Protective effects of human urinary kallidinogenase against corticospinal tract damage in acute ischemic stroke patients.

This study aimed to assess the effects of human urinary kallidinogenase (HUK) on motor function outcome and corticospinal tract recovery in patients with acute ischemic stroke (AIS). This study was a randomized, controlled, single-blinded trial. Eighty AIS patients were split into two groups: the HUK and control groups. The HUK group was administered HUK and standard treatment, while the control group received standard treatment only. At admission and discharge, the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and muscle strength were scored. The primary endpoint was the short-term outcomes of AIS patients under different treatments. The secondary endpoint was the degree of corticospinal tract fiber damage under different treatments. There was a significant improvement in the NIHSS Scale, BI and muscle strength scores in the HUK group compared with controls (Mann-Whitney U test; P  < 0.05). Diffusion tensor tractography classification and intracranial arterial stenosis were independent predictors of short-term recovery by linear regression analysis. The changes in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) decline rate were significantly smaller in the HUK group than in the control group ( P <  0.05). Vascular endothelial growth factor (VEGF) increased significantly after HUK treatment ( P  < 0.05), and the VEGF change was negatively correlated with changes in ADC. HUK is beneficial for the outcome in AIS patients especially in motor function recovery. It may have protective effects on the corticospinal tract which is reflected by the reduction in the FA and ADC decline rates and increased VEGF expression. The study was registered on ClinicalTrials.gov (unique identifier: NCT04102956).

Evaluation and Application of Silk Fibroin Based Biomaterials to Promote Cartilage Regeneration in Osteoarthritis Therapy.

Osteoarthritis (OA) is a common joint disease characterized by cartilage damage and degeneration. Traditional treatments such as NSAIDs and joint replacement surgery only relieve pain and do not achieve complete cartilage regeneration. Silk fibroin (SF) biomaterials are novel materials that have been widely studied and applied to cartilage regeneration. By mimicking the fibrous structure and biological activity of collagen, SF biomaterials can promote the proliferation and differentiation of chondrocytes and contribute to the formation of new cartilage tissue. In addition, SF biomaterials have good biocompatibility and biodegradability and can be gradually absorbed and metabolized by the human body. Studies in recent years have shown that SF biomaterials have great potential in treating OA and show good clinical efficacy. Therefore, SF biomaterials are expected to be an effective treatment option for promoting cartilage regeneration and repair in patients with OA. This article provides an overview of the biological characteristics of SF, its role in bone and cartilage injuries, and its prospects in clinical applications to provide new perspectives and references for the field of bone and cartilage repair.

Joint fluid interleukin-6 combined with the neutral polymorphonuclear leukocyte ratio (PMN%) as a diagnostic index for chronic periprosthesis infection after arthroplasty.

BACKGROUND: The diagnosis of periprosthetic joint infection (PJI) remains a challenge in clinical practice. Many novel serum and joint fluid biomarkers have important implications for the diagnosis of PJI. The presented study evaluated the value of joint fluid interleukin-6 (IL-6) combined with the neutral polymorphonuclear leukocyte (PMN%) ratio for chronic PJI diagnosis after arthroplasty. MATERIALS AND METHODS: Sixty patients with chronic PJI or aseptic failure who underwent hip or knee revision from January 2018 to January 2020 in our department were included in this retrospective study. According to the 2013 MSIS diagnostic criteria, the 60 patients were divided into a PJI group and a non-PJI group (30 patients per group). We collected the joint fluid before surgery and determined the level of IL-6 and the PMN% by ELISA, and the differences between the two groups were compared. The diagnostic efficacy of joint fluid IL-6 combined with PMN% in chronic PJI was analyzed using a receiver operating characteristic curve (ROC curve). RESULTS: The diagnosis of PJI using joint fluid IL-6 combined with PMN% presented an area under the curve of 0.983, which was more accurate than the areas under the curve for diagnosis using IL-6 and PMN% individually (0.901 and 0.914, respectively). The optimal threshold values for IL-6 and PMN% were 662.50 pg/ml and 51.09%, respectively. Their sensitivity and specificity were 96.67% and 93.33%, respectively. The accuracy of the diagnosis of PJI was 95.00%. CONCLUSIONS: Joint fluid IL-6 combined with PMN% can be used as an auxiliary method to detect chronic infection around the prosthesis after hip/knee arthroplasty. LEVEL OF EVIDENCE: Patients who underwent hip/knee revision at the First Hospital of Chongqing Medical University for periprosthetic infection or aseptic failure of the prosthesis after hip/knee arthroplasty from January 2018 to January 2020 were included. Trial registration This study was approved by the ethics committee of the First Hospital of Chongqing Medical University on September 26, 2018 (local ethics committee number: 20187101) and registered with the China Clinical Trials Registry (registration number: ChiCTR1800020440) with an approval date of December 29, 2018.

