Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Prognostic role of MUCIN family and its relationship with immune characteristics and tumor biology in diffuse-type gastric cancer.

The main component of O-glycoproteins, mucin, is known to play important roles in physiological conditions and oncogenic processes, particularly correlated with poor prognosis in different carcinomas. Diffuse-type gastric cancer (DGC) has long been associated with genomic stability and unfavorable clinical outcomes. To investigate further, we obtained clinical information and the RNA-seq data of the TCGA-STAD cohort. Through the use of unsupervised clustering methods and GSEA, we identified two distinct clusters, characterized by higher and lower expression of MUC2 and MUC20, denoted as cluster 1 and cluster 2, respectively. Subsequently, employing CIBERSORT, it was determined that cluster 2 exhibited a higher tumor mutation burden (TMB) and a greater abundance of CD8+ T cells and activated CD4+ memory T cells, in addition to immune checkpoints (ICPs). On the other hand, cluster 1 showed a lower TIDE score estimation, indicating a higher probability of tumor immune escape. Furthermore, overexpression of MUC15 and MUC20 was confirmed through qPCR and Western blotting, and their specific roles in mediating the epithelial-mesenchymal transition (EMT) process of GC cells (SNU484 and Hs746t) were validated via CCK-8 assay and wound healing assay in vitro. These findings highlight the potential prognostic value of MUC20 and offer insights into the prospects of immunotherapy for DGC by targeting MUC20.

Role of GSK-3ß in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats.

This study investigated the role of glycogen synthase kinase-3ß (GSK-3ß) in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. The hippocampi were dissected from aged rats which had been intraperitoneally administered lithium chloride (LiCl, 100 mg/kg) and then exposed to 1.4% isoflurane for 6 h. The expression of GSK-3ß was detected by Western blotting. The mRNA and protein expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Morris water maze was employed to detect spatial memory ability of rats. The results revealed that the level of GSK-3ß was upregulated after isofurane exposure. Real-time PCR analysis demonstrated that isoflurane anesthesia increased mRNA levels of TNF-α, IL-1ß and IL-6, which was consistent with the ELISA results. However, these changes were reversed by prophylactic LiCl, a non-selective inhibitor of GSK-3ß. Additionally, we discovered that LiCl alleviated isoflurane-induced cognitive impairment in aged rats. Furthermore, the role of GSK-3ß in isoflurae-induced neuroinflammation and cognitive dysfunction was associated with acetylation of NF-κB p65 (Lys310). In conclusion, these results suggested that GSK-3ß is associated with isoflurane-induced upregulation of proinflammatory cytokines and cognitive disorder in aged rats.

Nutrition management by a multidisciplinary team for prevention of nutritional deficits and morbidity following esophagectomy.

This study evaluated the effects of perioperative nutrition management by a multidisciplinary team on nutrition and postoperative complications of patients with esophageal cancer. A total of 239 patients with esophageal cancer who underwent esophagectomy and gastric conduit reconstruction for esophageal or esophagogastric junction cancer between February 2019 and February 2020 were included in the study. They were divided into the experimental group (120 patients) and the control group (119 patients) using the random number table method. Control group patients received routine diet management and experimental group patients received perioperative nutrition management by a multidisciplinary team. The differences of nutriture and postoperative complications between the two groups were compared. At 3 and 7 days after surgery, the experimental group patients had higher total protein and albumin levels (P<0.05), shorter postoperative anal exhaust time (P<0.05), lower incidence of postoperative gastrointestinal adverse reactions, pneumonia, anastomotic fistula, hypoproteinemia (P<0.05), and lower hospitalization costs (P<0.05) than the control group. Nutrition management by a multidisciplinary team effectively improved the nutriture of patients, promoted the rapid recovery of postoperative gastrointestinal function, reduced postoperative complications, and reduced hospitalization costs.

Digestive system involvement of infections with SARS-CoV-2 and other coronaviruses: Clinical manifestations and potential mechanisms.

Although coronavirus (CoV) infection is often characterized by respiratory symptoms, the virus can also result in extrapulmonary symptoms, especially the symptoms related to the digestive system. The outbreak of coronavirus disease 2019 (COVID-19) is currently the world's most pressing public health threat and has a significant impact on civil societies and the global economy. The occurrence of digestive symptoms in patients with COVID-19 is closely related to the development and prognosis of the disease. Moreover, thus far, there are no specific antiviral drug or vaccine approved for the treatment or prevention of COVID-19. Therefore, we elaborate on the effects of CoVs on the digestive system and the potential underlying mechanisms.

Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice.

