Associations of Plasma Metabolites With Risks of Incident Stroke and Its Subtypes in Chinese Adults.

BACKGROUND: Metabolomics studies have identified various metabolic markers associated with stroke risk, yet much uncertainty persists regarding heterogeneity in these associations between different stroke subtypes. We aimed to examine metabolic profiles associated with incident stroke and its subtypes in Chinese adults. METHODS AND RESULTS: We performed a nested case-control study within the Dongfeng-Tongji cohort, including 1029 and 266 incident cases of ischemic stroke (IS) and hemorrhagic stroke (HS), respectively, with a mean follow-up period of 6.1±2.3 years. Fifty-five metabolites in fasting plasma were measured by ultra-high-performance liquid chromatography-mass spectrometry. We examined the associations of metabolites with the risks of total stroke, IS, and HS, with a focus on the comparison of associations of plasma metabolite with IS and HS, using conditional logistic regression. We found that increased levels of asymmetrical/symmetrical dimethylarginine and glutamate were significantly associated with elevated risk of total stroke (odds ratios and 95%, 1.20 [1.08-1.34] and 1.22 [1.09-1.36], respectively; both Benjamini-Hochberg-adjusted P <0.05). When examining stroke subtypes, asymmetrical/symmetrical dimethylarginine was nominally associated with both IS and HS (odds ratios [95% CIs]: 1.16 [1.03-1.31] and 1.39 [1.07-1.81], respectively), while glutamate was associated with only IS (odds ratios [95% CI]: 1.26 [1.11-1.43]). The associations of glutamate with IS risk were significantly stronger among participants with hypertension and diabetes than among those without these diseases (both P for interaction <0.05). CONCLUSIONS: This study validated the positive associations of asymmetrical/symmetrical dimethylarginine and glutamate with stroke risk, mainly that of IS, in a Chinese population, and revealed a novel unanimous association of with both IS and HS. Our findings provided potential intervention targets for stroke prevention.

Longitudinal albuminuria patterns predict coronary artery calcification progression: Findings from the Coronary Artery Risk Development in Young Adults study.

BACKGROUND AND AIMS: Albuminuria is an established risk factor for adverse cardiovascular outcomes. However, few studies have characterized longitudinal albuminuria patterns based on long-term measurement of urine albumin-to-creatinine ratio (UACR) levels. We aimed to evaluate the association between longitudinal albuminuria patterns in midlife adults and subsequent CAC progression. METHODS: We included 1919 participants with CAC assessment by computed tomography from CARDIA (Coronary Artery Risk Development in Young Adults) study. CAC progression was determined for each individual as the difference of logarithmic CAC scores at follow-up and baseline. Albuminuria patterns across a 10-year span were estimated by longitudinal UACR levels. Multivariable general linear models were used to evaluate the association of long-term albuminuria patterns with CAC progression. RESULTS: Of the 1919 included participants, 583 (30.4 %) participants experienced CAC progression, and the mean (SD) age was 50.4 (3.5) years at year 25. A total of four dynamic albuminuria patterns were identified. After multivariable adjustment, there were significant differences in CAC progression by albuminuria patterns as demonstrated as percent change in CAC with 36.0 % (SE, 1.5) progression for mid- and late-life normoalbuminuria group, 46.0 % (SE, 7.6) for midlife normoalbuminuria and late-life high albuminuria group, 52.4 % (SE, 7.1) for midlife high albuminuria and late-life normoalbuminuria group, and 54.5 % (SE, 8.7) for mid- and late-life high albuminuria group (p = 0.019). Similar findings were also observed in CAC volume score changes. CONCLUSIONS: Longitudinal albuminuria patterns across a 10-year span were associated with worse CAC progression independent of baseline CAC level and albuminuria changes, suggesting that it may provide early identification of high-risk individuals with dynamic rises in albuminuria who may benefit from aggressive risk factor modification.

Arenethiolate-Catalyzed 1,5-HAT of Aryl Halides: Synthesis of γ-Spirolactams.

γ-Spirolactam is a privileged building block that is found in a wide range of natural products and bioactive compounds. Herein, we report an arenethiolate-catalyzed 1,5-HAT of aryl halides to obtain γ-spirolactams through a SET reduction/intramolecular 1,5-HAT/cyclization/HAT process. This protocol features metal-free conditions and a broad substrate scope, furnishing the γ-spirolactams in moderate to excellent yields. Notably, aryl bromides, aryl chlorides and even aryl fluorides are well tolerated in this transformation. A mechanism involving arenethiolate as a SET catalyst is proposed based on DFT calculation.

