A Novel Ultrasound Method of Evaluating Dynamic Extrusion of Lateral Meniscus in Healthy Population: Different Patterns of Dynamic Extrusion Revealed Between Lateral and Medial Meniscus.

OBJECTIVES: To establish a reliable ultrasound (US) method of evaluating dynamic extrusion of lateral meniscus in healthy population, and to investigate the pattern of dynamic meniscus extrusion (ME) in lateral meniscus under loading conditions. METHODS: The lateral ME was examined via US method in unloaded, double-leg standing, and single-leg standing positions. Two different US measurement methods were compared to the magnetic resonance imaging (MRI) results to determine the optimal measurement methods. The US results obtained by different researchers were tested for interobserver consistency and the results obtained by the same researcher on two separate days were tested for intraobserver consistency. The patterns of dynamic extrusion were compared between medial and lateral sides. RESULTS: A total of healthy 44 volunteers were included in the study, with 86 knees assessed by US, and 25 knees evaluated by MRI. The US evaluation of dynamic lateral ME demonstrated excellent interobserver and intraobserver reliability. The US measurements using method A were consistent with the MRI results with no significant difference (P = .861, intraclass correlation coefficient [ICC] = 0.868), while method B underestimated the lateral ME compared to MRI (P = .001, ICC = 0.649). Lateral ME decreased slightly from unloaded (1.0 ± 0.8 mm) to single-leg standing position (0.8 ± 0.8 mm), whereas medial ME increased significantly in both double-leg and single-leg standing positions (2.4 ± 0.7 mm, 2.6 ± 0.7 mm). CONCLUSION: A novel US evaluation method of lateral ME was established with reliable and accurate results compared to the MRI. Lateral ME in healthy populations decreased slightly as the loadings increased, which was different from the pattern of dynamic extrusion in medial meniscus.

Editorial Commentary: Meniscal Allograft Transplantation Results in Both Pain Relief and Chondroprotection.

Meniscal allograft transplantation (MAT) effectively alleviates symptoms of the meniscus deficiency. Thus, MAT is a widely accepted and recommended treatment for individuals with unicompartmental pain due to meniscus deficiency. Long-term follow-up studies have indicated that MAT yields favorable clinical outcomes, demonstrating high survivorship and low rates of serious complications. In addition, the ability of MAT to function akin to the native meniscus and shield the knee cartilage from osteoarthritis has been a subject of ongoing investigation, and recent direct magnetic resonance imaging evidence shows long-term chondroprotection following MAT. Cartilage lesions worsen during the meniscus deficiency period. Consequently, delaying MAT until patients become more symptomatic may lead to poor outcomes and low graft survivorship due to concomitant cartilage lesions. These findings prompt a reevaluation of the purpose and timing of MAT decisions for meniscectomy patients, suggesting a more proactive approach to recommending MAT, particularly for patients at high risk of postmeniscectomy syndrome and osteoarthritis progression.

A Deep Learning Model Enhances Clinicians' Diagnostic Accuracy to More Than 96% for Anterior Cruciate Ligament Ruptures on Magnetic Resonance Imaging.

PURPOSE: To develop a deep learning model to accurately detect anterior cruciate ligament (ACL) ruptures on magnetic resonance imaging (MRI) and to evaluate its effect on the diagnostic accuracy and efficiency of clinicians. METHODS: A training dataset was built from MRIs acquired from January 2017 to June 2021, including patients with knee symptoms, irrespective of ACL ruptures. An external validation dataset was built from MRIs acquired from January 2021 to June 2022, including patients who underwent knee arthroscopy or arthroplasty. Patients with fractures or prior knee surgeries were excluded in both datasets. Subsequently, a deep learning model was developed and validated using these datasets. Clinicians of varying expertise levels in sports medicine and radiology were recruited, and their capacities in diagnosing ACL injuries in terms of accuracy and diagnosing time were evaluated both with and without artificial intelligence (AI) assistance. RESULTS: A deep learning model was developed based on the training dataset of 22,767 MRIs from 5 centers and verified with external validation dataset of 4,086 MRIs from 6 centers. The model achieved an area under the receiver operating characteristic curve of 0.987 and a sensitivity and specificity of 95.1%. Thirty-eight clinicians from 25 centers were recruited to diagnose 3,800 MRIs. The AI assistance significantly improved the accuracy of all clinicians, exceeding 96%. Additionally, a notable reduction in diagnostic time was observed. The most significant improvements in accuracy and time efficiency were observed in the trainee groups, suggesting that AI support is particularly beneficial for clinicians with moderately limited diagnostic expertise. CONCLUSIONS: This deep learning model demonstrated expert-level diagnostic performance for ACL ruptures, serving as a valuable tool to assist clinicians of various specialties and experience levels in making accurate and efficient diagnoses. LEVEL OF EVIDENCE: Level III, retrospective comparative case series.

