Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties.

Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Bone mesenchymal stem cell extracellular vesicles delivered miR let-7-5p alleviate endothelial glycocalyx degradation and leakage via targeting ABL2.

BACKGROUND: Endothelial glycocalyx (EG) is an active player and treatment target in inflammatory-related vascular leakage. The bone marrow mesenchymal stem cells (bMSCs) are promising potential treatments for leakage; however, the therapeutic effect and mechanism of bMSC on EG degradation needs to be elucidated. METHODS: EG degradation and leakage were evaluated in both lipopolysaccharide (LPS)-induced mice ear vascular leakage model and LPS-stimulated human umbilical vein endothelial cells (HUVECs) model treated with bMSCs. Extracellular vesicles (EVs) were extracted from bMSCs and the containing microRNA profile was analyzed. EV and miR let-7-5p were inhibited to determine their function in the therapeutic process. The ABL2 gene was knockdown in HUVECs to verify its role as a therapeutic target in EG degradation. RESULTS: bMSCs treatment could alleviate LPS-induced EG degradation and leakage in vivo and in vitro, whereas EVs/let-7-5p-deficient bMSCs were insufficient to reduce EG degradation. LPS down-regulated the expression of let-7-5p while upregulated endothelial expression of ABL2 in HUVECs and induced EG degradation and leakage. bMSC-EVs uptaken by HUVECs could deliver let-7-5p targeting endothelial ABL2, which suppressed the activation of downstream p38MAPK and IL-6, IL-1ß levels, and thus reversed LPS-induced EG degradation and leakage. CONCLUSION: bMCSs alleviate LPS-induced EG degradation and leakage through EV delivery of miR let-7-5p targeting endothelial ABL2.

Background Inflammation-related Endothelial vascular leakage (EVL) is associated with poor clinical prognosis. Endothelial glycocalyx (EG) is a novel therapeutic target for EVL. bMSCs (Bone Mesenchymal Stem Cells) are potential therapies for EVL, but the effect of bMSCs on EG has not been investigated.Significance bMSCs alleviating EG degradation and leakage was firstly clarified in our LPS-induced vascular leakage mice model. Histology and electrophysiology experiments validated that bMSCs achieve therapeutic effects through paracrine extracellular vesicles (EVs). EV-delivered MicroRNA sequencing revealed that miR let-7-5p down-regulated endothelial ABL2/p38MAPK-related inflammation activation. The bMSC-EV delivered let-7-5p was proved as an effective element in alleviating inflammation-related EG degradation and leakage, providing an executable approach for bMSCs to treat EVL. Video Abstract.

Prediction of high-flow nasal cannula outcomes at the early phase using the modified respiratory rate oxygenation index.

BACKGROUND: This study was designed to explore the early predictive value of the respiratory rate oxygenation (ROX) index modified by PaO2 (mROX) in high-flow nasal cannula (HFNC) therapy in patients with acute hypoxemia respiratory failure (AHRF). METHOD: Seventy-five patients with AHRF treated with HFNC were retrospectively reviewed. Respiratory parameters at baseline and 2 h after HFNC initiation were analyzed. The predictive value of the ROX (ratio of pulse oximetry/FIO2 to respiratory rate) and mROX (ratio of arterial oxygen /FIO2 to respiratory rate) indices with two variations by adding heart rate to each index (ROX-HR and mROX-HR) was evaluated. RESULTS: HFNC therapy failed in 24 patients, who had significantly higher intensive care unit (ICU) mortality and longer ICU stay. Both the ROX and mROX indices at 2 h after HFNC initiation can predict the risk of intubation after HFNC. Two hours after HFNC initiation, the mROX index had a higher area under the receiver operating characteristic curve (AUROC) for predicting HFNC success than the ROX index. Besides, baseline mROX index of greater than 7.1 showed a specificity of 100% for HFNC success. CONCLUSION: The mROX index may be a suitable predictor of HFNC therapy outcomes at the early phase in patients with AHRF.

Studies on the effects of bone marrow stem cells on mitochondrial function and the alleviation of ARDS.

