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BackgroundLung transplantation (LTx) is the definitive treatment for end-stage pulmonary diseases, with venoarterial extracorporeal membrane oxygenation (VA-ECMO) used as a common perioperative support. However, it remains unclear if central (cVA-ECMO) or peripheral (pVA-ECMO) cannulation routes yield better outcomes in postoperative prognosis. This study compares the impact of these two cannulation strategies on primary graft dysfunction (PGD) incidence in LTx patients.MethodsA retrospective analysis was performed on 153 LTx patients supported with VA-ECMO at the Wuxi Lung Transplant Center (January 2019–March 2023). Patients were divided into central (n = 31) and peripheral (n = 91) groups. Data included recipient/donor demographics, preoperative status, and follow-up outcomes. The primary outcome was PGD within 72 h after reperfusion, whereas secondary outcomes included in-hospital mortality, 1-year survival, renal support needs, ventilation duration, intensive care unit (ICU) stay, and biochemical markers.ResultsPGD incidence was significantly higher in the peripheral group, with longer ECMO duration, ventilation, and ICU stay. Central VA-ECMO showed advantages in in-hospital mortality and 1-year survival rates.ConclusionCentral VA-ECMO cannulation may reduce postoperative complications and improve survival for LTx recipients. Prospective studies are needed to confirm these findings and refine perioperative ECMO management.

Abstract Background Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. Method To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. Results Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. Conclusion The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

Abstract Background Phenotypic age acceleration, which reflects the difference between phenotypic age and chronological age, is an assessment to measure accelerated aging. Klotho is a protein related to slower aging, but its association with accelerated aging remains unclear. Methods Based on data from the 2007–2010 National Health and Nutrition Examination Survey, phenotypic age was calculated using chronological age and 9 aging-related biomarkers. A total of 4388 participants aged 40 to 79 years with measured serum Klotho and calculated phenotypic age were enrolled. The association between serum Klotho and phenotypic age acceleration was estimated using multivariable linear regression models. The possible nonlinear relationship was examined with smooth curve fitting. We also conducted a segmented regression model to examine the threshold effect. Results The association between serum Klotho and phenotypic age acceleration followed a U-shaped curve (p for nonlinearity

Abstract Background Migraine, a complex brain disorder, is regarded as a possible clinical manifestation of brain energy dysfunction. The trigeminovascular system is considered the basis for the pathogenesis of migraine, hence we depicted the proteomics profiling of key regions in this system, then focusing on protein alterations related to mitochondrial function. The aim of this study is to illustrate the role of mitochondria in migraine. Methods A mouse model of chronic migraine (CM) was established by repeated nitroglycerin (NTG) stimulation and evaluated by von-Frey filaments, a hot plate and a light-dark box. Differentially expressed proteins (DEPs) in some subcortical brain regions of the trigeminovascular system were screened through liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyse the specificity of key signaling pathways in different brain regions. And then mitochondrial function, structure and dynamics were determined by qPCR, ELISA, and transmission electron microscope (TEM). Finally, the effect of mitochondrial intervention-Urolithin A (UA) on CM was investigated. Results Repeated NTG injection triggered photophobia, periorbital and hind paw allodynia in mice. The proteomics profiling of CM model showed that 529, 109, 163, 152 and 419 DEPs were identified in the thalamus, hypothalamus, periaqueductal grey (PAG), trigeminal ganglion (TG) and trigeminocervical complex (TCC), respectively. The most significant changes in the brain region-specific pathways pointed to thalamic mitochondrial impairment. NTG induced mitochondrial structural disruption, dysfunction and homeostatic dysregulation, which could be partially attenuated by UA intervention. Conclusion Our findings highlight the involvement of mitochondrial damage in the thalamus in central sensitization of CM, which provides evidence of possible metabolic mechanisms in migraine pathophysiology.

