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.

The role of microRNA-608 polymorphism on the susceptibility and survival of cancer: a meta-analysis.

The role of rs4919510 polymorphism in microRNA-608 (miR-608) and cancer susceptibility and prognosis remain controversial and debatable. We conducted a meta-analysis of twenty-four eligible publications on the association of rs4919510 polymorphism with cancer risk and/or prognosis. Odds ratios, hazard ratios, and 95% confidence interval were used to investigate the association between this polymorphism and susceptibility, overall survival, and recurrence-free survival of cancer. Overall, eighteen case-control studies and nine cohort studies evaluated the susceptibility and prognostic value of rs4919510 polymorphism in cancer, respectively. Pooled analysis showed that rs4919510 polymorphism was not associated with cancer risk in all five genetic models. When stratifying by different cancer sites, rs4919510 polymorphism was detected to have a significant association with a decreased risk of colorectal cancer in homozygous model (P = 0.006) and recessive model (P = 0.001), subgroup analysis also emerged a weakened correlation between rs4919510 polymorphism and an increased risk of papillary thyroid cancer in heterozygote model (P = 0.04). Furthermore, the prognosis of rs4919510 variant in cancer patients showed that rs4919510 GG genotype was significant association with poor recurrence-free survival in homozygous models (P = 0.04). The meta-analysis suggested that the microRNA-608 rs4919510 polymorphism maybe associate with a significantly decreased risk for colorectal cancer. Further investigations on larger populations are required to evaluate and confirm this relationship.

Uremic anorexia and ghrelin expression in the amygdala.

BACKGROUND/AIMS: Ghrelin can act as a signal for mealtime hunger and meal initiation. Amygdala is indispensable in appetitive behavior motivated by learned emotions. This study was to investigate the alteration of ghrelin in the amygdala of rats with chronic renal failure (CRF) and its relation with uremic anorexia. METHODS: SD rats were randomly classified into CRF group and control group (n=16 per group). The CRF model was constructed using 5/6 nephrectomy. When plasma creatinine (PCr) and blood urea nitrogen (BUN) in the CRF group were twice more than the normal level, food intake (g/24h) was measured and then all rats were killed for detection of ghrelin protein expression in the amygdala using immunohistochemical analysis and mRNA expression using RT-PCT. Statistics was conducted with one-way analysis of variance, Student-Newman-Keuls-q test and correlation analysis. RESULTS: By the 8th week after the surgery, the BUN and PCr of CRF rats exceeded double the normal level, and their food intake was obviously decreased compared with the controls (P<0.05). The protein and mRNA expression of ghrelin in the amygdala of CRF group were significantly reduced, and there was a positive correlation between this reduction and the decrease in food intake (P<0.05). CONCLUSION: The reduction of amygdala's ghrelin in CRF rats may be associated with uremic anorexia.

[Fas and TNFR1 expressions after cerebral ischemia and reperfusion in rats: association with cell apoptosis and the effects of Bcl-2 overexpression].

OBJECTIVE: To investigate the effect of Bcl-2 overexpression on Fas and TNFR1-mediated apoptosis and its possible mechanism in rat hippocampus following global ischemia/reperfusion (IR). METHODS: Ninety healthy male SD rats were randomly divided into sham operated group, IR group and Bcl-2 overexpression group (BT group). Rat model of global IR was established by the 4-V0 method. The expressions of Bcl-2, Fas and TNFR1 and the cell apoptosis in the CA1 and CA3 regions were examined by HE staining, immunohistochemistry and TUNEL method. RESULTS: In IR group, the neurons in the CA1 region showed an obvious reduction in number with disordered arrangement and interstitial edema 48 h after global IR. Such changes were not obvious in BT group. Immunohistochemistry showed that Fas expression in the CA1 region reached the peak level at 6 h in IR group with a greater expression intensity than that in BT group (P<0.05). TNFR1 was expressed at a higher level in IR group than in BT group (P<0.05), reaching the peak level at 24 h. In the sham group, the expression of Fas and TNFR1 was not detected the in CA1 and CA3 regions. Global IR caused increased cell apoptosis in the CA1 and CA3 regions, starting at 6 h and reached peak at 24 to 48 h. The cell apoptosis was less obvious in BT group (P<0.05). CONCLUSION: Fas and TNFR1 are expressed in the CA1 and CA3 regions after global IR in rats, suggesting the involvement of death receptor in cerebral IR injury. Bcl-2 overexpression decreases the expression of Fas and TNFR1 and cell apoptosis after global IR, thus offering protective effect against cerebral IR injury.

Relationship between transmembrane signal transduction pathway and DNA repair and the mechanism after global cerebral ischemia-reperfusion in rats.

OBJECTIVE: To investigate the protein levels of phospho-ERK and phospho-APE/Ref-1 in hippocampal neurons after global cerebral ischemia reperfusion in rats, and observe the relationship between transmembrane signal transduction and repair of DNA damage. The role of ERK signal transduction pathway following global cerebral ischemia reperfusion in rats is further discussed. METHODS: Ninety healthy male SD rats were divided into 3 groups randomly: Sham group (S group), Ischemia reperfusion group (IR group) and Pd98059 pretreatment/ischemia reperfusion group (PD group). Global cerebral ischemia reperfusion model was established by four-vessel occlusion (4-VO) method, and reperfusion was performed 5 minutes following ischemia. Protein levels of phospho-ERK and phospho-APE/Ref-1 were detected using immunohistochemical method at 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after reperfusion, and neuron apoptosis was observed by HE and TUNEL staining. RESULTS: In CA1 region of IR group, TUNEL positive cells began to appear at 6 h after IR, and reached the apex during 24 h to 48 h. However, TUNEL positive was most strongly exhibited in PD group. In IR group, phospho-ERK was obviously detected in CA3 region at 2 h after IR, and its level was gradually decreased from 6 h until totally absent at 48 h. Besides, phospho-ERK expression in PD group was weaker than that in IR group. For phospho-APE/Ref-1, its expression began to appear in CA1 region in IR group at 2 h after IR, with no obvious changes during 2 h to 12 h. Phospho-APE/Ref-1 expression began to decrease at 24 h and this decrease continued thereafter. Expression level of phospho-APE/Ref-1 in PD group was lower than that in IR group. Results showed the concurrence of decreased phospho-ERK expression level and increased neuron apoptosis after cerebral ischemia reperfusion, the former of which was consistent with the decrease of phospho-APE/Ref-1 expression. Also, the greater the inhibition of ERK phosphorylation was, the greater decrease of APE/Ref-1 expression occurred. CONCLUSION: Activation of ERK signal transduction pathway increased the expression of phospho-APE/Ref-1, and thus faciliated the repair of DNA damage. So, activation of ERK signal transduction pathway may protect neurons from apoptosis after cerebral ischemia reperfusion.