Gut microbiota-derived metabolite trimethylamine N-oxide aggravates cognitive dysfunction induced by femoral fracture operation in mice.

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N-oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO-induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ-free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO-related POCD and improving the quality of life for elderly patients.

NMT2 alleviates depression-like behavior in a rat model of chronic unpredictable stress: An integrated proteomic and phosphoproteomic analysis.

Proteomics has been widely used to investigate multiple diseases. Combining the analyses of proteomics with phosphoproteomics can be used to further explain the pathological mechanisms of depression. In this study, depression-like behavior was induced in a rat model of chronic unpredictable mild stress (CUMS). We subsequently conducted the sucrose preference test, open field experiment, and forced swimming test to assess depressive-like behavior. Proteomic and phosphoproteomic sequencing of the hippocampal tissues from depressive-like behavior and normal rats were analyzed to identify differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs). Differentially expressed phosphorylated proteins (DEPPs) were obtained by intersecting the DEPs and DPPs, and functional enrichment analysis, as well as ingenuity pathway analysis (IPA), were subsequently performed. The study also investigated correlations among the DEPPs and used qRT-PCR to quantify the expression levels of key genes. Five DEPPs were identified, Gys1, Nmt2, Lrp1, Bin1, and Atp1a1, which were found to activate the synaptogenesis signaling pathway, induce mitochondrial dysfunction, and activate the phosphoinositide biosynthesis and degradation pathways. The qRT-PCR results confirmed the proteomic findings for Gys1, Nmt2, Lrp1, and Atp1a1. Importantly, inhibiting Nmt2 was found to alleviate depression-like behavior and alleviate neuronal apoptosis in the hippocampus of CUMS rats. In conclusion, we identified five DEPPs associated with the synaptogenesis signaling pathway, mitochondrial dysfunction, and phosphoinositide biosynthesis and degradation in depression. Furthermore, NMT2 may be a potential target for the treatment or diagnosis of depression. Our findings provide novel insights into the molecular mechanisms of depression.

Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats.

PURPOSE: Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. METHODS: In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. RESULTS: Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. CONCLUSION: These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

Bibliometric Analysis of Anesthetic Drugs' Effects on Immune Function- Current Knowledge, Hotspots and Future Perspectives.

Objective: The objective of this study is to conduct a bibliometric analysis of the present status, areas of focus, and upcoming developments in the research of anesthetic drugs and their impact on immune function, along with other related research domains. Methods: From January 1, 2008 to June 9, 2023, A thorough exploration of anesthetic drug-related literature pertaining to immune function was carried out through the utilization of the Web of Science. The bibliometric analysis was predominantly executed by means of CiteSpace, GraphPad Prism 8.0, and the acquisition of data regarding the country, institution, author, journal, and keywords associated with each publication. Results: This study analyzed a comprehensive total of 318 publications, consisting of 228 articles and 90 reviews, to determine the publication output of anesthetic drugs on immune function. Notably, China exhibited the highest publication output with (109, 34.28%) articles. Among the institutions analyzed, Harvard University was found to be the most productive with (12, 3.77%) publications. The study findings indicate that Buggy, Donal J (5, 1.57%) and Yuki, Koichi (5, 1.57%) had the highest publication records. Anesthesiology was the most frequently cited journal with a total of (206) citations. The results also revealed that "surgery" was the most frequently used keyword, appearing (48 times), followed by "general anesthesia" (41 times) and "breast cancer" (37 times). The study has identified several current areas of interest, with a particular emphasis on "metastasis", "inflammation", "recurrence", "anesthesia technique", and "induction". It is anticipated that forthcoming research endeavors will concentrate on exploring the impacts of isoflurane, sevoflurane, and ketamine on immune function. Conclusion: This study provided a thorough analysis of the research trends and developments in investigating the impact of anesthetic drugs on immune function, incorporating pertinent research and collaborative entities such as authors, institutions, and countries.

The Emerging Roles of Ferroptosis in Pathophysiology and Treatment of Acute Lung Injury.