Exploration of agr types, virulence-associated genes, and biofilm formation ability in Staphylococcus aureus isolates from hemodialysis patients with vascular access infections.

Introduction: Staphylococcus aureus, is a pathogen commonly encountered in both community and hospital settings. Patients receiving hemodialysis treatment face an elevated risk of vascular access infections (VAIs) particularly Staphylococcus aureus, infection. This heightened risk is attributed to the characteristics of Staphylococcus aureus, , enabling it to adhere to suitable surfaces and form biofilms, thereby rendering it resistant to external interventions and complicating treatment efforts. Methods: Therefore this study utilized PCR and microtiter dish biofilm formation assay to determine the difference in the virulence genes and biofilm formation among in our study collected of 103 Staphylococcus aureus, isolates from hemodialysis patients utilizing arteriovenous grafts (AVGs), tunneled cuffed catheters (TCCs), and arteriovenous fistulas (AVFs) during November 2013 to December 2021. Results: Our findings revealed that both MRSA and MSSA isolates exhibited strong biofilm production capabilities. Additionally, we confirmed the presence of agr types and virulence genes through PCR analysis. The majority of the collected isolates were identified as agr type I. However, agr type II isolates displayed a higher average number of virulence genes, with MRSA isolates exhibiting a variety of virulence genes. Notably, combinations of biofilm-associated genes, such as eno-clfA-clfB-fib-icaA-icaD and eno-clfA-clfB-fib-fnbB-icaA-icaD, were prevalent among Staphylococcus aureus, isolates obtained from vascular access infections. Discussion: These insights contribute to a better understanding of the molecular characteristics associated with Staphylococcus aureus, infections in hemodialysis patients and provided more targeted and effective treatment approaches.

Chain mediation model of consultation empathy, resilience and resignation coping on depression: a cross-sectional study among patients with COVID-19 in China.

OBJECTIVES: This study aimed to explore the mediating role of resilience and resignation coping in the relationship between consultation empathy and depression in patients with COVID-19. DESIGN: Cross-sectional study. SETTING: Participants were recruited from a tertiary hospital in Guangzhou, Guangdong province. PARTICIPANTS: A total of 215 patients were recruited for this study. OUTCOME MEASURES: A total of 215 patients completed the Consultation and Relational Empathy Measure, Connor-Davidson Resilience Scale, Medical Coping Modes Questionnaire and Hospital Anxiety and Depression Scale. PROCESS 4.1 model 6 was used to analyse the moderated mediating effects. RESULTS: Consultation empathy had a positive correlation with resilience (r=0.34, p<0.001), and a negative correlation with resignation (r=-0.288, p<0.001) and depression (r=-0.379, p<0.001). Resilience had a negative correlation with resignation (r=-0.463, p<0.001) and depression (r=-0.605, p<0.001). Resignation had a positive correlation (r=0.547, p<0.001) with depression. In the moderated mediating model, consultation empathy had significant indirect predictive effects on depression through resilience (95% CI -0.093 to -0.030) or resignation (95% CI -0.043 to -0.005). Consultation empathy had significant indirect predictive effects on depression through both resilience and resignation (95% CI -0.030 to -0.008). CONCLUSIONS: Consultation empathy not only predicted depression directly, but also indirectly predicted depression through the chain mediating effects of resilience and resignation coping.

Quantitative two-dimensional phase-contrast magnetic resonance imaging characterization of lower extremity venous disease: venous reflux versus venous obstruction.