Mesenchymal stem cells (MSCs) can alleviate acute respiratory distress syndrome (ARDS), but the mechanisms involved are unclear, especially about their specific effects on cellular mitochondrial respiratory function. Thirty mice were allocated into the Control, LPS, and LPS + Bone marrow mesenchymal stem cell (BMSC) group (n = 10/group). Mouse alveolar epithelial cells (MLE-12) and macrophage cells (RAW264.7) were divided into the same groups. Pathological variation, inflammation-related factors, reactive oxygen species (ROS), ATP levels, and oxygen consumption rate (OCR) were analyzed. Pathologic features of ARDS were observed in the LPS group and were significantly alleviated by BMSCs. The trend in inflammation-related factors among the three groups was the LPS group > LPS + BMSC group > Control group. In the MLE-12 co-culture system, IL-6 was increased in the LPS group but not significantly reduced in the LPS + BMSC group. In the RAW264.7 co-culture system, IL-1ß, TNF-α, and IL-10 levels were all increased in the LPS group, IL-1ß and TNF-α levels were reduced by BMSCs, while IL-10 level kept increasing. ROS and ATP levels were increased and decreased respectively in both MLE-12 and RAW264.7 cells in the LPS groups but reversed by BMSCs. Basal OCR, ATP-linked OCR, and maximal OCR were lower in the LPS groups. Impaired basal OCR and ATP-linked OCR in MLE-12 cells were partially restored by BMSCs, while impaired basal OCR and maximal OCR in RAW264.7 cells were restored by BMSCs. BMSCs improved the mitochondrial respiration dysfunction of macrophages and alveolar epithelial cells induced by LPS, alleviated lung tissue injury, and inflammatory response in a mouse model of ARDS.

Pretic-I was a safe and effective artificial cervical disc prosthesis--a retrospective and comparative study with 5-year follow-up.

BACKGROUND: The newly designed cervical disc prosthesis, Pretic-I, had been finished its limited clinical use for over 5 years. At a short-term follow-up of 2 years, we obtained satisfactory clinical results. The long-term clinical efficacy and safety of Pretic-I will now be analyzed. METHODS: Peri-operative parameters included intra-operative blood loss, operation time, off-bed time. Clinical parameters included visual analogue scale (VAS) for arm and neck, neck disability index (NDI), and Japanese Orthopaedic Association (JOA) score. Radiological parameters included C2-7 Cobb angle, Shell angle, and the range of motion (ROM) of C2-7, functional segment unit (FSU), and adjacent FSU. The CDA-related complications included adjacent segment degeneration (ASDeg), adjacent segment disease (ASDis), heterotopic ossification (HO), prosthesis subsidence, prosthesis displacement, and dysphagia. RESULTS: A total 64 patients from two independent centers received a single-level CDA with Discover (n = 32) and Pretic-I (n = 32), and all of patients finished a 5-year follow-up. There're no significant differences between two groups in peri-operative parameters. The clinical parameters improved greatly in Pretic-I group (p<0.0001), and there's no statistical difference from Discover group. Furthermore, Pretic-I could slightly improve the cervical curvature (15.08 ± 11.75 to 18.00 ± 10.61, p = 0.3079) and perfectly maintain the Shell angle (3.03 ± 3.68 to 2.23 ± 4.10, p = 0.1988), cervical ROM (52.48 ± 14.31 to 53.30 ± 11.71, p = 0.8062) and FSU ROM (12.20 ± 4.52 to 10.73 ± 4.45, p = 0.2002). The incidence of high-grade HO (Grade III-IV) at the final follow-up was significantly lower in Pretic-I group than in Discover group (12.50% vs. 34.38%, p = 0.0389, Statistical Power = 95.36%). The incidences of other CDA-related complications in Pretic-I group were also well-accepted, comparable to the Discover group, without significant differences. CONCLUSION: CDA with Pretic-I demonstrated a well-accepted and sustained clinical outcome, with a significantly lower incidence of high-grade HO. This newly designed prosthesis is expected to become an alternative choice for cervical disc prosthesis in the future.

Downregulated miR-150 in bone marrow mesenchymal stem cells attenuates the apoptosis of LPS-stimulated RAW264.7 via MTCH2-dependent mitochondria transfer.

