Fundus photography,fundus fluorescein angiography,and optical coherence tomography of healthy cynomolgus monkey,New Zealand rabbit,Sprague Dawley rat,and BALB/c mouse retinas

Background:A variety of experimental animal models are used in basic ophthalmological research to elucidate physiological mechanisms of vision and disease pathogenesis.The choice of animal model is based on the measurability of specific parameters or structures,the applicability of clinical measurement technologies,and the similarity to human eye function.Studies of eye pathology usually compare optical parameters between a healthy and altered state,so accurate baseline assessments are critical,but few reports have comprehensively examined the normal anatomical structures and physiological functions in these models.Methods:Three cynomolgus monkeys,six New Zealand rabbits,ten Sprague Dawley(SD)rats,and BALB/c mice were examined by fundus photography(FP),fundus fluorescein angiography(FFA),and optical coherence tomography(OCT).Results:Most retinal structures of cynomolgus monkey were anatomically similar to the corresponding human structures as revealed by FP,FFA,and OCT.New Zealand rabbits have large eyeballs,but they have large optic disc and myelinated retinal nerve fibers in their retinas,and the growth pattern of retinal vessels were also different to the human retinas.Unlike monkeys and rabbits,the retinal vessels of SD rats and BALB/c mice were widely distributed and clear.The OCT performance of them were similar with human beings except the macular.Conclusions:Monkey is a good model to study changes in retinal structure associated with fundus disease,rabbits are not suitable for studies on retinal vessel diseases and optic nerve diseases,and rats and mice are good models for retinal vascular diseases.These measures will help guide the choice of model and measurement technology and reduce the number of experimental animals required.

Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury

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.

Effect of Sonic hedgehog gene-modified bone marrow mesenchymal stem cells on graft-induced retinal gliosis and retinal ganglion cells survival in diabetic mice

AIM:To investigate the effects of Sonic hedgehog(Shh)gene-modified bone marrow mesenchymal stem cells(MSCs)on graft-induced retinal gliosis and retinal ganglion cells(RGCs)survival in diabetic mice.METHODS:Bone marrow-derived MSCs were genetically modified with the Shh gene to generate a stably transfected cell line of Shh-modified MSCs(MSC-Shh).Intravitreal injections of MSC-Shh and green fluorescent protein-modified MSCs(MSC-Gfp;control)were administered in diabetic mice.After 4wk,the effects of MSC-Shh on retinal gliosis were evaluated using fundus photography,and markers of gliosis were examined by immunofluorescence and Western blotting.The neurotrophic factors expression and RGCs survival in the host retina were evaluated using Western blotting and immunofluorescence.The mechanisms underlying the effects of MSC-Shh was investigated.RESULTS:A significant reduction of proliferative vitreoretinopathy(PVR)was observed after intravitreal injection of MSC-Shh compared to MSC-Gfp.Significant downregulation of glial fibrillary acidic protein(GFAP)was demonstrated in the host retina after MSC-Shh administration compared to MSC-Gfp.The extracellular signal-regulated kinase 1/2(ERK1/2),protein kinase B(AKT)and phosphatidylin-ositol-3-kinase(PI3K)pathways were significantly downregulated after MSC-Shh administration compared to MSC-Gfp.Brain-derived neurotrophic factor(BDNF)and ciliary neurotrophic factor(CNTF)levels were significantly increased in the host retina,and RGCs loss was significantly prevented after MSC-Shh administration.CONCLUSION:MSC-Shh administration reduces graft-induced reactive gliosis following intravitreal injection in diabetic mice.The ERK1/2,AKT and PI3K pathways are involved in this process.MSC-Shh also increases the levels of neurotrophic factors in the host retina and promoted RGCs survival in diabetic mice.

