Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown ...Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.展开更多
The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well define...The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.展开更多
IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly exp...IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.展开更多
Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limit...Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.展开更多
AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-fou...AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.展开更多
AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
Non-traumatic headache is a common presentation in both emergency and outpatient settings,where timely identification of raised intracranial pressure(ICP)is crucial to prevent severe neurological complications.Convent...Non-traumatic headache is a common presentation in both emergency and outpatient settings,where timely identification of raised intracranial pressure(ICP)is crucial to prevent severe neurological complications.Conventional diagnostic methods such as computed tomography and lumbar puncture have important limitations,including invasiveness,delayed availability,and limited sensitivity in certain contexts.Point-of-care ultrasound measurement of the optic nerve sheath diameter(ONSD)has emerged as a rapid,non-invasive tool for detecting elevated ICP at the bedside.The technique is based on the anatomical continuity between the intracranial subarachnoid space and the optic nerve sheath,which expands in response to increased ICP.Evidence from multiple studies and meta-analyses indicates that ONSD measurements above 5.0-5.7 mm in adults strongly correlate with elevated ICP,showing pooled sensitivities and specificities approaching 90%.This modality enables immediate triage,guides urgency of neuroimaging,reduces unnecessary radiation exposure,and can be applied in outpatient and low-resource settings.Despite these advantages,ONSD assessment is subject to operator dependency,variability in threshold values,and reduced accuracy in patients with certain ocular or systemic conditions.Advances in artificial intelligence–assisted measurement,coupled with standardized training protocols,have the potential to improve reproducibility and broaden adoption.Overall,point-of-care ultrasound-based ONSD measurement represents a valuable adjunct in the early evaluation of patients with non-traumatic headache,facilitating faster diagnosis,better resource utilization,and improved patient outcomes.展开更多
BACKGROUND The optic nerve sheath diameter(ONSD)measured by ultrasound has emerged as a significant noninvasive method for detecting elevated intracranial pressure(ICP),guiding timely interventions,and monitoring trea...BACKGROUND The optic nerve sheath diameter(ONSD)measured by ultrasound has emerged as a significant noninvasive method for detecting elevated intracranial pressure(ICP),guiding timely interventions,and monitoring treatment response.Previous studies have shown that the baseline ONSD at admission is a prognostic indicator of mortality in adult patients with cerebrovascular events,traumatic brain injury,hepatic encephalopathy,and acute stroke.However,pediatric data on the dynamic changes in ONSD remain limited.AIM To study the association between within-48 hours admission dynamic ONSD changes and mortality in children with clinically relevant elevated ICP.METHODS This single-institution prospective study was performed at a tertiary Children’s Hospital in Vietnam,between November 2023 and August 2024.The primary outcome was in-hospital mortality rate.ONSD data were measured at admission,24 hours,and 48 hours post-admission to pediatric intensive care unit(PICU).Linear mixed-effects models accounting for repeated measures within individuals were used to analyze the association between ONSD changes and in-hospital mortality.RESULTS A total of 69 PICU-admitted children with clinically relevant raised ICP were enrolled and included in the analysis.The median patient age was 6 years(interquartile range:1-12),and males accounted for 54%of all patients.The inhospital mortality rate in children with clinically relevant raised ICP was 23.2%.Traumatic brain injury,sepsisassociated encephalopathy,and septic shock were the main causes of death in this cohort.Linear mixed-effects analysis showed that dynamic variability in ONSD values upon PICU admission and during the first 48 hours later correlated significantly with increased mortality.Nonsurvivors had a 5.3%increase in the mean ONSD at 48 hours compared to baseline levels,while the survivors showed a 5.6%reduction in ONSD.CONCLUSION Serial ultrasound-based ONSD measurements within 48 hours of admission better predicted mortality than baseline data in critically ill children,offering a practical,noninvasive tool for early prognosis in elevated ICP.展开更多