Sevoflurane, the most commonly used inhaled anesthetic in pediatric anesthesia, has been reported to induce cognitive impairment in developing brain in preclinical and clinical settings. However, the mechanism and therapeutic measures of this developmental neurotoxicity need to be further investigated. Resveratrol, a natural polyphenolic agent, has been reported to improve cognitive function in neurological disorders and aging models through anti-inflammatory activity. However, its effect on sevoflurane-induced cognitive impairment in developing mice remains unknown. The present study was designed to investigate the therapeutic potential of resveratrol on sevoflurane-induced cognitive impairment. Six-day-old mice received anesthesia with 3% sevoflurane 2 h daily on postnatal days (P) 6, P7 and P8. About 100 mg/kg resveratrol were intraperitoneally administered for 6 consecutive days to neonatal mice before anesthesia. Sevoflurane exposure significantly suppressed the expression of Sirtuin 1 (SIRT1) and activated microglia in hippocampi. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were markedly increased after sevoflurane exposure. Strikingly, resveratrol pretreatment ameliorated sevoflurane-induced SIRT1 inhibition and microglial activation. Of note, resveratrol reversed sevoflurane-induced imbalance of M1/M2 microglia ratio revealed by increasing mRNA level of clusters of differentiation 206 (CD206) and decreasing mRNA levels of clusters of differentiation 86 (CD86) and suppressor of cytokine signaling 3 (SOCS3). Consequently, sevoflurane-induced cognitive impairment in developing mice was ameliorated by resveratrol pretreatment. Taken together, repeated sevoflurane exposure to the developing brain resulted in SIRT1 inhibition, NF-κB acetylation, and microglial activation. Resveratrol pretreatment ameliorated cognitive impairment in developing mice received sevoflurane exposure by modulating SIRT1-NF-κB pathway in microglia. In this regard, our findings open novel directions to explore promising therapeutic targets for preventing the developmental neurotoxicity of sevoflurane.

Whole brain radiotherapy induces cognitive dysfunction in mice: key role of gut microbiota.

RATIONALE: Approximately 20-40% of patients with cancer will experience brain metastasis (BM), which has a great impact on the quality of life and survival rates of patients. Whole brain radiotherapy (WBRT) is an effective method for the treatment of BM. However, it cannot be ignored that WBRT might induce a series of neuropsychiatric side effects, including cognitive dysfunction (CD). Accumulating evidence shows that the gut microbiota and the gut-microbiota-brain axis may play a vital role in the pathogenesis of CD. OBJECTIVE AND METHODS: We adopted WBRT to mimic CD after a hierarchical cluster analysis of the Morris water maze test (MWMT) results. In addition, we observed the effects of antibiotics and prebiotics on WBRT-induced CD. Variations were revealed via the 16S rRNA sequencing analysis at different levels. RESULTS: The 16S rRNA sequencing analysis revealed an altered composition of gut microbiota between CD and non-CD phenotypes. Furthermore, we observed a decrease in the levels of Phylum-Bacteroidete, Class-Bacteroidia, and Order-Bacteroidales in the CD group and an increase in the Genus-Allobaculum level after WBRT. Pretreatment with antibiotics caused a significant decrease in the level of Phylum-TM7 01, whereas an increase in the levels of Class-Gammaproteobacteria, Order-Enterobacteriales, and Species-Escherichia coli. After pretreatment with probiotics, the levels of Phylum-Cyanobacteria, Class-4C0d-2, and Order-YS2 were decreased, while the levels of Family-Bacteroidaceae, Genus-Bacteroides, and Species-Parabacteroides distasonis were increased. CONCLUSIONS: WBRT-induced CD might be highly related to abnormal composition of gut microbiota. Strategies improving the composition of the gut microbiota may provide beneficial effects on CD in individuals exposed to WBRT.

Abnormal composition of gut microbiota contributes to delirium-like behaviors after abdominal surgery in mice.

AIMS: Anesthesia and surgery can cause delirium-like symptoms postoperatively. Increasing evidence suggests that gut microbiota is a physiological regulator of the brain. Herein, we investigated whether gut microbiota plays a role in postoperative delirium (POD). METHODS: Mice were separated into non-POD and POD phenotypes after abdominal surgery by applying hierarchical clustering analysis to behavioral tests. Fecal samples were collected, and 16S ribosomal RNA gene sequencing was performed to detect differences in gut microbiota composition among sham, non-POD, and POD mice. Fecal bacteria from non-POD and POD mice were transplanted into antibiotics-induced pseudo-germ-free mice to investigate the effects on behaviors. RESULTS: α-diversity and ß-diversity indicated differences in gut microbiota composition between the non-POD and POD mice. At the phylum level, the non-POD mice had significantly higher levels of Tenericutes, which were not detected in the POD mice. At the class level, levels of Gammaproteobacteria were higher in the POD mice, whereas the non-POD mice had significantly higher levels of Mollicutes, which were not detected in the POD mice. A total of 20 gut bacteria differed significantly between the POD and non-POD mice. Interestingly, the pseudo-germ-free mice showed abnormal behaviors prior to transplant. The pseudo-germ-free mice that received fecal bacteria transplants from non-POD mice but not from POD mice showed improvements in behaviors. CONCLUSIONS: Abnormal gut microbiota composition after abdominal surgery may contribute to the development of POD. A therapeutic strategy that targets gut microbiota could provide a novel alterative for POD treatment.