Classification of congenital cataracts based on multidimensional phenotypes and its association with visual outcomes

●AIM:To establish a classification for congenital cataracts that can facilitate individualized treatment and help identify individuals with a high likelihood of different visual outcomes.●METHODS:Consecutive patients diagnosed with congenital cataracts and undergoing surgery between January 2005 and November 2021 were recruited.Data on visual outcomes and the phenotypic characteristics of ocular biometry and the anterior and posterior segments were extracted from the patients’medical records.A hierarchical cluster analysis was performed.The main outcome measure was the identification of distinct clusters of eyes with congenital cataracts.●RESULTS:A total of 164 children(299 eyes)were divided into two clusters based on their ocular features.Cluster 1(96 eyes)had a shorter axial length(mean±SD,19.44±1.68 mm),a low prevalence of macular abnormalities(1.04%),and no retinal abnormalities or posterior cataracts.Cluster 2(203 eyes)had a greater axial length(mean±SD,20.42±2.10 mm)and a higher prevalence of macular abnormalities(8.37%),retinal abnormalities(98.52%),and posterior cataracts(4.93%).Compared with the eyes in Cluster 2(57.14%),those in Cluster 1(71.88%)had a 2.2 times higher chance of good best-corrected visual acuity[<0.7 logMAR;OR(95%CI),2.20(1.25–3.81);P=0.006].●CONCLUSION:This retrospective study categorizes congenital cataracts into two distinct clusters,each associated with a different likelihood of visual outcomes.This innovative classification may enable the personalization and prioritization of early interventions for patients who may gain the greatest benefit,thereby making strides toward precision medicine in the field of congenital cataracts.

Effect of lens surgery on health-related quality of life in preschool children with congenital ectopia lentis

AIM:To evaluate the effect of lens surgery on health-related quality of life(HRQoL)of preschool children with congenital ectopia lentis(CEL).METHODS:A prospective self-controlled study was conducted in Zhongshan Ophthalmic Center.Children aged from 5 to 7y whom were diagnosed with CEL and underwent phacoemulsification with scleral-fixated posterior chamber intraocular lens implantation and their parents were enrolled in this study.All of them completed the child and proxy(parental)PedsQL™4.0 before and after the surgery.Their preoperative scores were compared to their postoperative ones.Subgroup analyses were performed based on gender and preoperative bilateral presenting visual acuity of the children.RESULTS:Thirty-two children with CEL successfully underwent surgery without any complications,among whom 8 had monocular surgery and 24 had binocular surgery.Preoperative and postoperative questionnaires were completed by 32 child-parent pairs.Surgical intervention could significantly improve the vision of affected children(P<0.001).The medians of physical,psychosocial and total health scores self-reported by the children were 68.75(62.50,81.25),65.00(60.00,80.00)and 67.39(60.87,78.26)preoperatively and were 93.75(87.50,100.00),90.00(83.33,96.67)and 89.13(85.32,95.65)postoperatively.The preoperative scores of the affected children were significantly lower in all scales than age-matched healthy children(P<0.001).All the postoperative scores were significantly higher than the preoperative scores in affected children and their parents(P<0.001).In the physical functioning evaluation,the preoperative score reported by parents of girls was higher than parents of boys(P=0.041),and the postoperative score of girls was higher than that of boys(P=0.036).CONCLUSION:CEL is associated with significantly worse quality of life in preschool children.Surgical intervention can significantly improve the HRQoL in affected children from both personal and family perspective.

Clinical features and possible pathogenesis of multiple evanescent white dot syndrome with different retinal diseases and events:a narrative review

●Multiple evanescent white dot syndrome(MEWDS)is a rare fundus disease,characterized by acute vision loss and visual field defects.Many previous studies have explained the possible pathogenesis and clinical features of primary MEWDS.However,as the number of reported cases increases,secondary MEWDS occurs in other related retinal diseases and injuries,exhibiting some special characteristics.The associated retinal diseases include multifocal choroiditis/punctate inner choroidopathy(MFC/PIC),acute zonal occult outer retinopathy,best vitelliform macular dystrophy,pseudoxanthoma elasticum,and ocular toxoplasmosis.The related retinal injury is laser photocoagulation,surgery,and trauma.Although primary MEWDS often have a self-limiting course,secondary MEWDS may require treatment in some cases,according to the severity of concomitant diseases and complications.Notably,MEWDS secondary to MFC/PIC that is prone to forming choroidal neovascularization and focal choroidal excavation,needs positive treatment with corticosteroids.The possible underlying pathogenesis of secondary MEWDS is the exposure of choroidal antigen after the disruption of Bruch’s membrane.The MEWDS-related features in secondary MEWDS are still evanescent under most circumstances.Its prognosis and treatment depend on the severity of complications.Current studies propose that the etiology is associated with immune factors,including viral infection,inflammation in choroid and Bruch’s membrane,and antigen exposure caused by retinal and/or choroidal insults.More pathogenic studies should be conducted in the future.Accurate diagnosis for secondary MEWDS could benefit patients in aspects of management and prognosis.