Comparing the EU and Chinese carbon trading market operations and their spillover effects.

A carbon trading market (CTM) policy for trading carbon dioxide emission rights as a commodity was created to reduce greenhouse gas emissions. CTMs operate differently in different countries and regions, and their interactions deserve an in-depth study. This study focused on the world's largest CTM, the European Union (EU), and the CTM of China, largest carbon-emitting country. First, we evaluate the liquidity and volatility of the two CTMs. Subsequently, the VAR model is used to explore the mean spillover effect between the two markets and the BEKK-GARCH model is used to explore the volatility spillover effect between the two markets. The study concludes that: (1) The liquidity of China's CTM is better than that of the EU's CTM. (2) Both the EU and Chinese CTMs are unstable, but the volatility of the Chinese CTM is lower than that of the EU CTM. (3) Price changes in the EU and Hubei CTMs have a mutual influence. (4) There are interactions between the market fluctuations of the EU CTM and the Shanghai CTM and those of the EU CTM and the Hubei CTM. The results of this study have implications for the construction and development of CTMs in the EU and China.

Meniscal allograft transplantation in discoid meniscus patients achieves good clinical outcomes and superior chondroprotection compared to meniscectomy in the long term.

PURPOSE: To compare the long-term clinical and radiological results of meniscal allograft transplantation (MAT) for discoid lateral meniscus (DLM) patients with MAT for non-discoid lateral meniscus patients and meniscectomy (ME) for DLM patients and, thus, to determine whether DLM patients are suitable candidates for MAT. METHODS: Eight MAT cases in DLM patients were identified (discoid MAT group), six MAT cases in non-discoid lateral meniscus patients (non-discoid MAT group) and ten total meniscectomy cases in DLM patients (discoid ME group) were matched as controls. Subjective evaluations, postoperative radiography and magnetic resonance imaging (MRI) were conducted at 5 years and 10-14 years, respectively. Joint degeneration was evaluated by the Kellgren-Lawrance (KL) grade and joint space width (JSW). MRI with T2 mapping sequences was used to quantitatively evaluate degeneration of the joint cartilage and shrinkage of the allografts. Student's t test was used to compare quantitative variables and the Mann‒Whitney U test was used to compare categorical variables. RESULTS: There was no difference in Lysholm, IKDC, Tegner or VAS scores amongst the discoid MAT, non-discoid MAT and discoid ME groups at the final follow-up. No revision surgery was performed in any MAT patient. The JSW narrowing in the discoid MAT group was better than that in the discoid ME group (0.8 ± 0.4 mm vs. 2.1 ± 1.3 mm, p = 0.012) and worse than that in the non-discoid MAT group (0.1 ± 0.1 mm, p = 0.003). The KL progression of the discoid MAT group was less than that of the discoid ME group (1.3 ± 0.7 vs. 2.3 ± 0.9, p = 0.034). The discoid ME group had worse cartilage lesion progression than the discoid MAT and non-discoid MAT groups. The allograft width of the DLM patients shrank more than that of the non-discoid patients at the meniscus midbody (3.6 ± 0.9 mm vs. 6.2 ± 1.9 mm, p = 0.015). CONCLUSION: Compared to meniscectomy, MAT achieved similar long-term symptom relief and superior chondroprotection in discoid meniscus patients. Despite more graft shrinkage, the outcomes of MAT in discoid meniscus patients were comparable to those in non-discoid meniscus patients. Therefore, DLM patients may be suitable candidates for MAT procedures. LEVEL OF EVIDENCE: Level III.

Medial meniscus posterior root tears and partial meniscectomy significantly increase stress in the knee joint during dynamic gait.

