Association between the neutrophil-to-lymphocyte ratio and cognitive impairment: a meta-analysis of observational studies.

Background: Systemic inflammation is one of the underlying mechanisms of cognitive impairment. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a systemic inflammation indicator. This meta-analysis aimed to evaluate the association between high NLR and cognitive impairment (CI) risk. Method: A comprehensive systematic search was conducted to identify eligible studies published until May 30, 2023. The reference group comprised patients with the lowest NLR level, whereas the exposure group comprised those with the highest NLR level. The main outcome was to examine the relationship between NLR and CI risk. The secondary outcome included the association between patient characteristics or comorbidities and CI risk. Results: This meta-analysis included 11 studies published between 2018 and 2023, involving 10,357 patients. Patients with CI had a higher NLR than those without (mean difference=0.35, 95% confidence interval [CI]: 0.26-0.44, p < 00001, I2 = 86%). Consistently, pooled results revealed an association between high NLR and CI risk (odds ratio [OR]=2.53, 95% CI:1.67-3.82, p<0.0001, I2 = 84%). Furthermore, aging (mean difference =4.31 years, 95% CI:2.83-5.8, p < 0.00001, I2 = 92%), diabetes (OR=1.59, 95% CI:1.35-1.88, p < 0.00001, I2 = 66%), and hypertension (OR=1.36, 95% CI:1.19-1.57, p < 0.00001, I2 = 0%) were significant risk factors for CI. However, no significant associations were observed between CI and male gender (OR = 0.84, 95% CI:0.64-1.11, p = 0.22, I2 = 81%), body mass index (mean = -0.32 kg/m2, 95% CI: -0.82, 0.18, p = 0.2, I2 = 82%), alcohol consumption (OR = 1.11, 95% CI:0.95-1.3, p = 1.35, I2 = 0%), and smoking (OR = 0.99, 95% CI:0.87-1.13, p = 0.86, I2 = 0%). Meta-regression found that diabetes and hypertension, but not age, significantly moderated the association between NLR and CI. Conclusion: This meta-analysis showed a significant association between high NLR and increased CI risk. Moreover, meta-regression identified diabetes and hypertension, but not age, as significant moderating factors in the relationship between NLR and CI. To validate and strengthen these findings, further large-scale studies are required. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023430384, identifier CRD42023430384.

Elevated Surgical Pleth Index at the End of Surgery Is Associated with Postoperative Moderate-to-Severe Pain: A Systematic Review and Meta-Analysis.

Despite acceptance of the surgical pleth index (SPI) for monitoring the intraoperative balance between noxious stimulation and anti-nociception under general anesthesia, its efficacy for predicting postoperative moderate-to-severe pain remains unclear. We searched electronic databases (e.g., Google Scholar, MEDLINE, Cochrane Library, and EMBASE) to identify articles focusing on associations of SPI at the end of surgery with immediate moderate-to-severe pain in the postanesthesia care unit from inception to 7 July 2022. A total of six observational studies involving 756 adults published between 2016 and 2020 were eligible for quantitative syntheses. Pooled results revealed higher values of SPI in patients with moderate-to-severe pain than those without (mean difference: 7.82, 95% CI: 3.69 to 11.95, p = 0.002, I2 = 46%). In addition, an elevated SPI at the end of surgery was able to predict moderate-to-severe pain with a sensitivity of 0.71 (95% confidence interval (CI): 0.65-0.77; I2 = 29.01%) and a specificity of 0.58 (95% CI: 0.39-0.74; I2 = 79.31%). The overall accuracy based on the summary receiver operating characteristic (sROC) curve was 0.72. In conclusion, this meta-analysis highlighted the feasibility of the surgical pleth index to predict postoperative moderate-to-severe pain immediately after surgery. Our results from a limited number of studies warrant further investigations for verification.

Comparison of video-stylet and conventional laryngoscope for endotracheal intubation in adults with cervical spine immobilization: A PRISMA-compliant meta-analysis.

BACKGROUND: Although minimization of cervical spine motion by using a neck collar or manual in-line stabilization is recommended for urgent tracheal intubation (TI) in patients with known or suspected cervical spine injury (CSI), it may worsen glottic visualization. The overall performance of video-stylets during TI in patients with neck immobilization remains unclear. The current meta-analysis aimed at comparing the intubation outcomes of different video-stylets with those of conventional laryngoscopes in patients with cervical immobilization. METHOD: The databases of Embase, Medline, and the Cochrane Central Register of Controlled Trials were searched from inception to June 2021 to identify trials comparing intubation outcomes between video-stylets and conventional laryngoscopes. The primary outcome was first-pass success rate, while secondary outcomes included overall success rate, time to intubation, the risk of intubation-associated sore throat, or tissue damage. RESULTS: Five randomized controlled trials published between 2007 and 2013 involving 487 participants, all in an operating room setting, were analyzed. The video-stylets investigated included Bonfils intubation fiberscope, Levitan FPS Scope, and Shikani optical stylet. There was no difference in first-pass success rate (risk ratio [RR] =1.08, 95% confidence interval [CI]: 0.89-1.31, P = .46], overall success rate (RR = 1.06, 95% CI: 0.93-1.22, P = .4), intubation time [mean difference = 4.53 seconds, 95% CI: -8.45 to 17.51, P = .49), and risk of tissue damage (RR = 0.46, 95% CI: 0.16-1.3, P = .14) between the 2 groups. The risk of sore throat was lower with video-stylets compared to that with laryngoscopes (RR = 0.45, 95% CI: 0.23-0.9, P = .02). CONCLUSION: Our results did not support the use of video-stylets as the first choice for patients with neck immobilization. Further studies are required to verify the efficacy of video-stylets in the nonoperating room setting.

