Levosimendan mediates the BMP/Smad axis through upregulation of circUSP34-targeted miR-1298 to alleviate pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world's population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown. METHODS: We used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model. RESULTS: Our results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype. CONCLUSION: We have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms.

Brain regions differences in amyloid-ß and gene expression in early APP/PS1 mice and identification of Npas4 as a key molecule in Alzheimer's disease.

Distinct brain regions are differentially affected during the various stages of Alzheimer's disease (AD). While the hippocampus and cortex are known to play significant roles, the involvement of the cerebellum has received less attention. Understanding the changes in diverse brain regions is essential to unravel the neuropathological mechanism in early-stage AD. Our research aimed to explore and compare amyloid-ß (Aß) pathology and gene expression profiles across the hippocampus, cortex, and cerebellum in the early stages of the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model. By 7 months of age, significant Aß plaque accumulation was observed in the hippocampus and cortex of APP/PS1 mice, while no such deposits were found in the cerebellum. Gene expression analysis revealed predominant effects on immune response pathways in the hippocampus and cortex. Even in the absence of Aß deposition, notable gene expression changes were observed in the cerebellum of APP/PS1 mice. Intriguingly, Neuronal PAS Domain protein 4 (Npas4) expression was consistently down-regulated across all brain regions, independent of Aß plaque presence. Our findings reveal distinct transcriptomic alterations and Aß pathology in select cerebral regions during the initial phase of AD. Notably, the diminished expression of the Npas4 across three brain regions implies that Npas4 could play a pivotal role in the early pathogenesis of AD.

Rationally Designed Highly Potent NKT Cell Agonists with Different Cytokine Selectivity through Hydrogen-Bond Interaction.

Synthetic α-galactosylceramide (αGalCer) and its analogues as powerful agonists for natural killer T (NKT) cell manipulation have received significant attention in immunotherapy and adjuvant development. However, identifying new potent NKT cell agonists, especially those with Th1 selectivity that promote anticancer effects, remains a challenging task. In this work, we introduced a sulfonamide group into the acyl chain of αGalCer to form additional hydrogen bonds to intensify the glycolipid/CD1d interaction. Two compounds GCS-11 and GCS-12 demonstrated remarkable potency while exhibiting different cytokine induction patterns. Compared to αGalCer, the Th1-biased GCS-11 exhibited a 6-fold increase in IFN-γ but not IL-4, while the Th1/2-balanced GCS-12 elicited 7- and 5-fold increase in IFN-γ and IL-4, respectively, in vivo. These findings place them among the most potent NKT cell agonists, with superior antitumor effects. Therefore, hydrogen-bond-involved derivatization could be a powerful strategy to develop potent and polarized NKT cell agonists for various immunotherapies.

Development and validation of a machine learning-based interpretable model for predicting sepsis by complete blood cell parameters.

Background: Sepsis, a severe infectious disease, carries a high mortality rate. Early detection and prompt treatment are crucial for reducing mortality and improving prognosis. The aim of this research is to develop a clinical prediction model using machine learning algorithms, leveraging complete blood cell (CBC) parameters, to detect sepsis at an early stage. Methods: The study involved 572 patients admitted to West China Hospital of Sichuan University between July 2020 and September 2021. Among them, 215 were diagnosed with sepsis, while 357 had local infections. Demographic information was collected, and 57 CBC parameters were analyzed to identify potential predictors using techniques such as the Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost). The prediction model was built using Logistic Regression and evaluated for diagnostic specificity, discrimination, and clinical applicability including metrics such as the area under the curve (AUC), calibration curve, clinical impact curve, and clinical decision curve. Additionally, the model's diagnostic performance was assessed on a separate validation cohort. Shapley's additive explanations (SHAP), and breakdown (BD) profiles were used to explain the contribution of each variable in predicting the outcome. Results: Among all the machine learning methods' prediction models, the LASSO-based model (λ = min) demonstrated the highest diagnostic performance in both the discovery cohort (AUC = 0.9446, P < 0.001) and the validation cohort (AUC = 0.9001, P < 0.001). Furthermore, upon local analysis and interpretation of the model, we demonstrated that LY-Z, MO-Z, and PLT-I had the most significant impact on the outcome. Conclusions: The predictive model based on CBC parameters can be utilized as an effective approach for the early detection of sepsis.