PURPOSE: As a simple and invasive treatment, arthroscopic medial meniscal posterior horn resections (MMPHRs) can relieve the obstructive symptoms of medial meniscus posterior root tears (MMPRTs) but with the risk of aggravating biomechanical changes of the joint. The aim of this study was to analyze dynamic simulation of the knee joint after medial meniscus posterior root tear and posterior horn resection. METHODS: This study established static and dynamic models of MMPRTs and MMPHRs on the basis of the intact medial meniscus model (IMM). In the finite element analysis, the three models were subjected to 1000 N axial static load and the human walking gait load defined by the ISO14243-1 standard to evaluate the influence of MMPRTs and MMPHRs on knee joint mechanics during static standing and dynamic walking. RESULTS: In the static state, the load ratio of the medial and lateral compartments remained nearly constant (2:1), while in the dynamic state, the load ratio varied with the gait cycle. After MMPHRs, at 30% of the gait cycle, compared with the MMPRTs condition, the maximum von Mises stress of the lateral meniscus (LM) and the lateral tibial cartilage (LTC) were increased by 166.0% and 50.0%, respectively, while they changed by less than 5% during static analysis. The maximum von Mises stress of the medial meniscus (MM) decreased by 55.7%, and that of the medial femoral cartilage (MFC) increased by 53.5%. CONCLUSION: After MMPHRs, compared with MMPRTs, there was no significant stress increase in articular cartilage in static analysis, but there was a stress increase and concentration in both medial and lateral compartments in dynamic analysis, which may aggravate joint degeneration. Therefore, in clinical treatments, restoring the natural structure of MMPRTs is first recommended, especially for physically active patients.

Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock.

Pyroptosis is a type of acute cell death that mainly occurs in immune cells. It is characterized with robust release of inflammatory cytokines and has emerged to play a critical role in the pathogenesis of sepsis-associated immune disorders. In this study, we screened for pyroptotic inhibitors with the ultimate goal to benefit sepsis treatments. Accidentally, we identified that nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, inhibits noncanonical pyroptosis. Using murine immortalized BM-derived macrophage and human THP-1 cell line, we further discovered that NTS not only inhibits noncanonical pyroptosis mediated by caspase-11 or caspase-4 but also canonical pyroptosis mediated by caspase-1. Mechanistically, NTS directly inhibits the enzyme activities of these inflammatory caspases, and these inhibitory effects persist despite extensive washout of the drug. By contrast, apoptosis mediated by caspase-3/-7 was not affected by NTS. Mice pretreated with NTS intraperitoneally displayed improved survival rate and extended survival time in LPS- and polymicrobe-induced septic models, respectively. In conclusion, NTS is a selective inhibitor of inflammatory caspases that blocks both the noncanonical and canonical pyroptotic pathways. It is safe for intraperitoneal administration and might be used as a prototype to develop drugs for sepsis treatments.

Atrial myocyte-derived exosomal microRNA contributes to atrial fibrosis in atrial fibrillation.

BACKGROUND: Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF. METHODS: We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p. RESULTS: The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002). CONCLUSIONS: Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.

The immediate meniscal allograft transplantation achieved better chondroprotection and less meniscus degeneration than the conventional delayed transplantation in the long-term.