Ferroptosis, a programmed cell death discovered in recent years, is an iron-dependent lipid peroxidation accumulation. Unlike other modes of cell death (autophagy, necroptosis, pyroptosis, cuproptosis, etc.), ferroptosis has unique morphological characteristics and plays an important role in a variety of diseases. In recent years, there has been great progress in the study of ferroptosis. Studies have found that ferroptosis is associated with acute lung injury (ALI), a condition with a high mortality rate and limited treatment options. This paper summarizes the mechanism of ferroptosis from the perspectives of iron metabolism, lipid metabolism, amino acid metabolism, and glutathione metabolism. It also discusses the research progress of ferroptosis in ALI in order to find new directions for the prevention and treatment of this condition.

GABAB Receptor Activation Attenuates Neuronal Pyroptosis in Post-cardiac Arrest Brain Injury.

Brain injury is a major cause of death and disability after cardiac arrest (CA). Previous studies have shown that activating GABAB receptors significantly improves neurological function after CA, but the mechanism of this neuronal protection of damaged neurons remains unclear. Thus, the present study aimed to investigate whether GABAB receptor activation protects against neuronal injury and to reveal the underlying protective mechanisms. In this study, rats underwent 10 min of asphyxia to induce CA, and SH-SY5Y cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish in vivo and in vitro models of hypoxic neuronal injury. Differential gene expression between CA rats and sham-operated rats was identified using RNA-seq. TUNEL and Nissl staining were used to evaluate cortical neuron damage, while Western blotting, qRT-PCR, and immunofluorescence assays were conducted to measure pyroptosis-related indicators. Furthermore, cellular models with high expression of caspase-11 were established to reveal the novel molecular mechanisms by which GABAB receptor activation exerts neuroprotective effects. Intriguingly, our results showed that caspase-11 and GSDMD were highly expressed in rats experiencing cardiac arrest. Specifically, GSDMD was expressed in neurons in the M1 area of the cerebral cortex. Moreover, activation of the GABAB receptor exerted a protective effect on neurons both in vivo and in vitro. Baclofen attenuated caspase-11 activation and neuronal pyroptosis after CA, and the anti-neuronal pyroptosis effect of baclofen was abolished by overexpression of caspase-11 in neuronal cells. In conclusion, GABAB receptor activation may play a neuroprotective role by alleviating neuronal pyroptosis through a mechanism involving caspase-11.

PirB negatively regulates the inflammatory activation of astrocytes in a mouse model of sleep deprivation.

Reactive astrocytes play a potential regulatory role in sleep deprivation (SD). Paired immunoglobulin-like receptor B (PirB) is expressed in reactive astrocytes, suggesting that PirB may participate in regulating the inflammatory response of astrocytes. We used lentiviral and adeno-associated viral approaches to interfere with the expression of PirB in vivo and in vitro. C57BL/6 mice were sleep deprived for 7 days and neurological function was measured via behavioral tests. We found that overexpressed PirB in SD mice could decrease the number of neurotoxic reactive astrocytes, alleviate cognitive deficits, and promote reactive astrocytes tended to be neuroprotective state. IL-1α, TNFα, and C1q were used to induce neurotoxic reactive astrocytes in vitro. Overexpression of PirB relieved the toxicity of neurotoxic astrocytes. Silencing PirB expression had the opposite effect and exacerbated the transition of reactive astrocytes to a neurotoxic state in vitro. Moreover, PirB-impaired astrocytes demonstrated STAT3 hyperphosphorylation which could be reversed by stattic (p-STAT3 inhibitor). Furthermore, Golgi-Cox staining confirmed that dendrite morphology defects and synapse-related protein were significantly increased in PirB-overexpressed SD mice. Our data demonstrated that SD induced neurotoxic reactive astrocytes and contributed to neuroinflammation and cognitive deficits. PirB performs a negative regulatory role in neurotoxic reactive astrocytes via the STAT3 signaling pathway in SD.

Silencing EIF3A ameliorates pulmonary arterial hypertension through HDAC1 and PTEN/PI3K/AKT pathway in vitro and in vivo.

Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation, and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro. EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo. In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder.

Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.

