Influence of Neostigmine on Early Postoperative Cognitive Dysfunction in Older Adult Patients Undergoing Noncardiac Surgery: A Double-Blind, Placebo-Controlled, Randomized Controlled Trial.

BACKGROUND: The goal of this study was to investigate the efficacy of neostigmine on postoperative cognitive dysfunction (POCD) and determine its effect on systematic markers of oxidative stress in older patients. METHODS: This double-blind placebo-controlled trial enrolled 118 elderly patients (≥65 years) undergoing noncardiac surgeries who were allocated to a neostigmine treatment group (0.04 mg/kg) or a placebo control group (normal saline) postoperatively. POCD was diagnosed if the Z -scores for the mini-mental state examination and the Montreal Cognitive Assessment were both ≤-1.96. Postoperative serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were also compared. Multivariable regression analysis with dose adjustment of atropine was used to demonstrate the influence of neostigmine on the incidence of POCD. RESULTS: Patients receiving neostigmine had a significantly reduced incidence of POCD compared to patients who were treated with placebo on the first day after surgery (-22%, 95% confidence interval [CI], -37 to -7), but not on the third (8%, 95% CI, -4 to 20) or seventh day after surgery (3%, 95% CI, -7 to 13). Postoperative plasma MDA levels were significantly lower ( P = .016), but SOD and BDNF levels were increased ( P = .036 and .013, respectively) in the neostigmine group compared to the control group on the first day after surgery. CONCLUSIONS: Neostigmine reduced POCD on the first day after noncardiac surgery in older patients. Neostigmine treatment inhibited oxidative stress and increased serum BDNF levels. There was no significant influence of neostigmine on POCD on the third or seventh day after surgery. The clinical influence of neostigmine on POCD should be further investigated.

Effect of anesthesia induction with butorphanol on postoperative nausea and vomiting: A randomized controlled trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) are common complications that affect the recovery and well-being of elderly patients undergoing gastrointestinal laparoscopic surgery. AIM: To investigate the effect of butorphanol on PONV in this patient population. METHODS: A total of 110 elderly patients (≥ 65 years old) who underwent gastrointestinal laparoscopic surgery were randomly assigned to receive butorphanol (40 µg/kg) or sufentanil (0.3 µg/kg) during anesthesia induction in a 1:1 ratio. The measured outcomes included the incidence of PONV at 48 h after surgery, intraoperative dose of propofol and remifentanil, Bruggrmann Comfort Scale score in the postanesthesia care unit (PACU), number of compressions for postoperative patient-controlled intravenous analgesia (PCIA), and time to first flatulence after surgery. RESULTS: The results revealed a noteworthy reduction in the occurrence of PONV at 24 h after surgery in the butorphanol group, when compared to the sufentanil group (T1: 23.64% vs 5.45%, T2: 43.64% vs 20.00%, P < 0.05). However, no significant variations were observed between the two groups, in terms of the clinical characteristics, such as the PONV or motion sickness history, intraoperative and postoperative 48-h total infusion volume and hemodynamic parameters, intraoperative dose of propofol and remifentanil, number of postoperative PCIA compressions, time until the first occurrence of postoperative flatulence, and incidence of PONV at 48 h post-surgery (all, P > 0.05). Furthermore, patients in the butorphanol group were more comfortable, when compared to patients in the sufentanil group in the PACU. CONCLUSION: The present study revealed that butorphanol can be an efficacious substitute for sufentanil during anesthesia induction to diminish PONV within 24 h following gastrointestinal laparoscopic surgery in the elderly, simultaneously improving patient comfort in the PACU.

Improvement of Reinforcement Learning With Supermodularity.

Reinforcement learning (RL) is a promising approach to tackling learning and decision-making problems in a dynamic environment. Most studies on RL focus on the improvement of state evaluation or action evaluation. In this article, we investigate how to reduce action space by using supermodularity. We consider the decision tasks in the multistage decision process as a collection of parameterized optimization problems, where state parameters dynamically vary along with the time or stage. The optimal solutions of these parameterized optimization problems correspond to the optimal actions in RL. For a given Markov decision process (MDP) with supermodularity, the monotonicity of the optimal action set and the optimal selection with respect to state parameters can be obtained by using the monotone comparative statics. Accordingly, we propose a monotonicity cut to remove unpromising actions from the action space. Taking bin packing problem (BPP) as an example, we show how the supermodularity and monotonicity cut work in RL. Finally, we evaluate the monotonicity cut on the benchmark datasets reported in the literature and compare the proposed RL with some popular baseline algorithms. The results show that the monotonicity cut can effectively improve the performance of RL.