Potential Actions of Baicalein for Preventing Vascular Calcification of Smooth Muscle Cells In Vitro and In Vivo.

Vascular calcification (VC) is associated with cardiovascular disease. Baicalein, a natural flavonoid extract of Scutellaria baicalensis rhizome has several biological properties which may inhibit VC. We investigated whether baicalein suppresses Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP-2) and upregulates smooth muscle 22-alpha (SM22-α) and alpha-smooth muscle actin (α-SMA). In an in vitro experiment, primary rat aortic vascular smooth muscle cells (VSMCs) were pretreated with 0.1, 1, and 5 µM baicalein, followed by ß-glycerophosphate (ß-GP) to induce calcification. In an in vivo experiment, VC was generated by vitamin D3 plus nicotine (VDN) administration to male Sprague Dawley (SD) rats randomly assigned into a control group, a VC group, a VC group pretreated with baicalein, and a baicalein alone group. Each group comprised 10 rats. Left ventricular (LV) morphology, function and performance were assessed by echocardiography. Calcium content was measured by Alizarin red S staining and alkaline phosphatase (ALP) activity assays. Apoptotic VSMCs were detected by flow cytometry. Protein levels and superoxide changes were evaluated using Western blotting and immunofluorescence assays respectively. Plasma malondialdehyde (MDA) was assayed. Baicalein pretreatment significantly reduced calcium content in calcified VSMCs (p < 0.001) as well as in VC rat aortic smooth muscle (p < 0.001). Additionally, ALP activity was decreased in calcified VSMCs and VC rat aortic smooth muscle (p < 0.001). Apoptosis was significantly attenuated by 1 µM baicalein pretreatment in calcified VSMCs. Runx2 and BMP-2 expressions were downregulated by the baicalein in calcified VSMCs. Baicalein pretreatment increased typical VSMCs markers SM22-α and α-SMA in calcified VSMCs. Baicalein pretreatment was associated with adverse changes in LV morphometry. Markers of oxidative stress declined, and endogenous antioxidants increased in VC rats pretreated with baicalein. Baicalein mitigates VC through the inhibition of Runx2/BMP-2 signaling pathways, enhancement of vascular contractile phenotype and oxidative stress reduction. However, our study is of basic experimental design; more advanced investigations to identify other molecular regulators of VC and their mechanisms of action is required.

Honokiol Induces Autophagic Apoptosis in Neuroblastoma Cells through a P53-Dependent Pathway.

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood-brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24 h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.

Exogenous Heat Shock Cognate Protein 70 Suppresses LPS-Induced Inflammation by Down-Regulating NF-κB through MAPK and MMP-2/-9 Pathways in Macrophages.

Heat shock cognate protein 70 (HSC70), a molecular chaperone, is constitutively expressed by mammalian cells to regulate various cellular functions. It is associated with many diseases and is a potential therapeutic target. Although HSC70 also possesses an anti-inflammatory action, the mechanism of this action remains unclear. This current study aimed to assess the anti-inflammatory effects of HSC70 in murine macrophages RAW 264.7 exposed to lipopolysaccharides (LPS) and to explain its pathways. Mouse macrophages (RAW 264.7) in 0.1 µg/mL LPS incubation were pretreated with recombinant HSC70 (rHSC70) and different assays (Griess assay, enzyme-linked immune assay/ELISA, electrophoretic mobility shift assay/EMSA, gelatin zymography, and Western blotting) were performed to determine whether rHSC70 blocks pro-inflammatory mediators. The findings showed that rHSC70 attenuated the nitric oxide (NO) generation, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expressions in LPS-stimulated RAW264.7 cells. In addition, rHSC70 preconditioning suppressed the activities and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9. Finally, rHSC70 diminished the nuclear translocation of nuclear factor-κB (NF-κB) and reduced the phosphorylation of extracellular-signal regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPK), and phosphatidylinositol-3-kinase (PI3K/Akt). We demonstrate that rHSC70 preconditioning exerts its anti-inflammatory effects through NO production constriction; TNF-α, and IL-6 suppression following down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and MMP-2/MMP-9. Accordingly, it ameliorated the signal transduction of MAPKs, Akt/IκBα, and NF-κB pathways. Therefore, extracellular HSC70 plays a critical role in the innate immunity modulation and mechanisms of endogenous protective stimulation.

Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production.

Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions.

Unanticipated difficult nasotracheal extubation following oral surgery.

