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AIM: The optimal preparation conditions of Salmon decalcified bone matrix (S-DBM) were explored, and the properties of S-DBM bone particles and bone powder were studied respectively. The therapeutic effect of S-DBM on tibial defect in female Sprague Dawley (SD) rats was preliminarily verified. METHODS: This study assessed the structural and functional similarities of Salmon bone DBM (S-DBM). The biocompatibility assessment was conducted using both in vivo and in vitro experiments, establishing an animal model featuring tibial defects in rats and on the L929 cell line, respectively. The control group, bovine DBM (bDBM), was compared to the S-DBM-treated tibial defect rats. Imaging and histology were used to study implant material changes, defect healing, osteoinductive repair, and degradation. RESULTS: The findings of our study indicate that S-DBM exhibits favorable repairing effects on bone defects, along with desirable physicochemical characteristics, safety, and osteogenic activity. CONCLUSIONS: The S-DBM holds significant potential as a medical biomaterial for treating bone defects, effectively fulfilling the clinical demands for materials used in bone tissue repair engineering.
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BACKGROUND: The current recommended starting age for gastric cancer (GC) lacks unified guideline and individualized criteria. We aimed to determine risk-stratified starting age for GC screening in China based on individuals' risk profiles, and develop an online calculator for clinical application. METHODS: In this multi-center population-based prospective study, we divided participants enrolled during 2015-2017 (n = 59,771, aged 40-69) into screened and unscreened groups and observed them for primary endpoints-GC occurrence, all-cause and GC-specific deaths. The median follow-up was 6.07 years. To determine the reference starting age, the effectiveness of GC screening was assessed by age-groups after propensity-score-matching. Further, we categorized the calculated individual risk scores (using well-established risk factors) by quantiles. Subsequently, we used age-specific 10-year cumulative risk curves to estimate the risk-stratified starting age-when the individual's risk level matches reference starting age risk threshold. RESULTS: During follow-up, 475 GC cases, 182 GC deaths and 1,860 all-cause deaths occurred. All-cause and GC-specific mortality decreased among screened individuals aged ≥45 and 50-59 years, respectively. Thus, the average population (reference) starting age was set as 50 years. The 10-year cumulative risk of GC in average population aged 50 was 1.147%. We stratified the starting age using eight risk factors, and categorized participants as low-, medium-, and high-risk individuals, whose risk-stratified starting age was 58, 50, and 46, respectively. CONCLUSION: While high-risk individuals warrant 3-5 years earlier GC screening than average population (age 50), low-risk individuals can tolerate delayed screening. Our online, personalized starting-age calculator will help risk-adapted GC screening (https://web.consultech.com.cn/gastric/#/).
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The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors.
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Objective: To summarize the morphological characteristics of sagittal beak-like deformity of head-neck fragment in femoral intertrochanteric fractures and to investigate the technical skills in fracture reduction. Methods: A clinical data of 31 patients with femoral intertrochanteric fractures between May 2021 and April 2023 was retrospectively analyzed. The fractures had sagittal beak-like deformity of head-neck fragment in all patients. There were 13 males and 18 females, with an average age of 76.2 years (range, 68-83 years). The time from injury to operation was 36-76 hours (mean, 51.2 hours). Fractures were classified as type A1.2 in 10 cases, type A1.3 in 11 cases, type A2.2 in 6 cases, and type A2.3 in 4 cases according to the AO/Orthopaedic Trauma Association (AO/OTA)-2018 classification; and as type A1.3 in 10 cases, type A2.1 in 11 cases, type A2.2 in 6 cases, type A2.3 in 2 cases, and type A2.4 in 2 cases according to a novel comprehensive classification for femoral intertrochanteric fractures proposed by the "Elderly Hip Fracture" Research Group of the Reparative and Reconstructive Surgery Committee of the Chinese Rehabilitation Medical Association. Based on preoperative X-ray films, CT scan and three-dimensional reconstruction, the fractures were classified into two types: type 1 (14 cases), with uncomplicated fracture morphology, severe bone interlocking and (or) soft tissue incarceration; type 2 (17 cases), with severe fracture crushing, obvious dissociation between bone blocks, and severe soft tissue hinge destruction. After the failure of the closed