Cerebral collateral circulation as an independent predictor for in-stent restenosis after carotid artery stenting.

Background: In-stent restenosis is a crucial problem after carotid artery stenting, but the exact predictors of in-stent restenosis remain unclear. We aimed to evaluate the effect of cerebral collateral circulation on in-stent restenosis after carotid artery stenting and to establish a clinical prediction model for in-stent restenosis. Methods: This retrospective case-control study enrolled 296 patients with severe carotid artery stenosis of C1 segment (≥70%) who underwent stent therapy from June 2015 to December 2018. Based on follow-up data, the patients were divided into the in-stent restenosis and no in-stent restenosis groups. The collateral circulation of the brain was graded according to the criteria of the American Society for Interventional and Therapy Neuroradiology/Society for Interventional Radiology (ASITN/SIR). Clinical data were collected, such as age, sex, traditional vascular risk factors, blood cell count, high-sensitivity C-reactive protein, uric acid, stenosis degree before stenting and residual stenosis rate, and medication after stenting. Binary logistic regression analysis was performed to identify potential predictors of in-stent restenosis, and a clinical prediction model for in-stent restenosis after carotid artery stenting was established. Results: Binary logistic regression analysis showed that poor collateral circulation was an independent predictor of in-stent restenosis (P=0.003). We also found that a 1% increase in residual stenosis rate was associated with a 9% increase in the risk of in-stent restenosis (P=0.02). Ischemic stroke history (P=0.03), family history of ischemic stroke (P<0.001), in-stent restenosis history (P<0.001), and nonstandard medication after stenting (P=0.04) were predictors of in-stent restenosis. The risk of in-stent restenosis was lowest when the residual stenosis rate was 12.5% after carotid artery stenting. Furthermore, we used some significant parameters to construct a binary logistic regression prediction model for in-stent restenosis after carotid artery stenting in the form of a nomogram. Conclusions: Collateral circulation is an independent predictor of in-stent restenosis after successful carotid artery stenting, and the residual stenosis rate tends to be below 12.5% to reduce restenosis risk. The standard medication should be strictly carried out for patients after stenting to prevent in-stent restenosis.

Detection of inguinal lymph nodes is promising for the diagnosis of periprosthetic joint infection.

Background: Localized inguinal lymphadenopathy often represents lower extremity pathogen infection, while normalized lymphadenopathy is associated with infection regression. We hypothesized that inguinal lymph nodes (LNs) were enlarged in Periprosthetic Joint Infection (PJI) patients and that normalized inguinal LNs would be a promising way to determine the timing of reimplantation. Methods: We prospectively enrolled 176 patients undergoing primary and revision hip or knee arthroplasty. All patients underwent ultrasound examination of inguinal LNs preoperatively. The diagnostic value of inguinal LNs in PJI was evaluated by the receiver operating characteristic (ROC) curve. Results: The median level of inguinal LNs was 26mm in the revision for PJI group compared with 12 mm in the aseptic revision group (p< 0.0001). The size of the inguinal LNs well distinguishes PJI from aseptic failure (AUC= 0.978) compare with ESR (AUC= 0.707) and CRP (AUC= 0.760). A size of 19mm was determined as the optimal threshold value of the inguinal LNs for the diagnosis of PJI, with a sensitivity of 92% and specificity of 96%. Conclusion: Ultrasonic analysis of inguinal LNs is a valuable piece of evidence for the diagnosis of PJI and evaluation of persistent infection.