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract:a randomized clinical trial

●AIM:To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy(PPV)for proliferative diabetic retinopathy(PDR)compared to those of PPV with subsequent cataract surgery.●METHODS:This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR,aged>45y,with mild cataracts.The participants were randomly assigned to the combined(PPV combined with simultaneously cataract surgery,i.e.,phacovitrectomy)or subsequent(PPV with subsequent cataract surgery 6mo later)group and followed up for 12mo.The primary outcome was the change in best-corrected visual acuity(BCVA)from baseline to 6mo,and the secondary outcomes included complication rates and medical expenses.●RESULTS:In total,129 patients with PDR were recruited and equally randomized(66 and 63 in the combined and subsequent groups respectively).The change in BCVA in the combined group[mean,36.90 letters;95%confidence interval(CI),30.35–43.45]was significantly better(adjusted difference,16.43;95%CI,8.77–24.08;P<0.001)than in the subsequent group(mean,22.40 letters;95%CI,15.55–29.24)6mo after the PPV,with no significant difference between the two groups at 12mo.The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma(17.65%vs 3.77%,P=0.005).No significant differences were found in the photocoagulation spots,surgical time,and economic expenses between two groups.In the subsequent group,the duration of work incapacity(22.54±9.11d)was significantly longer(P<0.001)than that of the combined group(12.44±6.48d).●CONCLUSION:PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness,safety and convenience,compared to sequential surgeries.

Bilateral choroidal ganglioneuroma:a comprehensive analysis of vision decline in a 6-year-old boy

Dear Editor,We write to present a 6-year-old boy with bilateral choroidal ganglioneuroma(CG)by comprehensive multimodal imaging(MMI)in a duration of 6-year follow-up.To our knowledge,this is the first case report with elaborate data to delineate the natural history of visual function and MMI in a boy with rare bilateral CG,confirmed by choroid biopsy.

Changes in visual performance after implantation of different intraocular lenses

AIM:To evaluate the trending visual performance of different intraocular lenses(IOLs)over time after implantation.METHODS:Ninety-one patients received cataract surgery with implantations of monofocal(Mon)IOLs,segmental refractive(SegRef)IOLs,diffractive(Dif)IOLs,and extendeddepth-of-focus(EDoF)IOLs were included.The aberrations and optical quality collected with iTrace and OQAS within postoperative 6mo were followed and compared.RESULTS:Most of the visual parameters improved over the postoperative 6mo.The postoperative visual acuity(POVA)of the Mon IOL,SegRef IOL,and EDoF IOL groups achieved relative stability in earlier states compared with the Dif IOL group.Nevertheless,the overall visual performance of the 3 IOLs continued to upturn in small extents within the postoperative 6mo.The optical quality initially improved in the EDoF IOL group,then in the Mon IOL,SegRef IOL,and Dif IOL groups.POVA and objective visual performance of the Mon IOL and EDoF IOL groups,as well as POVA and visual quality of the Dif IOL group,improved in the postoperative 1mo and stabilized.Within the postoperative 6mo,gradual improvements were observed in the visual acuity and objective visual performance of the SegRef IOL group,as well as in the postoperative optical quality of the Dif IOL group.CONCLUSION:The visual performance is different among eyes implanted with different IOLs.The findings of the current study provide a potential reference for ophthalmologists to choose suitable IOLs for cataract patients in a personalized solution.

