Anesthesia via peripheral nerve blocks during total knee replacement has no effect on postoperative inflammation in elderly patients.

BACKGROUND: We have previously shown that, compared with general anesthesia (GA), the procedure of peripheral nerve blocks (PNB) facilitates faster recovery of elderly patients from total knee replacement (TKR). Here, we investigated whether the faster recovery is associated with decreased perioperative stress and inflammation and decreased incidences of postoperative complications. METHODS: After randomization, 165 patients aged ≥65 years underwent TKR under GA or PNB. The primary outcomes were the perioperative inflammation and stress levels, based on the serum C-reactive protein and interleukin-6 levels, erythrocyte sedimentation rate, white-blood cell and neutrophil counts, and blood-sugar level. The secondary outcomes were the postoperative complications, including cardiovascular, respiratory, and hepatic or renal complications, insomnia, delirium, electrolyte disturbances, and nausea and vomiting. RESULTS: The two groups were not significantly demographically different (p > .05). Of the cytokines related to stress and inflammation, the differences of time points were statistically significant between the two groups (p < .01), but two-way ANOVA revealed no interaction between the time points and groups. Incidences of postoperative complications were far lower in PNB group than in GA group (p = .006). Incidences of postoperative respiratory complications (p = .005) and postoperative nausea and vomiting (p = .040) were significantly lower in PNB group than in GA group. There were no significant differences in other complications between the two groups (p > .05). CONCLUSIONS: PNB does not alleviate the stress and inflammation in elderly patients post TKR but significantly reduces the incidences of postoperative complications, especially respiratory complications, and nausea and vomiting. (ClinicalTrials.gov Identifier: NCT01871012).

Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia.

Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.

Emergency tracheal intubation peri-operative risk factors and prognostic impact after esophagectomy.

BACKGROUND: Emergent endotracheal intubation (ETI) is a serious complication after Oesophagectomy. It is still unclear that perioperative risk factors and prognosis of these patients with ETI. METHODS: Between January 2015 and December 2018, 21 patients who received ETI after esophagectomy were enrolled (ETI group) at the department of thoracic surgery, Fujian Union hospital, China. Each study subject matched one patient who underwent the same surgery in the current era were included (control group). Patient characteristics and perioperative factors were collected. RESULTS: Patients with ETI were older than those without ETI (p = 0.022). The patients with history of smoking in ETI group were significantly more than those in control group (p = 0.013). The stay-time of postanesthesia care unit (PACU) in ETI group was significantly longer than that in control group (p = 0.001). The incidence of anastomotic leak or electrolyte disorder in ETI group was also higher than that in control group (p = 0.014; p = 0.002). Logistic regression analysis indicated history of smoke (HR 6.43, 95%CI 1.39-29.76, p = 0.017) and longer stay time of PACU (HR 1.04, 95%CI 1.01-1.83, p = 0.020) both were independently associated with higher risks of ETI. The 3-year overall survival (OS) rates were 47.6% in patients with ETI and 85.7% in patients without ETI (HR 4.72, 95%CI 1.31-17.00, p = 0.018). COX regression analysis indicated ETI was an independent risk factor affecting the OS. CONCLUSION: The study indicated that history of smoking and longer stay-time in PACU both were independently associated with higher risks of ETI; and ETI was an independent risk factor affecting the OS of patients after esophagectomy. TRIAL REGISTRATION: This trial was retrospectively registered with the registration number of ChiCTR2000038549.

Mdivi-1 improves postoperative neurocognitive disorders in aged rats undergoing splenectomy by inhibiting dynamin-related protein-1.

Background: The regulatory role of mitochondria in the inflammatory response of the nervous system postoperatively remains unclear. This study explored the relationship between mitochondria and postoperative neurocognitive dysfunction (PNCD) by regulating mitochondrial function in aged rats undergoing splenectomy. Methods: A total of 120 aged rats were randomly divided into five groups (n=24) as follows: Control group (not subjected to any form of treatment), Sham group (subjected only to sham-splenectomized operation after anesthesia), Splenectomy group (only underwent splenectomy after anesthesia), Synonyms Mitochondrial division inhibitor 1 (Mdivi-1) group [treated with Mdivi-1, a dynamin-relatedprotein 1 (Drp1) inhibitor], and Dimethyl Sulfoxide (DMSO) group (treated with DMSO, a solvent). Inflammatory markers, namely interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), were measured in the plasma and brains of the rats. Cognitive function was assessed using the Morris water maze test. Results: During the perioperative period, the physiological parameters did not differ among the five groups (P>0.05). The results of the Morris water maze experiments showed that the memory of the rats was significantly impaired after splenectomy, which was alleviated by Mdivi-1 administration (P=0.04). Postoperatively, the proinflammatory cytokine levels in the serum and hippocampus tissue were upregulated, while Mdivi-1 administration reduced this increase. The electron microscopy and hematoxylin-eosin (HE) staining results indicated that the structure of neurons and mitochondria was minimally impaired in the Mdivi-1 group. Conclusions: Aged rats that underwent splenectomy exhibited significant postoperative cognitive impairments. The selective inhibitor of Drp1, Mdivi-1, exerted protective effects against PNCD by ameliorating mitochondrial dysfunction and reducing the inflammatory response.