reduction, all patients underwent fracture reduction assisted with instrument via anterior minimal incision and proximal femoral nail antirotation nails internal fixation. The operation time, intraoperative fluoroscopy, intraoperative visible blood loss, length of hospital stay, and incidence of complications were recorded. The fracture reduction quality and stability score were assessed at immediate after operation under fluoroscopy. The fracture healing was evaluated and healing time was recorded by X-ray films. The pain visual analogue scale (VAS) score was performed at 48 hours after operation and Parker-Palmer activity score at 3 months after operation for function evaluation. Results: The operation time was 39-58 minutes (mean, 46.3 minutes); fluoroscopy was performed 13-38 times (mean, 23.5 times) during operation; the intraoperative visible blood loss was 45-90 mL (mean, 65.3 mL). The fracture reduction quality and stability score were rated as good in 29 cases and acceptable in 2 cases. The pain VAS score was 2-6 (mean, 3.1) at 48 hours after operation. Eleven patients developed deep vein thrombosis of the lower limbs after operation. Patients were hospitalized for 6-10 days (mean, 7.3 days). All patients were followed up 5-8 months (mean, 6.5 months). All fractures healed at 3.5-8.0 months after operation (mean, 4.5 months). Parker-Palmer activity score at 3 months after operation was 9 in 28 cases and 6 in 3 cases. Conclusion: The femoral intertrochanteric fracture with sagittal beak-like deformity of head-neck fragment is difficult to manually reduce. The pin combined with cannulated screw insertion to the neck cortex can hold the fragment and assist fracture reduction, which is a simple and effective technique.
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Fijación Interna de Fracturas , Fracturas de Cadera , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Anciano de 80 o más Años , Fijación Interna de Fracturas/métodos , Fracturas de Cadera/cirugía , Tornillos Óseos , Fijación Intramedular de Fracturas/métodosRESUMEN
Previously, we reported a cohort of Japanese encephalitis (JE) patients with Guillain-Barré syndrome. However, the evidence linking Japanese encephalitis virus (JEV) infection and peripheral nerve injury (PNI) remains limited, especially the epidemiology, clinical presentation, diagnosis, treatment, and outcome significantly differ from traditional JE. We performed a retrospective and multicenter study of 1626 patients with JE recorded in the surveillance system of the Chinese Center for Disease Control and Prevention, spanning the years 2016-2020. Cases were classified into type 1 and type 2 JE based on whether the JE was combined with PNI or not. A comparative analysis was conducted on demographic characteristics, clinical manifestations, imaging findings, electromyography data, laboratory results, and treatment outcomes. Among 1626 laboratory confirmed JE patients, 230 (14%) were type 2 mainly located along the Yellow River in northwest China. In addition to fever, headache, and disturbance of consciousness, type 2 patients experienced acute flaccid paralysis of the limbs, as well as severe respiratory muscle paralysis. These patients presented a greater mean length of stay in hospital (children, 22 years [range, 1-34]; adults, 25 years [range, 0-183]) and intensive care unit (children, 16 years [range, 1-30]; adults, 17 years [range, 0-102]). The mortality rate was higher in type 2 patients (36/230 [16%]) compared to type 1 (67/1396 [5%]). The clinical classification of the diagnosis of JE may play a crucial role in developing a rational treatment strategy, thereby mitigating the severity of the disease and potentially reducing disability and mortality rates among patients.
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PURPOSE: Through three neurocritical care unit (NCCU) surveys in China, we tried to understand the development status of neurocritical care and clarify its future development. METHODS: Using a cross-sectional survey method and self-report questionnaires, the number and quality of NCCUs were investigated through three steps: administering the questionnaire, sorting the survey data, and analyzing the survey data. RESULTS: At the second and third surveys, the number of NCCUs (76/112/206) increased by 47% and 84%, respectively. The NCCUs were located in tertiary grade A hospitals or teaching hospitals (65/100/181) in most provinces (24/28/29). The numbers of full-time doctors (359/668/1337) and full-time nurses (904/1623/207) in the NCCUs increased, but the doctor-bed ratio and nurse-bed ratio were still insufficient (0.4:1 and 1.3:1). CONCLUSION: In the past 20 years, the growth rate of NCCUs in China has accelerated, while the allocation of medical staff has been insufficient. Although most NCCU hospital bed facilities and instruments and equipment tend to be adequate, there are obvious defects in some aspects of NCCUs.
