle (HDA), combined deflection angle (CDA) and osteonecrosis of the femoral head (ONFH) after femoral neck fracture, in order to explore early predictive indicators for ONFH occurrence after femoral neck fracture. Methods: A study was conducted on patients with femoral neck fractures who underwent cannulated screw internal fixation between December 2018 and December 2020. Among them, 208 patients met the selection criteria and were included in the study. According to the occurrence of ONFH, the patients were allocated into ONFH group and non-NOFH group. PI, HDA, and CDA were measured based on the anteroposterior X-ray films of pelvis and axial X-ray films of the affected hip joint before operation, and the differences between the two groups were compared. The receiver operating characteristic curve (ROC) was used to evaluate the value of the above imaging indicators in predicting the occurrence of ONFH. Results: Among the 208 patients included in the study, 84 patients experienced ONFH during follow-up (ONFH group) and 124 patients did not experience ONFH (non-ONFH group). In the non-ONFH group, there were 59 males and 65 females, the age was 18-86 years (mean, 53.9 years), and the follow-up time was 18-50 months (mean, 33.2 months). In the ONFH group, there were 37 males and 47 females, the age was 18-76 years (mean, 51.6 years), and the follow-up time was 8-45 months (mean, 22.1 months). The PI, HDA, and CDA were significantly larger in the ONFH group than in the non-ONFH group ( P<0.05). ROC curve analysis showed that the critical value of PI was 19.82° (sensitivity of 40.5%, specificity of 86.3%, P<0.05); the critical value of HDA was 20.94° (sensitivity of 77.4%, specificity of 75.8%, P<0.05); and the critical value of CDA was 39.16° (sensitivity of 89.3%, specificity of 83.1%, P<0.05). Conclusion: There is a correlation between PI, HDA, CDA and the occurrence of ONFH after femoral neck fracture, in which CDA can be used as an important reference indicator. Patients with CDA≥39.16° have a higher risk of ONFH after femoral neck fracture.

[Correlation between combined deflection angle classification adduction typing and complications after internal fixation of adduction femoral neck fracture].

Objective: To analyze the correlation between postoperative complications and combined deflection angle classification adduction type (CDAC-ADT) of femoral neck fractures after cannulated screw internal fixation. Methods: The clinical data of 121 patients with CDAC-ADT femoral neck fracture admitted between January 2018 and December 2021 and met the selected criteria were retrospectively analyzed. There were 69 males and 52 females, the age ranged from 19 to 79 years (mean, 48.1 years). The causes of injury included 52 cases of traffic accident, 24 cases of falling from height, and 45 cases of fall. The time from injury to operation ranged from 2 to 12 days, with an average of 6.0 days. Among them, there were 18 cases of CDAC-ADT type Ⅰ, 46 cases of type Ⅱ, and 57 cases of type Ⅲ; 6 cases of Garden type Ⅱ, 103 cases of type Ⅲ, and 12 cases of type Ⅳ; and according to the location of the fracture line, there were 26 cases of subcapitate type, 88 cases of transcervical type, and 7 cases of basal type. All patients were treated with cannulated screw internal fixation. The occurrence of complications (including internal fixation failure, fracture nonunion, and osteonecrosis of the femoral head) was recorded, and the correlation between complications and CDAC-ADT typing, Garden typing, and fracture line location were analyzed. Results: The patients were followed up 8-44 months, with a mean of 24.9 months. There were 10 cases of internal fixation failure, 7 cases of fracture nonunion, and 30 cases of osteonecrosis of the femoral head after operation. Correlation analysis showed that patients' CDAC-ADT typing was significantly correlated with the overall incidence of complication and the incidence of internal fixation failure, fracture nonunion, and osteonecrosis of the femoral head ( P<0.05), and the Pearson coefficient of contingency were 0.435, 0.251, 0.254, and 0.241, respectively. Garden typing did not correlate with the overall incidence of complication and the incidence of internal fixation failure and fracture nonunion ( P>0.05), but correlated with the incidence of osteonecrosis of the femoral head ( P<0.05), and the Pearson coefficient of contingency was 0.251. Fracture line position typing had no correlation with the overall incidence of complication and the incidence of internal fixation failure, fracture nonunion, and osteonecrosis of the femoral head ( P>0.05). Conclusion: CDAC-ADT typing has obvious correlation with postoperative complications of femoral neck fracture and can be used to predict complications of femoral neck fracture.