Mesenchymal stem cells (MSCs) are promising therapeutic cells for preventing apoptosis and abrogating cellular injury. Apoptosis of macrophages and the resulting dysfunction play a critical pathogenic role in acute respiratory distress syndrome (ARDS). Herein, the anti-apoptosis effects of bone marrow MSCs (BMSCs) on RAW264.7 were investigated by transwell assay. Compared to lipopolysaccharide (LPS) stimulation, the treatment of BMSCs decreased the level of cleaved caspase-3 protein, the ratio of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, the level of caspase3-positive cells, and the accumulation of reactive oxygen species (ROS). Moreover, the expression of Bcl-2 and the level of mitochondrial membrane potential (MMP) were increased. Also, it was found that miR-150 disruption of BMSCs remarkably improved the efficiency of the treatment with LPS-stimulated RAW264.7 cells. The study demonstrated that the suppression of miR-150 facilitated the translation of MTCH2 gene and MTCH2-regulated mitochondria transfer from BMSCs to RAW264.7 cells, suggested that miR-150-mediated BMSCs has therapeutic potential for ARDS.

Effectiveness of tigecycline in the treatment of infections caused by carbapenem-resistant gram-negative bacteria in pediatric liver transplant recipients: A retrospective study.

INTRODUCTION: Tigecycline (TGC) is effective for the infections caused by carbapenem-resistant gram-negative bacteria (CRGNB) in adults, but it is not investigated systematically in children because of concern about adverse effects. This study aimed to analyze the effectiveness of TGC in treating CRGNB infections in children after receiving liver transplant. METHODS: The subjects in this retrospective study were pediatric liver transplant recipients treated with TGC for at least 3 days to fight microbiologically verified CRGNB infection after initial antibiotic failure during the period from January 2014 to May 2018. Clinical and microbiological outcomes were reviewed to evaluate the efficacy and safety of TGC. RESULTS: Of the 1177 pediatric liver transplant recipients, 13 patients were eligible for inclusion in this analysis. All the patients received TGC at dose of 2 mg/kg every 12 hours for a duration of 10.1 ± 5.1 days on average to treat CRGNB infections, including complicated intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. The isolates included Klebsiella pneumoniae (69.2%, 9/13) and Acinetobacter baumannii (30.8%, 4/13). Clinical efficacy was achieved in 84.6% (11/13) and pathogen eradicated in 69.2% (9/13) of the patients. The overall mortality rate was 15.4% (2/13). No TGC-related serious adverse event was reported. CONCLUSION: Tigecycline can be considered in combination antimicrobial regimen for treating CRGNB-related infections in pediatric liver transplant recipients.

An Absorbable Collagen Biomembrane Help Improve Swallowing Function After Anterior Cervical Spine Surgery.

The objective of this study is to investigate the changes in swallowing function after using an absorbable collagen biomembrane during anterior cervical spine surgery (ACSS). A prospective controlled study of patients who underwent two-level anterior cervical decompression and fusion (ACDF) with a zero-profile implant or single-level anterior cervical corpectomy and fusion (ACCF) with cage and plate fixation was performed in our hospital from January 2016. An absorbable collagen biomembrane was used after suturing the prevertebral fascia in the experimental groups. The thickness of prevertebral soft tissue (PST) was measured on lateral X-rays to determine the extent of swelling. In addition, the Bazaz grading system and the Swallowing-Quality of Life (SWAL-QOL) survey were used to assess the swallowing function. A total of 100 patients were included with a follow-up of 12 months. Significant differences in PST swelling were found between the experimental groups and control groups at 3 months, 6 months, and 12 months postoperatively (P < 0.05). Patients in the experimental groups had significantly increased SWAL-QOL scores compared with patients in the control groups at 3 months and 6 months after surgery (P < 0.05). A significant difference in the total incidence of dysphagia was observed at 3 months postoperatively between the experimental groups and control groups (P < 0.05). The application of absorbable collagen biomembrane in ACSS can reduce the total incidence of dysphagia and improve swallowing function early after surgery.

Optimal area of lateral mass mini-screws implanted in plated cervical laminoplasty: a radiography anatomy study.