Hypoxia-mimicking scaffolds with controlled release of DMOG and PTHrP to promote cartilage regeneration via the HIF-1α/YAP signaling pathway.

Efficiently driving chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) while avoiding undesired hypertrophy remains a challenge in the field of cartilage tissue engineering. Here, we report the sequential combined application of dimethyloxalylglycine (DMOG) and parathyroid hormone-related protein (PTHrP) to facilitate chondrogenesis and prevent hypertrophy. To support their delivery, poly(lactic-co-glycolic acid) (PLGA) microspheres were fabricated using a double emulsion method. Subsequently, these microspheres were incorporated onto a poly(l-lactic acid) (PLLA) scaffold with a highly porous structure, high interconnectivity and collagen-like nanofiber architecture to construct a microsphere-based scaffold delivery system. These functional constructs demonstrated that the spatiotemporally controlled release of DMOG and PTHrP effectively mimicked the hypoxic microenvironment to promote chondrogenic differentiation with phenotypic stability in a 3D culture system, which had a certain correlation with the interaction between hypoxia-inducible Factor 1 alpha (HIF-1α) and yes-associated protein (YAP). Subcutaneous implantation in nude mice revealed that the constructs were able to maintain cartilage formation in vivo at 4 and 8 weeks. Overall, this study indicated that DMOG and PTHrP controlled-release PLGA microspheres incorporated with PLLA nanofibrous scaffolds provided an advantageous 3D hypoxic microenvironment for efficacious and clinically relevant cartilage regeneration and is a promising treatment for cartilage injury.

Dietary Effects on Chronic Venous Disease.

BACKGROUND: Diet is fundamental to maintaining and improving human health. There is ample evidence identifying the beneficial and/or harmful effects of diet on noncommunicable diseases such as obesity, diabetes mellitus, and cardiovascular disease. However, the associations of the diet to chronic venous disease has not been fully described. METHODS: Data were collected through a cross-sectional survey conducted on 1,571 community-dwelling adults in 2018. Diet intake frequency was assessed using valid food group consumption frequency questionnaires. Multivariable logistic regression models were used to evaluate the association of diet with chronic venous disease. RESULTS: In total, 857 participants were diagnosed with chronic venous disease. Those who ate soybean products daily and 4-6 days/week had a 51-31% lower risk of chronic venous disease compared with those who only occasionally consumed soybean food, respectively. Participants who consumed eggs and egg products 1-3 days/week versus those who only occasionally ate eggs showed a lower risk of chronic venous disease [odds ratio (OR) 0.542, 95% confidence interval (CI) 0.375-0.782]. Eating fried food 4-6 days each week was associated with an increased risk of chronic venous disease (OR 3.872, 95% CI 1.263-11.599) compared with those who only occasionally ate fried foods. There is a decreasing tendency of the adjusted OR for eating soybean products daily with the severity of disease [chronic venous disease (C0-C2): OR 0.575, 95% CI 0.408-0.812; chronic venous insufficiency (C3-C6): OR 0.222, 95% CI 0.114-0.435]. CONCLUSIONS: A higher frequency in the consumption of soybean products and eggs were associated with a lower risk of chronic venous disease. High level of fried food consumption was positively associated with risk of chronic venous disease. There are certain specific trends in relation to dietary consumption and severity of disease, although these trends were less strong. These associations are largely independent of other dietary and nondietary factors.

Clinical outcomes of venous self-expanding stent placement for iliofemoral venous outflow obstruction.