In adult mammals,optic nerve injury leads to irreversible vision loss due to its extremely limited regenerative capacity.In contrast,adult zebrafish possess a robust capacity for spontaneous visual system regeneration...In adult mammals,optic nerve injury leads to irreversible vision loss due to its extremely limited regenerative capacity.In contrast,adult zebrafish possess a robust capacity for spontaneous visual system regeneration,although the spatiotemporal coordination of recovery across the retina,optic nerve,and brain remains poorly understood.In the present study,the regenerative dynamics following optic nerve transection were systematically characterized in adult zebrafish over a 5 week period using hematoxylin-eosin staining,immunohistochemistry,transmission electron microscopy,single-cell RNA sequencing,and optokinetic response(OKR)behavioral assessments.At 1 week post-injury(1 wpi),retinal ganglion cell depletion was evident but showed significant recovery by 2 wpi.Concurrently,the injured optic nerve displayed a marked increase in diameter and cell number at 2 wpi,including widespread expression of proliferating cell nuclear antigen,consistent with heightened proliferative activity.Single-cell transcriptomic profiling at 2 wpi revealed five principal cell populations:fibroblasts,mural cells,immune cells,mature oligodendrocytes,and myelin-forming oligodendrocytes.By 4-5 wpi,remyelination within the optic nerve and re-establishment of synaptic architecture in the optic tectum were strongly correlated with functional restoration of OKR behavior.These findings provide a comprehensive spatiotemporal framework of visual pathway regeneration in zebrafish,establishing a valuable model for elucidating conserved mechanisms of neural repair with translational potential for human vision restoration.展开更多
Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularize...Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.展开更多
BACKGROUND Neuromonitoring in medical intensive care units is challenging as most patients are unfit for invasive intracranial pressure(ICP)modalities or unstable to transport for imaging.Ultrasonography-based optic n...BACKGROUND Neuromonitoring in medical intensive care units is challenging as most patients are unfit for invasive intracranial pressure(ICP)modalities or unstable to transport for imaging.Ultrasonography-based optic nerve sheath diameter(ONSD)is an attractive option as it is reliable,repeatable and easily performed at the bedside.It has been sufficiently validated in traumatic brain injury(TBI)to be incorporated into the guidelines.However,currently the data for non-TBI patients is inconsistent for a scientific recommendation to be made.AIM To compile the existing evidence for understanding the scope of ONSD in measuring ICP in adult non-traumatic neuro-critical patients.METHODS PubMed,Google Scholar and research citation analysis databases were searched for studies in adult patients with non-traumatic causes of raised ICP.Studies from 2010 to 2024 in English languages were included.RESULTS We found 37 articles relevant to our search.The cutoff for ONSD in predicting ICP varied from 4.1 to 6.3 mm.Most of the articles used cerebrospinal fluid opening pressure followed by raised ICP on computed tomography/magnetic resonance imaging as the comparator parameter.ONSD was also found to be a reliable outcome measure in cases of acute ischaemic stroke,intracerebral bleeding and intracranial infection.However,ONSD is of doubtful utility in septic metabolic encephalopathy,dysnatremias and aneurysmal subarachnoid haemorrhage.CONCLUSION ONSD is a useful tool for the diagnosis of raised ICP in non-traumatic neuro-critically ill patients and may also have a role in the prognostication of a subset of patients.展开更多
Objective This study aimed to develop and test a model for predicting dysthyroid optic neuropathy(DON)based on clinical factors and imaging markers of the optic nerve and cerebrospinal fluid(CSF)in the optic nerve she...Objective This study aimed to develop and test a model for predicting dysthyroid optic neuropathy(DON)based on clinical factors and imaging markers of the optic nerve and cerebrospinal fluid(CSF)in the optic nerve sheath.Methods This retrospective study included patients with thyroid-associated ophthalmopathy(TAO)without DON and patients with TAO accompanied by DON at our hospital.The imaging markers of the optic nerve and CSF in the optic nerve sheath were measured on the water-fat images of each patient and,together with clinical factors,were screened by Least absolute shrinkage and selection operator.Subsequently,we constructed a prediction model using multivariate logistic regression.The accuracy of the model was verified using receiver operating characteristic curve analysis.Results In total,80 orbits from 44 DON patients and 90 orbits from 45 TAO patients were included in our study.Two variables(optic nerve subarachnoid space and the volume of the CSF in the optic nerve sheath)were found to be independent predictive factors and were included in the prediction model.In the development cohort,the mean area under the curve(AUC)was 0.994,with a sensitivity of 0.944,specificity of 0.967,and accuracy of 0.901.Moreover,in the validation cohort,the AUC was 0.960,the sensitivity was 0.889,the specificity was 0.893,and the accuracy was 0.890.Conclusions A combined model was developed using imaging data of the optic nerve and CSF in the optic nerve sheath,serving as a noninvasive potential tool to predict DON.展开更多
Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients ...Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients will have diabetic retinopathy,the leading cause of visual defects in working-age people worldwide.Although diabetes is considered a microvascular disease,recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system,albeit its mechanisms are still under investigation.Neuroinflammation and oxidative stress are intrinsically related phenomena,since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases,and both pathological processes are increased in the visual system during diabetes.The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.展开更多
Rho-associated kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway is closely related to the pathogenesis of several central nervous syst...Rho-associated kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway is closely related to the pathogenesis of several central nervous system (CNS) disorders, and involved in many aspects of neuronal functions including neurite outgrowth and retraction. In the adult CNS, the damaged neuron regeneration is very difficult due to the presence of myelin-associated axon growth inhibitors such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (Omgp), etc. The effects of these axon growth inhibitors are reversed by blocking the Rho/ROCK pathway 47 vitro, and the inhibition of Rho/ROCK pathway can promote axon regeneration and functional recovery in the injured CNS in viva In addition, the therapeutic effects of the Rho/ROCK inhibitors have also been demonstrated in some animal models and the Rho/ROCK pathway becomes an attractive target for the development of drugs for treating CNS disorders. In this review, we summarized on the effect of the Rho and the downstream factor ROCK in neural regeneration, and the potential therapeutic effect of Rho/ROCK inhibitors in the survival and axonal regeneration of retinal ganglion cell was also discussed.展开更多
Objective The optic nerve is a key component regarding research on visual prosthesis.Previous pharmacological and electrical studies has pinned down the main features of the mechanisms underlying the nerve impulse in ...Objective The optic nerve is a key component regarding research on visual prosthesis.Previous pharmacological and electrical studies has pinned down the main features of the mechanisms underlying the nerve impulse in the rat optic nerve,and this work proposed a mathematical model to simulate these phenomena.Methods The main active nodal channels：fast Na^＋,persistent Na^,slow K^＋ and a fast repolarizing K^＋（A-current）were added on a double layer representation of the axon.A simplified representation of K^＋ accumulation and clearance in the vicinity of the Ranvier node was integrated in this model.Results The model was able to generate the following features.In the presence of 4-aminopyridine （4-AP）,spike duration increased and a depolarizing afterpotential（DAP）appeared.In the presence of 4-AP and tetraethylammonium（TEA）,the DAP was followed by a hyperpolarizing afterpotential（AHP）and the amplitude of this AHP increased with the frequency of the stimulation.In normal conditions（no drugs）：DAP and AHP were absent after a single action potential（AP）and a short train of AP;there was a relative refractoriness in amplitude lasting for 30 ms after an AP;an early AHP was revealed by a continuous depolarizing current;and there was a partial spike adaptation for a long current step stimulus.Conclusion The model successfully reproduced previous experiments results including long-lasting stimulation experiment,which is known to modify nerve physiological parameter values and is a key issue for visual prosthesis research.展开更多
The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3K/AKT/mTOR signaling pathway has been shown to enhance the intrinsic growth capacity of ne...The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3K/AKT/mTOR signaling pathway has been shown to enhance the intrinsic growth capacity of neurons and to facilitate axonal regeneration in the central nervous system after injury. The deletion of the mTOR negative regulator phosphatase and tensin homolog （PTEN） enhances regeneration of adult corticospinal neurons and ganglion cells. In the present study, we used a tyrosine-mutated （Y444F） AAV2 vector to efficiently express a short hairpin RNA （shRNA） for silencing PTEN expression in retinal ganglion cells. We evaluated cell survival and axonal regeneration in a rat model of optic nerve axotomy. The rats received an intravitreal injection of wildtype AAV2 or Y444F mutant AAV2 （both carrying shRNA to PTEN） 4 weeks before optic nerve axotomy. Compared with the wildtype AAV2 vector, the Y444F mutant AAV2 vector enhanced retinal ganglia cell survival and stimulated axonal regeneration to a greater extent 6 weeks after axotomy. Moreover,post-axotomy injection of the Y444F AAV2 vector expressing the shRNA to PTEN rescued ～19% of retinal ganglion cells and induced axons to regenerate near to the optic chiasm. Taken together, our results demonstrate that PTEN knockdown with the Y444F AAV2 vector promotes retinal ganglion cell survival and stimulates long-distance axonal regeneration after optic nerve axotomy. Therefore, the Y444F AAV2 vector might be a promising gene therapy tool for treating optic nerve injury.展开更多
Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associate...Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demon- strated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.展开更多
AIM: To evaluate the value of quantitative diffusion tensor imaging (DTI) in assessing the axonal and myelin damage of the optic nerves and optic radiations in patients with chronic primary angle -closure glaucoma (PA...AIM: To evaluate the value of quantitative diffusion tensor imaging (DTI) in assessing the axonal and myelin damage of the optic nerves and optic radiations in patients with chronic primary angle -closure glaucoma (PACG) by using high -field magnetic resonance (MR) imaging (3T). METHODS: Twenty patients with bilateral chronic PACG and twenty age - and sex matched disease -free control subjects were enrolled. Conventional MRI and DTI were performed on all subjects using 3T MR scanner. Mean diffusivity (MD), fractional anisotropy (FA), axial diffusivities (AD) and radial diffusivities (RD) of each optic nerve and each optic radiation were measured by using post -processing software of DTI studio 2.3, and then compared between left eyes and right eyes and between patients group and control group. The pairedsample t- test were used. RESULTS: There was no abnormality in the shape and signal intensity of the optic nerves and optic radiations in patients group and control group on the conventional MRI. No significant differences were observed in the FA, MD, AD and RD between the right and left optic nerves and optic radiations within patients group and control group (P>0.05). The optic nerves and optic radiations of patients with chronic PACG, as compared with control subjects, had significantly higher MD, AD, RD and significantly lower FA (P<0.05). CONCLUSION: The diffusivity of optic nerves and optic radiations in chronic PACG group showed abnormal and diffusivity parameters could be used markers of axonal and myelin injury in glaucoma.展开更多
The SoxC transcription factors （Sox4, Sox11, and Sox12） play important roles in the development of the vertebrate eye and retina. However, their expression and function during retinal and optic nerve regeneration re...The SoxC transcription factors （Sox4, Sox11, and Sox12） play important roles in the development of the vertebrate eye and retina. However, their expression and function during retinal and optic nerve regeneration remain elusive. In this study, we investigated the expression and possible functions of the SoxC genes after retinal and optic nerve injury in adult zebrafish. We found that among the five SoxC members, Soxllb was strongly induced in BrdU-positive cells in the inner nuclear layer （INL） after retinal injury, and morpholino-mediated Soxllb-knockdown significantly reduced the number of proliferating cells in the INL at 4 days post-injury. After optic nerve lesion, both Soxl la and Soxl lb were strongly expressed in retinal ganglion cells （RGCs）, and knockdown of both Soxl la and Soxllb inhibited RGC axon regrowth in retinal explants. Our study thus uncovered a novel expression pattern of SoxC family genes after retinal and optic nerve injury, and suggests that they have important functions during retinal and optic nerve regeneration.展开更多
We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study （SCOTS）. SCOTS is an Institutional Review Board ap- proved clinical trial and has beco...We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study （SCOTS）. SCOTS is an Institutional Review Board ap- proved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date （www.clinicaltrials.gov Identifier NCT 01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient＇s previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and in- travitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient＇s visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82471123,82171053the Jilin Province Special Project for Talent in Medical and Health Sciences,No.2024WSXK-E01the Natural Science Foundation of Jilin Province,YDZJ202501ZYTS318(all to GL).
文摘Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.
基金supported by the Lanzadera TCUE and C2 program(Universidad de Salamanca)(to ASL)the Spanish National Research Council(CSIC)funded by the Junta de Castilla y León and co-financed by the European Regional Development Fund(ERDF“Europe drives our growth”):Internationalization Project“CL-EI-2021-08-IBFG Unit of Excellence”,Grant(PID2022-138478OA-100)funded by MICIU/AEI/10.13039/501100011033 and,by FEDER,UE(to MGM)+3 种基金Junta de Castilla y León(SA225P23)Gerencia Regional de Salud(2701/A1/2023)(to AV)the Plan Especial Grado Medicina(USAL)(to CPM)a Ramón y Cajal researcher:Grant RYC2021-033684-I funded by MICIU/AEI/10.13039/501100011033 and,by European Union NextGenerationEU/PRTR.