PURPOSE: Lateral mass mini-screws used in plated cervical laminoplasty might penetrate into facet joints. The objective is to observe this complication incidence and to identify the optimal areas for 5- and 7-mm-long mini-screws to implant on lateral mass. METHODS: 47 patients who underwent plated cervical laminoplasty were included. The optimal area for mini-screws implanting was set according to pre-operative 3D CT reconstruction data. Then, each posterior-lateral mass surface was divided into three regions: 7-mm region, 5-mm region, and dangerous area. The mini-screw implanted region was recorded. Post-operative CT images were used to identify whether the mini-screws penetrated into facet joints. RESULTS: 235 mini-plates and 470 lateral mass mini-screws were used in the study. 117 (24.9%) mini-screws penetrated 88 (37.4%) facet joints. The 5-mm-long mini-screw optimal area occupied the upper 72, 65, 65, 64, and 65 % area of the posterior-lateral mass surface for C3-7, while the 7-mm-long mini-screw optimal area encompassed the upper 54, 39, 40, 33, and 32 %. Only 7-mm-long mini-screws were used to fix the plate to the lateral mass. 4 of 240 mini-screws in 7-mm region, 67 of the 179 mini-screws in 5-mm region, and 46 of the 51 mini-screws in dangerous region penetrated into the facet joint. The differences in the rate of facet joint penetration related to region were statistically significant (P < 0.001). CONCLUSIONS: The facet joint destruction by mini-screws was not a rare complication in plated cervical laminoplasty. The optimal areas we proposed may help guide the mini-screw implantation positions.

High-mobility group box 1 accelerates lipopolysaccharide-induced lung fibroblast proliferation in vitro: involvement of the NF-κB signaling pathway.

The mechanism underlying lipopolysaccharide (LPS)-induced aberrant proliferation of lung fibroblasts in Gram-negative bacilli-associated pulmonary fibrosis is unknown. High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is released from the nuclei of lung fibroblasts after LPS stimulation. It can exasperate LPS-induced inflammation and hasten cell proliferation. Thus, this study investigated the effects of LPS- and/or HMGB1-stimulating murine lung fibroblasts on gene expression using various assays in vitro. Thiazolyl-diphenyl-tetrazolium bromide (MTT) assay data showed that either LPS or HMGB1 could induce lung fibroblast proliferation. Endogenous HMGB1 secreted from lung fibroblasts was detected by enzyme-linked immunosorbent assay (ELISA) 48 h after LPS stimulation. Pretreatment with an anti-HMGB1 antibody inhibited the proliferative effects of LPS on lung fibroblasts. DNA microarray data showed that the NF-κB signaling genes were upregulated in cells after stimulated with LPS, HMGB1, or both. Secretion of matrix metalloproteinase (MMP)-2 and MMP-9, and tissue inhibitor of metalloproteinase 2 (TIMP-2) was significantly upregulated after treatment with LPS, HMGB1, or their combination. However, an NF-κB inhibitor was able to downregulate levels of these proteins. In addition, levels of Toll-like receptor 4 (TLR4), Toll-like receptor 2 (TLR2), and receptors for advanced glycation end products (RAGE) mRNA and proteins were also upregulated in these cells after LPS treatment and further upregulated by LPS plus HMGB1. In conclusion, the data from the current study demonstrate that LPS-induced lung fibroblast secretion of endogenous HMGB1 can augment the proproliferative effects of LPS and, therefore, may play a key role in exacerbation of pulmonary fibrosis. The underlying molecular mechanisms are related to the activation of the TLR4/NF-κB signaling pathway and its downstream targets.

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts.

Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation.

[Elastic registration method to compute deformation functions for mitral valve].

Mitral valve disease is one of the most popular heart valve diseases. Precise positioning and displaying of the valve characteristics is necessary for the minimally invasive mitral valve repairing procedures. This paper presents a multi-resolution elastic registration method to compute the deformation functions constructed from cubic B-splines in three dimensional ultrasound images, in which the objective functional to be optimized was generated by maximum likelihood method based on the probabilistic distribution of the ultrasound speckle noise. The algorithm was then applied to register the mitral valve voxels. Numerical results proved the effectiveness of the algorithm.