[Effect of Nrf2/HO-1 signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis in mice].

The present study aimed to explore the effect of nuclear factor erythroid 2 related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis(UC). After the UC model was induced by 3% dextran sodium sulfate(DSS), experimental animals were randomly divided into control group, model group, salazosulfapyridine(SASP) group, and low-and high-dose Sishen Pills groups. Drug intervention(ig) was performed for seven consecutive days during modeling. On the 7 th day, the mice were euthanized. The body weight and colon length were recorded, and the histopathological changes of the colon were observed by HE staining. Serum interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and reactive oxygen species(ROS) were detected by ELISA. The protein and mRNA expression of Nrf2, HO-1, and NADPH quinine oxidoreductase-1(NQO-1) was determined by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Compared with the normal group, the model group exhibited reduced body weight, colon length, and T-AOC, increased IL-6, TNF-α, MDA, and ROS, and diminished protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. Compared with the model group, the SASP group and high-dose Sishen Pills group showed elevated body weight, colon length, and T-AOC, lowered IL-6, TNF-α, MDA, and ROS levels, and increased protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. As assessed by HE staining, Sishen Pills could improve the pathological changes of the colon. The findings suggested that Sishen Pills could protect the colon against UC induced by 3% DSS. The specific mechanism of action may be related to the anti-inflammatory and anti-oxidative stress effects by the activation of the Nrf2/HO-1 signaling pathway.

A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer.

Many cancers have developed resistance to 5-FU, due to removal by the enzyme uracil-DNA glycosylase (UDG), a type of base excision repair enzyme (BER) that can excise uracil and 5-fluorouracil (5-FU) from DNA. However, the development of UDG inhibitor screening methods, especially for the rapid and efficient screening of natural product/natural product-like compounds, is still limited so far. We developed herein a robust time-resolved photoluminescence method for screening UDG inhibitors, which could significantly improve sensitivity over the screening method based on the conventional steady-state spectroscopy, reducing the substantial fluorescence background interference. As a proof-of-concept, two potential UDG inhibitors were identified from a database of natural products and approved drugs. Co-treatment of these two compounds with 5-FU showed synergistic cytotoxicity, providing the basis for treating drug-resistant cancers. Overall, this method provides an avenue for the rapid screening of small molecule regulators of other BER enzyme activities that can avoid false negatives arising from the background fluorescence.

Retrospective comparison of the effects of epidural anesthesia versus peripheral nerve block on postoperative outcomes in elderly Chinese patients with femoral neck fractures.

BACKGROUND: Geriatric patients with femoral neck fracture (FNF) have unacceptably high rates of postoperative complications and mortality. The purpose of this study was to compare the effects of epidural anesthesia versus peripheral nerve block (PNB) on postoperative outcomes in elderly Chinese patients with FNF. METHODS: This retrospective study explored mortality and postoperative complications in geriatric patients with FNF who underwent epidural anesthesia or PNB at the Chinese People's Liberation Army General Hospital from January 2008 to December 2012. The electronic database at the Chinese People's Liberation Army General Hospital includes discharge records for all patients treated in the hospital. Information on patient demographics, preoperative comorbidity, postoperative complications, type of anesthesia used, and in-hospital, 30-day, and 1-year mortality after surgery was obtained from this database. RESULTS: Two hundred and fifty-eight patients were identified for analysis. The mean patient age was 79.7 years, and 71.7% of the patients were women. In-hospital, 30-day, and 1-year postoperative mortality was 4.3%, 12.4%, and 22.9%, respectively, and no differences in mortality or cardiovascular complications were found between patients who received epidural anesthesia and those who received PNB. More patients with dementia or delirium were given PNB. No statistically significant differences were found between groups for other comorbidities or intraoperative parameters. The most common complications were acute cardiovascular events (23.6%), electrolyte disturbances (20.9%), and hypoxemia (18.2%). Patients who received PNB had more postoperative delirium (P=0.027). Postoperative acute respiratory events were more common (P=0.048) and postoperative stroke was less common (P=0.018) in the PNB group. There were fewer admissions to intensive care (P=0.024) in the epidural anesthesia group. Key factors with a negative influence on mortality were acute cardiovascular events, dementia, male sex, age, American Society of Anesthesiologists score, acute respiratory events, intensive care admission, and comorbidities. CONCLUSION: PNB was not associated with lower mortality or lower cardiovascular complication rates when compared with epidural anesthesia in elderly patients with FNF.