COL11A1-driven positive feedback loop modulates fibroblast transformation and activates pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common leading causes of cancer death. The cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) aggravate the malignant behavior of PDAC. However, it is still unknown how PDAC induces normal fibroblasts (NFs) to CAFs. In present research, we found that PDAC-derived collagen type XI alpha 1 (COL11A1) promoted the conversion of NFs to CAF-like cells. It included morphological and corresponding molecular marker changes. Activation of the nuclear factor-κB (NF-κB) pathway was involved in this process. Corresponding, CAFs cells could secrete interleukin 6 (IL-6), which promoted the invasion and the epithelial-mesenchymal transition of PDAC cells. Furthermore, IL-6 promoted the expression of transcription factor Activating Transcription Factor 4 by activating the Mitogen-Activated Protein Kinase/extracellular-signal-regulated kinase pathway. The latter directly promotes the expression of COL11A1. This way, a feedback loop of mutual influence was constructed between PDAC and CAFs. Our research proposed a novel concept for PDAC-educated NFs. PDAC-COL11A1-fibroblast-IL-6-PDAC axis might contribute to the cascade between PDAC and TME.

Efficacy and safety of propofol target-controlled infusion combined with butorphanol for sedated colonoscopy.

BACKGROUND: Propofol is a short-acting, rapid-recovering anesthetic widely used in sedated colonoscopy for the early detection, diagnosis and treatment of colon diseases. However, the use of propofol alone may require high doses to achieve the induction of anesthesia in sedated colonoscopy, which has been associated with anesthesia-related adverse events (AEs), including hypoxemia, sinus bradycardia, and hypotension. Therefore, propofol co-administrated with other anesthetics has been proposed to reduce the required dose of propofol, enhance the efficacy, and improve the satisfaction of patients receiving colonoscopy under sedation. AIM: To evaluate the efficacy and safety of propofol target-controlled infusion (TCI) in combination with butorphanol for sedation during colonoscopy. METHODS: In this controlled clinical trial, a total of 106 patients, who were scheduled for sedated colonoscopy, were prospectively recruited and assigned into three groups to receive different doses of butorphanol before propofol TCI: Low-dose butorphanol group (5 µg/kg, group B1), high-dose butorphanol group (10 µg/kg, group B2), and control group (normal saline, group C). Anesthesia was achieved by propofol TCI. The primary outcome was the median effective concentration (EC50) of propofol TCI, which was measured using the up-and-down sequential method. The secondary outcomes included AEs in perianesthesia and recovery characteristics. RESULTS: The EC50 of propofol for TCI was 3.03 µg/mL [95% confidence interval (CI): 2.83-3.23 µg/mL] in group B2, 3.41 µg/mL (95%CI: 3.20-3.62 µg/mL) in group B1, and 4.05 µg/mL (95%CI: 3.78-4.34 µg/mL) in group C. The amount of propofol necessary for anesthesia was 132 mg [interquartile range (IQR), 125-144.75 mg] in group B2 and 142 mg (IQR, 135-154 mg) in group B1. Furthermore, the awakening concentration was 1.1 µg/mL (IQR, 0.9-1.2 µg/mL) in group B2 and 1.2 µg/mL (IQR, 1.025-1.5 µg/mL) in group B1. Notably, the propofol TCI plus butorphanol groups (groups B1 and B2) had a lower incidence of anesthesia AEs, when compared to group C. Furthermore, no significant differences were observed in the rates of AEs in perianesthesia, including hypoxemia, sinus bradycardia, hypotension, nausea and vomiting, and vertigo, among group C, group B1 and group B2. CONCLUSION: The combined use with butorphanol reduces the EC50 of propofol TCI for anesthesia. The decrease in propofol might contribute to the reduced anesthesia-related AEs in patients undergoing sedated colonoscopy.

Anesthetic effect of different doses of butorphanol in patients undergoing gastroscopy and colonoscopy.