Association of age at diagnosis of diabetes with subsequent risk of age-related ocular diseases and vision acuity

BACKGROUND The importance of age on the development of ocular conditions has been reported by numerous studies.Diabetes may have different associations with different stages of ocular conditions,and the duration of diabetes may affect the development of diabetic eye disease.While there is a dose-response relationship between the age at diagnosis of diabetes and the risk of cardiovascular disease and mortality,whether the age at diagnosis of diabetes is associated with incident ocular conditions remains to be explored.It is unclear which types of diabetes are more predictive of ocular conditions.AIM To examine associations between the age of diabetes diagnosis and the incidence of cataract,glaucoma,age-related macular degeneration(AMD),and vision acuity.METHODS Our analysis was using the UK Biobank.The cohort included 8709 diabetic participants and 17418 controls for ocular condition analysis,and 6689 diabetic participants and 13378 controls for vision analysis.Ocular diseases were identified using inpatient records until January 2021.Vision acuity was assessed using a chart.RESULTS During a median follow-up of 11.0 years,3874,665,and 616 new cases of cataract,glaucoma,and AMD,respectively,were identified.A stronger association between diabetes and incident ocular conditions was observed where diabetes was diagnosed at a younger age.Individuals with type 2 diabetes(T2D)diagnosed at<45 years[HR(95%CI):2.71(1.49-4.93)],45-49 years[2.57(1.17-5.65)],50-54 years[1.85(1.13-3.04)],or 50-59 years of age[1.53(1.00-2.34)]had a higher risk of AMD independent of glycated haemoglobin.T2D diagnosed<45 years[HR(95%CI):2.18(1.71-2.79)],45-49 years[1.54(1.19-2.01)],50-54 years[1.60(1.31-1.96)],or 55-59 years of age[1.21(1.02-1.43)]was associated with an increased cataract risk.T2D diagnosed<45 years of age only was associated with an increased risk of glaucoma[HR(95%CI):1.76(1.00-3.12)].HRs(95%CIs)for AMD,cataract,and glaucoma associated with type 1 diabetes(T1D)were 4.12(1.99-8.53),2.95(2.17-4.02),and 2.40(1.09-5.31),respectively.In multivariable-adjusted analysis,individuals with T2D diagnosed<45 years of age[β95%CI:0.025(0.009,0.040)]had a larger increase in LogMAR.Theβ(95%CI)for LogMAR associated with T1D was 0.044(0.014,0.073).CONCLUSION The younger age at the diagnosis of diabetes is associated with a larger relative risk of incident ocular diseases and greater vision loss.

Pterygial body epithelium domination of pterygial proliferation with TCF4 as a potential key factor

AIM： To characterize the proliferative capacity of pterygial epithelium in different regions（head, neck and body） of pterygium and explore the function of transcription factor 4（TCF4） in pterygium proliferation.METHODS： Thirty pterygium tissues and 10 normal conjunctival tissues were obtained from Zhongshan Ophthalmic Center（ZOC） and Guangdong Eye Bank, respectively. Proliferative capacity of head, neck and body in pterygial epithelium was measured using clonal analysis, fold growth analysis and expression profile of proliferative markers revealed by immunofluorescent staining and real-time PCR. The expression of TCF4 was highlighted by double immunofluorescent staining with other proliferation related markers such as proliferating cell nuclear antigen（PCNA） and ATP-binding cassette subfamily G member 2（ABCG2）.RESULTS： The proliferative potential of pterygial epithelium was higher than that of normal conjunctival epithelium. High expression levels of proliferative markers（P63α, PCNA and ABCG2） in pterygial body epithelium were observed in immunofluorescent staining and real-time PCR（P〈0.05）. Also, epithelial cells isolated from pterygial body demonstrated higher proliferative capacity in clonal analysis and fold growth analysis, than those isolated from the head and neck regions. The TCF4 expression in pterygial epithelium was similar to other proliferative markers（P63α, PCNA and ABCG2）, as higher in pterygial body than head and neck. Moreover, TCF4 showed coexpression with other proliferation-related markers（PCNA and ABCG2） in the double immunofluorescent staining experiment.CONCLUSION： The proliferative capacity in pterygial body epithelium is prominent than the head and neck regions, and upregulated TCF4 may be associated with enhanced proliferation in the pterygium.