Identification of Potential Diagnoses Based on Immune Infiltration and Autophagy Characteristics in Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a serious mental illness characterized by mood changes and high suicide rates. However, no studies are available to support a blood test method for MDD diagnosis. The objective of this research was to identify potential peripheral blood biomarkers for MDD and characterize the novel pathophysiology. Methods: We accessed whole blood microarray sequencing data for MDD and control samples from public databases. Biological functions were analysed by GO and KEGG pathway enrichment analyses using the clusterprofile R package. Infiltrated immune cell (IIC) proportions were identified using the CIBERSORT algorithm. Clustering was performed using the ConsensusClusterPlus R package. Protein-protein interactions (PPI) were assessed by constructing a PPI network using STRING and visualized using Cytoscape software. Rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks to induce stress behaviour. Stress behaviour was evaluated by open field experiments and forced swimming tests. Flow cytometry was used to analyse the proportion of CD8+ T cells. The expression of the corresponding key genes was detected by qRT-PCR. Results: We divided MDD patients into CD8H and CD8L clusters. The functional enrichment of marker genes in the CD8H cluster indicated that autophagy-related terms and pathways were significantly enriched. Furthermore, we obtained 110 autophagy-related marker genes (ARMGs) in the CD8H cluster through intersection analysis. GO and KEGG analyses further showed that these ARMGs may regulate a variety of autophagy processes and be involved in the onset and advancement of MDD. Finally, 10 key ARMGs were identified through PPI analysis: RAB1A, GNAI3, VAMP7, RAB33B, MYC, LAMP2, RAB11A, HIF1A, KIF5B, and PTEN. In the CUMS model, flow cytometric analysis confirmed the above findings. qRT-PCR revealed significant decreases in the mRNA levels of Gnai3, Rab33b, Lamp2, and Kif5b in the CUMS groups. Conclusion: In this study, MDD was divided into two subtypes. We combined immune infiltrating CD8+ T cells with autophagy-related genes and screened a total of 10 ARMG genes. In particular, RAB1A, GNAI3, RAB33B, LAMP2, and KIF5B were first reported in MDD. These genes may offer new hope for the clinical diagnosis of MDD.

Baclofen attenuates cognitive deficits in post-cardiac arrest brain injury.

Between 30% and 50% of survivors of cardiac arrest (CA) suffer from cognitive deficits. However, no effective medical intervention is available to alleviate cognitive deficits. Baclofen is known to protect damaged neurons, but researchers have still not clearly whether baclofen alleviates CA-induced cognitive deficits. The present study aimed to investigate whether baclofen protects against post-CA cognitive deficits and to reveal the protective mechanism of baclofen. Rats underwent 10 min of asphyxia to establish CA models. Intriguingly, our results indicated that baclofen improved spatial memory 72 h after CA. Baclofen increased plasticity-related protein (PSD95, and GAP43) expression in the brain after CA. Baclofen reduced microglial number and the release of inflammatory factors (IL-1ß and IL-18). Furthermore, baclofen significantly reduced the expression of pyroptosis-related molecules after CA. Notably, activation of NLRP3 abolished the anti-pyroptosis effect of baclofen and reduced the expression of synaptic plasticity-related proteins after CA. Taken together, this study first shows that baclofen attenuates cognitive deficits induced by brain injury after CA. The mechanism is at least partially attributed to baclofen regulating pyroptosis by inhibition of NLRP3 activation.

Location matters: Overlooked ethnic-geographic effect in China and Austria on propofol/cisatracurium sex differences among a population pharmacokinetic/pharmacodynamic (PopPK/PD) covariate analysis in men, women, and one transgender subject.