Aircraft secondary flow systems are small-flow circulation devices that are used for thermal and cold management, flow control, and energy generation on aircraft. The aerodynamic characteristics of main-flow-based inlets have been widely studied, but the secondary-flow-based small inlets, jets, and blowing and suction devices have seldom been studied. Two types of secondary flow systems embedded in a supersonic aircraft wing, a ram-air intake and a submerged intake, are researched here. Firstly, wind tunnel tests under subsonic, transonic, and supersonic conditions are carried out to test the total pressure recovery and total pressure distortion. Secondly, numerical simulations are used to analyze the flow characteristics in the secondary flow systems. The numerical results are validated with experimental data. The calculating errors of the total pressure recovery on the ram-air and submerged secondary flow systems are 8% and 10%, respectively. The simulation results demonstrate that the total pressure distortion tends to grow while the total pressure recovery drops with the increasing Mach number. As the Mach number increases from 0.4 to 2, the total pressure recovery of the ram-air secondary flow system decreases by 68% and 71% for the submerged system. Moreover, the total pressure distortion of the ram-air and submerged secondary flow systems is increased by 19.7 times and 8.3 times, respectively. Thirdly, a detailed flow mechanism is studied based on the simulation method. It is found that the flow separation at the front part of the tube is induced by adverse pressure gradients, which primarily determine the total pressure recovery at the outlet. The three-dimensional vortex in the tube is mainly caused by the change in cross-sectional shape, which influences the total pressure distortion.

Abstract Background Migraine is a highly disabling health burden with multiple symptoms; however, it remains undertreated because of an inadequate understanding of its neural mechanisms. Neuropeptide Y (NPY) has been demonstrated to be involved in the modulation of pain and emotion, and may play a role in migraine pathophysiology. Changes in NPY levels have been found in patients with migraine, but whether and how these changes contribute to migraine is unknown. Therefore, the purpose of this study was to investigate the role of NPY in migraine-like phenotypes. Methods Here, we used intraperitoneal injection of glyceryl trinitrate (GTN, 10 mg/kg) as a migraine mouse model, which was verified by light-aversive test, von Frey test, and elevated plus maze test. We then performed whole-brain imaging with NPY-GFP mice to explore the critical regions where NPY was changed by GTN treatment. Next, we microinjected NPY into the medial habenula (MHb), and further infused Y1 or Y2 receptor agonists into the MHb, respectively, to detect the effects of NPY in GTN-induced migraine-like behaviors. Results GTN effectively triggered allodynia, photophobia, and anxiety-like behaviors in mice. After that, we found a decreased level of GFP+ cells in the MHb of GTN-treated mice. Microinjection of NPY attenuated GTN-induced allodynia and anxiety without affecting photophobia. Furthermore, we found that activation of Y1—but not Y2—receptors attenuated GTN-induced allodynia and anxiety. Conclusions Taken together, our data support that the NPY signaling in the MHb produces analgesic and anxiolytic effects through the Y1 receptor. These findings may provide new insights into novel therapeutic targets for the treatment of migraine. Graphical Abstract

Background: Cardiac fibrosis has gradually gained significance in the field of cardiovascular disease; however, its specific pathogenesis remains unclear. This study aims to establish the regulatory networks based on whole-transcriptome RNA sequencing analyses and reveal the underlying mechanisms of cardiac fibrosis. Methods: An experimental model of myocardial fibrosis was induced using the chronic intermittent hypoxia (CIH) method. Expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) were acquired from right atrial tissue samples of rats. Differentially expressed RNAs (DERs) were identified, and functional enrichment analysis was performed. Moreover, a protein-protein interaction (PPI) network and competitive endogenous RNA (ceRNA) regulatory network that are related to cardiac fibrosis were constructed, and the relevant regulatory factors and functional pathways were identified. Finally, the crucial regulators were validated using qRT-PCR. Results: DERs, including 268 lncRNAs, 20 miRNAs, and 436 mRNAs, were screened. Further, 18 relevant biological processes, such as "chromosome segregation, " and 6 KEGG signaling pathways, such as "cell cycle, " were significantly enriched. The regulatory relationship of miRNA–mRNA–KEGG pathways showed eight overlapping disease pathways, including "pathways in cancer." In addition, crucial regulatory factors, such as Arnt2, WNT2B, GNG7, LOC100909750, Cyp1a1, E2F1, BIRC5, and LPAR4, were identified and verified to be closely related to cardiac fibrosis. Conclusion: This study identified the crucial regulators and related functional pathways in cardiac fibrosis by integrating the whole transcriptome analysis in rats, which might provide novel insights into the pathogenesis of cardiac fibrosis.