The value of ictal scalp EEG in focal epilepsies surgery: a retrospective analysis.

OBJECTIVE: To describe the association between preoperative ictal scalp electroencephalogram (EEG) results and surgical outcomes in patients with focal epilepsies. METHODS: The data of consecutive patients with focal epilepsies who received surgical treatments at our center from January 2012 to December 2021 were retrospectively analyzed. RESULTS: Our data showed that 44.2% (322/729) of patients had ictal EEG recorded on video EEG monitoring during preoperative evaluation, of which 60.6% (195/322) had a concordant ictal EEG results. No significant difference of surgery outcomes between patients with and without ictal EEG was discovered. Among MRI-negative patients, those with concordant ictal EEG had a significantly better outcome than those without ictal EEG (75.7% vs. 43.8%, p = 0.024). Further logistic regression analysis showed that concordant ictal EEG was an independent predictor for a favorable outcome (OR = 4.430, 95%CI 1.175-16.694, p = 0.028). Among MRI-positive patients, those with extra-temporal lesions and discordant ictal EEG results had a worse outcome compared to those without an ictal EEG result (44.7% vs. 68.8%, p = 0.005). Further logistic regression analysis showed that discordant ictal EEG was an independent predictor of worse outcome (OR = 0.387, 95%CI 0.186-0.807, p = 0.011) in these patients. Furthermore, our data indicated that the number of seizures was not associated with the concordance rates of the ictal EEG, nor the surgical outcomes. CONCLUSIONS: The value of ictal scalp EEG for epilepsy surgery varies widely among patients. A concordant ictal EEG predicts a good surgical outcome in MRI-negative patients, whereas a discordant ictal EEG predicts a poor postoperative outcome in lesional extratemporal lobe epilepsy.

Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR.

BACKGROUND: Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. PURPOSE: We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). METHODS: Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5 % ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. RESULTS: BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. CONCLUSION: BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.

Inhibition of Glycyrrhiza Polysaccharide on Human Cytochrome P450 46A1 in vitro and in vivo: Implications in Treating Neurological Diseases.

BACKGROUND: Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications. It has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown. OBJECTIVE: This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins. MATERIALS AND METHODS: The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated in vivo and in vitro. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected. RESULTS: The in vitro results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the in vivo experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP. CONCLUSION: GP exhibits a significant inhibitory effect on CYP46A1 activity in vitro and in vivo, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.

Case Report: Right aortic arch with isolation of left brachiocephalic artery and ventricular septal defect.

Right aortic arch with isolation of left brachiocephalic artery is a rare congenital aortic arch anomaly. Herein, we reported a case of this rare anomaly with ventricular septal defect in a 9-month-old infant. We successfully reconstructed the islolated left brachiocephalic artery and repaired the ventricular septal defect in one stage.

Microstructure and Mechanical Properties of Refill Friction Stir Spot-Welded Joints of 2A12Al and 7B04Al: Effects of Tool Size and Welding Parameters.

To solve problems in dissimilarly light metal joints, refilled friction stir spot welding (RFSSW) is proposed instead of resistance spot welding. However, rotation speed, dwell time, plunge depth, and the diameter of welding tools all have a great influence on joints, which brings great challenges in optimizing welding parameters to ensure their mechanical properties. In this study, the 1.5 mm thick 2A12Al and 2 mm thick 7B04Al lap joints were prepared by Taguchi orthogonal experiment design and RFSSW. The welding tool (shoulder) diameters were 5 mm and 7 mm, respectively. The macro/microstructures of the cross-section, the geometrical characteristics of the effective welding depth (EWD), the stir zone area (SZA), and the stir zone volume (SZV) were characterized. The shear strength and failure mode of the lap joint were analyzed using an optical microscope. It was found that EWD, SZA, and SZV had a good correlation with tensile-shear force. The optimal welding parameters of 5 mm diameter joints are 1500 rpm of rotation speed, 2.5 mm of plunge depth, and 0 s of dwell time, which for 7 mm joints are 1200 rpm, 1.5 mm, and 2 s. The tensile-shear force of 5 mm and 7 mm joints welded with these optical parameters was 4965 N and 5920 N, respectively. At the same time, the 5 mm diameter joints had better strength and strength stability.

Recent Progress in Semitransparent Organic Solar Cells: Photoabsorbent Materials and Design Strategies.