A quick literature search using "sex/gender" vs. the commonly used hypnotic propofol or neuromuscular-blocking agent cisatracurium will reveal numerous contradictory sex difference publications depending on the ethnic-geographic location of where these studies were conducted. We induced anesthesia with cisatracurium besylate (GlaxoSmithKline) 100 µg kg-1 administered exactly 1 minute following propofol (AstraZeneca) 2 mg kg-1 . In 20 male and 20 female ethnic Han-Chinese test set patients (Xi'an China), and in similar ethnic white Austrian validation set patients (Graz Austria), we quantified propofol/cisatracurium pharmacodynamic parameters namely propofol onset time, lag time, plasma concentrations (Cp ) at loss-of-behavioral response (LOBR) using bispectral index (BIS); cisatracurium onset time, lag time, and Cp at T1 % (first twitch of train-of-four) complete twitch suppression using mechanomyography (MMG). Serial arterial blood samples were collected for population pharmacokinetic (PopPK) analysis of all demographic and biological covariates (region, sex, age, weight, and height) versus volumes of distribution and clearances pharmacokinetic parameters. In Chinese women (but not in white women), propofol Cp at LOBR was 33.60% lower than men and cisatracurium Cp at T1 % complete twitch suppression was 21.49% lower than men, a clear pharmacodynamic assertion. Region and weight were significant PopPK covariates. We demonstrated that sex differences are influenced by ethnic-geographic location as only in Chinese women (but not in white women) propofol Cp at LOBR and cisatracurium Cp at T1 % complete twitch suppression were lower than in men. When defining sex differences, ethnic-geographic location should be taken into consideration as a predictive factor for optimizing propofol/cisatracurium initial loading recommended dosages.

Roles of miR-432 and circ_0000418 in mediating the anti-depressant action of ADAR1.

Adenosine deaminase acting on RNA1 (ADAR1) is a newly discovered epigenetic molecule marker that is sensitive to environmental stressors. A recent study has demonstrated that ADAR1 affects BDNF expression via miR-432 and is involved in antidepressant action. However, the detailed molecular mechanism is still unclear. We have uncovered a new molecular mechanism showing the involvement of miR-432 and circ_0000418 in mediating the antidepressant action of ADAR1. We demonstrate that the ADAR1 inducer (IFN-γ) alleviates the depressive-like behaviors of BALB/c mice treated with chronic unpredictable stress (CUS) exposure. Moreover, both in vivo and in vitro studies show that ADAR1 differently impacts miR-432 and circ_0000418 expressions. Furthermore, the in vitro results demonstrate that circ_0000418 oppositely affects BDNF expression. Together, our results indicate that ADAR1 affects CUS-induced depressive-like behavior and BDNF expression by acting on miR-432 and circ_0000418. Elucidation of this new molecular mechanism will not only provide insights into further understanding the important role of ADAR1 in stress-induced depressive-like behavior but also suggest a potential therapeutic strategy for developing novel anti-depressive drugs.

A multicenter survey of perioperative anxiety in China: Pre- and postoperative associations.

OBJECTIVES: To describe patient characteristics associated with preoperative anxiety and subsequently assess the relationship between preoperative anxiety and postoperative anxiety, pain, sleep quality, nausea and vomiting. METHODS: The study collected data from patients undergoing elective operation from 12 hospitals in China. The State-Trait Anxiety Inventory (STAI) and the Athens Insomnia Scale (AIS) were used to assess anxiety and sleep quality before surgery. Evaluations of anxiety, pain, sleep quality, nausea and vomiting were quantified using the Visual Analogue Scale on postoperative days 1 and 2. RESULTS: Data from 997 patients were analyzed. Preoperatively, 258 (25.9%) patients had high anxiety (STAI-State>44). Multivariate analyses showed a significant relationship between high anxiety and female gender (OR: 1.66, 95% CI: 1.08-2.57, p = 0.02), highly invasive surgery (OR: 2.29, 95% CI: 1.29-4.06, p = 0.005), higher trait anxiety (OR: 1.24, 95% CI: 1.20-1.28, p < 0.001) and insomnia (AIS ≥ 6, OR: 1.79, 95% CI: 1.17-2.76, p = 0.008). Preoperative anxiety demonstrated a negative correlation with postoperative anxiety following highly invasive surgery; this became a positive relationship following less invasive surgery. Preoperative anxiety was also positively related to postoperative pain and poor sleep quality. The correlation between preoperative anxiety and postoperative nausea and vomiting was not statistically significant. CONCLUSION: Female gender, highly invasive surgery, higher trait anxiety and insomnia are independent risk factors for high preoperative anxiety. Surgical invasiveness influences association between pre- and postoperative anxiety. Higher preoperative anxiety is related to poorer sleep quality and more severe pain postoperatively.

The involvement of ADAR1 in antidepressant action by regulating BDNF via miR-432.