Summary: Medication overuse headache (MOH) is a serious global condition. The interaction between headache attacks and medication overuse complicates the understanding of its pathophysiology. In this study, we developed a preclinical MOH model that incorporates these two key factors by overusing rizatriptan benzoate (RIZ, 4 mg/kg, i.g.) in a glyceryl trinitrate (GTN, 10 mg/kg, i.p.) induced chronic migraine mouse model. We observed that RIZ overuse aggravated GTN-induced cutaneous allodynia and caused a prolonged state of latent sensitization. We also detected a significant upregulation of Annexin-A1 (ANXA1), a protein mainly expressed in the microglia of the spinal trigeminal nucleus caudalis (SPVC), in GTN+RIZ mice. Intracerebroventricular injection of ANXA1-derived peptide Ac2-26 trifluoroacetic acid (TFA) (5 μg/mouse) inhibited bright light stress (BLS) induced acute allodynia via the formyl peptide receptor (FPR) in GTN+RIZ mice. These results suggest that ANXA1 may have an analgesic effect in triptan-associated MOH and could potentially serve as a therapeutic target.

Background and aimsThe role of circular RNAs (circRNAs) in the pathophysiology of cardiovascular disease is gradually being elucidated; however, their roles in atrial fibrillation (AF)-related fibrosis are largely unknown. This study aimed to characterize the different circRNA profiles in the rapid-pacing atria of dogs and explore the mechanisms involved in atrial fibrosis.MethodsA rapid right atrial-pacing model was established using electrical stimulation from a pacemaker. After 14 days, atrial tissue was collected for circRNA sequencing analysis. In vitro fibrosis was established by stimulating canine atrial fibroblasts with angiotensin II (Ang II). The fibroblasts were transfected with siRNA and overexpressing plasmids to explore the effects of cfa-circ002203 on fibroblast proliferation, migration, differentiation, and the expression of fibrosis-related proteins.ResultsIn total, 146 differentially expressed circRNAs were screened, of which 106 were upregulated and 40 were downregulated. qRT-PCR analysis showed that cfa-circ002203 was upregulated in both in vivo and in vitro fibroblast fibrosis models. The upregulation of cfa-circ002203 enhanced proliferation and migration while weakening the apoptosis of fibroblasts. Western blotting showed that cfa-circ002203 overexpression increased the protein expression levels of fibrosis-related indicators (Col I, Col III, MMP2, MMP9, and α-SMA) and decreased the protein expression levels of pro-apoptotic factors (Bax and Caspase 3) in Ang II-induced fibroblast fibrosis.ConclusionCfa-circ002203 might serve as an active promoter of the proliferation, migration, and fibrosis of atrial fibroblasts and is involved in AF-induced fibroblast fibrosis.

Abstract Background Gut microbial dysbiosis and gut-brain axis dysfunction have been implicated in the pathophysiology of migraine. However, it is unclear whether migraine-related cephalic allodynia could induce the alteration of gut microbial composition. Methods A classic migraine rat model was established by repeated dural infusions of inflammatory soup (IS). Periorbital mechanical threshold and nociception-related behaviors were used to evaluate IS-induced cephalic allodynia and the preventive effect of topiramate. The alterations in gut microbial composition and potential metabolic pathways were investigated based on the results of 16 S rRNA gene sequencing. Microbiota-related short-chain fatty acids and tryptophan metabolites were detected and quantified by mass spectrometry analysis. Results Repeated dural IS infusions induced cephalic allodynia (decreased mechanical threshold), migraine-like behaviors (increased immobility time and reduced moving distance), and microbial composition alteration, which were ameliorated by the treatment of topiramate. Decreased Lactobacillus was the most prominent biomarker genus in the IS-induced alteration of microbial composition. Additionally, IS infusions also enhanced metabolic pathways of the gut microbiota in butanoate, propanoate, and tryptophan, while the increased tryptophan-related metabolites indole-3-acetamide and tryptophol in feces could be the indicators. Conclusions Inflammatory dural stimulation-induced cephalic allodynia causes the alterations of gut microbiota profile and microbial metabolic pathways.