Fate of the distal aorta following root replacement in Marfan syndrome: a propensity score matched study.

Objective: The aortic root is the most frequent segment involved in Marfan syndrome. However, Marfan syndrome is a systemic hereditary connective tissue disorder, and knowledge regarding the outcomes of the native distal aorta after prophylactic aortic root surgery is limited. Methods: From April 2010 to December 2020, 226 patients with Marfan syndrome and 1,200 patients without Marfan syndrome who underwent Bentall procedures were included in this study. By propensity score matching, 134 patients were assigned to each group. Clinical manifestations and follow-up data were acquired from hospital records and telephone contact. The cumulative incidence of aortic events was estimated in Marfan and non-Marfan patients with death as a competing risk. Results: Patients with and without Marfan syndrome had similar baseline characteristics after propensity score matching. Differences in the aortic root (62.25 ± 11.96 vs. 54.03 ± 13.76, P < .001) and ascending aorta (37.71 ± 9.86 vs. 48.16 ± 16.01, P < .001) remained after matching. No difference was observed in the frequency of aortic adverse events between the two groups (10.5% vs. 4.6%, P = 0.106). The cumulative incidence of aortic events was not different between Marfan and non-Marfan patients (15.03% ± 4.72% vs. 4.18% ± 2.06%, P = 0.147). Multivariate Cox regression indicated no significant impact of Marfan syndrome on distal aortic events (HR: 1.172, 95% CI: 0.263-5.230, P = 0.835). Descending and abdominal aortic diameter above normal at the initial procedure were associated with the risk of distal aortic events (HR: 20.735, P = .003, HR: 22.981, P = .002, respectively). Conclusions: New-onset events of the residual aorta in patients undergoing Bentall procedures between the Marfan and non-Marfan groups were not significantly different. Distal aortic diameter above normal at initial surgery was associated with a higher risk of adverse aortic events.

The Role of the Interface of PLA with Thermoplastic Starch in the Nonisothermal Crystallization Behavior of PLA in PLA/Thermoplastic Starch/SiO2 Composites.

Corn starch was plasticized by glycerol suspension in a twin-screw extruder, in which the glycerol suspension was the pre-dispersion mixture of glycerol with nano-SiO2. Polylactide (PLA)/thermoplastic starch/SiO2 composites were obtained through melt-blending of PLA with thermoplastic starch/SiO2 in a twin-screw extruder. The nonisothermal crystallization behavior of PLA in the composites was investigated by differential scanning calorimetry. An interface of PLA with thermoplastic starch was proven to exist in the composites, and its interfacial bonding characteristics were analyzed. The interfacial binding energy stemming from PLA with thermoplastic starch exerts a significant influence on the segmental mobility of PLA at the interface. The segmental mobility of PLA is gradually improved by increasing interfacial binding energy, and consequently, the relative crystallinity on the interface exhibits progressive promotion. The Jeziorny model could well describe the primary crystallization of PLA in the composites. The extracted Avrami exponents based on the Jeziorny model indicate that the primary crystallization of PLA follows heterogeneous nucleation and three-dimensional growth. This study has revealed the intrinsic effect of the interfacial segmental mobility on the nonisothermal crystallization behavior of PLA in composites, which is of technological significance for its blow molding.

METTL3 achieves lipopolysaccharide-induced myocardial injury via m6A-dependent stabilization of Myh3 mRNA.