Brain-derived neurotrophic factor (BDNF) is a biomarker of depression. Recent studies have found adenosine deaminase acting on RNA1 (ADAR1) is a novel target being sensitive to stress at epigenetic level. The epigenetic regulation mechanism of stress-related depression is still unclear so far. To explore the potential regulating mechanism of ADAR1 on BDNF, over and low expression of ADAR1 in PC12 and SH-SY5Y cell lines are prepared. In the meanwhile, chronic unpredictable stress (CUS) mice are treated with ADAR1 inducer (interferon-γ, IFN-γ). ADAR1 regulates BDNF expression, which is proven by that over and low expressions of ADAR1 increase and decrease BDNF mRNA and protein respectively in vitro. Additionally, ADAR1 inducer alleviates the depressive-like behavior of CUS mice by recovering the decreased BDNF protein in brain and serum. Moreover, over and low expressions of ADAR1 reduce and enhance microRNA-432 (miR-432) expression respectively in vitro. Furtherly, over and low miR-432 expressions lead to decreased and increased BDNF and ADAR1 mRNA, protein and immunoreactivity respectively in vitro. The above results demonstrate that ADAR1 is involved in antidepressant action by regulating BDNF via miR-432. Those novel findings can provide a new idea for the study of epigenetic regulation mechanism, early diagnosis, and effective treatment of stress-related depression.

Bicuspidization reconstruction for regurgitant quadricuspid pulmonary valve concomitant pulmonary artery aneurysm graft replacement.

Large pulmonary artery aneurysm with severe pulmonary valve regurgitation due to the quadricuspid pulmonary valve (Type F) was found in a 54-year-old woman with fatigue and dyspnea on exertion, and in New York Heart Association (NYHA) functional class III. The annulus plication and bicuspidization technique were successfully used for the pulmonary valvular reconstruction. Then, the main pulmonary artery was replaced with Dacron graft and the left pulmonary arterioplasty was performed. Postoperative echocardiography confirmed a satisfactory motion of the reconstructed pulmonary valve with trivial regurgitation and no stenosis.

L-lactate preconditioning promotes plasticity-related proteins expression and reduces neurological deficits by potentiating GPR81 signaling in rat traumatic brain injury model.

Currently, there is no efficacious pharmacological treatment for traumatic brain injury (TBI). Previous studies revealed that L-lactate preconditioning has shown rich neuroprotective effects against cerebral ischemia, and therefore has the potential to improve neurological outcomes after TBI. L-lactate played a neuroprotective role by activating GPR81 in diseases of the central nervous system (CNS) such as TBI and cerebral ischemia. In this study we investigated the effects of L-lactate preconditioning on TBI and explored the underlying mechanisms. In this study, the mNSS test revealed that L-lactate preconditioning alleviates the neurological deficit caused by TBI in rats. L-lactate preconditioning significantly increased the expression of GPR81, PSD95, GAP43, BDNF, and MCT2 24 h after TBI in the cortex and hippocampus compared with the sham group. Taken together, these data suggested that L-lactate preconditioning is an effective method with which to recover neurological function after TBI. This reveals the mechanism of L-lactate preconditioning on TBI and provides a potential therapeutic method for TBI in humans.

Age progression from vicenarians (20-29 year) to nonagenarians (90-99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task. METHODS: Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29 year) to nonagenarians (90-99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (Cp) to gradually reach 3.5 µg mL-1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis. RESULTS: Age was significant covariate for baseline BIS effect (E0), inhibitory propofol concentration at 50% BIS decline (IC50) and maximum BIS decline (Emax). First-order rate constant Ke0 of 0.47 min-1 in vicenarians (20-29 year) gradually increased with age-progression to 1.85 min-1 in nonagenarians (90-99 year). Simulation modelling showed that clinically recommended Cp of 3.5 µg mL-1 for 20-29 year BIS 50 should be reduced to 3.0 for 30-49 year, 2.5 for 50-69 year and 2.0 for 80-89 year. CONCLUSION: We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades' age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5 µg mL-1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5 µg mL-1 for 20-29 year should be gradually decreased to 2.0 µg mL-1 for 80-89 year. CLINICAL TRIAL REGISTRY NUMBERS: European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.