Comparison of Remimazolam Tosilate and Propofol Sedation on the Early Postoperative Quality of Recovery in Patients Undergoing Day Surgery: A Prospective Randomized Controlled Trial.

Purpose: Remimazolam tosilate is a novel ultrafast-acting benzodiazepine that has a rapid emergence even after continuous infusion when using flumazenil. So far, relatively few articles are still focusing on the quality of recovery after general anesthesia with remimazolam, especially in day surgery. This study aimed to compare the early postoperative quality of recovery of remimazolam tosilate with flumazenil and propofol in patients undergoing day surgery. Patients and Methods: 137 patients scheduled for day surgery were randomly divided into the remimazolam tosilate or propofol group. The primary endpoint was the incidence of overall recovery assessed with the early postoperative quality of recovery scale (PostopQRS) on postoperative day 1 (POD 1). The Richmond Agitation-Sedation Scale (RASS) scores in the post-anesthesia care unit (PACU), extubation time, postoperative recovery profiles, and perioperative data were documented. Any adverse events were recorded. Results: The incidence of overall recovery on POD1 was 47.7% in the remimazolam tosilate group and 65.1% in the propofol group (odds ratio, 0.52; 95% confidence interval (CI) 0.26 to 1.06; P = 0.072). In general, the overall recovery of the PostopQRS increased over time, and its interaction between time and group was significant (P = 0.003). Among the five dimensions of PostopQRS, there exist statistical differences between groups including emotional state and cognitive recovery. Upon arrival at the PACU, the remimazolam group was more sedated and took longer to recover to a RASS score similar to propofol. The frequency of application of vasoactive drugs during anesthesia was similar in both groups (P = 0.119). Despite rapid emergence with remimazolam after flumazenil reversal, re-sedation (10.8%) or somnolence (60%) in the PACU was observed, and the length of PACU stay in patients treated with remimazolam tosilate was longer than that of the propofol (35 min vs 30 min, P<0.001). Conclusion: General anesthesia with remimazolam tosilate in conjunction with flumazenil reversal permits rapid recovery of consciousness in day surgery, but there was a notable occurrence of re-sedation or somnolence observed in PACU.

A case of precipitate in intravenous line when general anesthesia implemented with remimazolam.

Adverse reactions caused by drug compatibility are more common in clinical practice, including discoloration, precipitation, crystallization, which can be life-threatening in severe cases. We report a 63-year-old man who developed precipitation during maintenance of general anesthesia with remimazolam tosylate for prostate resection. There were many precipitates in the infusion pipeline and the three-way stopcock, and at that time the infusion liquid was Ringer's acetate solution. Then we investigated the possibility of precipitation with different infusion fluids and remimazolam tosylate. In conclusion, precipitates may not form at a lower remimazolam tosylate concentration and a faster liquid infusion rate and require appropriate attention.

The Reliability and Validity of the "Activity and Participation" Component in the Brief ICF Core Set for Chronic Obstructive Pulmonary Diseases Based on Rasch Analysis.

Purpose: To analyze the reliability and validity of the "activity and participation" component of the brief international classification of functioning, disability and health (ICF) core set for chronic obstructive pulmonary disease (COPD) using a Multi-faceted Rasch model. Patients and Methods: A total of 103 patients with COPD were selected by two raters to evaluate their ability levels in the four categories of the "activity and participation" component of brief ICF core set for COPD. The Multi-faceted Rasch model was used for data analysis. The analysis software used FACETS (Minifac) 3.67.0. Results: The "activity and participation" of brief ICF core set for COPD had a high internal consistency (separation index of 5.08, reliability of 0.96, P <0.05) and good inter-rater reliability (mean-square fit statistic range was 0.97-1.04, the separation index was 0.00, the reliability was 0.00, P >0.05), the construct validity was good (mean-square fit statistic range was 0.79-1.36), and the consistency of each category measurement was high (the separation index was 1.70, the reliability was 0.74). Conclusion: The "activity and participation" of brief ICF core set for COPD has good reliability and validity, which can be used to test the daily activities of patients with COPD.

Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling.