Flipped classroom approach to ophthalmology clerkship courses for Chinese students of eight-year program

Background:The“flipped classroom”is a learner-centered approach that centers on delivering videos,podcasts or slide-based material to learners prior to a lecture or class session.The class session is then dedicated to discussion,analysis,and problem-solving activities.The aim of this study was to investigate whether the flipped classroom could be adapted to medical(ophthalmology)students learning about ocular trauma and to assess the impact of the flipped classroom on those students’performance and attitudes.Methods:Questionnaires(using a 4-point scale)were distributed to 93 fifth-year medical students at Sun Yat-sen University,and the data showed that the majority of students preferred the flipped classroom approach to the traditional lecture method.Results:The results of pre-and post-test scores were 14.35±3.404 and 20.37±4.356,which showed a significant improvement in students’performance after the flipped classroom was introduced(P<0.05).Conclusions:Student response to the flipped classroom strategy was largely positive,indicating that the strategy received a high level of approval in an ophthalmology clerkship course taken by medical students in China.

Selective deletion of zinc transporter 3 in amacrine cells promotes retinal ganglion cell survival and optic nerve regeneration after injury

Vision depends on accurate signal conduction from the retina to the brain through the optic nerve,an important part of the central nervous system that consists of bundles of axons originating from retinal ganglion cells.The mammalian optic nerve,an important part of the central nervous system,cannot regenerate once it is injured,leading to permanent vision loss.To date,there is no clinical treatment that can regenerate the optic nerve and restore vision.Our previous study found that the mobile zinc(Zn^(2+))level increased rapidly after optic nerve injury in the retina,specifically in the vesicles of the inner plexiform layer.Furthermore,chelating Zn^(2+)significantly promoted axonal regeneration with a long-term effect.In this study,we conditionally knocked out zinc transporter 3(ZnT3)in amacrine cells or retinal ganglion cells to construct two transgenic mouse lines(VGAT^(Cre)ZnT3^(fl/fl)and VGLUT2^(Cre)ZnT3^(fl/fl),respectively).We obtained direct evidence that the rapidly increased mobile Zn^(2+)in response to injury was from amacrine cells.We also found that selective deletion of ZnT3 in amacrine cells promoted retinal ganglion cell survival and axonal regeneration after optic nerve crush injury,improved retinal ganglion cell function,and promoted vision recovery.Sequencing analysis of reginal ganglion cells revealed that inhibiting the release of presynaptic Zn^(2+)affected the transcription of key genes related to the survival of retinal ganglion cells in postsynaptic neurons,regulated the synaptic connection between amacrine cells and retinal ganglion cells,and affected the fate of retinal ganglion cells.These results suggest that amacrine cells release Zn^(2+)to trigger transcriptomic changes related to neuronal growth and survival in reginal ganglion cells,thereby influencing the synaptic plasticity of retinal networks.These results make the theory of zinc-dependent retinal ganglion cell death more accurate and complete and provide new insights into the complex interactions between retinal cell networks.

Identification of retinal thickness and blood flow in agerelated macular degeneration with reticular pseudodrusen

AIM:To investigate thickness characteristics and vascular plexuses in retinas with reticular pseudodrusen(RPD)as an early detection strategy for age-related macular degeneration(AMD).METHODS:This retrospective study included 24 subjects(33 eyes)with RPD and 25 heathy control subjects(34 eyes).The superficial capillary plexus(SCP)and the deep capillary plexus(DCP)of the retinal posterior poles were investigated with optical coherence tomography angiography(OCTA).Retinal thicknesses and vessel densities were analyzed statistically.RESULTS:The general retinal thicknesses of RPD eyes were significantly decreased(95%CI-14.080,-0.655;P=0.032).The vessel densities of DCP in RPD eyes were significantly increased in the global(95%CI 1.067,7.312;P=0.027),parafoveal(95%CI 0.417,5.241;P=0.022),and perifoveal(95%CI 0.181,6.842;P=0.039)quadrants.However,the vessel densities of the SCP were rarely increased in the eyes with RPD.CONCLUSION:The thinning of retinas in the RPD group suggests a reduction in the number of cells.Additionally,the increased vessel density of the DCP in retinas with RPD indicates a greater demand for blood supply,possibly due to the hypoxia induced RPD compensation caused by RPD in the outer retina.This study highlights the pathological risks associated with RPD and emphasizes the importance of early intervention to retard the progression of AMD.