BackgroundRemnant cholesterol (RC) has been suggested to be implicated in atherosclerosis. The objective of the study was to evaluate the association between RC and first-ever stroke in the Chinese general population and to investigate whether the association is mediated via hypertension or diabetes.MethodsThis study is a retrospective cohort analysis of participants from the China Health and Nutrition Survey. Participants without previous stroke and myocardial infarction in 2009 were enrolled and followed up in 2011 and 2015. Logistic regression analyses were adopted to explore the association of RC with stroke risk. Propensity score methods and doubly robust estimation method were used to ensure the robustness of our findings. Potential mediators were identified by mediation analyses.ResultsA total of 7,035 participants were involved, and during 6 years of follow-up, 78 (1.1%) participants experienced a first-ever stroke. Participants with high RC had a significantly higher incidence of stroke (1.4% versus 0.8%; p = 0.007). High RC was associated with 74% higher stroke risk after adjusting for multiple relevant variables (odds ratio [OR], 1.74; 95% CI, 1.06–2.85). The association was consistent in analyses using propensity score methods and doubly robust estimation method. Hypertension showed a significant mediating effect on the association between RC and stroke, while the mediating effect of diabetes was not significant.ConclusionHigh RC increased the risk of first-ever stroke in the Chinese general population without previous stroke and myocardial infarction, partially through the pathway of hypertension. RC might be a potential target for the primary prevention of stroke.

It has yet to be determined whether medication overuse headache (MOH) is an independent disorder or a combination of primary headache and substance addiction. To further explore the causes of MOH, we compared MOH with substance use disorder (SUD) in terms of the brain regions involved to draw more targeted conclusions. In this review, we selected alcohol use disorder (AUD) as a representative SUD and compared MOH and AUD from two aspects of neuroimaging and basic research. We found that in neuroimaging studies, there were many overlaps between AUD and MOH in the reward circuit, but the extensive cerebral cortex damage in AUD was more serious than that in MOH. This difference was considered to reflect the sensitivity of the cortex structure to alcohol damage. In future research, we will focus on the central amygdala (CeA), prefrontal cortex (PFC), orbital-frontal cortex (OFC), hippocampus, and other brain regions for interventions, which may have unexpected benefits for addiction and headache symptoms in MOH patients.

Abstract Background Neuroimmunology is a rapidly expanding field, and there have been recent discoveries of new antibodies and neurological syndromes. Most of the current clinical studies have focused on disorders involving one specific antibody. We have summarized a class of antibodies that target common neuronal epitopes, and we have proposed the term “anti-neuron antibody syndrome” (ANAS). In this study, we aimed to clarify the clinical range and analyse the clinical features, cytokines/chemokines and predictors in ANAS. Methods This was a retrospective cohort study investigating patients with neurological manifestations that were positive for anti-neuron antibodies. Results A total of 110 patients were identified, of which 43 patients were classified as having autoimmune encephalitis (AE) and the other 67 were classified as having paraneoplastic neurological syndrome (PNS). With regards to anti-neuron antibodies, 42 patients tested positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody, 19 for anti-Hu, 14 for anti-Yo and 12 for anti-PNMA2 (Ma2). There were significant differences between the ANAS and control groups in serum B cell-activating factor (BAFF) levels and in cerebrospinal fluid (CSF) C-X-C motif chemokine10 (CXCL10), CXCL13, interleukin10 (IL10), BAFF and transforming growth factor β1 (TGFβ1) levels. Predictors of poor outcomes included having tumours (P = 0.0193) and having a chronic onset (P = 0.0306), and predictors of relapses included having lower levels of CSF BAFF (P = 0.0491) and having a larger ratio of serum TGFβ1/serum CXCL13 (P = 0.0182). Conclusions Most patients with ANAS had a relatively good prognosis. Having tumours and a chronic onset were both associated with poor outcomes. CSF BAFF and the ratio of serum TGFβ1/serum CXCL13 were associated with relapses.