BACKGROUND: This study aimed to investigate the anesthetic effect of butorphanol with different doses in patients undergoing gastroscopy and colonoscopy. METHODS: 480 patients undergoing gastroscopy and colonoscopy were recruited and randomly divided into four groups to receive different doses of butorphanol (Group A = 2.5 µg/kg, Group B = 5 µg/kg, Group C = 7.5 µg/kg and Group D = 10 µg/kg). Butorphanol was administered 5 min before propofol infusion. The primary outcome was the incidence of body movement. Secondary outcomes were postoperative recovery time, length of stay in the Post-Anesthesia Care Unit (PACU), the total dose of propofol, and the incidence of intraoperative hypoxemia, propofol injection pain, cough, postoperative nausea and vomiting, drowsiness, and dizziness. RESULTS: The incidence of body movement and the dose of propofol in Group C and D were lower than those in Group A and B (P < 0.05). The incidence and intensity of propofol injection pain and the incidence of cough in Group B, C, and D were lower than those in Group A (P < 0.05). The length of stay in PACU and the incidence of postoperative drowsiness and dizziness were higher in Group D than in Group A, B, and C (P < 0.05). CONCLUSION: Intravenous pre-injection of 7.5 µg/kg butorphanol with propofol can be the optimal dosage for patients undergoing gastroscopy and colonoscopy. TRIAL REGISTRATION: Trial registration: Chinese Clinical Trial Registry, ChiCTR2000031506. Registered 3 April 2020-Retrospectively registered, http://www.medresman.org.cn .

Subgroup analysis in the heterogeneous Cox model.

In the analysis of censored survival data, to avoid a biased inference of treatment effects on the hazard function of the survival time, it is important to consider the treatment heterogeneity. Without requiring any prior knowledge about the subgroup structure, we propose a data driven subgroup analysis procedure for the heterogeneous Cox model by constructing a pairwise fusion penalized partial likelihood-based objective function. The proposed method can determine the number of subgroups, identify the group structure, and estimate the treatment effect simultaneously and automatically. A majorized alternating direction method of multipliers algorithm is then developed to deal with the numerically challenging high-dimensional problems. We also establish the oracle properties and the model selection consistency for the proposed penalized estimator. Our proposed method is evaluated by simulation studies and further illustrated by the analysis of the breast cancer data.

The effects of neostigmine on postoperative cognitive function and inflammatory factors in elderly patients - a randomized trial.

BACKGROUND: Postoperative cognitive dysfunction is a common postoperative complication in elderly patients. In elderly patients, the decline of organ function and neuromuscular junction function make them more sensitive to muscle relaxants. They are more likely to experience residual muscle relaxation after surgery, which may cause various adverse events. Neostigmine, a commonly used muscle relaxant antagonist, can reduce the expression of inflammatory factors, thereby reducing the pro-inflammatory response and neurodegeneration of the cerebral cortex and hippocampus after surgery. The study aimed at observing the effect of different doses of neostigmine on postoperative cognitive function and peripheral inflammatory factors in elderly patients. METHODS: One hundred thirty-two elderly patients who underwent a radical section of gastrointestinal cancer at First Affiliated Hospital of Dalian Medical University were divided into neostigmine and saline groups at a 2:1 ratio. Neostigmine was intravenously injected in the post-anesthesia care unit (PACU) according to the train-of-four ratio (TOFR) T4/T1. When TOFR was ≤0.5, 0.04 mg/kg neostigmine was administered, whereas when TOFR was > 0.5, 0.02 mg/kg neostigmine was injected. The main observation indexes were cognitive function, interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in peripheral blood at the different times before and after the surgery. Secondary observation indicators include the number of atropine injection, extubating time, PACU residence time, incidence of hypoxemia, hypercapnia, and postoperative nausea and vomiting in PACU, time of exhaustion, and length of hospitalization. RESULTS: The extubating and PACU times in 0.04 mg/kg and 0.02 mg/kg groups were significantly shorter than those in the control group (P < 0.001). The incidence of early postoperative cognitive decline in 0.04 mg/kg and 0.02 mg/kg groups was 10 and 15.7%, respectively, which were significantly lower than those in the control group (P = 0.013). CONCLUSION: In elderly patients, 0.02-0.04 mg/kg neostigmine could significantly reduce the incidence of early postoperative cognitive decline without affecting peripheral inflammatory factors. TRIAL REGISTRATION: Trial registration: Chinese Clinical Trial Registry, ChiCTR2000031739. Registered 8 April 2020 - Retrospectively registered, http://www.medresman.org.cn .

