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The aim of this study was to explore the role of autophagy in response to blue light damage in aged mice and in human retinal pigmented epithelium (hRPE) cells. Blue light damage to the retina was induced in 10-month-old (10 mo) C57 mice and hRPE cells. Flash electroretinography was used to assess retinal function. Retinal structure changes were observed by electron microscopy. Western blot was conducted to determine the expression levels of the following proteins: cleaved caspase-3, p38 mitogen-activated protein kinases, protein kinase R-like endoplasmic reticulum kinase (PERK), autophagy marker light chain 3 (LC3), P62, and Beclin-1. On day 1 after light damage to the 10 mo mice, retinal function was changed. The latent periods of a-wave and b-wave were delayed, and amplitude was reduced. The electron microscopy results revealed mitochondria damage in the retinal pigmented epithelium and a disorganized photoreceptor outer segment (OS). PERK, LC3, and Beclin-1 were upregulated, whereas P62 was not. On day 5 after the blue light damage, restoration of electroretinography and OS was observed. PERK, LC3, and Beclin-1 were downregulated, whereas P62 was not. Protein changes in vitro were consistent with in vivo. The present study provided structural and functional evidence that autophagy plays an important role in the response to blue lightinduced retinal damage.

Semaphorins form a family of secreted and membrane-bound molecules that were identified originally as axonal guidance factors during neuronal development. Given their wide distribution in many including mature tissues, semaphorin 4D (sema4D) and its main functional receptor plexin B1 (plxnB1) are expected to fulfill additional functions that remain to be uncovered. A main characteristic of the plexin receptor family is its ability to reorganize the cytoskeleton. PlxnB1 specifically may directly interact with Rho family GTPases to regulate F-actin driven pathways in cells in culture. Diurnal clearance phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segment fragments (POS) is critical for photoreceptor function and longevity. In this process, rearrangement of RPE cytoskeletal F-actin via activation of the Rho family GTPase Rac1 is essential for POS internalization. Here, we show a novel role in POS phagocytosis by RPE cells in culture and in vivo for plexin B1 and its ligand sema4D. Exogenous sema4D abolishes POS internalization (but not binding) by differentiated RPE cells in culture by decreasing the GTP load of Rac1. In the rat eye, sema4D localizes to retinal photoreceptors, while PlxnB1 is expressed by neighboring RPE cells. At the peak of diurnal retinal phagocytosis after light onset, plxnB1 phosphorylation and sema4D levels are reduced in wild-type rat retina in situ but not in mutant RCS rat retina in which the RPE lacks phagocytic activity. Finally, increased POS phagosome content after light onset is observed in the RPE in situ of mice with either plxnB1 or sema4D gene deletion. Altogether, our results demonstrate a novel physiological function for sema4D/plxnB1 signaling in RPE phagocytosis serving as attenuating brake prior to light onset whose release enables the diurnal phagocytic burst.

This prospective observational case series study aimed to observe the clinical characteristics of acute zonal occult outer retinopathy (AZOOR) and its prognosis in Chinese Han patients. Six eyes of 5 female patients diagnosed with AZOOR were followed up for 4 months to observe the natural disease course. All enrolled subjects underwent a series of ocular examinations at the onset and each return visit, including best corrected visual acuity (BCVA), split lamp microscopy, fundus photography, optical coherence tomography (OCT), perimetry, multifocal electroretinogram and fundus fluorescein angiography. Over the follow-up, all enrolled patients recovered on BCVA, perimetry and OCT in different degrees. Among them, one patient recovered completely since the ocular examination results returned to normal. AZOOR is a rare ocular disorder in Chinese population. Our results demonstrated that visual functions of enrolled patients significantly improved spontaneously, indicating that Chinese female Han patients with AZOOR have good visual outcomes during the follow-up period without any specific managements.

We evaluated the preoperative optical coherence tomographic (OCT) findings in eyes with macula-off rhegmatogenous retinal detachment (RRD) and determined the factors that were significantly correlated with the postoperative best-corrected visual acuity (BCVA). The length of the preoperative photoreceptors was defined as the distance between the external limiting membrane (ELM) and the outer end of the outer segments of the photoreceptors in the OCT images. The mean length of the photoreceptors was 102.8 ± 28.7 µm with a range of 20 to 159 µm in eyes with RRD. The length of the preoperative photoreceptors was not significantly correlated with the preoperative BCVA but it was significantly correlated with the postoperative BCVA (r = −0.353, P = 0.003). Multivariate regression analyses revealed that the length of the photoreceptors (β = −0.388, P = 0.001) and the preoperative BCVA (β = 0.274, P = 0.021) were the only independent factors that were significantly associated with the postoperative BCVA. The length of the preoperative photoreceptors was significantly correlated with the postoperative photoreceptor length (r = 0.486, P