BACKGROUND: There are seven insulin-like growth factor binding proteins (IGFBPs) that bind insulin-like growth factors (IGFs). IGFBP like protein1 (IGFBPL1) is a new member of this family. The function and mechanism of IGFBPL1 in esophageal cancer remains to be elucidated. METHODS: Eight esophageal cancer cell lines, 114 cases of esophageal dysplasia, and 501 cases of primary esophageal cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), immunohistochemistry, Western blot, flow cytometry, RNA interference assay, and xenograft mouse models were employed. RESULTS: The expression of IGFBPL1was lost and complete methylation was found in KYSE150 and KYSE410 cells. Reduced expression and partial methylation of IGFBPL1 was found in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells. High expression and unmethylation was detected in KYSE510 cells. Restoration of IGFBPL1 expression was found in KYSE150 and KYSE410 cells and the expression of IGFBPL1 was increased in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells, after 5-AZA-2'-deoxycytidine treatment. IGFBPL1 was methylated in 47.3% (53/114) of esophageal dysplasia and 49.1% (246/501) of human primary esophageal squamous cell carcinoma (ESCC). Methylation of IGFBPL1 was significantly associated with TNM stage (p = 0.012), and tumor size (p = 0.009). IGFBPL1 inhibited esophageal cancer cell clonal formation and proliferation and induced cell apoptosis and G1/S phase arrest. Further study found that IGFBPL1 is involved in PI3K-AKT signaling and IGFBPL1 suppressed human ESCC xenografts growth in mice. CONCLUSION: IGFBPL1 suppresses esophageal cancer cell growth by inhibiting PI3K-AKT signaling in vitro and in vivo. IGFBPL1 is a novel tumor suppressor in human esophageal cancer.

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.

Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy.

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions. However, Acp1(-/-) mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the postnatal stage, and increased in the adult mouse failing heart. We also show that LMPTP expression increases in end-stage heart failure in humans. Consistent with their protected phenotype, Acp1(-/-) mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of fibrotic genes. Transcriptional profiling and analysis of molecular signalling show that the resistance of Acp1(-/-) mice to pathological cardiac stress correlates with marginal re-expression of fetal cardiac genes, increased insulin receptor beta phosphorylation, as well as PKA and ephrin receptor expression, and inactivation of the CaMKIIδ pathway. Our data show that ablation of Lmptp inhibits pathological cardiac remodelling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of human heart failure.

Association of the glucocorticoid receptor D641V variant with steroid-resistant asthma: a case-control study.

OBJECTIVES: Several mutations of the glucocorticoid receptor (GR) gene cause malfunction of the protein, resulting in steroid resistance. In diseases other than asthma, the GR variants I559N, D641V, and V729I have been linked to steroid resistance. The aim of this study was to evaluate the link of these GR variants in steroid-resistant (SR) asthma in the Chinese Han population. METHODS: GR polymorphisms were determined in 64 SR asthma patients, 217 steroid-sensitive (SS) asthma patients and 221 healthy control (CTR) individuals. The analysis of the GR variants was performed using PCR-sequence specific primers according to the European Molecular Biology Laboratory database (NC_000005.8). In addition, ligand binding and serum cortisol levels were determined. RESULTS: Compared with SS asthma patients and CTRs, a significant lower frequency of the GR D641V variant AA genotype (P=0.003, 0.014, respectively) and the A allele (P=0.001, 0.009, respectively) was found in SR asthma patients. Furthermore, the equilibrium dissociation constant (Kd) of GR ligand binding in SR asthma patients with the GR D641V variant AA genotype was significantly lower compared with the AT or the TT genotype carriers (P=0.006, 0.016, respectively). There was no significant difference between the I559N and V729I GR variants on comparing SR asthma patients with SS asthma patients or CTRs. CONCLUSION: This study suggests that the D641V variant of the GR is probably associated with SR asthma in the Chinese Han population.

Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.

A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.

Regulation of lymphoid tyrosine phosphatase activity: inhibition of the catalytic domain by the proximal interdomain.

The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, recently emerged as a major player and candidate drug target for human autoimmunity. The enzyme includes a classical N-terminal protein tyrosine phosphatase catalytic domain and a C-terminal PEST-enriched domain, separated by an approximately 300-amino acid interdomain. Little is known about the regulation of LYP. Herein, by analysis of serial truncation mutants of LYP, we show that the phosphatase activity is strongly inhibited by protein regions C-terminal to the catalytic domain. We mapped the minimal inhibitory region to the proximal portion of the interdomain. We show that the activity of LYP is inhibited by an intramolecular mechanism, whereby the proximal portion of the interdomain directly interacts with the catalytic domain and reduces its activity.

[Construction of antisense recombinant adenoviral vector for c-myc and its antiproliferative effect on rat lymphocytes].

AIM: To observe the antiproliferative effect of antisense recombinant adenoviral vector for c-myc on rat thymus lymphocytes. METHODS: Antisense and sense bacterial plasmids for c-myc were constructed. Bacterial plasmids and El detected adenoviral plasmid were cotransfected into 293 cells. Recombinant adenoviral vectors were obtained after cotransfection. The antiproliferative effects were assayed by MTS. The expression of c-myc mRNA was detected by RT-PCR. RESULTS: The results showed that antisense recombinant adenoviral vector for c-myc could inhibit rat thymus lymphocytes proliferation. The expression of c-myc mRNA was decreased after antisense recombinant adenoviral vector for c-myc was transfected into cells. CONCLUSION: Recombinant antisense adenoviral vector for c-myc could inhibit rat thymus lymphocytes proliferation.