Comprehensive analysis of miRNAs-lncRNAs-mRNAs modules and ceRNA network in acute liver failure: Hsa-miR3175 and C-reactive protein determination.

Acute liver failure (ALF), also known as fulminant hepatitis, coagulation disorders, and worsening mental status. It has a poor prognosis and high mortality rate. Among these, the top 10 upregulated genes included GKA-DPA1, IGLL5, PLA2G7, CCL5, IGLJ, GUSBP11, RHOBT1, IGLL3P, CCL18, and ADRBK2. On the other hand, the top 10 downregulated genes were SLC6A1, PID1, AVPR1A, PP1R1A, ST3GAL6, TPST, ERO1LB, SLCO4C1, and KLF15. Furthermore, the DEGs were found to be enriched in processes related to LIAO metastasis and creighton endocrine therapy resistance. To explore the interactions among the DEGs, we constructed a PPI network. This network revealed 16 hub genes that play crucial roles in ALF pathogenesis. Within this network, hsa-mir-375 and hsa-mir-650 were identified as central nodes, indicating their potential importance in ALF. By identifying and analyzing the transcriptional-level ceRNA network, we have provided valuable insights into the etiology of ALF.

Cervical Alignment and Range of Motion Change after Anterior 3-Level Hybrid Surgery Compared with Cervical Laminoplasty: A Matched Cohort Study.

OBJECTIVES: Cervical alignment and range of motion (ROM) changes after cervical spine surgery are related to cervical biomechanical and functions. Few studies compared these parameters between posterior laminoplasty and anterior 3-level hybrid surgery incorporating anterior cervical discectomy and fusion (ACDF) with cervical disc replacement (CDR). This study is aimed to detect the differences of cervical alignment and ROM changes of the two surgeries in a matched-cohort study. METHODS: From January 2018 and May 2020, 51 patients who underwent 3-level hybrid surgery incorporating ACDF with ACDR were included. A 1:1 match of the patients who underwent cervical laminoplasty based on age, gender, duration of symptoms, body mass index, and cervical alignment type was utilized as control group. General data (operative time, blood loss, etc.), Japanese Orthopaedic Association (JOA) score, VAS (Visual Analog Score), NDI (The Neck Disability Index), cervical sagittal alignment, and cervical range of motion (ROM) were recorded and compared. RESULTS: Both groups gained significant improvement in JOA, VAS, NDI scores postoperatively (p < 0.05). Cervical alignment significantly increased in hybrid group and decreased in control group after surgeries (p < 0.001). ROM decrease was similar in two groups. For cervical lordosis, though cervical alignment angle in control group decreased, the final follow-up cervical alignment and cervical alignment changes were not significantly different between hybrid and control groups. For cervical non-lordosis, cervical alignment decreased in control group while increased in hybrid group. At final follow-up, cervical alignment and the changes between the two groups were significantly different. Both control group and hybrid group had similar ROM decrease after the surgery no matter whether there was cervical lordosis or non-lordosis. Hybrid surgery showed cervical alignments significantly improved and similar ROM preservation compared with control group at final follow-up both for 1-level and 2-level disc replacement subgroups. CONCLUSIONS: The hybrid surgery demonstrated advantages of preserving cervical alignment and gaining similar cervical ROM preservation compared with cervical laminoplasty, especially for cervical non-lordosis. Given the importance of restoring lordotic cervical alignment, hybrid surgery may be preferred over laminoplasty to treat multilevel cervical disc herniation.

Does Screw Number of Zero-profile Implants in Fusion Segment Influence Intervertebral Stability?