文摘The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.
基金supported by the National Natural Science Foundation of China(31670876 and 82171761).
文摘IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
基金supported by the National Natural Science Foundation of China,No.82271114the Natural Science Foundation of Zhejiang Province of China,No.LZ22H120001(both to ZLC).
文摘Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
文摘AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
文摘Non-traumatic headache is a common presentation in both emergency and outpatient settings,where timely identification of raised intracranial pressure(ICP)is crucial to prevent severe neurological complications.Conventional diagnostic methods such as computed tomography and lumbar puncture have important limitations,including invasiveness,delayed availability,and limited sensitivity in certain contexts.Point-of-care ultrasound measurement of the optic nerve sheath diameter(ONSD)has emerged as a rapid,non-invasive tool for detecting elevated ICP at the bedside.The technique is based on the anatomical continuity between the intracranial subarachnoid space and the optic nerve sheath,which expands in response to increased ICP.Evidence from multiple studies and meta-analyses indicates that ONSD measurements above 5.0-5.7 mm in adults strongly correlate with elevated ICP,showing pooled sensitivities and specificities approaching 90%.This modality enables immediate triage,guides urgency of neuroimaging,reduces unnecessary radiation exposure,and can be applied in outpatient and low-resource settings.Despite these advantages,ONSD assessment is subject to operator dependency,variability in threshold values,and reduced accuracy in patients with certain ocular or systemic conditions.Advances in artificial intelligence–assisted measurement,coupled with standardized training protocols,have the potential to improve reproducibility and broaden adoption.Overall,point-of-care ultrasound-based ONSD measurement represents a valuable adjunct in the early evaluation of patients with non-traumatic headache,facilitating faster diagnosis,better resource utilization,and improved patient outcomes.
文摘BACKGROUND The optic nerve sheath diameter(ONSD)measured by ultrasound has emerged as a significant noninvasive method for detecting elevated intracranial pressure(ICP),guiding timely interventions,and monitoring treatment response.Previous studies have shown that the baseline ONSD at admission is a prognostic indicator of mortality in adult patients with cerebrovascular events,traumatic brain injury,hepatic encephalopathy,and acute stroke.However,pediatric data on the dynamic changes in ONSD remain limited.AIM To study the association between within-48 hours admission dynamic ONSD changes and mortality in children with clinically relevant elevated ICP.METHODS This single-institution prospective study was performed at a tertiary Children’s Hospital in Vietnam,between November 2023 and August 2024.The primary outcome was in-hospital mortality rate.ONSD data were measured at admission,24 hours,and 48 hours post-admission to pediatric intensive care unit(PICU).Linear mixed-effects models accounting for repeated measures within individuals were used to analyze the association between ONSD changes and in-hospital mortality.RESULTS A total of 69 PICU-admitted children with clinically relevant raised ICP were enrolled and included in the analysis.The median patient age was 6 years(interquartile range:1-12),and males accounted for 54%of all patients.The inhospital mortality rate in children with clinically relevant raised ICP was 23.2%.Traumatic brain injury,sepsisassociated encephalopathy,and septic shock were the main causes of death in this cohort.Linear mixed-effects analysis showed that dynamic variability in ONSD values upon PICU admission and during the first 48 hours later correlated significantly with increased mortality.Nonsurvivors had a 5.3%increase in the mean ONSD at 48 hours compared to baseline levels,while the survivors showed a 5.6%reduction in ONSD.CONCLUSION Serial ultrasound-based ONSD measurements within 48 hours of admission better predicted mortality than baseline data in critically ill children,offering a practical,noninvasive tool for early prognosis in elevated ICP.