The increasing energy demands of the global community can be met with solar energy. Solution-processed organic solar cells have seen great progress in power conversion efficiencies (PCEs). Semitransparent organic solar cells (ST-OSCs) have made enormous progress in recent years and have been considered one of the most promising solar cell technologies for applications in building-integrated windows, agricultural greenhouses, and wearable energy resources. Therefore, through the synergistic efforts of transparent electrodes, engineering in near-infrared photoabsorbent materials, and device engineering, high-performance ST-OSCs have developed, and PCE and average visible transmittance reach over 10% and 40%, respectively. In this review, we present the recent progress in photoabsorbent material engineering and strategies for enhancing the performance of ST-OSCs to help researchers gain a better understanding of structure-property-performance relationships. To conclude, new design concepts in material engineering and outlook are proposed to facilitate the further development of high-performance ST-OSCs.

Incidence, Severity, and Risk Factors of Hemorrhagic Complications of Epilepsy Surgery After 2026 Craniotomies from 2003 to 2019: A Single Center Experience.

BACKGROUND: Surgery is effective in the treatment of epilepsy, particularly focal epilepsy. The aim of this work was to report the incidence and grade of severity of hemorrhagic complications after cranial epilepsy surgery, and investigate the risk factors. METHODS: Patients who underwent epilepsy surgery via craniotomy between October 2003 and April 2019 were retrospectively analyzed. The incidence of hemorrhagic complications occurring in a 3-month period after cranial surgery was recorded. Other outcomes included the grade of hemorrhagic severity and risk factors. RESULTS: During the inclusion period, 2026 surgical procedures were performed. Sixty-six hemorrhagic complications were recorded. The total incidence of hemorrhagic complications after cranial epilepsy surgery was 3.3%. The most common type of hemorrhagic complications was epidural hemorrhage (57.6%), followed by intraparenchymal hemorrhage (33.3%). Forty-five patients (68.2%) had grade I complications, 4 (6.1%) grade II, 16 (24.2%) grade III, and 1 (1.5%) grade IV. The mortality due to hemorrhagic complications was 1.5% (1 of 66) and hemorrhagic mortality among all cranial surgery was 0.05% (1 of 2026). Left craniotomy induced a higher percentage of severe hemorrhage than the right (34.2% vs. 14.3%). Extratemporal lobe epilepsy induced a higher percentage of severe hemorrhage than other epilepsy type (34.2% vs. 14.3%). However, no statistically significant difference was observed between these two factors (P = 0.067). CONCLUSIONS: Hemorrhagic complications were uncommon after open surgery for epilepsy. Most hemorrhagic complications were mild while the severe were rare. Patients with hemorrhagic complications had a good prognosis after effective treatment.

Analysis of characteristics of movement disorders in patients with anti-N-methyl-D-aspartate receptor encephalitis.

Objective: Movement disorders (MDs) are common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis but are poorly studied. This study aimed to investigate the clinical characteristics of MDs and the clinical differences between patients with and without MDs in anti-NMDAR encephalitis. Methods: A retrospective study was conducted on patients with anti-NMDAR encephalitis who were first diagnosed and treated in the First People's Hospital of Yunnan Province from January 2017 to September 2022. According to the presence or absence of MDs, all patients were divided into two groups, and the clinical manifestations, auxiliary examinations, and prognosis of the two groups were compared. Patients in the MDs group were further subgrouped by different ages (<12 years, 12-17 years, and ≥ 18 years) and genders, and the prevalence of each MD was compared in different age and gender groups. Results: (1) In our study there were 64 patients, of whom 76.6% (49/64) presented with MDs; the median age of onset in patients with MDs was 21 (15,35) years and 65.3% (32/49) were female. The three most common MDs were orofacial dyskinesia (OFLD) (67.3%), dystonia (55.1%), and stereotypies (34.7%). Patients <12 years were more likely to experience chorea than patients in other age groups (p = 0.003). (2) Compared with the non-MDs group, patients in the MDs group showed higher rates of prodromal manifestations, autonomic dysfunction, consciousness disorders, as well as pulmonary infection and gastrointestinal dysfunction (all p < 0.05). Peripheral blood neutrophil to lymphocyte ratio (NLR) (p = 0.014), the proportion of cerebrospinal fluid (CSF) NMDAR antibody titers ≥1:32 (p = 0.047), ICU admission rate (p = 0.04), length of stay (p = 0.007), maximum mRS score in the course of disease (p = 0.001) and mRS score at discharge (p = 0.006) in the MDs group were significantly higher than the non-MDs group. Conclusion: MDs associated with anti-NMDAR encephalitis were predominantly hyperkinetic. Chorea occurred more commonly in patients aged <12 years. Patients with MDs were prone to autonomic dysfunction, consciousness disorders, pulmonary infection, and gastrointestinal dysfunction; they had more intense inflammation, more severe disease, and a poorer short-term prognosis.