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Japanese encephalitis virus (JEV) infection is considered a global public health emergency. Severe peripheral neuropathy caused by JEV infection has increased disability and mortality rates in recent years. Because there are very few therapeutic options for JEV infection, prompt investigations of the ability of clinically safe, efficacious and globally available drugs to inhibit JEV infection and ameliorate peripheral neuropathy are urgently needed. In this study, we found that high doses of intravenous immunoglobulin, a function inhibitor of acid sphingomyelinase (FIASMA), inhibited acid sphingomyelinase (ASM) and ceramide activity in the serum and sciatic nerve of JEV-infected rats, reduced disease severity, reversed electrophysiological and histological abnormalities, significantly reduced circulating proinflammatory cytokine levels, inhibited Th1 and Th17 cell proliferation, and suppressed the infiltration of inflammatory CD4 + cells into the sciatic nerve. It also maintained the peripheral nerve-blood barrier without causing severe clinical side effects. In terms of the potential mechanisms, ASM was found to participate in immune cell differentiation and to activate immune cells, thereby exerting proinflammatory effects. Therefore, immunoglobulin is a FIASMA that reduces abnormal immune responses and thus targets the ASM/ceramide system to treat peripheral neuropathy caused by JEV infection.
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Ceramidas , Encefalitis Japonesa , Inmunoglobulinas Intravenosas , Enfermedades del Sistema Nervioso Periférico , Esfingomielina Fosfodiesterasa , Animales , Humanos , Masculino , Ratas , Ceramidas/metabolismo , Citocinas/metabolismo , Virus de la Encefalitis Japonesa (Especie)/inmunología , Virus de la Encefalitis Japonesa (Especie)/fisiología , Encefalitis Japonesa/tratamiento farmacológico , Encefalitis Japonesa/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/farmacología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/virología , Ratas Sprague-Dawley , Nervio Ciático/patología , Transducción de Señal/efectos de los fármacos , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Esfingomielina Fosfodiesterasa/metabolismo , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.
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Enfermedades Desmielinizantes , Exosomas , Animales , Ratones , Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes/tratamiento farmacológico , Oligodendroglía , Ligandos , Exosomas/metabolismo , Triyodotironina/metabolismo , Triyodotironina/farmacología , Triyodotironina/uso terapéutico , Cuprizona/toxicidad , Ratones Endogámicos C57BL , Vaina de Mielina/patología , Modelos Animales de EnfermedadRESUMEN
Existing research on non-suicidal self-injury (NSSI) among adolescents has primarily concentrated on general risk factors, leaving a significant gap in understanding the specific NSSI characteristics that predict diverse psychopathological outcomes. This study aims to address this gap by using Random Forests to discern the significant predictors of different clinical outcomes. The study tracked 348 adolescents (64.7% girls; mean age = 13.31, SD = 0.91) over 6 months. Initially, 46 characteristics of NSSI were evaluated for their potential to predict the repetition of NSSI, as well as depression, anxiety, and suicidal risks at a follow-up (T2). The findings revealed distinct predictors for each psychopathology. Specifically, psychological pain was identified as a significant predictor for depression, anxiety, and suicidal risks, while the perceived effectiveness of NSSI was crucial in forecasting its repetition. These findings imply that it is feasible to identify high-risk individuals by assessing key NSSI characteristics, and also highlight the importance of considering diverse NSSI characteristics when working with self-injurers.
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Depresión , Conducta Autodestructiva , Humanos , Conducta Autodestructiva/psicología , Femenino , Masculino , Adolescente , Depresión/psicología , Factores de Riesgo , Ansiedad/psicología , Conducta del Adolescente/psicología , Ideación Suicida , Bosques AleatoriosRESUMEN
Introduction: Academic stress is a significant and prevalent phenomenon among college students. According to the Demands-Resources Model, when individuals are unable to cope with stress that exceeds their capacity, burnout may occur. Although English courses hold a significant position in university education, there has been limited research on the mechanisms linking English academic stress to English academic burnout. Methods: This study recruited 1,130 undergraduate students taking English courses. Participants completed online questionnaires assessing English academic stress, rumination, English academic burnout, and neuroticism traits. A moderated mediation model was constructed to examine the relationship among these variables. Results: The results indicate that (1) Rumination serves as a mediator in the relationship between English academic stress and burnout; (2) neuroticism significantly moderates the pathway between English academic stress and rumination. Specifically, students with high neuroticism tendencies are more prone to developing rumination when faced with high levels of English academic stress. Conclusion: These findings offer valuable insights into the psychological mechanisms underlying the association between English learning stress and academic burnout. They emphasize the importance of addressing rumination as a mediator and considering individuals' levels of neuroticism in interventions aimed at preventing and alleviating academic burnout among university students.