基金supported by National Key R&D Program of China(2021YFA1101200)National Natural Science Foundation of China(82171048+6 种基金81800842)Key R&D Program of Zhejiang Province(2021C03065)Key R&D Program of Wenzhou Eye Hospital(YNZD1201902)Key R&D Program of Wenzhou(ZY2022021)R&D Program of Wenzhou(H20220008)Research Initiation Funds from Wenzhou Eye Hospital(KYQD20221203)China Postdoctoral Science Foundation(2023M742674)。
文摘In adult mammals,optic nerve injury leads to irreversible vision loss due to its extremely limited regenerative capacity.In contrast,adult zebrafish possess a robust capacity for spontaneous visual system regeneration,although the spatiotemporal coordination of recovery across the retina,optic nerve,and brain remains poorly understood.In the present study,the regenerative dynamics following optic nerve transection were systematically characterized in adult zebrafish over a 5 week period using hematoxylin-eosin staining,immunohistochemistry,transmission electron microscopy,single-cell RNA sequencing,and optokinetic response(OKR)behavioral assessments.At 1 week post-injury(1 wpi),retinal ganglion cell depletion was evident but showed significant recovery by 2 wpi.Concurrently,the injured optic nerve displayed a marked increase in diameter and cell number at 2 wpi,including widespread expression of proliferating cell nuclear antigen,consistent with heightened proliferative activity.Single-cell transcriptomic profiling at 2 wpi revealed five principal cell populations:fibroblasts,mural cells,immune cells,mature oligodendrocytes,and myelin-forming oligodendrocytes.By 4-5 wpi,remyelination within the optic nerve and re-establishment of synaptic architecture in the optic tectum were strongly correlated with functional restoration of OKR behavior.These findings provide a comprehensive spatiotemporal framework of visual pathway regeneration in zebrafish,establishing a valuable model for elucidating conserved mechanisms of neural repair with translational potential for human vision restoration.
基金supported by grants from the National Key R&D Program of China,No.2017YFA0104704(to BQL)the Young Elite Scientist Sponsorship Program(YESS)by China Association for Science and Technology(CAST),No.2018QNRC001(to BQL)+1 种基金the Fundamental Research Funds for the Central Universities,China,No.18ykpy38(to BQL)the National Natural Science Foundation of China,Nos.81971157(to BQL),81891003(to YSZ).
文摘Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.
文摘BACKGROUND Neuromonitoring in medical intensive care units is challenging as most patients are unfit for invasive intracranial pressure(ICP)modalities or unstable to transport for imaging.Ultrasonography-based optic nerve sheath diameter(ONSD)is an attractive option as it is reliable,repeatable and easily performed at the bedside.It has been sufficiently validated in traumatic brain injury(TBI)to be incorporated into the guidelines.However,currently the data for non-TBI patients is inconsistent for a scientific recommendation to be made.AIM To compile the existing evidence for understanding the scope of ONSD in measuring ICP in adult non-traumatic neuro-critical patients.METHODS PubMed,Google Scholar and research citation analysis databases were searched for studies in adult patients with non-traumatic causes of raised ICP.Studies from 2010 to 2024 in English languages were included.RESULTS We found 37 articles relevant to our search.The cutoff for ONSD in predicting ICP varied from 4.1 to 6.3 mm.Most of the articles used cerebrospinal fluid opening pressure followed by raised ICP on computed tomography/magnetic resonance imaging as the comparator parameter.ONSD was also found to be a reliable outcome measure in cases of acute ischaemic stroke,intracerebral bleeding and intracranial infection.However,ONSD is of doubtful utility in septic metabolic encephalopathy,dysnatremias and aneurysmal subarachnoid haemorrhage.CONCLUSION ONSD is a useful tool for the diagnosis of raised ICP in non-traumatic neuro-critically ill patients and may also have a role in the prognostication of a subset of patients.
基金supported financially by grants from the National Natural Science Foundation of China(No.81771793).
文摘Objective This study aimed to develop and test a model for predicting dysthyroid optic neuropathy(DON)based on clinical factors and imaging markers of the optic nerve and cerebrospinal fluid(CSF)in the optic nerve sheath.Methods This retrospective study included patients with thyroid-associated ophthalmopathy(TAO)without DON and patients with TAO accompanied by DON at our hospital.The imaging markers of the optic nerve and CSF in the optic nerve sheath were measured on the water-fat images of each patient and,together with clinical factors,were screened by Least absolute shrinkage and selection operator.Subsequently,we constructed a prediction model using multivariate logistic regression.The accuracy of the model was verified using receiver operating characteristic curve analysis.Results In total,80 orbits from 44 DON patients and 90 orbits from 45 TAO patients were included in our study.Two variables(optic nerve subarachnoid space and the volume of the CSF in the optic nerve sheath)were found to be independent predictive factors and were included in the prediction model.In the development cohort,the mean area under the curve(AUC)was 0.994,with a sensitivity of 0.944,specificity of 0.967,and accuracy of 0.901.Moreover,in the validation cohort,the AUC was 0.960,the sensitivity was 0.889,the specificity was 0.893,and the accuracy was 0.890.Conclusions A combined model was developed using imaging data of the optic nerve and CSF in the optic nerve sheath,serving as a noninvasive potential tool to predict DON.