Peripheral blood mononuclear cells (PBMC) were donated by a healthy 25-year-old Han Chinese man and reprogrammed with human transcription factors (Oct4, Sox2, Klf4, and c-Myc) using CytoTune™-iPS 2.0 Sendai Reprogramming Kit. The pluripotency was confirmed by pluripotency markers. The iPSC lines could be differentiated into three germ layers and be used as a control in drug development and studies on pathological mechanisms.

This paper presents a new-concept aircraft with a diamond joined-wing morphing configuration, which simultaneously adjusts the sweep angles of both the front wing and rear wings by a telescopic support rod. The compressible Navier-Stokes equations in the conservative form are solved to analyze the configuration characteristics and the aerodynamic benefits of this aircraft with different values of sweep angle (15°, 60°) and Mach number. The maximum lift-to-drag ratio is about 13.5 at M=0.5 and α=4°, 12.8 at M=0.75 and α=4°, and 3.4 at M=1.5 and α=6°, respectively. Compared with traditional morphing aircraft, the main advantages of this configuration include better transonic and supersonic performance, better lift characteristics in the state of a high-aspect ratio, and lower zero-lift drag in the supersonic state. The lift ratio of the front and rear wings shows a good similarity at different Mach numbers, especially for the 15° model, and the value eventually tends to be 1.3 at α=12°. Meanwhile, the flow field characteristics and interference characteristics of the front and rear wings are studied. The increase in the angle of attack, incoming flow velocity, and distance between the front and rear wings can reduce the interference between front and rear wings. The influence from upstream components is proven to improve the aerodynamic characteristics of the rear wing, especially at α=8°.

Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.

Objective To compare short-axis versus long-axis plane for ultrasound-guided internal jugular vein puncture. Methods PubMed, Embase, Cochrane Library and CNKI databases were searched for randomized controlled trials, published to 1 June 2019, that compared short- versus long-axis plane in ultrasound-guided internal jugular vein puncture. Statistical analyses were performed using RevMan software, version 5.3. Statistical results are presented as risk ratio (RR) (95% confidence interval [CI]) for dichotomous data and standard mean difference (SMD) (95% CI) for continuous data. Results Ten studies fulfilled the inclusion criteria. Analyses of pooled results showed no statistically significant differences in arterial puncture incidence between the two planes (RR 0.73 [95% CI 0.38, 1.39]). First-pass success rate (RR 1.08 [95% CI 0.95, 1.22]), total success rate (RR 1.00 [95% CI 0.99, 1.02]) and number of attempts required (SMD –0.09 [95% CI –0.37, 0.18]) were also similar between the two approaches. Trial sequential analysis indicated that the available evidence was insufficient to detect potential differences between the two techniques. Conclusions There is insufficient data for an evidence-based choice of either short- or long-axis plane in ultrasound-guided internal jugular vein puncture.

Objective This meta-analysis was performed to evaluate the safety and efficacy of the oblique-axis plane in ultrasound-guided internal jugular vein puncture. Methods We searched Embase, PubMed, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure for relevant randomized clinical trials comparing the oblique axis with the short axis in ultrasound-guided internal jugular vein puncture. Results Five randomized clinical trials were included in this meta-analysis. The pooled meta-analysis showed that the incidence of arterial puncture in the oblique-axis group was significantly lower than that in the short-axis group. No significant difference was found in the first-pass success rate between the oblique-axis group and short-axis group. Additionally, there were no significant differences in the puncture success rate or number of attempts required between the two groups. Conclusion Ultrasound-guided internal jugular vein puncture using the oblique-axis plane reduced the risk of arterial puncture, but no difference was found in the first-pass success rate, puncture success rate, or number of attempts required.

Background/Aims: Anti-oxidation is an effective strategy for curing acute kidney injury (AKI). Herein, we suggest that extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) might play an anti-oxidative role by enhancing Nrf2/ARE activation in AKI. Methods: EVs isolated from the conditioned medium of human Wharton's Jelly mesenchymal stromal cells and human foreskin fibroblast were intravenously injected in rats immediately after 45 min of unilateral kidney ischemia. Animals were sacrificed 24 h after injury. Results: Results showed that renal tubular injury was alleviated and renal function was improved by MSC-EVs. Cell apoptosis and sNGAL levels, which reflect kidney cell injury, were reduced. Moreover, MSC-EVs decreased oxidative stress in injured kidney tissues and NRK-52E cells under hypoxia injury. Nrf2/antioxidant response element (ARE) enhancement and HO-1 up-regulation were further observed after MSC-EV treatment both in vivo and in vitro. Conclusions: MSC-EVs may protect against AKI possibly through anti-oxidation by enhancing Nrf2/ARE activation.