Septic cardiomyopathy (SCM) was an important pathological component of severe sepsis and septic shock. N6-methyladenosine (m6A) modification was a common RNA modification in both mRNA and non-coding RNAs and was proved to be involved in sepsis and immune disorders. Therefore, the purpose of this study was to investigate the role and mechanism of METTL3 in lipopolysaccharide-induced myocardial injury. We firstly analyzed the expression changes of various m6A-related regulators in human samples in the GSE79962 data and the Receiver Operating Characteristic curve of significantly changed m6A enzymes, showing that METTL3 had a high diagnostic ability in patients with SCM. Western blotting confirmed the high expression of METTL3 in LPS-treated H9C2 cells, which was consistent with the above results in human samples. In vitro and in vivo, the deficiency of METTL3 could improve the cardiac function, cardiac tissue damage, myocardial cell apoptosis and reactive oxygen species levels in LPS-treated H9C2 cells and LPS-induced sepsis rats, respectively. In addition, we obtained 213 differential genes through transcriptome RNA-seq analysis, and conducted GO enrichment analysis and KEGG pathway analysis through DAVID. We also found that the half-life of Myh3 mRNA was significantly reduced after METTL3 deletion and that Myh3 carried several potential m6A modification sites. In conclusion, we found that downregulation of METTL3 reversed LPS-induced myocardial cell and tissue damage and reduced cardiac function, mainly by increasing Myh3 stability. Our study revealed a key role of METTL3-mediated m6A methylation in septic cardiomyopathy, which may offer a potential mechanism for the therapy of septic cardiomyopathy.

Thermally Conductive and Antistatic Properties of Silicone Rubber Reinforced by the Modified Graphene Oxide.

Silicone rubber (SR)/vinyl-graphene oxide (vinyl-GO) nanocomposites were prepared through the hydrosilylation reaction of silicon hydrogen polydimethylsiloxane (H-PDMS) with vinyl polydimethylsiloxane (vinyl-PDMS), in which vinyl-GO was used as a nano filler. The thermally conductive and antistatic properties of the nanocomposites, and their tensile strength and thermal stability were evaluated. The thermally conductive and antistatic properties increased naturally when the nanocomposites had eight to nine parts of vinyl-GO. The addition of 9 parts of vinyl-GO increased the thermal conductivity to 0.44 from 0.17 W/m-1·K-1 of neat SR and the surface resistance value to 108 from 1014 Ω of neat SR. Vinyl-GO is effective in improving the tensile strength and toughness of the nanocomposites. The tensile strength and elongation at break of the nanocomposites were much higher than that of neat SR, especially for 10 parts of vinyl-GO in the nanocomposite, and the tensile strength was 1.84 MPa and the elongation at break was 314.1%. Additionally, compared with neat SR, the nanocomposites had a much higher thermal stability. For eight parts of vinyl-GO in the nanocomposites, H-PDMS with the selected silicon hydrogen content and vinyl-PDMS with the selected vinyl content could offer an appropriate cross-linking degree that suits the character of GO. When the nanocomposite had eight parts of vinyl-GO, its scanning electron microscope exhibited a monolayer GO with folded, twisted, and local surface folds. However, there was a certain amount of multilayer aggregation of GO for 10 parts of vinyl-GO in the nanocomposite.

Blood Transfusion Predicts Prolonged Mechanical Ventilation in Acute Stanford Type A Aortic Dissection Undergoing Total Aortic Arch Replacement.

Background: This research aimed to evaluate the impacts of transfusing packed red blood cells (pRBCs), fresh frozen plasma (FFP), or platelet concentrate (PC) on postoperative mechanical ventilation time (MVT) in patients with acute Stanford type A aortic dissection (ATAAD) undergoing after total arch replacement (TAR). Methods: The clinical data of 384 patients with ATAAD after TAR were retrospectively collected from December 2015 to October 2017 to verify whether pRBCs, FFP, or PC transfusion volumes were associated with postoperative MVT. The logistic regression was used to assess whether blood products were risk factors for prolonged mechanical ventilation (PMV) in all three endpoints (PMV ≥24 h, ≥48 h, and ≥72 h). Results: The mean age of 384 patients was 47.6 ± 10.689 years, and 301 (78.39%) patients were men. Median MVT was 29.5 (4-574) h (h), and 213 (55.47%), 136 (35.42%), and 96 (25.00%) patients had PMV ≥24 h, ≥48 h, and ≥72 h, respectively. A total of 36 (9.38%) patients did not have any blood product transfusion, the number of patients with transfusion of pRBCs, FFP, and PC were 334 (86.98%), 286 (74.48%), and 189 (49.22%), respectively. According to the multivariate logistic regression of three PMV time-endpoints, age was a risk factor [PMV ≥ 24 h odds ratio (OR PMV≥24) = 1.045, p = 0.005; OR PMV≥48 = 1.060, p = 0.002; OR PMV≥72 = 1.051, p = 0.011]. pRBC transfusion (OR PMV≥24 = 1.156, p = 0.001; OR PMV≥48 = 1.156, p < 0.001; OR PMV≥72 = 1.135, p ≤ 0.001) and PC transfusion (OR PMV≥24 = 1.366, p = 0.029; OR PMV≥48 = 1.226, p = 0.030; OR PMV≥72 = 1.229, p = 0.011) were independent risk factors for PMV. FFP had no noticeable effect on PMV [OR PMV≥48 = 0.999, 95% confidence interval (CI) 0.998-1.000, p = 0.039; OR PMV≥72 = 0.999, 95% CI: 0.998-1.000, p = 0.025]. Conclusions: In patients with ATAAD after TAR, the incidence of PMV was very high. Blood products transfusion was closely related to postoperative mechanical ventilation time. pRBC and PC transfusions and age increased the incidence of PMV at all three endpoints.