A universal descriptor based on pz-orbitals for the catalytic activity of multi-doped carbon bifunctional catalysts for oxygen reduction and evolution.

Dual-/multi-heteroatom-doped carbon nanomaterials have been demonstrated to be effective bi-/multi-functional catalysts for the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER), the critical reactions in fuel cells and metal-air batteries, respectively. However, trial-and-error routes are usually used to search for better catalysts from multi-doped complex material systems, and establishing design principles or intrinsic descriptors would accelerate the discovery of new efficient catalysts. Here, a descriptor based on pz-orbitals of active sites is proposed to describe the catalytic performance of dual-/tri-element-doped graphene catalysts for the ORR and the OER. In addition to multiple doping, the established descriptor is universal in nature and can also predict the contributions of defects and edges or their combinations. The prediction capacity of the descriptor is further enhanced by introducing a correction factor based on crystal orbital Hamilton population (COHP) analysis, which reveals the differences between the adsorption mechanism of edged C and graphitic C on graphene. The predictions are consistent with DFT calculations and experimental results. This work provides a powerful tool for rapidly screening multi-doped complex material systems for the desired ORR and OER bifunctional catalysts.

Identification of RE1-Silencing Transcription Factor as a Promoter of Metastasis in Pancreatic Cancer.

Pancreatic cancer is characterized by its rapid progression and early metastasis. This requires further elucidation of the key promoters for its progression and metastasis. In this study, we identified REST as the hub gene of a gene module which is closely associated with cancer stage by weighted gene correlation network analysis. Validation with the TCGA database, western blot analysis of human pancreatic cancer cell lines (AsPC-1, Capan-2, SW-1990, and PANC-1) and immunohistochemical analysis of paraffin-embedded pancreatic cancer tissue sections showed that REST was enriched in tissue samples of advanced stage and metastatic phenotype cell lines. Survival analysis with the TCGA database and our own follow-up data suggested that patients with higher expression level of REST showed worse overall survival rate. In vitro functional experiments suggested that knockdown of REST suppressed proliferation, migration, invasion and epithelial-mesenchymal transition of AsPC-1 and PANC-1 cells. In vivo experiments (a subcutaneous BALB/c nude mouse model and a superior mesenteric vein injection BALB/c nude mouse model) suggested that knockdown of REST suppressed growth and metastasis of xenograft tumor. Finally, we investigated the underlying molecular mechanism of REST and identified REST as a potential downstream target of MAPK signaling pathway. In conclusion, our results of bioinformatic analysis, in vitro and in vivo functional analysis suggested that REST may serve as a promoter of metastasis in pancreatic cancer.

Integrated whole genome microarray analysis and immunohistochemical assay identifies COL11A1, GJB2 and CTRL as predictive biomarkers for pancreatic cancer.

BACKGROUND: Pancreatic cancer is characterized by its unsatisfying early detection rate, rapid disease progression and poor prognosis. Further studies on molecular mechanism and novel predictive biomarkers for pancreatic cancer based on a large sample volume are required. METHODS: Multiple bioinformatic analysis tools were utilized for identification and characterization of differentially expressed genes (DEGs) from a merged microarray data (100 pancreatic cancer samples and 62 normal samples). Data from the GEO and TCGA database was utilized to validate the diagnostic and prognostic value of the top 5 upregulated/downregulated DEGs. Immunohistochemical assay (46 paired pancreatic and para- cancerous samples) was utilized to validate the expression and prognostic value of COL11A1, GJB2 and CTRL from the identified DEGs. RESULTS: A total number of 300 DEGs were identified from the merged microarray data of 100 pancreatic cancer samples and 62 normal samples. These DEGs were closely correlated with the biological characteristics of pancreatic cancer. The top 5 upregulated/downregulated DEGs showed good individual diagnostic/prognostic value and better combined diagnostic/prognostic value. Validation of COL11A1, GJB2 and CTRL with immunohistochemical assay showed consistent expression level with bioinformatics analysis and promising prognostic value. CONCLUSIONS: Merged microarray data with bigger sample volume could reflect the biological characteristics of pancreatic cancer more effectively and accurately. COL11A1, GJB2 and CTRL are novel predictive biomarkers for pancreatic cancer.