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Non-suicidal self-injury (NSSI) is a significant public health problem, but there is no consistent evidence of its risk factors. One possibility is that there are subtypes NSSI that have different risk factors and clinical symptoms. In this review we evaluated the evidence of subtypes to determine if there were consistent subtypes of NSSI that emerged across studies. Four databases (Medline; Embase; PsycINFO; Web of Science) were searched to identify studies that used data-driven approaches and were published before November 9, 2022. There were 21 studies with 23 unique samples for review. Most of the included studies used NSSI symptoms or personal characteristics as the subtyping indicators, revealing 2-5 subtypes of NSSI. Variations in subtyping indicators, sample characteristics, and statistical methods may have contributed to the inconsistent number and characteristics of subtypes across studies. A new conceptual framework is proposed to integrate these diverse findings, highlighting the important roles of NSSI function and psychological pain in differentiating NSSI subtypes. This framework sheds light on the differences among self-injurers and offers insights for future endeavors to address the complexities of NSSI.
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Conducta Autodestructiva , Conducta Autodestructiva/psicología , Conducta Autodestructiva/clasificación , Humanos , Factores de RiesgoRESUMEN
Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.
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Encefalomielitis Autoinmune Experimental , Exosomas , MicroARNs , Vaina de Mielina , Animales , Ratones , Exosomas/metabolismo , Microglía/metabolismo , MicroARNs/genéticaRESUMEN
Subacute progressive neuropsychiatric symptoms with cognitive and motor impairment and autoimmune seizures are some of the typical symptoms of antiNmethylDaspartate receptor (antiNMDAR) encephalitis. The mechanisms underlying this disease are yet to be elucidated, which could be partly attributed to the lack of appropriate animal models. The present study aimed to establish an active immune mouse model of antiNMDAR encephalitis. Mice were immunized with the extracellular segment of the NMDA1 protein, then subjected to openfield and novel object recognition experiments. Plasma was collected after euthanasia on day 30 after immunization and antiNMDA1 antibodies were detected using ELISA. Furthermore, brain slices were analyzed to measure postsynaptic density protein 95 (PSD95) and NMDA1 expression. Western blot analysis of NMDA1 and PSD95 protein expression levels in the hippocampus was also performed. In addition, protein expression levels of PSD95 and NMDA1 in mouse neuronal HT22 cells were evaluated. Compared with controls, mice immunized with NMDA1 exhibited anxiety, depression and memory impairment. Moreover, high antiNMDA1 antibody titers were detected with ELISA and the levels of antiNMDA1 antibody reduced postsynaptic NMDA1 protein density in the mouse hippocampus. These findings demonstrated the successful construction of a novel mouse model of antiNMDAR encephalitis by actively immunizing the mice with the extracellular segment of the NMDA1 protein. This model may be useful for studying the pathogenesis and drug treatment of antiNMDAR encephalitis in the future.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Ratones , Animales , Vacunación , Receptores de N-Metil-D-Aspartato , Homólogo 4 de la Proteína Discs Large , Apolipoproteínas ERESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, with occasional involvement of the extrapyramidal system. Mutations in the sigma non-opioid intracellular receptor 1 (SIGMAR1) gene have been identified as one of the causes of ALS. Here, we present a case of a 49-year-old man diagnosed with ALS-Parkinson's disease (PD) complex. The patient exhibited bradykinesia and tremor, and whole-exome sequencing revealed homozygous mutations in the SIGMAR1 gene (c.446-2A > T). In addition, we conducted an investigation into the clinical and molecular phenotype of previously reported variants of SIGMAR1 associated with ALS. This case report aims to raise awareness among physicians regarding atypical phenotypes of amyotrophic lateral sclerosis and to encourage further research on the factors leading to SIGMAR1 mutations in patients.