The Role of Cardiokines in Heart Diseases: Beneficial or Detrimental?

Cardiovascular disease remains the leading cause of morbidity and mortality, imposing a major disease burden worldwide. Therefore, there is an urgent need to identify new therapeutic targets. Recently, the concept that the heart acts as a secretory organ has attracted increasing attention. Proteins secreted by the heart are called cardiokines, and they play a critical physiological role in maintaining heart homeostasis or responding to myocardial damage and thereby influence the development of heart diseases. Given the critical role of cardiokines in heart disease, they might represent a promising therapeutic target. This review will focus on several cardiokines and discuss their roles in the pathogenesis of heart diseases and as potential therapeutics.

Nutrition management by a multidisciplinary team for prevention of nutritional deficits and morbidity following esophagectomy

This study evaluated the effects of perioperative nutrition management by a multidisciplinary team on nutrition and postoperative complications of patients with esophageal cancer. A total of 239 patients with esophageal cancer who underwent esophagectomy and gastric conduit reconstruction for esophageal or esophagogastric junction cancer between February 2019 and February 2020 were included in the study. They were divided into the experimental group (120 patients) and the control group (119 patients) using the random number table method. Control group patients received routine diet management and experimental group patients received perioperative nutrition management by a multidisciplinary team. The differences of nutriture and postoperative complications between the two groups were compared. At 3 and 7 days after surgery, the experimental group patients had higher total protein and albumin levels (P<0.05), shorter postoperative anal exhaust time (P<0.05), lower incidence of postoperative gastrointestinal adverse reactions, pneumonia, anastomotic fistula, hypoproteinemia (P<0.05), and lower hospitalization costs (P<0.05) than the control group. Nutrition management by a multidisciplinary team effectively improved the nutriture of patients, promoted the rapid recovery of postoperative gastrointestinal function, reduced postoperative complications, and reduced hospitalization costs.

Differential expression of serum biomarkers in hemodialysis patients with mild cognitive decline: A prospective single-center cohort study.

Studies suggest that hemodialysis patients are at a higher risk for cognitive decline than healthy individuals; however, underlying mechanisms have not been fully elucidated. We aimed to investigate the roles of serum biomarkers, such as brain-derived neurotrophic factor (BDNF), inflammatory cytokines, fibroblast growth factor (FGF)-23 and its co-receptor α-klotho and platelet (PLT) count in mild cognitive decline (MCD) of patients undergoing hemodialysis in this prospective cohort study. Serum levels of BDNF, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and the number of PLT were significantly altered in the MCD group compared with those in healthy controls (HCs) or those with normal cognitive function (NCF). Although serum α-klotho and FGF-23 levels were significantly altered in the MCD group, there were no statistical differences between the MCD and NCF groups. Serum BDNF levels and PLT counts were significantly correlated with cognitive test scores. Receiver operating characteristic (ROC) curves demonstrated that BDNF and PLT were potential biomarkers for improved MCD diagnosis in patients with hemodialysis. These findings suggest that hemodialysis-related MCD is associated with altered BDNF, TNF-α and IL-6 levels as well as PLT counts and that serum BDNF levels and PLT counts are potential biomarkers for hemodialysis-related MCD diagnosis.

Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice.