OBJECTIVE: In the present study, we evaluated the feasibility of a self-expanding venous stent for treating iliofemoral venous obstruction. METHODS: The present retrospective study reviewed the data from 49 patients who had undergone Zilver Vena (Cook Medical, Bloomington, Ind) stent placement for treatment of iliofemoral venous obstruction from September 2017 to March 2019. All patients had undergone received follow-up duplex ultrasound examinations to assess for stent patency. The Villalta scores and Venous Clinical Severity Scores (VCSSs) were also calculated to stratify the postoperative improvement in disease. RESULTS: Of the 49 patients, 19 had had acute deep vein thrombosis, 7, nonthrombotic iliac venous lesions, and 23, post-thrombotic syndrome. At 1 year after Zilver Vena stent placement, the primary, assisted primary, and secondary patency rates were 93.8%, 95.9%, and 97.9%, respectively. The baseline median Villalta score before treatment for those with post-thrombotic syndrome was 19 (range, 11-30), and the median VCSS for the patients with post-thrombotic syndrome and nonthrombotic iliac venous lesions was 11 (range, 6-25). At 1 year after stent placement, the median Villalta score for the post-thrombotic syndrome patients was 4.0 (range, 2-18), and the median VCSS for the post-thrombotic syndrome and nonthrombotic iliac venous lesions patients was 3.0 (range, 2-12). CONCLUSIONS: Venous placement of self-expanding stents offers excellent 1-year patency rates and improved the outcomes of patients with iliofemoral venous obstruction caused by acute deep vein thrombosis, nonthrombotic iliac venous lesions, and post-thrombotic syndrome.

Association of High Serum Homocysteine Levels and Severe Chronic Venous Disease.

BACKGROUND: Homocysteine (Hcy) is considered as a modifiable risk factor for vascular disease. This study was aimed to explore the association between serum concentration and the severity of primary chronic venous disease (CVD). METHODS: Clinical data of 582 patients diagnosed with primary CVD were collected and analyzed retrospectively. The Clinical Etiology Anatomy Pathophysiology classification system was used to grade the severity of chronic venous disease. Patients were divided into 2 groups (group A: C1-C3; group B: C4-C6). The association between serum homocysteine levels and the severity of primary chronic venous disease was investigated using rank sum test and logistic regression. RESULTS: The difference between the level of homocysteine in each grade has statistical significance. Group A has higher median Hcy concentrations than Group B (15.40 µmol/L vs. 14.05 µmol/L, P< 0.01). Further binary logistic regression showed no statistical significance among the level of Hcy (11.00-14.75 µmol/L [OR 0.66, 95% CI 0.40-1.11, P= 0.12], 14.75-20.38µmol/L [OR 0.97, 95% CI 0.59-1.69, P = 0.89], ≥20.38 µmol/L [OR 0.67, 95% CI 0.41-1.10, P = 0.11]), but age (OR 1.03, 95% CI 1.01-1.04, P< 0.01) and female (OR 0.41, 95% CI 0.28-0.59, P< 0.01) are associated with more severe stages of CVD. CONCLUSIONS: Higher level of Hcy is associated with more severe stages of CVD, but it not an independent risk factor. However, Advanced age and female are risk factors for CVD development based on logistic regression analysis.

Predictive Model for Pulmonary Embolism in Patients with Deep Vein Thrombosis.