Effects of chronic elevated intraocular pressure on parameters of optical coherence tomography in rhesus monkeys

AIM: To determine the progression of parameters from optical coherence tomography(OCT) in chronic elevated intraocular pressure(IOP) monkeys.METHODS: A chronic elevated IOP model of rhesus monkeys was induced by laser photocoagulation. Representative OCT parameters, including the average and four-quadrant retinal nerve fiber layer(RNFL) thickness, and parameters from optic nerve head(ONH) analysis were collected before and after laser treatments biweekly for up to 28 wk. The performance of each parameter for early progression detection was analyzed. The progressive trends toward elevated IOP were analyzed using a linear mixed-effects model.RESULTS: There were 10 successfully maintained high IOP eyes in 7 monkeys. The follow-up time was 24±5.37 wk. With cumulative IOP elevation, the cup area, rim area and C/D area ratio were statistically significantly changed as early as 2 wk after elevated IOP induction(P<0.05). The quadrant RNFL thickness changed at 6wk after high IOP induction, and the superior and inferior RNFL thicknesses exhibited more obvious reductions than other quadrants. The average RNFL thickness was the last one to show a significant decrease at 8wk.CONCLUSION: The parameters of ONH are most sensitive to elevated IOP in a primate glaucomatous model. These findings suggest that we should focus on those parameters instead of RNFL thickness in patients with elevated IOP, as they might present with earlier glaucomatous changes.

Use of a tissue clearing technique combined with retrograde trans-synaptic viral tracing to evaluate changes in mouse retinorecipient brain regions following optic nerve crush

Successful establishment of reconnection between retinal ganglion cells and retinorecipient regions in the brain is critical to optic nerve regeneration.However,morphological assessments of retinorecipient regions are limited by the opacity of brain tissue.In this study,we used an innovative tissue cleaning technique combined with retrograde trans-synaptic viral tracing to observe changes in retinorecipient regions connected to retinal ganglion cells in mice after optic nerve injury.Specifically,we performed light-sheet imaging of whole brain tissue after a clearing process.We found that pseudorabies virus 724(PRV724)mostly infected retinal ganglion cells,and that we could use it to retrogradely trace the retinorecipient regions in whole tissue-cleared brains.Unexpectedly,PRV724-traced neurons were more widely distributed compared with data from previous studies.We found that optic nerve injury could selectively modify projections from retinal ganglion cells in the hypothalamic paraventricular nucleus,intergeniculate leaflet,ventral lateral geniculate nucleus,central amygdala,basolateral amygdala,Edinger-Westphal nucleus,and oculomotor nucleus,but not the superior vestibular nucleus,red nucleus,locus coeruleus,gigantocellular reticular nucleus,or facial nerve nucleus.Our findings demonstrate that the tissue clearing technique,combined with retrograde trans-synaptic viral tracing,can be used to objectively and comprehensively evaluate changes in mouse retinorecipient regions that receive projections from retinal ganglion cells after optic nerve injury.Thus,our approach may be useful for future estimations of optic nerve injury and regeneration.

Exercise combined with administration of adipose-derived stem cells ameliorates neuropathic pain after spinal cord injury

Experimental studies have shown that exercise and human adipose-derived stem cells(ADSCs)play positive roles in spinal cord injury(SCI).However,whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear.Thus,there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI.In this study,a thoracic 11(T11)SCI contusion model was established in adult C57BL/6 mice.Exercise was initiated from 7 days post-injury and continued to 28 days post-injury,and approximately 1×105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI.Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale,von Frey filament test,Hargreaves method,and cold plate test.Histological studies(Eriochrome cyanine staining and immunohistochemistry)were performed at the end of the experiment(28 days post-injury).Exercise combined with administration of ADSCs partially improved early motor function(7,14,and 21 days postinjury),mechanical allodynia,mechanical hypoalgesia,thermal hyperalgesia,and thermal hypoalgesia.Administration of ADSCs reduced white and gray matter loss at the lesion site.In addition,fewer microglia and astrocytes(as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein,respectively)were present in the lumbar dorsal horn in the SCI+ADSCs and SCI+exercise+ADSCs groups compared with the sham group.Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCIinduced neuropathic pain.