Batoclimab vs Placebo for Generalized Myasthenia Gravis: A Randomized Clinical Trial.

Importance: Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective: To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and Participants: This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention: Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure: The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results: A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance: Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. Trial Registration: ClinicalTrials.gov Identifier: NCT05039190.

Autoimmune nodopathy with anti-contactin 1 antibody characterized by cerebellar dysarthria: a case report and literature review.

Background: Autoimmune nodopathy (AN) has emerged as a novel diagnostic category that is pathologically different from classic chronic inflammatory demyelinating polyneuropathy. Clinical manifestations of AN include sensory or motor neuropathies, sensory ataxia, tremor, and cranial nerve involvement. AN with a serum-positive contactin-1 (CNTN1) antibody usually results in peripheral nerve demyelination. In this study, we reported a rare case of AN with CNTN1 antibodies characterized by the presence of CNTN1 antibodies in both serum and cerebrospinal fluid, which is associated with cerebellar dysarthria. Methods: A 25-year-old man was admitted to our hospital due to progressive dysarthria with limb tremors. The patient was initially diagnosed with peripheral neuropathy at a local hospital. Three years after onset, he was admitted to our hospital due to dysarthria, apparent limb tremor, and limb weakness. At that time, he was diagnosed with spinocerebellar ataxia. Eight years post-onset, during his second admission, his condition had notably deteriorated. His dysarthria had evolved to typical distinctive cerebellar characteristics, such as tremor, loud voice, stress, and interrupted articulation. Additionally, he experienced further progression in limb weakness and developed muscle atrophy in the distal limbs. Magnetic resonance imaging (MRI), nerve conduction studies (NCS), and autoimmune antibody tests were performed. Results: The results of the NCS suggested severe demyelination and even axonal damage to the peripheral nerves. MRI scans revealed diffuse thickening of bilateral cervical nerve roots, lumbosacral nerve roots, cauda equina nerve, and multiple intercostal nerve root sheath cysts. Furthermore, anti-CNTN1 antibody titers were 1:10 in the cerebrospinal fluid (CSF) and 1:100 in the serum. After one round of rituximab treatment, the patient showed significant improvement in limb weakness and dysarthria, and the CSF antibodies turned negative. Conclusion: Apart from peripheral neuropathies, cerebellar dysarthria (central nervous system involvement) should not be ignored in AN patients with CNTN1 antibodies.

The Screening of Piwi-Interacting RNA Biomarkers in Sporadic Parkinson's Disease.

Background: piRNAs play key roles in various diseases. However, the role of piRNAs in sporadic Parkinson's disease (PD) remains unclear. This study was conducted to explore key piRNAs that can be used as biomarkers for sporadic Parkinson's disease. Methods: Differentially expressed piRNAs (DEPs) and their interaction were investigated using bioinformatics analysis, while the diagnostic value and expression of the selected piRNAs were detected. Results: 42 DEPs were screened between PD and controls. Moreover, most of the physiological piRNA-piRNA interactions and linkages in normal samples had been altered in the sporadic PD samples. 14 overlapping piRNAs were selected, and six key piRNA biomarkers were screened. The different expressions of piR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, and piR-hsa-2524778 had high efficiency and sensitivity in the diagnosis of PD. Conclusion: PiR-hsa-327831, piR-hsa-1968818, piR-hsa-3770447, piR-hsa-1325354, piR-hsa-758566 and piR-hsa-2524778 could be biomarkers of PD.

Arthroscopic debridement improves range of motion for heterotopic ossification after total knee replacement: a retrospective cohort study.

