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Objectives. Nonhepatic hyperammonemia often occurs in patients with sepsis. Ammonia plays an essential role in the occurrence of hepatic encephalopathy. However, the relationship between nonhepatic serum ammonia levels and sepsis-associated encephalopathy (SAE) remains unclear. Thus, we aimed to evaluate the association between serum ammonia levels and patients with SAE. Methods. Data of critically ill adults with sepsis who were admitted to the intensive care unit were retrieved from the Medical Information Mart for Intensive Care IV (MIMIC IV) between 2008 and 2019 and retrospectively analyzed. Data of patients with sepsis patients and serum ammonia not related to acute or chronic liver disease were not included. Results. Data from 720 patients with sepsis were included. SAE was found to have a high incidence (64.6%). After adjusting for other risk factors, a serum ammonia level of ≥45 μmol/L (odds ratio (OR): 3.508, 95% confidence interval (CI): 2.336–5.269, p < 0.001) was found to be an independent risk factor for patients with SAE; moreover, as the serum ammonia level increased, the hospital mortality of SAE gradually increased in a certain range (serum ammonia <150 μmol/L). Serum ammonia levels of ≥45 μmol/L were associated with higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment (SOFA) scores in patients with SAE. Besides, our study found that patients with SAE used opioid analgesics (OR:3.433, 95% CI: 1.360–8.669, p = 0.009) and the SOFA scores of patients with SAE (OR: 1.126, 95% CI: 1.062–1.194, p < 0.001) were significantly higher than those without SAE. Conclusions. Nonhepatic serum ammonia levels of ≥45 μmol/L evidently increased the incidence of SAE. Serum ammonia levels should be closely monitored in patients with sepsis. [ABSTRACT FROM AUTHOR]

TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2. [ABSTRACT FROM AUTHOR]

TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression. [ABSTRACT FROM AUTHOR]

Background: Pre-operative prediction of postoperative nausea and vomiting (PONV) is primarily based on the patient's medical history. The predictive value of gastric morphological parameters observed on ultrasonography has not been comprehensively assessed., Methods: A prospective observational study was conducted to evaluate the pre-operative ultrasonographic measurement of gastric morphology for predicting PONV. The gastric antrum of the participants was assessed using ultrasound before anesthesia, and the occurrence of PONV in the first 6 hours and during the 6-24 hours after surgery was reported. The main indicators included the thickness of the muscularis propria (TMP) and the cross-sectional area of the inner side of the muscularis propria (CSA-ISMP). These were recorded and analyzed. Logistic regression analysis was applied to identify factors for PONV., Results: A total of 72 patients scheduled for elective gynecological laparoscopic surgery were investigated in the study. The pre-operative CSA-ISMP of patients with PONV in the first 6 hours was significantly greater than that of those without PONV (2.765 ± 0.865 cm² vs 2.349 ± 0.881 cm², P=0.0308), with an area under the curve of 0.648 (95% CI, 0.518 to 0.778, P=0.031). Conversely, the pre-operative TMP of patients with PONV during the 6-24 hours was significantly smaller than that of those without PONV (1.530 ± 0.473 mm vs 2.038 ± 0.707 mm, P=0.0021), with an area under the curve of 0.722 (95% CI, 0.602 to 0.842, P=0.003). Logistic regression analysis confirmed that CSA-ISMP was an independent risk factor for PONV in the first 6 hours (OR=2.986, P=0.038), and TMP was an independent protective factor for PONV during the 6-24 hours after surgery (OR=0.115, P=0.006)., Conclusion: Patients with a larger pre-operative CSA-ISMP or a thinner TMP are prone to develop PONV in the first 6 hours or during the 6-24 hours after surgery, respectively., China Clinical Trial Registration Center: http://www.chictr.org.cn (ChiCTR2100055068)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qiu, Yin, Liang, Shi, Liu, Zhang, Bai, Chen and Xiong.)

Introduction: In elderly patients infected with the Omicron variant, disease progression to severe infection can result in poor outcomes. This study aimed to identify risk and protective factors associated with disease progression to severe infection and viral clearance time in elderly Omicron-infected patients., Methods: Shanghai Fourth People's Hospital, School of Medicine, Tongji University, was officially designated to provide treatment to patients with COVID-19. This study was conducted on confirmed Omicron cases admitted to the hospital between 10 April 2022 and 21 June 2022. In total, 1,568 patients aged 65 years or older were included. We conducted a retrospective, observational study using logistic regression to analyze risk and protective factors for the development of severe disease and Cox proportional hazards regression models to analyze factors influencing viral clearance time., Results: Aged over 80 years, having 2 or more comorbidities, combined cerebrovascular disease, chronic neurological disease, and mental disorders were associated with the development of severe disease, and full vaccination was a protective factor. Furthermore, aged over 80 years, combined chronic respiratory disease, chronic renal disease, cerebrovascular disease, mental disorders, and high viral load were associated with prolonged viral clearance time, and full vaccination was a protective factor., Discussion: This study analyzed risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly Omicron-infected patients. Aged patients with comorbidities had a higher risk of developing severe infection and had longer viral clearance, while vaccination protected them against the Omicron infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Man, Zhu, Yu, Chen, Wang, Lu, Shi, Suo and Xiong.)