BACKGROUND: To develop and verify a risk predictive model/scoring system for pulmonary embolism (PE) among hospitalized patients with deep venous thrombosis of the lower extremities (LDVT). METHODS: 776 patients with LDVT were enrolled in a case-control study between January 2016 and June 2017 from the Vascular Surgery Department of Shanxi Dayi Hospital, China. They were randomly divided into development (543 patients, 70%) and validation (233 patients, 30%) databases. Based on the results of pulmonary computed tomography arteriography, patients were divided into 2 categories; those with PE were designated as the case group, whereas those without comprised the controls. A logistic regression model and scoring system for PE in patients with LDVT was established in the development database and verified in the validation database. Scoring system (Shanxi Dayi Hospital score [SDH score]) was tabulated as follows: right lower extremity or bilateral lower extremities, 1; surgery or immobilization, 1; malignant tumor, 1; history of venous thromboembolism (VTE), 2; D-dimer >1,000 ng/mL, 2; and unprovoked, 2. Calibration and discrimination of the model were assessed by the Hosmer-Lemeshow goodness of fit test and the area under the receiver operating characteristic curve (AUC). Wells score, the Revised Geneva score, and the SDH score for predictive value of PE by AUC in the validation database were compared. RESULTS: 776 patients with LDVT were divided into 2 risk categories based on the scores from the risk model as follows: PE unlikely (score <3) and PE likely (score ≥3). Sensitivity, specificity, and crude agreement of the SDH score in the development database were 76.39%, 55.89%, and 61.33%, respectively. In the validation database, the logistic regression model showed good calibration and discriminative power. The Hosmer-Lemeshow goodness of fit test P value was >0.05, and the AUC was 0.705 (95% CI: 0.634-0.776, P < 0.001). The SDH score also showed good discriminative power, and the AUC was 0.702 (95% CI: 0.631-0.774, P < 0.001). Sensitivity, specificity, and crude agreement of the SDH score in the validation database were 67.61%, 61.73%, and 63.52%, respectively. AUC for the Wells score and the Revised Geneva score was 0.611 (95% CI: 0.533-0.688, P = 0.007) and 0.585 (95% CI: 0.503-0.666, P = 0.040), respectively. Difference of the AUC was not statistically significant between the Wells score and the SDH score (0.611 vs. 0.702, P = 0.059) but was so between the Revised Geneva score and the SDH score (0.585 vs. 0.702, P = 0.016). Sensitivity of the Wells score, Revised Geneva score, and the SDH score (64.79%, 67.61% vs. 67.61%) was not statistically significant. However, the specificity of the Wells score and Revised Geneva score was significantly lower than that of the SDH score (48.77%, 39.51% vs. 61.73%). CONCLUSIONS: Our logistic regression model and the SDH score based on 7 risk factors as right lower extremity, bilateral lower extremities, unprovoked, surgery or immobilization, malignant tumor, history of VTE, and D-dimer>1,000 ng/mL showed good calibration and discriminative power for the assessment of PE risk in patients with LDVT. The SDH score is more specific for PE prediction in the Chinese population, compared with the Wells score and the Revised Geneva score.

Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through AMPK.

BACKGROUND: Gestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy, which influences the health of maternal-child in clinical practice. It is still urgent to develop new effective treatment for GDM. Naringenin is a bioactive ingredient with multiple activities including anti-diabetic. In current study, the effects of naringenin on GDM symptoms, insulin tolerance, inflammation, and productive outcomes were evaluated and the underlying mechanisms were explored. METHODS: We administrated naringenin to GDM mice and monitored the GDM symptoms, glucose and insulin tolerance, inflammation and productive outcomes. We established tumor necrosis factor alpha (TNF-α)-induced insulin resistance skeletal muscle cell model and evaluated the effects of naringenin on reactive oxygen species (ROS) production, glucose uptake and glucose transporter type 4 (GLUT4) membrane translocation. RESULTS: We found that naringenin ameliorated GDM symptoms, improved glucose and insulin tolerance, inhibited inflammation, and improved productive outcomes. It was further found that naringenin inhibited TNF-α-induced ROS production, enhanced GLUT4 membrane translocation, and glucose uptake, which were abolished by inhibition of AMP-activated protein kinase (AMPK). CONCLUSION: Naringenin improves insulin sensitivity in gestational diabetes mellitus mice in an AMPK-dependent manner.

Cyclic mechanical stretch enhances BMP9-induced osteogenic differentiation of mesenchymal stem cells.

PURPOSE: The purpose of this study was to investigate whether mechanical stretch can enhance the bone morphogenetic protein 9 (BMP9)-induced osteogenic differentiation in MSCs. METHODS: Recombinant adenoviruses were used to overexpress the BMP9 in C3H10T1/2 MSCs. Cells were seeded onto six-well BioFlex collagen I-coated plates and subjected to cyclic mechanical stretch [6% elongation at 60 cycles/minute (1 Hz)] in a Flexercell FX-4000 strain unit for up to 12 hours. Immunostaining and confocal microscope were used to detect cytoskeleton organization. Cell cycle progression was checked by flow cytometry. Alkaline phosphatase activity was measured with a Chemiluminescence Assay Kit and was quantified with a histochemical staining assay. Matrix mineralization was examined by Alizarin Red S Staining. RESULTS: Mechanical stretch induces cytoskeleton reorganization and inhibits cell proliferation by preventing cells entry into S phase of the cell cycle. Although mechanical stretch alone does not induce the osteogenic differentiation of C3H10T1/2 MSCs, co-stimulation with mechanical stretch and BMP9 enhances alkaline phosphatase activity. The expression of key lineage-specific regulators (e.g., osteocalcin (OCN), SRY-related HMG-box 9, and runt-related transcription factor 2) is also increased after the co-stimulation, compared to the mechanical stretch stimulation along. Furthermore, mechanical stretch augments the BMP9-mediated bone matrix mineralization of C3H10T1/2 MSCs. CONCLUSIONS: Our results suggest that mechanical stretch enhances BMP9-induced osteoblastic lineage specification in C3H10T1/2 MSCs.