Background: Lower extremity venous disease (LEVD) is a complex disorder, and determining the etiology of LEVD is paramount for treatment selection. Two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) can provide an objective measure of hemodynamic status and may help differentiate between different etiologies of LEVD. A total of 271 participants, including 256 symptomatic patients with venous lower extremity disease and 15 healthy volunteers, were collected in this cohort study. Methods: It is a single-center prospective observational study using 2D PC-MRI analysis to assess the hemodynamic characteristics of patients with LEVD among participants recruited between April 2017 and October 2021 at a tertiary hospital. The approval institutional review board number for this study were 201802137B0, 201901058B0, 202100938B0, and 202102344B0. Participants were classified as venous reflux (VR) and venous obstruction (VO) by standard ultrasonography. 2D PC-MRI by 1.5 T scanner revealed stroke volume (SV), forward flow volume (FFV), absolute stroke volume (ASV), mean flux (MF), velocity time integral (VTI), and mean velocity (MV) for each selected venous segments. Results: 2D PC-MRI assessed 167 diseased legs from the 116 VR patients [mean age ± standard deviation (SD): 57.9±12.8 years; 39 males] and 113 diseased legs from the 95 VO patients (mean age ± SD: 66.4±12.8 years; 42 males). 2D PC-MRI analysis demonstrated discrimination ability to differentiate from VR to VO [SV, FFV, ASV, MF, VTI, and MV in the various venous segments, respectively, P≤0.001; area under the curve (AUC) =62-68.8%, P≤0.001 by Mann-Whitney U test]. The ratio data (morbid limb to normal limb) in the same individual with single-leg disease revealed differences between VR and VO (SV, FFV, ASV, and MF in the various venous segments, respectively; P<0.05; AUC =60.2-68.7%, P≤0.05 by Mann-Whitney U test). The most favorable differentiating variables of ratios were FFV in the great saphenous veins [AUC =68.7%, 95% confidence interval (CI): 59.8-77.6%] and ASV in the external iliac veins (AUC =67.4%, 95% CI: 58.7-76.2%). Conclusions: Quantitative 2D PC-MRI analysis is capable of differentiating VR from VO. It also provides an important diagnostic capability for preoperative evaluation.

Glutamate-releasing BEST1 channel is a new target for neuroprotection against ischemic stroke with wide time window.

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.

Nontargeted Metabolomics Revealed Novel Association Between Serum Metabolites and Incident Acute Coronary Syndrome: A Mendelian Randomization Study.

Background This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair.

Stem cell-based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Despite this, the functional and phenotypical immaturity of 2D-cultured hiPSC-CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif-RGD, and saccharide-glucose (Bio-Gluc-RGD) is designed to enable the 3D spheroid formation of hiPSC-CMs, promoting cell-cell and cell-matrix interactions that occur during spontaneous morphogenesis. HiPSC-CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p-AKT/Gata4 pathway. Monodispersed hiPSC-CMs encapsulated in the Bio-Gluc-RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC-CMs delivered with the hydrogels also displayed angiogenic effect and anti-apoptosis capacity in the peri-infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC-CM maturation by spheroid induction, which has the potential for post-MI heart regeneration.

Functional reconstruction of the impaired cortex and motor function by hMGEOs transplantation in stroke.

Stroke is the leading cause of death and long-term disability worldwide. But treatments are not available to promote functional recovery, and efficient therapies need to be investigated. Stem cell-based therapies hold great promise as potential technologies to restore function in brain disorders. Loss of GABAergic interneurons after stroke may result in sensorimotor defects. Here, by transplanting human brain organoids resembling the MGE domain (human MGE organoids, hMGEOs) derived from human induced pluripotent stem cells (hiPSCs) into the infarcted cortex of stroke mice, we found that grafted hMGEOs survived well and primarily differentiated into GABAergic interneurons and significantly restored the sensorimotor deficits of stroke mice for a long time. Our study offers the feasibility of stem cell replacement therapeutics strategy for stroke.

Efficacy and safety of intravenous tranexamic acid in urologic surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This meta-analysis compared the effects of intravenous Tranexamic acid (TXA) and a placebo on hemostasis, hospital course, and complications in adult patients undergoing various urologic surgeries. METHODS: The literature was extensively searched using various databases. The primary outcomes were standardized mean differences (SMDs) of intraoperative blood loss and odds ratios (ORs) of necessary blood product transfusion. The secondary outcomes included SMDs of operative time, SMDs of decreased hemoglobulin levels at 24 hours after surgery, and ORs of thromboembolic events. RESULTS: The meta-analysis included 13 randomized controlled trials (RCT) comprising 1814 participants in total. The SMD of intraoperative blood loss for TXA versus placebo was -0.705 (95% confidence interval [CI]: -1.113 to -0.297). The pooled ORs of transfusion in the TXA group compared with the placebo group was 0.426 (95% CI: 0.290-0.625). These findings indicated a significantly lower intraoperative blood loss and a reduced need for transfusion following intravenous TXA. The pooled ORs of thromboembolic events in the TXA group compared with the placebo group was 0.664 (95% CI: 0.146-3.024). CONCLUSIONS: Intravenous TXA can reduce intraoperative blood loss, decrease the need for transfusion, and shorten operative time, and it does not increase the risk of thromboembolic events.