Background: Several systemic inflammatory biomarkers have been associated with poor overall survival (OS) and disease severity in patients with coronavirus disease 2019 (COVID-19). However, it remains unclear which markers are better for predicting prognosis, especially for COVID-19 Omicron BA.2 infected patients. The present study aimed to identify reliable predictors of prognosis of COVID-19 Omicron BA.2 from inflammatory indicators., Methods: A cohort of 2645 COVID-19 Omicron BA.2 infected patients were retrospectively analyzed during the Omicron BA.2 surge in Shanghai between April 12, 2022, and June 17, 2022. The patients were admitted to the Shanghai Fourth People's Hospital, School of Medicine, Tongji University. Six systemic inflammatory indicators were included, and their cut-off points were calculated using maximally selected rank statistics. The analysis involved Kaplan-Meier curves, univariate and multivariate Cox proportional hazard models, and time-dependent receiver operating characteristic curves (time-ROC) for OS-associated inflammatory indicators., Results: A total of 2347 COVID-19 Omicron BA.2 infected patients were included. All selected indicators proved to be independent predictors of OS in the multivariate analysis (all P < 0.01). A high derived neutrophil to lymphocyte ratio (dNLR) was associated with a higher mortality risk of COVID-19 [hazard ratio, 4.272; 95% confidence interval (CI), 2.417-7.552]. The analyses of time-AUC and C-index showed that the dNLR (C-index: 0.844, 0.824, and 0.718 for the 5 th , 10 th , and 15 th day, respectively) had the best predictive power for OS in COVID-19 Omicron BA.2 infected patients. Among different sub-groups, the dNLR was the best predictor for OS regardless of age (0.811 for patients aged ≥70 years), gender (C-index, 0.880 for men and 0.793 for women) and disease severity (C-index, 0.932 for non-severe patients and 0.658 for severe patients). However, the platelet to lymphocyte ratio was superior to the other indicators in patients aged <70 years., Conclusions: The prognostic ability of the dNLR was higher than the other evaluated inflammatory indicators for all COVID-19 Omicron BA.2 infected patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qiu, Shi, Chen, Wu, Yu and Xiong.)

Aims: Postoperative cognitive dysfunction (POCD) is a neurological disorder associated with neuroinflammation. Connexin 43 (Cx43), an essential component of gap junction, plays a crucial role in neuroinflammation. The present study was designed to investigate the role of Cx43 in the process of POCD., Methods: POCD model was established in aged mice with internal fixation of tibial fractures. Cognitive function was examined using the Morris water maze test. Hippocampus was collected for reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunofluorescence assays., Results: In the water maze test, mice undergoing surgery took longer time to reach target platform than the controls. IL-1β and TNF-α mRNA expressions in the hippocampus were significantly increased in surgery mice. Cx43 protein presence in the hippocampus was increased in the surgery group. Treatment of Gap26, a specific blocker of Cx43 hemichannel, reduced the Cx43 protein presence, decreased mRNA expressions of IL-1β and TNF-α, and improved cognitive score in the maze test., Conclusion: Internal fixation of tibial fractures in aged mice induces Cx43 hemichannels opening and enhances neuroinflammation in the hippocampus, leading to cognitive impairment. Administration of Gap26 reduces neuroinflammation in the hippocampus and improves postoperative cognitive function., Competing Interests: None.

Sepsis is a systemic inflammation caused by infection. The balance between M1-M2 macrophage polarization has an essential role in the pathogenesis of sepsis. However, the exact mechanism underlying macrophage polarization is unclear. We previously showed that levels of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) were significantly elevated in septic patients compared with those in nonseptic patients, and involved in the activation of Toll-like receptor (TLR) 2/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB pathway. In the present study, we explored whether MFHAS1 was involved in macrophage polarization and determined the effect of MFHAS1 on inflammation. We performed in vitro pulldown assays and in vivo co-immunoprecipitation assays and found that E3 ubiquitin ligase praja2 could directly bind to MFHAS1. In situ immunostaining analysis confirmed the colocalization of endogenous praja2 with MFHAS1. We first reported that praja2 promotes the accumulation of ubiquitylated MFHAS1 but does not degrade it. Moreover, our results indicate that MFHAS1 ubiquitylation by praja2 positively regulates TLR2-mediated JNK/p38 pathway and promotes M1 macrophage polarization, M2 to M1 macrophage transformation and inflammation.

The perioperative stress response is one of the factors leading to postoperative cognitive dysfunction (POCD). Dexmedetomidine (Dex) can reduce the stress response and hippocampus neuroapoptosis, but its mechanism of action on POCD remains unknown. This study investigated the protective effect and possible mechanism of Dex on POCD in aged rats. Ninety-six aged male rats were randomly divided into four groups (n = 24 rats per group): a non-surgical control group, a surgical (model) group, a surgical group receiving a high dose of Dex (12 μg/kg), and a surgical group receiving a low dose of Dex (3 μg/kg). Cognitive function and neuronal apoptosis were evaluated after splenectomy. Compared with the control group, the model group had significantly longer escape latencies and fewer platform crossings in the Morris water-maze test. Immunohistochemistry showed that relaxin-3 and c-fos positive neurons in the hippocampus increased on postoperative days 1 and 3. Greater downregulation of the Bcl-2 protein and upregulation of Fas, caspase-8, and caspase-9 significantly increased neuroapoptosis in the model group. Compared with the model group, rats given Dex had (1) shorter escape latencies, (2) more platform crossings, (3) fewer relaxin-3 and c-fos positive neurons in the hippocampal CA1 area, (4) upregulation of Bcl-2, (5) downregulation of Fas, caspase-8, and caspase-9 proteins, and (6) decreased neuroapoptosis in the hippocampus. Thus, our data suggest that Dex may improve cognitive functioning in aged rats by inhibiting neural over-excitability. The mechanism may operate by restraining relaxin-3 and c-fos expression.