PURPOSE: The purpose of this study was to compare the long-term clinical and radiological outcomes between the immediate and delayed meniscus allograft transplantation (MAT). METHODS: Nine menisci were transplanted immediately after total meniscectomy (immediate group, IM), and 10 menisci were delayed transplanted in patients with the median of 35 months (range 9-92 months) after total meniscectomy (delayed group, DE). Patient's subjective clinical outcomes including VAS, IKDC, Lysholm and Tegner scores as well as muscle strength measures were compared. Joint degeneration was evaluated by both radiographs to assess joint space width narrowing, Kellegren-Lawrence (KL) grade and MRI with T2 mapping sequences to quantitatively analyze both cartilage and meniscal allograft degeneration. RESULTS: The median follow-up time was 10.8 years (range 10-14 years). The IKDC (IM vs DE, 89.8 vs 80.9, n.s.) and Lysholm scores (IM vs DE, 87.7 vs 78.0, n.s.) were close in two groups, while the IM group showed slightly lower VAS (IM vs DE, 0.2 vs 1.5, p = 0.031), higher Tegner score (IM vs DE, 7 vs 3.5 p = 0.021) and better quadriceps muscle strength. The IM group had less joint space narrowing (IM vs DE, 0.35 mm vs 0.71 mm, n.s.), less KL grade progression (IM vs DE, 0.6 vs 1.7, p = 0.041) on radiographs and less chondral lesions development on MRIs (Cartilage Degeneration Index, IM vs DE, 252 vs 2038, p = 0.025). All meniscal grafts exhibited degeneration by showing grade 3 signal on MRI, and 4 (4/9) in the IM group and 8 (8/10) cases in the DE group. The T2 value of cartilage and meniscal allograft in the IM group was close to that of the healthy control and was significantly lower than that of the DE group. CONCLUSION: Compared to the conventional delayed MAT, the immediate MAT achieved better cartilage and meniscus protection in the long-term, while its superiority in patient-reported outcomes was limited. LEVEL OF EVIDENCE: IV.

Hypertonic saccharide solution delays pyroptosis in murine macrophages regardless of the membrane binding of gasdermin D N-terminal.

Pyroptosis is a type of programmed lytic cell death that could be activated by either the canonical or noncanonical inflammasome pathway. In this study, we aimed to examine the effect of hypertonic solution on noncanonical pyroptosis in macrophage. We found that although hypertonic solution had a general inhibitory effect on noncanonical pyroptosis, the underlying mechanism varied by the solute causing hypertonicity. Specifically, hypertonic NaCl or KCl solution inhibited the cleavage of gasdermin D, the pore-forming protein in pyroptosis, whereas hypertonic saccharide solution did not affect the cleavage or membrane binding of gasdermin D. In this case, nevertheless, pyroptosis was still inhibited as evidenced by the preserved mitochondria activity and cell membrane permeability.

Epidermis-Activated Gasdermin-A3 Enhances Thermogenesis of Brown Adipose Tissue through IL-6/Stat3 Signaling.

Missense mutations in the gasdermin-A3 (Gsdma3) gene are associated with skin inflammation and hair loss in mice. However, the physiological function of Gsdma3 remains unclear. Herein, we reported that mice carrying the Gsdma3 Y344H mutation that encodes a presumptive activated form of Gsdma3 show increased heat production along with lower body fat percentages. Detailed analysis indicated that this metabolic phenotype is mediated by serum IL-6-induced up-regulation of thermogenesis in brown adipose tissue. The mutant form of Gsdma3 promotes the expression of IL-6 in the epidermis in a c-Jun N-terminal kinase (JNK) signaling-dependent manner. The higher whole-body heat production in alopecia and excoriation mice could be suppressed by an IL-6 receptor/GP130 inhibitor. Our results uncovered Gsdma3/IL-6-dependent cross talk between the skin and brown adipose tissue.

Vascular Compromising Effect of Drilling for Osteochondral Lesions of the Talus: A Three-Dimensional Micro-Computed Tomography Study.

PURPOSE: To explore an optimal drilling depth and direction for osteochondral lesions of the talus based on a 3-dimensional vascular microarchitecture model constructed with micro-computed tomography (microCT). METHODS: Twelve tali were perfused with the contrast agent and then scanned with microCT. The talar dome was divided into 9 zones, and the vessel densities were measured at the subchondral depths of 0 to 5 mm, 5 to 10 mm and 10 to 15 mm in each zone. The anterolateral (AL) and posterolateral (PL) approaches of retrograde drilling were simulated and the vascular compromising effect was evaluated. RESULTS: The vessel density of the 0- to 5-mm depth was lower than that of the 5- to 10-mm (P = .001) and 10- to 15-mm (P = .007) depths, but no significant difference was found between the 5- to 10-mm and 10- to 15-mm depths (P > .9999). The vessel density in the 5- to 10-mm depth of medial talar dome was similar to that of the adjacent zones (P = .05). Vessel density in the 5- to 10-mm depth around the lateral talar dome was higher in the anterior and medial side. The anterolateral approach disturbed the main intraosseous vessels from the tarsal canal-tarsal sinus, causing extensive vascular compromise in the talus neck and body, whereas the posterolateral approach disturbed only the vessels near the tunnel. CONCLUSIONS: The vessel density changed greatly from the subchondral 0- to 5-mm to the 5- to 10-mm depth. The vessel densities of the 5- to 10-mm depth around the medial talar dome were similar, whereas the anterior and medial side of the lateral talar dome was better vascularized. The posterolateral approach caused less vascular damage than the anterolateral approach. CLINICAL RELEVANCE: The anterograde drilling depth was preferable to the subchondral 5- to 10-mm depth. There was no preferred drilling direction for the osteochondral lesion in the medial talar dome, whereas it is preferable to drill anteriorly or medially in the lateral dome. The posterolateral approach might be a safer alternative for retrograde drilling.

Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice.

Endothelial dysfunction occurs in obese patients and high-fat diet (HFD) fed experimental animals. While geraniol has been reported to ameliorate inflammation and oxidative stress, inhibit tumor cell proliferation, and improve atherosclerosis, its direct effect on endothelial function remains uncharacterized. The present study therefore investigated the effect of geraniol on endothelial function in HFD mice and its underlying mechanisms. C57 BL/6 mice were fed an HFD (n = 40) or a normal diet (n = 20) for 8 weeks. HFD fed mice then were randomized to intraperitoneal treatment with geraniol (n = 20) or vehicle (n = 20) for another 6 weeks. Acetylcholine (Ach)-induced endothelial dependent vasorelaxation was measured on wire myography; reactive oxygen species (ROS) generation was assessed by fluorescence imaging, and NADPH oxidases (NOXs) and adhesive molecules VCAM-1 and ICAM-1 protein expression by western blotting. Geraniol improved endothelial function in HFD fed mice, as evidenced by its: 1. restoring endothelial dependent vasorelaxation induced by Ach, and reversing increased VCAM-1 and ICAM-1 expression; 2. attenuating HFD induced increased serum TBARS and aortic ROS generation; and 3. downregulating aortic NOX-2 expression in both HFD fed mice and in palmitic acid treated endothelial cells. Geraniol therefore protects against endothelial dysfunction induced by HFD through reducing NOX-2 associated ROS generation.

Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway.

Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.

Protein-Binding Function of RNA-Dependent Protein Kinase Promotes Proliferation through TRAF2/RIP1/NF-κB/c-Myc Pathway in Pancreatic ß cells.

Double-stranded RNA-dependent protein kinase (PKR), an intracellular pathogen recognition receptor, is involved both in insulin resistance in peripheral tissues and in downregulation of pancreatic ß-cell function in a kinase-dependent manner, indicating PKR as a core component in the progression of type 2 diabetes. PKR also acts as an adaptor protein via its protein-binding domain. Here, the PKR protein-binding function promoted ß-cell proliferation without its kinase activity, which is associated with enhanced physical interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. In addition, the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-dependent survival gene c-Myc was upregulated significantly and is necessary for proliferation. Upregulation of the PKR protein-binding function induced the NF-κB pathway, as observed by dose-dependent degradation of IκBα, induced nuclear translocation of p65 and elevated NF-κB-dependent reporter gene expression. NF-κB-dependent reporter activity and ß-cell proliferation both were suppressed by TRAF2-siRNA, but not by TRAF6-siRNA. TRAF2-siRNA blocked the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) induced by PKR protein binding. Furthermore, RIP1-siRNA inhibited ß-cell proliferation. Proinflammatory cytokines (TNFα) and glucolipitoxicity also promoted the physical interaction of PKR with TRAF2. Collectively, these data indicate a pivotal role for PKR's protein-binding function on the proliferation of pancreatic ß cells through TRAF2/RIP1/NF-κB/c-Myc pathways. Therapeutic opportunities for type 2 diabetes may arise when its kinase catalytic function, but not its protein-binding function, is downregulated.

Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea.

AIMS: Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol. METHODS: Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg· kg(-1)· day(-1)) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis-inducing factor (AIF), caspase 3, Bcl-2, Bax, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting. RESULTS: Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, α-SMA, and TGF-ß1 as well as downregulation of Bcl-2 was markedly recovered by metoprolol, which was mediated by p38 MAPK. CONCLUSION: Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA.