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.

Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

The reaction pathway and mechanism of 2,4-dichlorophenol removal by modified fly ash-loaded nZVI/Ni particles.

Nanoscale zero-valent iron (nZVI) is more valuable in environmental restoration than other materials. Chemical treatment of fly ash (CFA) was employed as a support material to disperse iron nickel bimetal nanoparticles (CFA-nZVI/Ni) to remove 2,4-dichlorophenol (2,4-DCP). Batch experiments showed that 2,4-DCP was completely removed by CFA-nZVI/Ni, and an optimal loading ratio was 8:1. The degradation of 2,4-DCP by CFA-nZVI/Ni was a chemical control reaction with an activation energy of 95.6 kJ mol-1 and followed pseudo-first-order kinetics. The addition of Cl- increased the removal rate of 2,4-DCP by 4%, while the addition of CO32- and SO42- decreased the removal rate of 2,4-DCP by 32% and 72.3%, respectively. The removal process of 2,4-DCP by CFA-nZVI/Ni included adsorption and reduction. The 2-CP (7.1 mg/L) and 4-CP (11.6 mg/L) could be converted to phenol using the CFA-nZVI/Ni system. Cl on the para-position of 2,4-DCP was simpler to remove than on the ortho-position. The following steps were taken in the electrophilic substitution reaction between substituted phenols and hydrogen radicals: 2,4-DCP > 2-CP > 4-CP > phenol. This research provides a novel concept to effectively remove 2,4-DCP and mechanism analysis.

Preclinical evaluation of ZL006-05, a new antistroke drug with fast-onset antidepressant and anxiolytic effects.

BACKGROUND: Poststroke depression and anxiety, independent predictor of poor functional outcomes, are common in the acute phase of stroke. Up to now, there is no fast-onset antidepressive and anxiolytic agents suitable for the management of acute stroke. ZL006-05, a dual-target analgesic we developed, dissociates nitric oxide synthase from postsynaptic density-95 while potentiates α2-containing γ-aminobutyric acid type A receptor. This study aims to determine whether ZL006-05 can be used as an antistroke agent with fast-onset antidepressant and anxiolytic effects. METHODS: Photothrombotic stroke and transient middle cerebral artery occlusion were induced in rats and mice. Infarct size was measured by TTC(2,3,5-Triphenyltetrazolium chloride) staining or Nissl staining. Neurological defects were assessed by four-point scale neurological score or modified Neurological Severity Scores. Grid-walking, cylinder and modified adhesive removal tasks were conducted to assess sensorimotor functions. Spatial learning was assessed using Morris water maze task. Depression and anxiety were induced by unpredictable chronic mild stress. Depressive behaviours were assessed by tail suspension, forced swim and sucrose preference tests. Anxiety behaviours were assessed by novelty-suppressed feeding and elevated plus maze tests. Pharmacokinetics, toxicokinetics and long-term toxicity studies were performed in rats. RESULTS: Administration of ZL006-05 in the acute phase of stroke attenuated transient and permanent ischaemic injury and ameliorated long-term functional impairments significantly, with a treatment window of 12 hours after ischemia, and reduced plasminogen activato-induced haemorrhagic transformation. ZL006-05 produced fast-onset antidepressant and anxiolytic effects with onset latency of 1 hour in the normal and CMS mice, had antidepressant and anxiolytic effects in stroke mice. ZL006-05 crossed the blood-brain barrier and distributed into the brain rapidly, and had a high safety profile in toxicokinetics and long-term toxicological studies. CONCLUSION: ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy, safety and targeting of clinical issues.

Endovascular Treatment for Spontaneous bilateral carotid artery dissection with acute ischemic stroke: A Case Report with automated postprocessing CT perfusion findings and Review of the Literature.

Carotid artery dissection (CAD) is a common cause of stroke, accounting for up to 25% of all ischemic strokes in young and middle-aged patients. CAD should be considered in young patients with unexplained head and neck pain, with or without focal neurological symptoms and signs. While the clinical features may raise suspicion for CAD, the diagnosis is confirmed by its typical neuroimaging findings. Meanwhile, simultaneous spontaneous dissection of the bilateral carotid artery has rarely been reported. We herein describe a clinically challenging case of a simultaneous bilateral CAD that was successfully treated with bilateral carotid artery stenting (CAS). The patient recovered satisfactorily after completing the whole course of treatment. Keywords: Acute stroke, Bilateral Spontaneous carotid artery dissection, Endovascular treatment.

Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling.

Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that ß-hydroxybutyrate (ß-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of ß-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilateral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical approaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.

Noncontrast MRI in assessing venous reflux of legs using QFlow analysis and radial basis function neural network technique.

Since venous reflux is difficult to quantify, triggered angiography non-contrast-enhanced (TRANCE)-magnetic resonance imaging (MRI) is a novel tool for objectively evaluating venous diseases in the lower extremities without using contrast media. This study included 26 pre-intervention patients with superficial venous reflux in the lower extremities and 15 healthy volunteers. The quantitative flow (QFlow) analyzed the phase shift information from the pixels within the region of interest from MRI. The fast and simple radial basis function neural network (RBFNN) learning model is constructed by determining the parameters of the radial basis function and the weights of the neural network. The input parameters were the variables generated through QFlow, while the output variables were morbid limbs with venous reflux and normal limb classification. The stroke volume, forward flow volume, absolute stroke volume, mean flux, stroke distance, and mean velocity of greater saphenous veins from QFlow analysis could be used to discriminate the morbid limbs of pre-intervention patients and normal limbs of healthy controls. The neural network successfully classified the morbid and normal limbs with an accuracy of 90.24% in the training stage. The classification of venous reflux using the RBFNN model may assist physicians in clinical settings.

Enhanced AMPAR-dependent synaptic transmission by S-nitrosylation in the vmPFC contributes to chronic inflammatory pain-induced persistent anxiety in mice.

Chronic pain patients often have anxiety disorders, and some of them suffer from anxiety even after analgesic administration. In this study, we investigated the role of AMPAR-mediated synaptic transmission in the ventromedial prefrontal cortex (vmPFC) in chronic pain-induced persistent anxiety in mice and explored potential drug targets. Chronic inflammatory pain was induced in mice by bilateral injection of complete Freund's adjuvant (CFA) into the planta of the hind paws; anxiety-like behaviours were assessed with behavioural tests; S-nitrosylation and AMPAR-mediated synaptic transmission were examined using biochemical assays and electrophysiological recordings, respectively. We found that CFA induced persistent upregulation of AMPAR membrane expression and function in the vmPFC of anxious mice but not in the vmPFC of non-anxious mice. The anxious mice exhibited higher S-nitrosylation of stargazin (an AMPAR-interacting protein) in the vmPFC. Inhibition of S-nitrosylation by bilaterally infusing an exogenous stargazin (C302S) mutant into the vmPFC rescued the surface expression of GluA1 and AMPAR-mediated synaptic transmission as well as the anxiety-like behaviours in CFA-injected mice, even after ibuprofen treatment. Moreover, administration of ZL006, a small molecular inhibitor disrupting the interaction of nNOS and PSD-95 (20 mg·kg-1·d-1, for 5 days, i.p.), significantly reduced nitric oxide production and S-nitrosylation of AMPAR-interacting proteins in the vmPFC, resulting in anxiolytic-like effects in anxious mice after ibuprofen treatment. We conclude that S-nitrosylation is necessary for AMPAR trafficking and function in the vmPFC under chronic inflammatory pain-induced persistent anxiety conditions, and nNOS-PSD-95 inhibitors could be potential anxiolytics specific for chronic inflammatory pain-induced persistent anxiety after analgesic treatment.

Modified Le Fort I Arc Osteotomy Combined With Autologous Bone Grafts to Improve Midface Hypoplasia Combined With Skeletal Class III Malocclusion: A Technical Note.

Midface hypoplasia sometimes appears in patients with skeletal class III malocclusion in the Asian population, often requires additional surgical treatments. The technical note is intended to introduce a modified Le Fort I arc osteotomy combined with autologous bone grafts harvested from proximal segments after bilateral sagittal split ramus osteotomy to improve the profile for skeletal class III malocclusion patients with midface hypoplasia. The benefit of the modified technology is that the size and position of the arc can be adjusted according to the severity of the deformity to suit different patients. In addition, the application of autologous bone grafts increased the extra height of osteotomy line and enhanced the surgical effect, and maintained bone consolidation. More importantly, the osteotomy line of the modified Le Fort I arc osteotomy can be easily designed and this modification will not cause additional injuries. Therefore, we believe that for skeletal class III malocclusion patients with midface hypoplasia in Asia modified Le Fort I arc osteotomy combined with autologous bone grafts will be an efficient surgical method to improve midface hypoplasia.