Introduction: Medial compartment osteoarthritis is usually accompanied by medial meniscal tear. The treatment of symptomatic mild medial compartment osteoarthritis and medial meniscal tears in middle-aged and elderly patients is controversial. Aim: This study aimed to assess the efficacy of proximal fibulectomy combined with Arthroscopic Partial Meniscectomy (APM) for symptomatic middle-aged and elderly patients with mild medial compartment osteoarthritis and medial meniscal tears. Materials and Methods: Consecutive hospitalised patients treated with concomitant proximal fibulectomy and APM from April 2013 to June 2014 were included in the study. Proximal fibulectomy and APM were done by the same group of surgeons. APM was performed initially to manage medial meniscal tears. This was followed by the proximal fibulectomy, during which a 20-mm long proximal fibular segment was excised. Preoperative and postoperative Visual Analog Scale (VAS) pain scores, Hospital for Special Surgery (HSS) knee scores, and Ahlbäck grading of knee osteoarthritis were collected. Postoperative complications and subjective patient satisfaction were recorded. For statistical analysis of the VAS and HSS score, Wilcoxon signed-rank test and the paired t-test were used to compare over time, respectively. Results: A total of 31 out of 38 patients were included. Seven patients were excluded due to follow up loss. The mean follow up duration was 25.3±1.5 months. The postoperative median VAS score and Interquartile Range (IQR) were 0 (0–1), which was significantly lower than the preoperative median VAS score and interquartile range 6 (5–7) (p< 0.001). The mean HSS score improved from 78.2±8.2 points preoperatively to 90.1±4.5 points postoperatively (p< 0.001). No patients had radiographic evidence of osteoarthritis progression or fibular bony union, or required conversion to other surgeries. Subjective patient satisfaction was rated very satisfied in 7 patients (22.6%), satisfied in 20 patients (64.5%), fairly satisfied in 3 patients (9.7%), and not satisfied in 1 patient (3.2%). Complication in a single patient included a temporary palsy of the superficial peroneal nerve. Conclusion: Proximal fibulectomy combined with APM produced satisfactory surgical outcomes in our patient cohort at two years after treatment. Concomitant proximal fibulectomy and APM may be considered to be a safe and minimally invasive treatment.

ObjectiveTo describe and analyze the clinical characteristics, laboratory data, management, and outcome of patients with onconeural antibody-associated disorders (OAAD) and identify predictors for poor outcome.MethodsThis was a retrospective review of all patients with potential OAAD, who were hospitalized in Jinan General Hospital between September 2009 and July 2017. We clarified the diagnosis, collected comprehensive information and categorized patients into three groups: paraneoplastic neurological disorders (PNDs), autoimmune encephalitis (AE), and possible OAAD. Within the three groups, we analyzed a range of clinical and laboratory parameters and used univariate and multivariate regression analysis to identify predictors for poor outcome [modified Rankin Scale (mRS) = 3–6].ResultsFrom 158 patients, we identified 70 who fulfilled the criteria for OAAD, including 44 men (62.9%) and 26 women (37.1%). There were 38 patients (54.3%) in the PNDs group, 14 patients (20%) in the AE group, and 18 patients (25.7%) in the possible OAAD group. After the last follow-up, 14 (36.8%), 9 (64.2%), and 12 (66.7%) had a good outcome (mRS = 0–2). However, 6 (15.8%), 2 (14.3%), and 3 (16.7%) died, respectively. Univariate analysis showed that duration prior to the hospital (p = 0.0224) and urinary incontinence/retention (p = 0.0043) were associated with poor outcome (mRS = 3–6). After multivariate regression analysis, urinary incontinence/retention (p = 0.0388) and an immunocompromised state (p = 0.0247) remained as significant factors for poor outcome.ConclusionUrinary incontinence/retention and an immunocompromised state represent significant predictors of a worse prognosis for patients with OAAD. By contrast, cerebrospinal fluid analysis showed that serum autoantibodies and tumor markers, the function of crucial organs, electrophysiology, and radiological findings were not associated with a poor outcome.