Integrating transient cellular and nuclear motions to comprehensively describe cell migration patterns.

Various subcellular activities, such as protrusion and detachment, compose a cell migration process. The molecular mechanisms of these subcellular activities have been elucidated. However, there is no method that can assess the contributions of these subcellular activities to the global cell migration pattern of a given cell type. Hence, we develop a powerful approach based on CN correlations that quantitatively profiles the cell migration pattern of a given cell type in terms of assembled subcellular activities. In this way, we bridge migration data at the cellular level with underlying molecular mechanisms. The CN correlation profile is found to uniquely and consistently represent the cell migration pattern of each cell type probed. It can clearly reveal the effects of molecular perturbations, such as Y27632 and Cdc42 knockdown on each subcellular migratory activity. As a result, the CN correlation approach serves as a cell dynamic descriptor that can extract comprehensive quantitative data from cell migration movies for integrative biological analyses.

Low Aromatase Activity and Estradiol/Sex Hormone Binding Globulin Ratio are Associated with Total Hip Bone Mineral Density and the Presence of Osteoporosis: A Study in Chinese Postmenopausal Women.

Several groups have reported the important role of estradiol (E2) and testosterone (T) in postmenopausal osteoporosis (PMOP). Because aromatase catalyzes the conversion of T to E2, the purpose of this study was to determine the influence of aromatase activity on the bone mineral density (BMD) in postmenopausal women. A total of 344 postmenopausal women were selected for this study. Serum E2, T, sex hormone-binding globulin (SHBG), calcium (Ca), alkaline phosphatase (ALP), C-terminal telopeptide of type I collagen (CTX), and procollagen type I amino-terminal propeptide (PINP) were examined. The E2/T was positively associated with total hip BMD and PINP (p<0.05). When E2/T was divided into quartiles, participants in lower quartiles of E2/T were likely to have higher PINP and lower BMD (p<0.05). The prevalence of osteoporosis significantly increased as E2/T ratio decreased. The receiver operating characteristic (ROC) curves were constructed for serum E2, free E2 index (FEI), and E2/T, to assess their diagnostic accuracy in PMOP. The overall area under the curve (AUC) were 0.83 (95% CI=0.77-0.88) for E2, 0.87 (95% CI=0.82-0.92) for FEI, and 0.89 (95% CI=0.85-0.94), respectively. In conclusion, the study suggests that in postmenopausal women, aromatase activity could be an important determinant of skeletal health. The women with lower aromatase activity may have greater likelihood of PMOP and the E2/T was expected to be a valuable indicator for the prediction of PMOP and to monitor the process of osteoporosis.

Characterization of two novel cry8 genes from Bacillus thuringiensis strain BT185.

Two novel cry8-type genes, cry8Ea1 and cry8Fa1, obtained from a Holotrichia parallela-specific Bacillus thuringiensis strain, BT185, were characterized. Findings showed that cry8Ea1 and cry8Fa1 encoded polypeptides of 1164 and 1174 amino acid residues, respectively. The deduced amino acid sequences of both Cry8Ea1 and Cry8Fa1 polypeptides are the most similar to that of Cry8Ba1. Eight conserved blocks (blocks 1-8) exist in Cry8Ea1 and Cry8Fa1 polypeptides compared with known Cry proteins. Cry8Ea1 and the Cry8Fa1 toxins could form spheric crystals when they were expressed in the acrystalliferous mutant strain HD73(-). The spores and crystals from the recombinant strain containing cry8Ea1 were toxic to Holotrichia parallela, with an LC(50) of 0.0875 x 10(8) colony-forming units (CFU)/g. However, Cry8Fa1 expressed in the recombinant strain was not toxic to H. parallela, Anomala corpulenta, or H. oblita.