Valsartan Reduced Atrial Fibrillation Susceptibility by Inhibiting Atrial Parasympathetic Remodeling through MAPKs/Neurturin Pathway.

BACKGROUND/AIMS: Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. METHODS: Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. RESULTS: Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. CONCLUSION: Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway.

Chronic obstructive sleep apnea causes atrial remodeling in canines: mechanisms and implications.

Obstructive sleep apnea (OSA) is closely related to atrial fibrillation (AF). However, the roles and mechanisms of chronic OSA in atrial remodeling are still unclear. Canine model of chronic OSA was simulated by stopping the ventilator and closing the airway for 4 h per day and lasting for 12 weeks. AF inducibility and duration was increased while atrial effective refractory period (AERP) was shortened after chronic apnea. Meanwhile, upregulation of proteins encoding inward rectifier K(+) current (IK1), delayed rectifier K(+) current (IKr and IKs), acetylcholine activated K(+) current (IKACh), transient outward K(+) current (Ito) and ultra-rapid delayed rectifier potassium current (IKur) as well as downregulation of protein encoding L-type Ca(2+) current (ICa,L) were found after chronic OSA. Besides abnormal electrical activity, chronic OSA induced apoptosis and interstitial fibrosis of atrial myocytes, which was partly mediated by caspase 9, phosphorylation of extracellular-regulated kinase 1/2, and α-smooth muscle actin. In addition, atrial sympathetic and parasympathetic hyperinnervation were found manifesting by enhanced growth-associated protein 43, tyrosine hydroxylase and elevated choline acetyltransferase. Moreover, protein expression of ß1, ß2, and M2 receptor were markedly increased by chronic OSA. In summary, we firstly demonstrated in canine model that chronic OSA could shorten AERP and lead to altered expression of important channel proteins, moreover, induce atrial structure remodeling by increased atrial apoptosis, fibrosis, and autonomic remodeling, eventually promoting the development of a substrate of AF. Our findings suggested that reversing atrial remodeling might be a potential therapeutic strategy for OSA-induced AF.

How robot-assisted gait training affects gait ability, balance and kinematic parameters after stroke: a systematic review and meta-analysis.

INTRODUCTION: Gait ability is often cited by stroke survivors. Robot-assisted gait training (RAGT) can help stroke patients with lower limb motor impairment regain motor coordination. EVIDENCE ACQUISITION: PubMed, Cochrane Library, Embase were systematically searched until September 2023, to identify randomized controlled trials presenting: stroke survivors as participants; RAGT as intervention; conventional rehabilitation as a comparator; gait assessment, through scales or quantitative parameters, as outcome measures. EVIDENCE SYNTHESIS: Twenty-seven publications involving 1167 patients met the inclusion criteria. Meta-analysis showed no significant differences in speed, cadence, spatial symmetry, and changes in joint mobility angles between the RAGT group and the control group. In addition, RAGT was associated with changes in affected side step length (SMD=0.02, 95% CI: 0.01, 0.03; P<0.0001), temporal symmetry (SMD=-0.38, 95% CI: -0.6, -0.16; P=0.0006], Six-Minute Walk Test (SMD=25.14, 95% CI: 10.19, 40.09; P=0.0010] and Functional Ambulation Categories (SMD=0.32, 95% CI: 0.01, 0.63; P=0.04). According to the PEDro scale, 19 (70.4%) studies were of high quality and eight were of moderate quality (29.6%). CONCLUSIONS: Taken together, the review synthesis showed that RAGT might have a potential role in the recovery of walking dysfunction after stroke. However, its superiority over conventional rehabilitation requires further research. Additionally, it may provide unexpected benefits that the effects of RAGT with different types or treatment protocols were further compared.

Conquer coronary artery perforation with magic hands.

Coronary artery perforation (CAP) poses a significant challenge for interventional cardiologists. Management of CAP depends on the location and severity of the perforation. The conventional method for addressing the perforation of large vessels involves the placement of a covered stent, while the perforation of distal and collateral vessels is typically managed using coils, autologous skin, subcutaneous fat, microspheres, gelatin sponge, thrombin or other substances. However, the above techniques have certain limitations and are not applicable in all scenarios. Our team has developed a range of innovative strategies for effectively managing CAP. This article provides an insightful review of the various tips and tricks for the treatment of CAP.