Difficult tracheal extubation is a rare but potentially dangerous problem that can be life threatening especially when it is unexpected and there is a lack of preparation. Most of these cases are associated with orofacial surgery. We herein present two patients with oral cavity cancer who experienced unexpected postoperative difficult nasotracheal extubation by a Kirschner pin penetrating the endotracheal tube and fixing the tube at the maxillary bone following tumor resection. The pins were found by fiberoptic bronchoscopy. Both patients were returned to the operating theater immediately for removal of the penetrating pins as well as the endotracheal tubes. The common causes of difficult tracheal extubation and strategies of managing these situations are discussed in the article.

The Translational Proteome Modulated by 20(S)-Protopanaxadiol in Endothelial Cells.

BACKGROUND: 20(S)-protopanaxadiol (PPD), a natural compound of dammarane ginsenoside purified from the ginseng plant, exhibits strong anticancer properties. It has also been reported to have strong antioxidant activity and plays a role in cardiovascular protection. However, the downstream signaling mechanism PPD employs is still unclear and requires further elucidation. METHODS: Endothelial cells (ECs) EAhy 926 were used to investigate the growth promoting effect of PPD. The protein lysates extracted from both mock- and PPD-treated cells were separated by two-dimensional gel electrophoresis (2-DE) to monitor protein changes. After image analysis, proteins with significant change in the expression level were further identified by mass spectrometry. Western blot was applied to further confirm the protein variations in the 2-DE assay. RESULTS: In the current study, we found that treatment with PPD (10 µg/ml) significantly increased ECs healing. The translational proteome was established according to 16 up-regulated and 8 down-regulated proteins identified in 2-DE. These proteins were reported to function as energy homeostasis and in the prevention of oxidative stress. The elevated expressions of heme oxygenase 1 (HO-1) and glutathione synthetase (GSS) were further confirmed in the western blot analysis. CONCLUSIONS: According to the information obtained from translational proteome, we delineated that PPD mediated vascular homeostasis through the up-regulation of anti-oxidative proteins. Additional functional investigations are necessary regarding the HO-1 and GSS proteins. KEY WORDS: Dammarane sapogenins; Endothelial cell; Glutathione synthetase; Heme oxygenase 1; Proteome; 20(S)-protopanaxadiol.

Anesthetic propofol causes glycogen synthase kinase-3ß-regulated lysosomal/mitochondrial apoptosis in macrophages.

BACKGROUND: Overdose propofol treatment with a prolong time causes injury to multiple cell types; however, its molecular mechanisms remain unclear. Activation of glycogen synthase kinase (GSK)-3ß is proapoptotic under death stimuli. The authors therefore hypothesize that propofol overdose induces macrophage apoptosis through GSK-3ß. METHODS: Phagocytic analysis by uptake of Staphylococcus aureus showed the effects of propofol overdose on murine macrophages RAW264.7 and BV2 and primary human neutrophils in vitro. The authors further investigated cell apoptosis in vitro and in vivo, lysosomal membrane permeabilization, and the loss of mitochondrial transmembrane potential (MTP) by propidium iodide, annexin V, acridine orange, and rhodamine 123 staining, respectively. Protein analysis identified activation of apoptotic signals, and pharmacologic inhibition and genetic knockdown using lentiviral-based short hairpin RNA were further used to clarify their roles. RESULTS: A high dose of propofol caused phagocytic inhibition and apoptosis in vitro for 24 h (25 µg/ml, in triplicate) and in vivo for 6 h (10 mg/kg/h, n = 5 for each group). Propofol induced lysosomal membrane permeabilization and MTP loss while stabilizing MTP and inhibiting caspase protected cells from mitochondrial apoptosis. Lysosomal cathepsin B was required for propofol-induced lysosomal membrane permeabilization, MTP loss, and apoptosis. Propofol decreased antiapoptotic Bcl-2 family proteins and then caused proapoptotic Bcl-2-associated X protein (Bax) activation. Propofol-activated GSK-3ß and inhibiting GSK-3ß prevented Mcl-1 destabilization, MTP loss, and lysosomal/mitochondrial apoptosis. Forced expression of Mcl-1 prevented the apoptotic effects of propofol. Decreased Akt was important for GSK-3ß activation caused by propofol. CONCLUSIONS: These results suggest an essential role of GSK-3ß in propofol-induced lysosomal/mitochondrial apoptosis.

Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKß/NF-κB signaling.

BACKGROUND: Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKß (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. CONCLUSIONS/SIGNIFICANCE: These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKß/NF-κB signaling pathways.

Fatal venous air embolism during emergence from anesthesia.

We describe a case of the sudden onset of cardiovascular collapse during emergence from anesthesia resulting from a massive venous air embolism, which was detected by transesophageal echocardiography. We present this case to remind anesthesiologists to be aware of the risk of a sudden return of air trapped in the venous system during emergence from anesthesia. The air is freed because the sympathetic tone is increased, muscle-pumping power is regained, ventilation shifts from positive-pressure to negative-pressure spontaneous ventilation, and the patient is repositioned after surgery.