基金FAPERJ for the individual research fellowshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)+2 种基金Instituto Nacional de Ciencia e Tecnologia de Neurociencia Translacional(INCT-INNT)Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro(FAPERJ)/Pensa Rio supported this workFAPERJ/CAPES for the individual scholarship
文摘Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients will have diabetic retinopathy,the leading cause of visual defects in working-age people worldwide.Although diabetes is considered a microvascular disease,recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system,albeit its mechanisms are still under investigation.Neuroinflammation and oxidative stress are intrinsically related phenomena,since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases,and both pathological processes are increased in the visual system during diabetes.The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.
基金Supported by National Nature Science Foundation of China (No.81070728)Shanghai "Science and Technology Innovation Action Plan" Basic Research Key Project,China (No.11JC1407700 and 11 JC1407701)+1 种基金Shanghai Nature Science Foundation, China (No.08ZR1413900)Shanghai Leading Academic Discipline Project, China(No.S30205)
文摘Rho-associated kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase RhoA. The Rho/ROCK pathway is closely related to the pathogenesis of several central nervous system (CNS) disorders, and involved in many aspects of neuronal functions including neurite outgrowth and retraction. In the adult CNS, the damaged neuron regeneration is very difficult due to the presence of myelin-associated axon growth inhibitors such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (Omgp), etc. The effects of these axon growth inhibitors are reversed by blocking the Rho/ROCK pathway 47 vitro, and the inhibition of Rho/ROCK pathway can promote axon regeneration and functional recovery in the injured CNS in viva In addition, the therapeutic effects of the Rho/ROCK inhibitors have also been demonstrated in some animal models and the Rho/ROCK pathway becomes an attractive target for the development of drugs for treating CNS disorders. In this review, we summarized on the effect of the Rho and the downstream factor ROCK in neural regeneration, and the potential therapeutic effect of Rho/ROCK inhibitors in the survival and axonal regeneration of retinal ganglion cell was also discussed.
基金the National Basic Research Development Program of China（973 Program）（No.2005CB724302）；the National Natural Science Foundation of China（No.60588101）；Shanghai Science and Technology Commission（No.05DZ22318，No.04DZ05114）.
文摘Objective The optic nerve is a key component regarding research on visual prosthesis.Previous pharmacological and electrical studies has pinned down the main features of the mechanisms underlying the nerve impulse in the rat optic nerve,and this work proposed a mathematical model to simulate these phenomena.Methods The main active nodal channels：fast Na^＋,persistent Na^,slow K^＋ and a fast repolarizing K^＋（A-current）were added on a double layer representation of the axon.A simplified representation of K^＋ accumulation and clearance in the vicinity of the Ranvier node was integrated in this model.Results The model was able to generate the following features.In the presence of 4-aminopyridine （4-AP）,spike duration increased and a depolarizing afterpotential（DAP）appeared.In the presence of 4-AP and tetraethylammonium（TEA）,the DAP was followed by a hyperpolarizing afterpotential（AHP）and the amplitude of this AHP increased with the frequency of the stimulation.In normal conditions（no drugs）：DAP and AHP were absent after a single action potential（AP）and a short train of AP;there was a relative refractoriness in amplitude lasting for 30 ms after an AP;an early AHP was revealed by a continuous depolarizing current;and there was a partial spike adaptation for a long current step stimulus.Conclusion The model successfully reproduced previous experiments results including long-lasting stimulation experiment,which is known to modify nerve physiological parameter values and is a key issue for visual prosthesis research.