The presence of heterotopic ossification (HO) after primary total knee replacement (TKR) is rare and associated with limited mobility and stiffness of the knee. This study aimed to identify if the arthroscopic debridement after TKR could decrease HO and improve the function and range of motion. Thirty HO patients after TKR were retrospectively separated into 2 cohorts. 15 patients of group A accepted the arthroscopic debridement, while 15 patients of group B only had non-operative treatment, mainly including oral nonsteroidal anti-inflammatory drugs (NSAIDs) and rehabilitative treatment. Visual analog scale (VAS) scores, knee society knee scores (KSS), range of motion (knee flexion and knee extension) were obtained before treatment and at 1 month, 3 months, and 6 months after treatment. Radiography of after-treatment was also evaluated to assess the changes in HO. There were 3 males and 27 females with a mean age of 67.4 ± 0.8 years in group A and 68.2 ± 1.3 in group B. The onset time of HO was 3-6 months. The maximum size of the ossification was < 2 cm in 23 knees, 2 cm < heterotopic bone < 5 cm in 6 knees and > 5 cm in 1 knee. The size of HO decreased gradually in all knees by X-ray film at the last follow-up. There were no significant differences in VAS scores after replacement between two groups (p > 0.05). The average range of motion preoperatively in group A was - 15.2-90.6°, which postoperatively increased to - 4.2-110.0°. Meanwhile, the KSS scores and average range of motion of the group A were better than those of the group B at each follow-up time after treatment. Arthroscopic debridement can decrease HO seen from postoperative X-rays, improve the function and range of motion, as well as the pain remission between two groups are comparable. Consequently, arthroscopic resection of HO after TKR is recommended as soon as there is aggravating joint stiffness.

Mannose modified targeted immersion vaccine delivery system improves protective immunity against Infectious spleen and kidney necrosis virus in mandarin fish (Siniperca chuatsi).

Vaccination is an effective method to prevent viral diseases. However, the biological barrier prevents the immersion vaccine from achieving the best effect without adding adjuvants and carriers. Researches on the targeted presentation technology of vaccines with nanocarriers are helpful to develop immersion vaccines for fish that can break through biological barriers and play an effective role in fish defense. In our study, functionally modified single-walled carbon nanotubes (SWCNTs) were used as carriers to construct a targeted immersion vaccine (SWCNTs-M-MCP) with mannose modified major capsid protein (MCP) to target antigen-presenting cells (APCs), against iridovirus diseases. After bath immunization, our results showed that SWCNTs-M-MCP induced the presentation process and uptake of APCs, triggering a powerful immune response. Moreover, the highest relative percent survival (RPS) was 81.3% in SWCNTs-M-MCP group, which was only 41.5% in SWCNTs-MCP group. Altogether, this study indicates that the SWCNTs-based targeted immersion vaccine induces strong immune response and provided an effective protection against iridovirus diseases.

Veno-arterial extracorporeal membrane oxygenation for respiratory and cardiac support in neonates: a single center experience.

Objective: Extracorporeal membrane oxygenation (ECMO) is an advanced life support that has been utilized in the neonate for refractory respiratory and circulatory failure. Striving for the best outcomes and understanding optimal surgical techniques continue to be at the forefront of discussion and research. This study presents a single-center experience of cervically cannulated neonatal patients on V-A ECMO, a description of our cannulation/decannulation techniques and our patient outcomes. Methods: Single center retrospective review of neonates who received neck V-A ECMO support from January 2012 to December 2022. The data and outcomes of the patients were retrospectively analyzed. Results: A total of 78 neonates received V-A ECMO support. There were 66 patients that received ECMO for respiratory support, the other 12 patients that received ECMO for cardiac support. The median duration of ECMO support was 109 (32-293) hours for all patients. During ECMO support, 20 patients died and 5 patients discontinued treatment due to poor outcome or the cost. A total of 53 (68%) patients were successfully weaned from ECMO, but 3 of them died in the subsequent treatment. Overall 50 (64%) patients survived to hospital discharge. In this study, 48 patients were cannulated using the vessel sparing technique, the other 30 patients were cannulated using the ligation technique. We found no significant difference in the rates of normal cranial MRI at discharge between survivors with and without common carotid artery ligation. Conclusion: We achieved satisfactory outcomes of neonatal ECMO in 11-year experience. This study found no significant difference in early neuroimaging between survivors with and without common carotid artery ligation. The long-term neurological function of ECMO survivors warranted further follow-up and study.

FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease.

BACKGROUND AND PURPOSE: Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. METHODS: The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS). RESULTS: FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. CONCLUSIONS: FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.