OBJECTIVE: The unclear clinical outcomes of two different zero-profile implants with different number of screws in hybrid surgery restricts the choice of patient-specific implants. This study aims to compare two different implants on its postoperative subsidence, motion stabilization and clinical outcomes. It also provides references to the most reasonable implant choice in fusion surgery. METHODS: This was a retrospective study. From February 2014 to March 2022, 173 patients who underwent hybrid surgery were included. Among them, 122 received surgery with a four screw implant, while 51 received a two screw implant. We analyzed the significance of patient-specific factors, radiographic factors and clinical outcomes. The Wilcoxon rank sum test, t tests/analysis of variance (ANOVA) test and stepwise multivariate logistic regression were adopted for statistical analysis. RESULTS: No statistically significant difference was observed between the two screw and four screw groups in terms of immediate, middle, and long-term stability and fusion rate (p > 0.05). However, the two screws group had higher FSU height subsidence at 3, 6, and 12 months postoperatively and higher rates of significant subsidence at three and 6 months postoperatively (p < 0.05). Both groups showed significant clinical improvements at the final follow-up. CONCLUSION: Two screw and four screw implants provide comparable stability, fusion rates and clinical outcomes. However, the two screw implant was inferior to the four screw implant in subsidence prevention. Therefore, the two-screw implant is non-inferior to the four-screw implant in most patients. It can be used as the priority choice in the fusion segment by its easy manageability. However, the patients with a high risk of subsidence such as multilevel surgery, the elderly, lower BMD, bad cervical alignment should receive a four screw implant rather than a two screw implant.

Epigenetic regulation of Thy-1 gene expression by histone modification is involved in lipopolysaccharide-induced lung fibroblast proliferation.

Lipopolysaccharide (LPS)-induced pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. Epigenetic regulation of thymocyte differentiation antigen 1 (Thy-1) is associated with lung fibroblast phenotype transformation that results in aberrant cell proliferation. However, it is not clear whether the epigenetic regulation of Thy-1 expression is required for LPS-induced lung fibroblast proliferation. To address this issue and better understand the relative underlying mechanisms, we used mouse lung fibroblasts as model to observe the changes of Thy-1 expression and histone deacetylation after LPS challenge. The results showed that cellular DNA synthesis, measured by BrdU incorporation, was impacted less in the early stage (24 hrs) after the challenge of LPS, but significantly increased at 48 or 72 hrs after the challenge of LPS. Meanwhile, Thy-1 expression, which was detected by real-time PCR and Western blot, in lung fibroblasts decreased with increased time after LPS challenge and diminished at 72 hrs. We also found that the acetylation of either histone H3 or H4 decreased in the LPS-challenged lung fibroblasts. ChIP assay revealed that the acetylation of histone H4 (Ace-H4) decreased in the Thy-1 promoter region in response to LPS. In addition, all the above changes could be attenuated by depletion of TLR4 gene. Our studies indicate that epigenetic regulation of Thy-1 gene expression by histone modification is involved in LPS-induced lung fibroblast proliferation.

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury.

Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.

Isoflurane prevents neurocognitive dysfunction after cardiopulmonary bypass in rats.

OBJECTIVE: Postoperative cognitive dysfunction occurs frequently after cardiac surgeries with cardiopulmonary bypass (CPB). Available data from rat CPB models are conflicting. However, none of them was designed to investigate the role of isoflurane (the main anesthetic in all of these studies) in the neurocognitive dysfunction after CPB. Isoflurane has documented neuroprotective effects so the present authors hypothesized that isoflurane prevents the neurocognitive dysfunction in rats after CPB. DESIGN: A prospective, interventional study. SETTING: A university research laboratory. PARTICIPANTS: Male Sprague-Dawley rats. INTERVENTIONS: Male Sprague-Dawley rats were divided into 5 groups: the isoflurane CPB group, the animals were anesthetized with isoflurane and underwent 60 minutes of normothermic CPB; the chloral hydrate CPB group, the animals were anesthetized with chloral hydrate and underwent 60 minutes of normothermic CPB; the isoflurane sham group, the animals were subjected only to cannulation and the same duration of anesthesia but no CPB; the chloral hydrate sham group, the animals received only cannulation and the same duration of anesthesia but no CPB; and the naive group, the animals received no treatment. The neurocognitive function of all rats was measured on days 4 to 6 (short-term) and 31 to 33 after CPB (long-term). After the behavior tests, the animals were sacrificed, and the brain was harvested for the measurement of acetylcholinesterase (AChE) and choline acetyltransferase protein levels. MEASUREMENTS AND MAIN RESULTS: Short-term (days 4-6 after CPB) learning and memory were impaired after CPB when the animals were anesthetized with chloral hydrate. When isoflurane was used, the learning and memory did not change after CPB. No long-term (days 31-33 after CPB) neurocognitive changes were found after CPB. AChE decreased significantly after isoflurane anesthesia regardless of whether CPB was performed. CONCLUSIONS: Isoflurane prevented the neurocognitive dysfunction induced by CPB, which might involve the cerebral cholinergic system.