Flow injection chemiluminescence determination of 2-methoxyestradiol based on inhibition of luminol-potassium ferricyanide reaction.

A novel flow-injection chemiluminescence (FI-CL) method is described for the determination of 2-methoxyestradiol (2-ME). The method is based on the inhibitory effect of 2-ME on the CL reaction of luminol and potassium ferricyanide in alkaline solution. Under optimal conditions, net CL intensity was proportional to 2-ME concentration in synthetic and mouse plasma samples. Corresponding linear regression equations were 8.0 x 10(-9) -1.0 x 10(-7) g/mL for synthetic samples and 2.0 x 10(-9) -1.0 x 10(-7) g/mL for plasma samples. Detection limit for synthetic samples and limits for quantification of plasma samples were 8.4 x 10(-10) g/mL (3σ) for synthetic samples and 4.0 x 10(-9) g/mL for mouse samples. A complete analysis was performed for 60 s, including washing and sampling, resulting in a throughput of ≈ 60/h. The proposed method was applied for the determination of 2-ME in synthetic and mouse plasma samples. Percentage recoveries were 101.0-102.8% and 98.0-105.0%, respectively. A possible mechanism responsible for CL reaction is proposed.

Flurbiprofen axetil promotes neuroprotection by activation of cerebral peroxisome proliferator-activated receptor gamma after focal cerebral ischemia in rats.

BACKGROUND: Our previous papers indicate that flurbiprofen axetil (FA), a cyclooxygenase inhibitor, is a promising therapeutic strategy for cerebral ischemia in rats. This study aimed to investigate whether FA could promote a neuroprotective effect by activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) after focal cerebral ischemia in rats. METHODS: Totally 48 male Sprague-Dawley (SD) rats were randomly assigned into six groups (n = 8 in each group): animals in group ischemia/reperfusion (I/R) only received 120-minute transient middle cerebral artery occlusion (tMCAO); animals in group I/R + FA were administered FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R + FA + GW9662 were administered GW9662 (a PPAR-γ inhibitor, 1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset and FA (10 mg/kg) by caudal vein just after 120-minute tMCAO; animals in group I/R + GW9662 were administered GW9662 (1 mg/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in group I/R + DMSO were administered 3% DMSO (vehicle of GW9662, 1 ml/kg) intraperitoneally 30 minutes before cerebral ischemia onset; animals in sham group experienced the identical surgery apart from the insertion of the nylon filament. The neurologic deficit score (NDS) were performed at 72 hours after reperfusion, and then mean brain infarct volume percentage (MBIVP) was determined with 2,3,5-triphenyltetrazolium chloride (TTC) 10 g/L staining. RESULTS: NDS was significantly increased in group I/R + FA (12.0 (10.0 - 15.0)), group I/R + FA + GW9662 (10.0 (8.0 - 12.0)), and in group I/R + FA + DMSO (12.0 (9.0 - 14.0)) at 72 hours after reperfusion compared with those in group I/R (7.5 (6.0 - 10.0)). NDS was conspicuously different between group I/R + FA (12.0 (10.0 - 15.0)) and group I/R + FA + GW9662 (10.0 (8.0 - 12.0)). MBIVP in group I/R ((45.82 - 8.83)%) was significantly greater than that in group I/R + FA ((23.52 - 9.90)%), group I/R + FA + GW9662 ((33.17 - 7.15)%); MBIVP in group I/R + FA ((23.52 - 9.90)%) was significantly smaller than that in group I/R + FA + GW9662 ((33.17 - 7.15)%). CONCLUSIONS: FA confers the neuroprotective effect on tMCAO in rats and the selective PPAR-γ antagonist GW9662 attenuates the effect of FA. FA could promote a neuroprotective effect by, or in part, activation of PPAR-γ after focal cerebral ischemia in rats.

Effects of 2-methoxyestradiol on proliferation, apoptosis and gene expression of cyclin B1 and c-Myc in esophageal carcinoma EC9706 cells.

2-Methoxyestradiol (2-ME) is an endogenous metabolite of 17ß-estradiol. In this study, we determined the antitumour activities of 2-ME on the well-differentiated EC9706 esophageal carcinoma cells in vitro. 2-ME had a strong antiproliferative effect on EC9706 cells and caused an increase in the population of apoptotic cells, detected by flow cytometry. A significant number of cells were blocked in the G(2)/M phase of the cell cycle. 2-ME-treated cells demonstrated an increase in cyclin B1 and c-Myc protein levels, as well as an increase in the percentage of G(2)/M phase. Their up-regulation may be involved in 2-ME-induced apoptosis and G(2)/M cell cycle arrest of the EC9706 cells, and it precedes the onset of apoptosis.