Dose-dependent effects of intravenous methoxamine infusion during hip-joint replacement surgery on postoperative cognitive dysfunction and blood TNF-α level in elderly patients: a randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD), common in elderly patients, is thought to be closely associated with intraoperative instability of hemodynamics and excessive excretion of tumor necrosis factor-α (TNF-α). Methoxamine is a blood-pressure increasing drug commonly used for maintaining intraoperative hemodynamics. Methoxamine potentially promotes TNF-α expression, leading to an increased risk of POCD. This study aimed to investigate the dose-dependent effect of methoxamine on the incidence of early POCD and blood TNF-α level. METHODS: This single-center prospective double-blind controlled clinical trial included a total of 300 adult patients (75-90 years old, American Society of Anesthesiologists class II-III) who underwent unilateral hip-joint replacement surgery under epidural anesthesia. Patients were randomly divided into three methoxamine groups (M1, M2, and M3), and one control group (n = 75 per group). During surgery, M1, M2, and M3 patients received intravenous infusion of methoxamine at 2, 3, or 4 µg·kg-1·min-1, respectively; the control group received saline of same volume at the same infusion rate. All patients received standard transfusion to maintain stable circulation. Hemodynamics, cardiovascular events, and serum TNF-α levels were monitored. Mini Mental State Examination was performed both before and after surgery to diagnose POCD. RESULTS: The primary outcome of this study was the incidence of POCD, which was higher in the M3 group (18.7%) than in the control group (5.3%), the M1 group (6.7%), or the M2 group (6.7%) (all P < 0.05). The secondary outcomes were the postoperative blood TNF-α level and intraoperative hemodynamic parameters. The postoperative TNF-α level was found to be higher than baseline in all groups and was highest in M3 patients (P < 0.05). The intraoperative hemodynamic parameters showed improved stability in the M1 and M2 groups compared with the control group. However, in the M3 group, abnormally increased intraoperative blood pressure, cardiac output, and systolic stroke volume were observed. CONCLUSIONS: Intravenous infusion of methoxamine at 2-3 µg·kg-1·min-1 can maintain stable hemodynamics in elderly patients during epidural anesthesia for hip-joint replacement surgery, without increasing the incidence of POCD. Increasing the dose to 4 µg·kg-1·min-1 provided no further advantages but induced adverse effects on the intraoperative hemodynamics. TRIAL REGISTRATION: Chinese Clinical Trial Register (Unique identifier: ChiCTR-INR-15007607 , retrospectively registered 18 Dec 2015).

Effects of Intraoperative Hemodynamics on Incidence of Postoperative Delirium in Elderly Patients: A Retrospective Study.

BACKGROUND: Postoperative delirium (POD) is a common complication in the elderly. This retrospective study investigated the effect of intraoperative hemodynamics on the incidence of POD in elderly patients after major surgery to explore ways to reduce the incidence of POD. MATERIAL/METHODS: Based on the incidence of POD, elderly patients (81±6 y) were assigned to a POD (n=137) or non-POD group (n=343) after elective surgery with total intravenous anesthesia. POD was diagnosed based on the guidelines of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), using the confusion assessment method. The hemodynamic parameters, such as mean arterial pressure, were monitored 10 min before anesthesia (baseline) and intraoperatively. The incidence of intraoperative hypertension, hypotension, tachycardia, and bradycardia were calculated. RESULTS: At 30 min and 60 min after the initiation of anesthesia and at the conclusion of surgery, the monitored hemodynamic parameter values of the POD group, but not those of the non-POD group, were significantly higher than at baseline. Multivariate logistic regression analysis showed that intraoperative hypertension and tachycardia were significantly associated with POD. CONCLUSIONS: Intraoperative hypertension and tachycardia were significantly associated with POD. Maintaining intraoperative stable hemodynamics may reduce the incidence of POD in elderly patients undergoing surgery.

Effects of vasodilator and esmolol-induced hemodynamic stability on early post-operative cognitive dysfunction in elderly patients: a randomized trial.