Development and validation of a nomogram for postoperative severe acute kidney injury in acute type A aortic dissection.

BACKGROUND: Postoperative acute kidney injury (AKI) is a major complication associated with increased morbidity and mortality after surgery for acute type A aortic dissection (AAAD). To the best of our knowledge, risk prediction models for AKI following AAAD surgery have not been reported. The goal of the present study was to develop a prediction model to predict severe AKI after AAAD surgery. METHODS: A total of 485 patients who underwent AAAD surgery were enrolled and randomly divided into the training cohort (70%) and the validation cohort (30%). Severe AKI was defined as AKI stage III following the Kidney Disease: Improving Global Outcomes criteria. Preoperative variables, intraoperative variables and postoperative data were collected for analysis. Multivariable logistic regression analysis was performed to select predictors and develop a nomogram in the study cohort. The final prediction model was validated using the bootstrapping techniques and in the validation cohort. RESULTS: The incidence of severe AKI was 23.0% (n = 78), and 14.7% (n = 50) of patients needed renal replacement treatment. The hospital mortality rate was 8.3% (n = 28), while for AKI patients, the mortality rate was 13.1%, which increased to 20.5% for severe AKI patients. Univariate and multivariate analyses showed that age, cardiopulmonary bypass time, serum creatinine, and D-dimer were key predictors for severe AKI following AAAD surgery. The logistic regression model incorporated these predictors to develop a nomogram for predicting severe AKI after AAAD surgery. The nomogram showed optimal discrimination ability, with an area under the curve of 0.716 in the training cohort and 0.739 in the validation cohort. Calibration curve analysis demonstrated good correlations in both the training cohort and the validation cohort. CONCLUSIONS: We developed a prognostic model including age, cardiopulmonary bypass time, serum creatinine, and D-dimer to predict severe AKI after AAAD surgery. The prognostic model demonstrated an effective predictive capability for severe AKI, which may help improve risk stratification for poor in-hospital outcomes after AAAD surgery.

Early and Long-Term Follow-Up for Chronic Type B and Type Non-A Non-B Aortic Dissection Using the Frozen Elephant Trunk Technique.

Background: This study aimed to evaluate the early and long-term outcomes of a single center using a frozen elephant trunk (FET) procedure for chronic type B or non-A non-B aortic dissection. Methods: From February 2009 to December 2019, 79 patients diagnosed with chronic type B or non-A non-B aortic dissection who underwent the FET procedure were included in the present study. We analyzed operation mortality and early and long-term outcomes, including complications, survival and interventions. Results: The operation mortality rate was 5.1% (4/79). Spinal cord injury occurred in 3.8% (3/79), stroke in 2.5% (2/79), and acute renal failure in 5.1% (4/79). The median follow-up time was 53 months. The overall survival rates were 96.2, 92.3, 88.0, 79.8, and 76.2% at 1/2, 1, 3, 5 and 7 years, respectively. Moreover, 79.3% of patients did not require distal aortic reintervention at 7 years. The overall survival in the subacute group was superior to that in the chronic group (P = 0.047). Conclusion: The FET technique is a safe and feasible approach for treating chronic type B and non-A non-B aortic dissection in patients who have contraindications for primary endovascular aortic repair. The technique combines the advantages of both open surgical repair and endovascular intervention, providing comparable early and long-term follow-up outcomes and freedom from reintervention.