Increased Platelet Aggregation in Adults After Orthotopic Liver Transplantation Indicates Higher Probability of Early Postoperative Survival.

BACKGROUND Studies have shown that increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death, but studies on the association between platelet aggregation function and early postoperative survival in orthotopic liver transplantation (OLT) patients are rare. We conducted a retrospective study to investigate whole-blood platelet aggregation during the perioperative period of OLT patients and its association with clinical outcomes. MATERIAL AND METHODS Adult patients who underwent OLT between January 1 and April 30, 2021 were retrospectively reviewed. Laboratory test results indicating primary hemostasis were analyzed. The generalized linear model was used to investigate the association between primary hemostasis parameters and survival. RESULTS A total of 256 patients were enrolled. The median platelet count (PLT) was 61.5 (39.5-106.3)×109/L before transplantation. The median MA value was 43.1 (34.5-56.2) mm. From the 1st to the 3rd day after transplantation, PLT and MA both indicated a significant decrease. Two weeks after transplantation, PLT rose to 143.0 (85.0-209.0)×109/L, and the MA value rose to 56.7 (52.2-62.7) mm. On multivariate analysis, PLT at 1 week after transplantation (OR: 1.07; P=0.006) and MA value (OR: 1.12; P=0.003) were independently associated with outcome. The AUROC of the model combined with MA value, MELD score, and age was 0.945 (95% CI: 0.911-0.978). CONCLUSIONS The change in primary hemostasis during the early postoperative period of adult OLT is mainly characterized by the increase of platelet count and function 14 days after transplantation. Higher PLT was associated with higher survival at 14 days after transplantation, while a higher PLT ratio was associated with survival at 3 months after transplantation. Based on comprehensive consideration, the model combined with MA value, MELD score, and age more reliably indicated the associated with early survival after transplantation.

Cervical sagittal balance after consecutive three-level hybrid surgery versus anterior cervical discectomy and fusion: radiological results from a single-center experience.

INTRODUCTION: According to the different numbers and relative locations of cervical disc replacement (CDR) and anterior cervical discectomy and fusion (ACDF), three-level hybrid surgery (HS) has many constructs. The purpose of this retrospective study was to compare the sagittal alignment parameters of HS and ACDF for cervical degenerative disc disease (CDDD) and the association of the respective parameters. METHODS: This study involved patients with three-level CDDD who underwent ACDF or HS at our institution between June 2012 and August 2021. This follow-up included one-level CDR and two-level ACDF (type I group), two-level CDR and one-level ACDF (type II group) and three-level ACDF. Cervical sagittal alignment parameters included cervical lordosis (CL), segment alignment (SA), T1 slope (T1S), C2-C7 sagittal vertical axis (SVA), T1S-CL, C2 slope (C2S), occipital to C2 angle (O-C2A) and segment range of motion (ROM). Postoperative complications included adjacent segment degeneration, imbalance, prosthetic subsidence and heterotopic ossification. RESULTS: The three groups with a total of 106 patients were better matched in terms of demographics. Patients who underwent HS had significantly higher CL than those who underwent ACDF at 1 week, 6 months, 12 months and the final follow-up after surgery, as well as significantly better SA at 12 months and the final follow-up. There was no significant difference in T1S, SVA, T1S-CL, C2S, O-C2A or segment ROM among the three groups after surgery. The T1S-CL was significantly associated with C2S in the type I and type II groups at the preoperative and final follow-up. There was no significant difference in postoperative complications among the three groups. CONCLUSIONS: Most improvements in cervical sagittal alignment (CL, SA, T1S, SVA, T1S-CL, C2S, O-C2A, and segmental ROM) were observed in all three groups postoperatively. HS was more advantageous than ACDF in the maintenance of postoperative CL and SA. Thus, three-level HS may be better for maintaining cervical curvature. The number of replacement segments differed in those who underwent HS but did not affect the correlation between T1S-CL and C2S, both of which are well balanced.