基金supported by the Research Foundation of Jiangsu Provincial Commission of Health and Family Planning of China,No.H201653the Research Foundation of Changshu Science and Technology Bureau of China,No.CS201616
文摘The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3K/AKT/mTOR signaling pathway has been shown to enhance the intrinsic growth capacity of neurons and to facilitate axonal regeneration in the central nervous system after injury. The deletion of the mTOR negative regulator phosphatase and tensin homolog （PTEN） enhances regeneration of adult corticospinal neurons and ganglion cells. In the present study, we used a tyrosine-mutated （Y444F） AAV2 vector to efficiently express a short hairpin RNA （shRNA） for silencing PTEN expression in retinal ganglion cells. We evaluated cell survival and axonal regeneration in a rat model of optic nerve axotomy. The rats received an intravitreal injection of wildtype AAV2 or Y444F mutant AAV2 （both carrying shRNA to PTEN） 4 weeks before optic nerve axotomy. Compared with the wildtype AAV2 vector, the Y444F mutant AAV2 vector enhanced retinal ganglia cell survival and stimulated axonal regeneration to a greater extent 6 weeks after axotomy. Moreover,post-axotomy injection of the Y444F AAV2 vector expressing the shRNA to PTEN rescued ～19% of retinal ganglion cells and induced axons to regenerate near to the optic chiasm. Taken together, our results demonstrate that PTEN knockdown with the Y444F AAV2 vector promotes retinal ganglion cell survival and stimulates long-distance axonal regeneration after optic nerve axotomy. Therefore, the Y444F AAV2 vector might be a promising gene therapy tool for treating optic nerve injury.
基金supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region,China(HKU 776109M)supported by the Fundamental Research Funds for the Central Universities Grant 21609101
文摘Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demon- strated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.
文摘AIM: To evaluate the value of quantitative diffusion tensor imaging (DTI) in assessing the axonal and myelin damage of the optic nerves and optic radiations in patients with chronic primary angle -closure glaucoma (PACG) by using high -field magnetic resonance (MR) imaging (3T). METHODS: Twenty patients with bilateral chronic PACG and twenty age - and sex matched disease -free control subjects were enrolled. Conventional MRI and DTI were performed on all subjects using 3T MR scanner. Mean diffusivity (MD), fractional anisotropy (FA), axial diffusivities (AD) and radial diffusivities (RD) of each optic nerve and each optic radiation were measured by using post -processing software of DTI studio 2.3, and then compared between left eyes and right eyes and between patients group and control group. The pairedsample t- test were used. RESULTS: There was no abnormality in the shape and signal intensity of the optic nerves and optic radiations in patients group and control group on the conventional MRI. No significant differences were observed in the FA, MD, AD and RD between the right and left optic nerves and optic radiations within patients group and control group (P>0.05). The optic nerves and optic radiations of patients with chronic PACG, as compared with control subjects, had significantly higher MD, AD, RD and significantly lower FA (P<0.05). CONCLUSION: The diffusivity of optic nerves and optic radiations in chronic PACG group showed abnormal and diffusivity parameters could be used markers of axonal and myelin injury in glaucoma.
基金supported by grants from National Natural Science Foundation of China(31401234)Natural Science Foundation of Jiangsu Province,China(BK20140428)+1 种基金the Basic Research Program of Education Department of Jiangsu Province,China(14KJB180019)the Science and Technology Project of Nantong Municipality,Jiangsu Province,China(MS22015002)
文摘The SoxC transcription factors （Sox4, Sox11, and Sox12） play important roles in the development of the vertebrate eye and retina. However, their expression and function during retinal and optic nerve regeneration remain elusive. In this study, we investigated the expression and possible functions of the SoxC genes after retinal and optic nerve injury in adult zebrafish. We found that among the five SoxC members, Soxllb was strongly induced in BrdU-positive cells in the inner nuclear layer （INL） after retinal injury, and morpholino-mediated Soxllb-knockdown significantly reduced the number of proliferating cells in the INL at 4 days post-injury. After optic nerve lesion, both Soxl la and Soxl lb were strongly expressed in retinal ganglion cells （RGCs）, and knockdown of both Soxl la and Soxllb inhibited RGC axon regrowth in retinal explants. Our study thus uncovered a novel expression pattern of SoxC family genes after retinal and optic nerve injury, and suggests that they have important functions during retinal and optic nerve regeneration.
文摘We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study （SCOTS）. SCOTS is an Institutional Review Board ap- proved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date （www.clinicaltrials.gov Identifier NCT 01920867）. SCOTS utilizes autologous bone marrow-derived stem cells （BMSCs） for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient＇s previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and in- travitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient＇s visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.