Poly[tetra-aqua-di-µ(4)-malonato-barium(II)cadmium(II)].

In the title complex, [BaCd(C(3)H(2)O(4))(2)(H(2)O)(4)](n), the Ba(II) atoms, located on crystallographic twofold axes, adopt slightly distorted square-anti-prismatic coordination geometries, while the Cd(II) atoms, which lie on crystallographic centres of symmetry, have a distorted octa-hedral coordination. Each malonate dianion binds two different Cd(II) atoms and two different Ba(II) atoms. This connectivity generates alternating layers along [100] in the structure, with one type containing Cd(II) cations and malonate dianions, while the other is primarily composed of Ba(II) ions and coordinated water mol-ecules. The water mol-ecules also participate in extensive O-H⋯O hydrogen bonding.

Photosensitizer-loaded cell membrane biomimetic nanoparticles for enhanced tumor synergetic targeted therapy.

Photodynamic therapy (PDT) has the advantages of low toxicity and specificity, but photosensitizers usually fail to accumulate efficiently at the tumor site. In this study, a new multifunctional nano-drug delivery system was exploited by a biomimetic strategy to improve the PDT effects. The self-assembled methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA) nanoparticles encapsulated with the photosensitizer chlorin e6 (Ce6) by microfluidics were employed as the nano-core, followed by coating red blood cell (RBC) membranes as the biomimetic agent to prolong the circulation time in vivo. In order to boost the therapeutic effect, doxorubicin (Dox) was preloaded into RBC nanovesicles. The cell membrane surface was modified with folic acid (FA) to further enhance the tumor targeting efficiency. The prepared biomimetic nanoparticles with a homogeneous size (70 nm) can trigger sufficient reactive oxygen species (ROS), leading to significant tumor ablation without side effects. In addition, the system had high tumor targeting efficiency, with an increase of 25% compared with no FA-modified nanoparticles. Therefore, this biomimetic multifunctional nanodrug delivery system possesses a prolonged circulation time and higher tumor targeting efficiency and can exert better tumor cytotoxicity for improved PDT due to homophilic targeting in vivo.

Minimally invasive and conventional surgical treatment of primary benign cardiac tumors.

BACKGROUND: Primary cardiac tumors are rare and the majorities are benign. Conventional surgical treatment uses median sternotomy, while minimally invasive surgery from right anterolateral minithoracotomy has become an alternative method in recent years. In this study, we summarized the surgical outcomes of both approaches. METHODS: From January 2008 to August 2018, 50 patients with primary benign cardiac tumors underwent either conventional or minimally invasive surgery in our department. The baseline data were collected. The peri-operative data and follow up results were compared between the two groups. RESULTS: There were19 men and 31 women enrolled in this study with a mean age of 55.0 ± 17.5 years. The most common site of the tumor was left atrium (n = 40, 80%), followed by right atrium (n = 8, 16.0%), right ventricle (n = 1, 2.0%) and left ventricle (n = 1, 2.0%). All patients underwent surgery uneventfully, including 33 cases (66.0%) of median sternotomy and 17 cases (34.0%) of right anterolateral minithoracotomy. No significant differences were found between the two groups in terms of cardiopulmonary bypass time, aortic cross-clamp time, postoperative intubation time, intensive care unit days and length of the hospital stay. Patients with right anterolateral minithoracotomy had less post-operative chest drainage (536 ± 159 vs 773 ± 255 ml, P < 0.01) and transfusion rate (5.9% vs 33.3%, P = 0.033) than those who had sternotomy. There was no peri-operative death, and all the patients were alive and free of recurrence at the latest follow-up. CONCLUSIONS: Surgical resection of primary benign cardiac tumors is safe, effective and durable. The right anterolateral minithoracotomy provides the same postoperative recovery as standard median sternotomy, but less transfusion. It can be considered as a promising alternative approach.