During acute kidney injury (AKI), tubular cell dedifferentiation initiates cell regeneration; hepatocyte growth factor (HGF) is involved in modulating cell dedifferentiation. Mesenchymal stem cell (MSC)-derived microvesicles (MVs) deliver RNA into injured tubular cells and alter their gene expression, thus regenerating these cells. We boldly speculated that MVs might induce HGF synthesis via RNA transfer, thereby facilitating tubular cell dedifferentiation and regeneration. In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery. One of the mechanisms of action is the acceleration of tubular cell dedifferentiation and growth. Both in vivo and in vitro, rat HGF expression in damaged rat tubular cells was greatly enhanced by MV treatment. In addition, human HGF mRNA present in MVs was delivered into rat tubular cells and translated into the HGF protein as another mechanism of HGF induction. RNase treatment abrogated all MV effects. In the in vitro experimental setting, the conditioned medium of MV-treated injured tubular cells, which contains a higher concentration of HGF, strongly stimulated cell dedifferentiation and growth, as well as Erk1/2 signaling activation. Intriguingly, these effects were completely abrogated by either c-Met inhibitor or MEK inhibitor, suggesting that HGF induction is a crucial contributor to the acceleration of cell dedifferentiation and growth. All these findings indicate that MV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitates cell dedifferentiation and growth, which are important regenerative mechanisms.

In our previous study, microvesicles (MVs) released from human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) retard the growth of bladder cancer cells. We would like to know if MVs have a similar effect on human renal cell carcinoma (RCC). By use of cell culture and the BALB/c nu/nu mice xeno-graft model, the influence of MVs upon the growth and aggressiveness of RCC (786-0) was assessed. Cell counting kit-8 (CCK-8) assay, incidence of tumor, tumor size, Ki-67 or TUNEL staining was used to evaluate tumor cell growth in vitro or in vivo. Flow cytometry assay (in vitro) or examination of cyclin D1 expression (in vivo) was carried out to determine the alteration of cell cycle. The aggressiveness was analyzed by Wound Healing Assay (in vitro) or MMP-2 and MMP-9 expression (in vivo). AKT/p-AKT, ERK1/2/p-ERK1/2 or HGF/c-MET expression was detected by real-time PCR or western blot. Our data demonstrated that MVs promote the growth and aggressiveness of RCC both in vitro and in vivo. In addition, MVs facilitated the progression of cell cycle from G0/1 to S. HGF expression in RCC was greatly induced by MVs, associated with activation of AKT and ERK1/2 signaling pathways. RNase pre-treatment abrogated all effects of MVs. In summary, induction of HGF synthesis via RNA transferred by MVs activating AKT and ERK1/2 signaling is one of crucial contributors to the pro-tumor effect.

Oxidative stress is known as one of the main contributors in renal ischemia/reperfusion injury (IRI). Here we hypothesized that Micro-vesicles (MVs) derived from human Wharton Jelly mesenchymal stromal cells (hWJMSCs) could protect kidney against IRI through mitigating oxidative stress. MVs isolated from hWJMSCs conditioned medium were injected intravenously in rats immediately after unilateral kidney ischemia for 60 min. The animals were sacrificed at 24 h, 48 h and 2 weeks respectively after reperfusion. Our results show that the expression of NOX2 and reactive oxygen species (ROS) in injured kidney tissues was declined and the oxidative stress was alleviated in MVs group at 24 h and 48 h in parallel with the reduced apoptosis and enhanced proliferation of cells. IRI-initiated fibrosis was abrogated by MVs coincident with renal function amelioration at 2 weeks. NOX2 was also found down-regulated by MVs both in human umbilical vein endothelial cells (HUVEC) and NRK-52E cell line under hypoxia injury model in vitro. In conclusion, a single administration of hWJMSC-MVs might protect the kidney by alleviation of the oxidative stress in the early stage of kidney IRI through suppressing NOX2 expression. Moreover, it could reduce the fibrosis and improved renal function.