Ischemic stroke leads to high potentiality of mortality and disability. The current treatment for ischemic stroke is mainly focused on intravenous thrombolytic therapy. However, ischemia/ reperfusion induces neuronal damage, which significantly influences the outcome of patients with ischemic stroke, and the exact mechanism implicated in ischemia/reperfusion injury remains unclear, although evidence shows that oxidative stress is likely to be involved. Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities. Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase. Thus, we hypothesized that betulinic acid may protect against brain ischemic injury in the animal model of stroke. Focal cerebral ischemia was achieved by using the standard intraluminal occlusion method and reperfusion enabled after 2 h ischemia. Neurological deficits were scored. Infarct size was determined with 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and the mRNA expression of NADPH oxidase 4 (NOX4) was determined by RT-PCR in infarct tissue. ROS generation and apoptosis in ischemic tissue were analyzed by measuring the oxidative conversion of cell permeable 2',7'-dichloro-fluorescein diacetate (DCF-DA) to fluorescent dichlorofluorescein (DCF) in fluorescence microplate reader and TUNEL assay, respectively. In Kunming mice, 2 h of middle cerebral artery (MCA) occlusion followed by 24 or 72 h of reperfusion led to an enhanced NOX4 expression in the ischemic hemisphere. This was associated with elevated levels of ROS generation and neuronal apoptosis. Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production. In addition, treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis. Finally, betulinic acid reduced infarct volume and ameliorated the neurological deficit in this stroke mouse model. Our results suggest that betulinic acid protects against cerebral ischemia/reperfusion injury in mice and the down-regulation of NOX4 may represent a mechanism contributing to this effect.

Risk factors for acute kidney injury after orthotopic liver transplantation: A single-center data analysis.

Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration (especially > 480 min), and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT.

Minocycline mitigates isoflurane-induced cognitive impairment in aged rats.

Postoperative cognitive dysfunction (POCD) is a severe neurological sequela that occurs in individuals who have undergone anesthesia and surgery, especially in the geriatric surgical population. Although it is known that isoflurane exposure impairs cognitive function in aged rodents, there are few clinical interventions for the prophylaxis and treatment of this disorder. Minocycline, a derivative of tetracycline, produces neuroprotection from several neurodegenerative diseases. Therefore, we set out to investigate the effects of minocycline pretreatment on isoflurane-induced cognitive impairment in aged rats. We found that pretreatment with minocycline remarkably alleviated isoflurane-induced cognitive dysfunction and inhibited the isoflurane-induced over expression of TNF-α, IL-1ß, and IL-6, possibly by inhibiting the degradation of IκBα. In addition, minocycline downregulated the isoflurane-induced increase in the protein levels of cleaved caspase 3 and bax, and upregulated the bcl-2 protein level. These findings highlight the beneficial role of minocycline in preventing isoflurane-induced cognitive impairment and suggested that minocycline can be used as a clinical treatment to mitigate the cognitive impairment induced by isoflurane in elderly patients.

Down-regulation of NOX4 by Betulinic Acid Protects against Cerebral Ischemia-reperfusion in Mice / 华中科技大学学报（医学）（英德文版）

Ischemic stroke leads to high potentiality of mortality and disability.The current treatment for ischemic stroke is mainly focused on intravenous thrombolytic therapy.However,ischemia/reperfusion induces neuronal damage,which significantly influences the outcome of patients with ischemic stroke,and the exact mechanism implicated in ischemia/reperfusion injury remains unclear,although evidence shows that oxidative stress is likely to be involved.Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities.Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase.Thus,we hypothesized that betulinic acid may protect against brain ischemic injury in the animal model of stroke.Focal cerebral ischemia was achieved by using the standard intraluminal occlusion method and reperfusion enabled after 2 h ischemia.Neurological deficits were scored.Infarct size was determined with 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and the mRNA expression of NADPH oxidase 4 (NOX4) was determined by RT-PCR in infarct tissue.ROS generation and apoptosis in ischemic tissue were analyzed by measuring the oxidative conversion of cell permeable 2',7'-dichloro-fluorescein diacetate (DCF-DA) to fluorescent dichlorofluorescein (DCF) in fluorescence microplate reader and TUNEL assay,respectively.In Kunming mice,2 h of middle cerebral artery (MCA) occlusion followed by 24 or 72 h of reperfusion led to an enhanced NOX4 expression in the ischemic hemisphere.This was associated with elevated levels of ROS generation and neuronal apoptosis.Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production.In addition,treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis.Finally,betulinic acid reduced infarct volume and ameliorated the neurological deficit in this stroke mouse model.Our results suggest that betulinic acid protects against cerebral ischemia/reperfusion injury in mice and the down-regulation of NOX4 may represent a mechanism contributing to this effect.

Risk Factors for Acute Kidney Injury after Orthotopic Liver Transplantation: A Single-center Data Analysis / 华中科技大学学报（医学）（英德文版）

Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality.The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT.A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital,China,were retrospectively analyzed.Their demographic characteristics and perioperative parameters were collected,and AKI was diagnosed using 2012 Kidney Disease:Improving Global Outcomes (KDIGO) staging criteria.It was found that the incidence of AKI was 40.8％ in this cohort and AKI was significantly associated with body mass index,urine volume,operation duration (especially ＞ 480 min),and the postoperative use of vasopressors.It was concluded that relative low urine output,long operation duration,and the postoperative use of vasopressors are risk factors for AKI following OLT.