OBJECTIVE: To investigate the effect of continuous intravenous injection of nicardipine and/or nitroglycerin with or without esmolol on the occurrence of early post-operative cognitive dysfunction (POCD) in elderly patients. METHODS: Elderly patients (n=340) who underwent radiofrequency ablation for atrial fibrillation were randomized into five groups: A, nicardipine; B nicardipine+esmolol; C, (nitroglycerin) group; D nitroglycerin+esmolol; E (control) groups. The hemodynamic parameters were recorded, and Mini Mental State Examination was used to assess cognitive function. RESULTS: At 30 min and 60 minutes after anesthesia and at the conclusion of surgery, the rate pressure product value was significantly lower in Groups B (10621.1±321.7, 10544.2±321.8, and 10701.3±325.5, respectively) and D (10807.4±351.1, 10784.3±360.3, and 10771.7±345.7, respectively) than in Group E (13217.1±377.6, 13203.5±357.3, and 13119.2±379.5, respectively). The heart rate was significantly higher in Groups A (104.1±10.3, 104.9±11.1, and 103.9±11.8, respectively) and C (103.7±11.3, 105.5±10.5, and 107.7±11.7, respectively) than in Group E (89.3±12.0, 88.5±11.5, and 85.5±11.6, respectively). The incidence of POCD was significantly lower in Groups A and B than in Groups C, D, and E. Univariate regression analysis showed that regimens in Groups A, B, and E and doses of propofol and fentanyl were risk factors for POCD. Multivariate logistic regression analysis revealed significant associations between the incidence of POCD and interventions in Groups A and B. CONCLUSION: Maintenance of stable intraoperative hemodynamics using nicardipine and nitroglycerin or their combinations with esmolol, especially nicardipine with esmolol, reduced the incidence of POCD in the elderly with potential cardiovascular diseases.

Intranasal administration of butorphanol benefits old patients undergoing H-uvulopalatopharyngoplasty: a randomized trial.

BACKGROUND: To evaluate intranasal administration of butorphanol on postoperative pain and early postoperative cognitive dysfunction in old patients undergoing H-uvulopalatopharyngoplasty (H-UPPP). METHODS: A total of 260 male patients (65 to 77 years old) with obstructive sleep apnea hypopnea syndrome and scheduled for H-UPPP were divided randomly to receive intranasal butorphanol, intravenous butorphanol, intranasal fentanyl, or intravenous saline (controls). The definition of preemptive analgesia is that the tested drugs are given before anesthesia induction. Visual analog scale (VAS) and Bruggrmann comfort scale (BCS) scores were recorded at postoperative 1, 6, 12, 18, 24, 36, and 48 h. Postoperative cognitive dysfunction (POCD) was evaluated by Mini-Mental State Examination (MMSE) scores assessed one day before, and 1, 3, and 7 days postsurgery. RESULTS: Compared with control group, those given preemptive analgesia required significantly less sufentanil during surgery, had less pain at postoperative 6-12 h; those given butorphanol experienced less nausea and vomiting, less pain at postoperative 6-24 h, and less POCD. Compared with patients given fentanyl, those given butorphanol required significantly less postoperative fentanyl, had less pain at postoperative 18-24 h, less nausea and vomiting, and less POCD. Compared with patients given intravenous butorphanol, those who received butorphanol by nasal route required significantly less postoperative fentanyl, had less pain at 36 and 48 h, and less POCD. CONCLUSION: Intranasal administration of butorphanol is safe and effective, reducing postoperative usage of analgesics and the incidence of POCD in old patients undergoing H-UPPP. TRIAL REGISTRATION: ChiCTR-TRC-14004121.

Effects of continuous intravenous infusion of methoxamine on the intraoperative hemodynamics of elderly patients undergoing total hip arthroplasty.