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HEADINGS: Kelch-like protein 11antibody is a recently identified biomarker for paraneoplastic neurological syndromes associated with germ-cell tumors that was first described as an onconeural antibody causing autoimmune encephalitis associated with seminoma in 2019. Ataxia is the most prevalent presenting symptom, with other neurological symptoms including vertigo, double vision, hearing loss, tinnitus and dysarthria. Magnetic resonance imaging scans reveal that the lesions are mostly located in the cerebellum and brainstem, particularly in the pontine region, and may also exhibit cerebellar atrophy. AIM OF THE STUDY: In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome. MATERIALS AND METHODS: We present a middle-aged female patient who presented with vertigo, cognitive decline, ataxia and limb weakness. A cell-based assay (CBA) showed positive IgG Kelch-like protein 11 in both her serum and CSF, as well as positive oligoclonal bands in her CSF. She was diagnosed with KLHL11 antibody-associated autoimmune encephalomyelitis and received high-dose intravenous methylprednisolone pulse therapy. RESULT AND CONCLUSIONS: Clinical outcomes suggest that patients with Kelch-like protein 11 antibody mostly have poor prognoses, excepting our case. We propose that early and appropriate treatments are critical for timely diagnosis and rapid improvement.
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We sought to evaluate whether the neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features of the substantia nigra (SN) have utility in the differential diagnosis of Parkinson's disease (PD) and essential tremor (ET). This study enrolled 23 patients with PD, 20 patients with ET, and 18 healthy participants. All subjects underwent clinical examination, motor and cognitive assessments, and NM-MRI scans. The area and contrast-to-noise ratio (CNR) values of SN were defined according to NM-MRI images. Then, receiver operating characteristic (ROC) analysis was conducted to characterize the diagnostic power of the SN area and CNR values of SN. Compared with ET and control groups, the PD group showed a significant reduction of the area of SN (P = 0.003, PD vs. ET; P = 0.001, PD vs. control) and in the SN to midbrain area ratio in the same layer (P = 0.006, PD vs. ET; P = 0.005, PD vs. control). The SN area had a sensitivity of 65% and a specificity of 87% for distinguishing ET from PD, with an area under the curve (AUC) of 0.7630 and a Youden index of 0.5200, whereas the ratio of the SN area to midbrain area in the same layer had a sensitivity of 60% and a specificity of 87% for distinguishing ET from PD, with an AUC of 0.7478 and a Youden index of 0.4700. Compared with the ET group, the mean CNR value of the SN and the respective CNR values of the three subregions were all weakened in the PD group, and only the CNR in the middle part was significantly different from the control group (P = 0.006). The sensitivity of the CNR value of the middle part of the SN for differentiating ET from PD was 65%, the specificity was 87%, the AUC was 0.7500, and the Youden index was 0.5200.Based on our findings, we conclude that NM-MRI can improve diagnostic accuracy in PD and can be used as a specific and sensitive potential diagnostic biomarker for PD.
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Temblor Esencial , Enfermedad de Parkinson , Humanos , Diagnóstico Diferencial , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Temblor Esencial/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
Guillain-Barré syndrome (GBS) is an acute idiopathic polyneuropathy which is related to infection and immune mechanism. The exact pathogenesis of the disease is unknown and treatment is limited. Thus, the purpose of the study is to identify biomarkers of GBS serum and elucidate their involvement in the underlying pathogenesis of GBS that could help to treat GBS more accurately. Antibody array technology was used to detect the expression levels of 440 proteins in serum of 5 GBS group and 5 healthy control group. Sixty-seven differentially expressed proteins (DEPs) were identified by antibody array, among which FoLR1, Legumain, ErbB4, IL-1α, MIP-1α and IGF-2 were down-regulated, while 61 proteins were up-regulated. Bioinformatics analysis indicated that most DEPs were associated with leukocytes, among which IL-1α, SDF-1b, B7-1, CD40, CTLA4, IL-9, MIP-1α and CD40L were in the center of protein-protein interaction (PPI) network. Subsequently, the ability of these DEPs to distinguish GBS from healthy control was further evaluated. CD23 was identified by means of Random Forests Analysis (RFA) and verified by enzyme-linked immunosorbent assay (ELISA). The ROC curve result of CD23 respectively displayed that its sensitivity, specificity and AUC were 0.818, 0.800 and 0.824. We speculate that activation of leukocyte proliferation and migration in circulating blood might be associated with inflammatory recruitment of peripheral nerves, leading to the occurrence and development of GBS, but this conclusion still requires deeper confirmation. More importantly, central proteins may play a pivotal role in the pathogenesis of GBS. In addition, we detected IL-1α, IL-9, and CD23 in the serum of GBS patients for the first time, which may be promising biomarkers for the treatment of GBS.