Chinese Guideline on the Management of Polypoidal Choroidal Vasculopathy (2022)

Background In China's Mainland,patients with neovascular age-related macular degeneration(nAMD)have approximately an 40%prevalence of polypoidal choroidal vasculopathy(PCV).This disease leads to recurrent retinal pigment epithelium detachment(PED),extensive subretinal or vitreous hemorrhages,and severe vision loss.China has introduced various treatment modalities in the past years and gained comprehensive experience in treating PCV.Methods A total of 14 retinal specialists nationwide with expertise in PCV were empaneled to prioritize six questions and address their corresponding outcomes,regarding opinions on inactive PCV,choices of anti-vascular endothelial growth factor(anti-VEGF)monotherapy,photodynamic therapy(PDT)monotherapy or combined therapy,patients with persistent subretinal fluid(SRF)or intraretinal fluid(IRF)after loading dose anti-VEGF,and patients with massive subretinal hemorrhage.An evidence synthesis team conducted systematic reviews,which informed the recommendations that address these questions.This guideline used the GRADE(Grading of Recommendations,Assessment,Development,and Evaluation)approach to assess the certainty of evidence and grade the strengths of recommendations.Results The panel proposed the following six conditional recommendations regarding treatment choices.(1)For patients with inactive PCV,we suggest observation over treatment.(2)For treatment-na?ve PCV patients,we suggest either anti-VEGF monotherapy or combined anti-VEGF and PDT rather than PDT monotherapy.(3)For patients with PCV who plan to initiate combined anti-VEGF and PDT treatment,we suggest later/rescue PDT over initiate PDT.(4)For PCV patients who plan to initiate anti-VEGF monotherapy,we suggest the treat and extend(TE)regimen rather than the pro re nata(PRN)regimen following three monthly loading doses.(5)For patients with persistent SRF or IRF on optical coherence tomography(OCT)after three monthly anti-VEGF treatments,we suggest proceeding with anti-VEGF treatment rather than observation.(6)For PCV patients with massive subretinal hemorrhage(equal to or more than four optic disc areas)involving the central macula,we suggest surgery(vitrectomy in combination with tissue-plasminogen activator(tPA)intraocular injection and gas tamponade)rather than anti-VEGF monotherapy.Conclusions Six evidence-based recommendations support optimal care for PCV patients'management.

Transient vacuolar changes of the crystalline lens in patients using a dispersive ophthalmic viscosurgical device

AIM:To report the clinical prognosis and pathological findings of accidental lens vacuolar changes in eyes with intraoperative exposure to a dispersive ophthalmic viscosurgical device(OVD).METHODS:Two patients who developed transient lens vacuolar changes during uneventful persistent pupillary membrane(PPM)removal surgery were presented and followed up.This event was speculated to be associated with an intraoperative dispersive OVD DisCoVisc(hyaluronic acid 1.6%-chondroitin sulfate 4.0%)exposure.Then,to provide the pathological basis for our speculation,another four cataract patients were randomly exposed to different OVDs,and their anterior lens capsules were investigated with transmission electron microscopy(TEM).RESULTS:After months,the subcapsular vacuoles in both PPM cases were gradually disappeared without visual deterioration.For the cataract patients,similar lens changes were observed intraoperatively in those exposed to a dispersive DisCoVisc but not a cohesive OVD IVIZ(sodium hyaluronate gel 1.0%).In addition,marked ultrastructural changes,including chromatin condensation,extensive cytoplasmic vacuoles,and obvious intercellular space between lens epithelial cells in the anterior lens capsules of all eyes exposed to DisCoVisc,were observed by TEM.CONCLUSION:The lens vacuolar changes may be associated with a dispersive OVD exposure.Therefore,it is not preferable to use dispersive OVDs in patients with transparent lenses or without the intention of lens extraction.In addition,close follow-ups instead of immediate lens extraction are recommended for the occurrence of similar lens lesions.