BACKGROUND: Hemodynamic disturbances are common during continuous epidural anesthesia in elderly patients undergoing total hip arthroplasty. This study aimed to investigate the effects of methoxamine on the intraoperative hemodynamics in elderly patients undergoing total hip arthroplasty under epidural anesthesia. MATERIAL AND METHODS: This prospective study included 150 elderly patients undergoing elective total hip arthroplasty under epidural anesthesia. Patients were randomly assigned into 5 groups (n=30 per group): a control group receiving saline (Group C), a dopamine group receiving 7 µg/kg/min dopamine (Group D), and methoxamine groups receiving 1, 2, or 3 µg/kg/min methoxamine (Groups M1, M2, and M3, respectively). Hemodynamic parameters were assessed 10 min before anesthesia (T1); 10 min (T2), 20 min, (T3), 30 min (T4), and 60 min (T5) after anesthesia; and at the conclusion of surgery (T6). RESULTS: At T2-T6, the mean arterial pressure, central venous pressure, cardiac output, stroke volume, stroke volume ratio, and pulmonary vascular resistance were higher in Groups D, M2, and M3 compared to Group C (p<0.05). Compared to Group D, the heart rate and rate pressure product were significantly lower in Groups M1-M3. Infusion volume, ephedrine dose, and postoperative 24-h urine volume were significantly lower and intraoperative urine volume was significantly greater in Groups D, M2, and M3 compared with Group C. Hypertension occurred more frequently in Group M3 than in any other group. CONCLUSIONS: Continuous intravenous infusion of 2 µg/kg/min methoxamine is safe and effective in maintaining hemodynamic stability in elderly patients undergoing total hip arthroplasty.

Effect of intravenous infusion of dobutamine hydrochloride on the development of early postoperative cognitive dysfunction in elderly patients via inhibiting the release of tumor necrosis factor-α.

To investigate the effects of dobutamine hydrochloride on early postoperative cognitive dysfunction (POCD) and plasma tumor necrosis factor (TNF)-α concentration in patients undergoing hip arthroplasty, 124 patients undergoing unilateral total hip arthroplasty, aged 70-92 years old, were randomly assigned to four groups (n=31) as follows: a control group of patients receiving only saline (intravenous infusion, i.v.); and groups receiving 2, 4, or 6µgkg(-1)min(-1) (i.v.) of dobutamine hydrochloride. Cognitive functions were assessed on the day before surgery (T1), and the 1st day (T2), 3rd day (T3), and 7th day (T4) postsurgery using the Mini Mental State Examination (MMSE). The plasma TNF-α protein level was determined 10min before anesthesia (Ta), and 10min (Tb), 30min (Tc), and 60min (Td) after anesthesia by an enzyme-linked immunosorbent assay. Cognitive disorder was observed within the first 3 days after hip arthroplastic surgery, and it had recovered 7 days after the operation in the control group of patients. Administration of 2 or 4µgkg(-1)min(-1) dobutamine hydrochloride was able to reverse the early POCD. Simultaneously, an increase of plasma TNF-α levels 30min after anesthesia was observed (41.34±9.61 vs. 27.75±5.45), which was significantly suppressed by the administration of low-dose dobutamine hydrochloride (29.23±7.32 vs. 41.34±9.61) but not by high-dose dobutamine hydrochloride (45.9±12.11 vs. 41.34±9.61). Together, our data indicated that the plasma concentration of TNFα was engaged in the effect of dobutamine hydrochloride on POCD.

Polymorphic expression of UDP-glucuronosyltransferase UGTlA gene in human colorectal cancer.

BACKGROUND: Polymorphism of genes encoding drug-metabolizing enzymes is known to play an important role in increased susceptibility of colorectal cancer. UGT1A gene locus has been suggested to define tissue-specific glucuronidation activity. Reduced capacity of glucuronidation is correlated with the development of colorectal cancer. Therefore, we sought to explore polymorphism of UGTlA gene in human colorectal cancer. METHODS: Cancerous and healthy tissues were obtained from selectedpatients. Blood samples were collected and UGTlA mRNA transcriptions were analyzed. Genomic DNA was prepared and UGTlA8 exon-1 sequences were amplified, visualized and purified. The extracted DNA was subcloned and sequenced. Two-tailed Fisher's exact test, Odds ratios (ORs), confidence interval (CIs) and Logistics Regression Analysis were used for statistical analysis. RESULTS: UGTlA mRNA expression was reduced in cancerous tissues compared with healthy tissues from the same patient . The UGTlA mRNA expression of healthy tissue in study patients was lower than control . The mRNA expression of cancerous tissue was down-regulated in UGTlAl, 1A3, 1A4, lA6, 1A9 and up-regulated in UGTlA8 and UGTlAl0 UGT1A5 and UGT1A7 were not expressed in colonic tissue of either group. The allele frequency of WT UGTlA8*1 was higher (p = 0.000), frequency of UGTlA8*3 was lowered in control group (p = 0.000). The expression of homozygous UGTlA8*1 was higher in control group (p = 0.000). Higher frequency of both heterozygous UGTlA8*1/*3 and UGTlA8*2/*3 were found in study group (p = 0.000; p = 0.000). The occurrence of colorectal cancer was mainly related to the presence of polymorphic UGTlA8*3 alleles (p = 0.000). CONCLUSION: Regulation of human UGT1A genes is tissue-specific. Individual variation in polymorphic expressions of UGTlA gene locus was noted in all types of colonic tissue tested, whereas hepatic tissue expression was uniform. The high incidence of UGTlA8 polymorphism exists in colorectal cancer patients. UGTlA8*1 allele is a protective factor and UGTlA8*3 allele is a risk factor.