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Citocinas , Síndrome de Guillain-Barré , Humanos , Quimiocina CCL3 , Interleucina-9 , Anticuerpos , Receptor 1 de FolatoRESUMEN
Japanese encephalitis virus (JEV), with neurotoxic and neuroinvasive properties, is the major cause of human viral encephalitis in Asia. Although Guillain-Barré syndrome caused by JEV infections is not frequent, a few cases have been reported in recent years. To date, no existing animal model for JEV-induced peripheral nerve injury (PNI) has been established, and thus the pathogenic mechanism is not clarified. Therefore, an animal model is urgently required to clarify the correlation between JEV infection and PNI. In the present study, we used JEV GIb strain of NX1889 to establish a mouse model of JEV infection. The general neurological signs emerged on day 3 of modeling. The motor function continued to deteriorate, reaching a maximum at 8 to 13 days postinfection (dpi) and gradually recovered after 16 dpi. The injuries of 105 PFU and 106 PFU groups were the most severe. Transmission electron microscopy and immunofluorescence staining showed varying degrees of demyelination and axonal degeneration in the sciatic nerves. The electrophysiological recordings demonstrated the presence of demyelinating peripheral neuropathy with reduced nerve conduction velocity. The decreased amplitudes and the prolonged end latency revealed axonal-type motor neuropathy. Demyelination is predominant in the early stage, followed by axonal injury. The expression level of JEV-E protein and viral RNA was elevated in the injured sciatic nerves, suggesting that it may cause PNI at the early stage. Inflammatory cell infiltration and increased inflammatory cytokines indicated that neuroinflammation is involved in JEV-induced PNI. IMPORTANCE JEV is a neurotropic flavivirus belonging to the Flaviviridae family and causes high mortality and disability rates. It invades the central nervous system and induces acute inflammatory injury and neuronal death. Thus, JEV infection is a major global public health concern. Previously, motor dysfunction was mainly attributed to central nervous system damage. Our knowledge regarding JEV-induced PNI is vague and neglected. Therefore, a laboratory animal model is essential. Herein, we showed that C57BL/6 mice can be used to study JEV-induced PNI through multiple approaches. We also demonstrated that viral loads might be positively correlated with lesion severity. Therefore, inflammation and direct virus infection may be the putative mechanisms underlying JEV-induced PNI. The results of this study laid the foundation for further elucidation of the pathogenesis mechanisms of PNI caused by JEV.
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Modelos Animales de Enfermedad , Virus de la Encefalitis Japonesa (Especie) , Encefalitis Japonesa , Traumatismos de los Nervios Periféricos , Animales , Humanos , Ratones , Enfermedades Desmielinizantes , Virus de la Encefalitis Japonesa (Especie)/fisiología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Japanese encephalitis virus (JEV; Flaviridae: Flavivirus) causes Japanese encephalitis (JE), which is the most important arboviral disease in Asia and the western Pacific. Among the five JEV genotypes (GI-V), GI has dominated traditional epidemic regions in the past 20 years. We investigated the transmission dynamics of JEV GI through genetic analyses. METHODS: We generated 18 JEV GI near full length sequences by using multiple sequencing approaches from mosquitoes collected in natural settings or from viral isolates obtained through cell culture. We performed phylogenetic and molecular clock analyses to reconstruct the evolutionary history by integrating our data with 113 publicly available JEV GI sequences. RESULTS: We identified two subtypes of JEV GI (GIa and GIb), with a rate of 5.94 × 10-4 substitutions per site per year (s/s/y). At present, GIa still circulates within a limited region, exhibited no significant growth, the newest strain was discovered in China (Yunnan) in 2017, whereas most JEV strains circulating belong to the GIb clade. During the past 30 years, two large GIb clades have triggered epidemics in eastern Asia: one epidemic occurred in 1992 [95% highest posterior density (HPD) = 1989-1995] and the causative strain circulates mainly in southern China (Yunnan, Shanghai, Guangdong, and Taiwan) (Clade 1); the other epidemic occurred in 1997 (95% HPD = 1994-1999) and the causative strain has increased in circulation in northern and southern China during the past 5 years (Clade 2). An emerging variant of Clade 2 contains two new amino acid markers (NS2a-151V, NS4b-20K) that emerged around 2005; this variant has demonstrated exponential growth in northern China. CONCLUSION: JEV GI stain circulating in Asia have shifted during the past 30 years, spatiotemporal differences were observed among JEV GI subclade. GIa is still circulating within a limited range, exhibite no significant growth. Two large GIb clades have triggered epidemics in eastern Asia, all JEV sequences identified in northern China during the past 5 years were of the new emerging variant of G1b-clade 2.