Expression of UDP-glucuronosyltransferase 1A, nuclear factor erythroid-E2-related factor 2 and Kelch-like ECH-associated protein 1 in colonic mucosa, adenoma and adenocarcinoma tissue.

We investigated the expression of UDP-glucuronosyltransferase 1A (UGT1A), nuclear factor erythroid-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in normal colonic mucosa, adenoma tissue and adenocarcinoma tissue, to analyze the correlation between their expression and the clinicopathological features of adenocarcinoma and their roles in colonic carcinogenesis. Using immunohistochemical analysis, we investigated the expression of UGT1A, Nrf2 and Keap1 in normal colonic mucosa (n=24), adenoma tissue (n=30) and adenocarcinoma tissue (n=77). We found that the positive rate of UGT1A was 83.3% in normal colonic mucosa, 80.0% in adenoma tissue and significantly lower, 53.2%, in adenocarcinoma tissue (normal colonic vs. adenoma tissue, P=0.071; normal colonic vs. adenocarcinoma tissue, P=0.023; adenoma vs. adenocarcinoma tissue, P=0.019). The expression levels of Nrf2 were high in adenoma and adenocarcinoma tissues, with positive rates of 70.0 and 87.0%, respectively, but were significantly lower in normal colonic tissue, with a positive rate of 41.7% (normal colonic vs. adenoma tissue, P=0.000; normal colonic vs. adenocarcinoma tissue, P=0.000; adenoma vs. adenocarcinoma tissue, P=0.000). The positive rate of Keap1 was 54.2% in normal mucosa, 70.0% in adenoma tissue and 61.0% in adenocarcinoma tissue (normal colonic mucosa vs. adenoma tissue, P=0.200; normal colonic vs. adenocarcinoma tissue, P=0.040; adenoma vs. adenocarcinoma, P=0.002). In addition, there was no correlation between the expression of Nrf2/Keap1 in adenoma and adenocarcinoma tissues (r=0.067, P=0.723; r=0.042, P=0.715, respectively). The results suggest that decreased expression of UGT1A and the dysregulation of the Nrf2/Keap1 system may be related to colonic carcinogenesis.

Effects of phytochemicals sulforaphane on uridine diphosphate-glucuronosyltransferase expression as well as cell-cycle arrest and apoptosis in human colon cancer Caco-2 cells.

Our study investigated the effects of the chemopreventive agent sulforaphane (SFN) on human colon cancer Caco-2 cells and potential underlying mechanisms of the effects. When treated with SFN at hypotoxic levels, UDP-glucuronosyltransferase 1A (UGT1A) was induced in a dose-dependent manner. SFN at 25 µM showed the highest UGT1A-induction activity, inducing UGT1A1, UGT1A8, and UGT1A10 mRNA expression, and increasing UGT-mediated N-hydroxy-PhIP glucuronidation. SFN- induced UGT1A expression may have resulted from Nrf2 nuclear translocation or activation. At higher concentrations, e.g. 75 µM, SFN caused G1/G2 cell cycle arrest and induced apoptosis possibly through reducing anti-apoptotic bcl-2 expression and increasing apoptosis-inducing bax expression in Caco-2 cells. Taken together, these results demonstrated the chemopreventive effects of SFN on human colon cancer Caco-2 cells may have been partly attributed to Nrf2-mediated UGT1A induction and apoptosis induction, and our studies provided theoretic and experimental basis for clinical application of SFN to human colon cancer prevention.