To evaluate the changes of outer retinal tubulations (ORTs) as seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) where treatment was switched from intravitreal ranibizumab to intravitreal aflibercept. This was a prospective study of eyes diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept, conducted at a single centre (Department of Ophthalmology at Pitie Salpetriere Hospital, Paris VI University) from January to July 2015. Before and after treatment was switched from ranibizumab to aflibercept, SD-OCT was used to evaluate the presence of ORTs. Additional assessments in this patient group included best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA). Changes in pigment epithelium detachments (PED), presence of intraretinal cysts, and presence of subretinal fluid (SRF) were also noted. Twenty-four eyes of 24 consecutive patients (15 female/nine male, mean age 70 years) diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept were included in the analysis. After receiving aflibercept, patients were followed for a mean of 6.1 months. Prior to treatment switch, 97 % of eyes showed ORTs, while after treatment switch to aflibercept, at the end of the study period, 75 % had ORTs (p = 0.219). Changes in BCVA (LogMAR) were not statistically significant (1.16 ± 0.44 to 1.18 ± 1.06, p = 0.12), however, a significant reduction in central macular thickness (CMT) (from 406 μm ± 112 to 263 μm ± 68, p = 0.001), PED (from 70.8 % to 41.7 % , p = 0.016), presence of intraretinal cysts (from 83.3 % to 33.3 %, p = 0.002) and SRF (from 91.7 % to 25 %, p = 0.001 ) were noted. After switching from ranibizumab treatment to aflibercept, ORTs remained present in 75 % of eyes, and significant reductions in CMT, PED, and SRF, and presence of intraretinal cysts were observed.

To investigate the relationship between vision and foveal maturity, especially in foveal hypoplasia exhibiting severe structural immaturity.This retrospective observational case series included 42 eyes of 23 patients (mean age, 7.0 ± 5.0 years; 9 patients with foveal hypoplasia as an isolated entity and 14 patients with aniridia). A complete ophthalmic examination included measurement of best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT). The sensory retina, ganglion cell complex (GCC), and outer retinal layers, including Henle's fiber layer (HFL), were measured and analyzed.Using SD-OCT images, eyes were classified as having a differentiated (6 eyes), diffuse (19 eyes), or no HFL (17 eyes), based on the appearance of the HFL around the foveal region. The logMAR BCVA was significantly worse (p 0.0001) in eyes with diffuse HFL and those with no HFL than in those with differentiated HFL. Outer retinal thickness (outer plexiform layer + HFL + outer nuclear layer) was less (p = 0.0051) in eyes with no HFL than in those with differentiated HFL. The logMAR BCVA, GCC thickness, and outer retinal thickness in eyes with foveal hypoplasia with aniridia were significantly worse (p = 0.0083), thicker (p = 0.0039), and thinner (p = 0.0001), respectively, than in eyes with foveal hypoplasia as an isolated entity.In eyes with foveal hypoplasia with severe structural immaturity, diffuse HFL or no HFL was associated with worse vision. There was greater foveal immaturity in eyes with foveal hypoplasia with aniridia compared with foveal hypoplasia as an isolated entity.

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Background KIF17, a kinesin-2 motor that functions in intraflagellar transport, can regulate the onset of photoreceptor outer segment development. However, the function of KIF17 in a mature photoreceptor remains unclear. Additionally, the ciliary localization of KIF17 is regulated by a C-terminal consensus sequence (KRKK) that is immediately adjacent to a conserved residue (mouse S1029/zebrafish S815) previously shown to be phosphorylated by CaMKII. Yet, whether this phosphorylation can regulate the localization, and thus function, of KIF17 in ciliary photoreceptors remains unknown. Results Using transgenic expression in zebrafish photoreceptors, we show that phospho-mimetic KIF17 has enhanced localization along the cone outer segment. Importantly, expression of phospho-mimetic KIF17 is associated with greatly enhanced turnover of the photoreceptor outer segment through disc shedding in a cell-autonomous manner, while genetic mutants of kif17 in zebrafish and mice have diminished disc shedding. Lastly, cone expression of constitutively active tCaMKII leads to a kif17-dependent increase in disc shedding. Conclusions Taken together, our data support a model in which phosphorylation of KIF17 promotes its photoreceptor outer segment localization and disc shedding, a process essential for photoreceptor maintenance and homeostasis. While disc shedding has been predominantly studied in the context of the mechanisms underlying phagocytosis of outer segments by the retinal pigment epithelium, this work implicates photoreceptor-derived signaling in the underlying mechanisms of disc shedding. Electronic supplementary material The online version of this article (10.1186/s12860-018-0177-9) contains supplementary material, which is available to authorized users.

To analyze the influence of spectral-domain optical coherence tomography (SD-OCT) features on visual acuity changes in patients with idiopathic epiretinal membranes (ERMs). Seventy-nine eyes of 71 patients were included in this study. SD-OCT was performed for all patients; data were collected upon ERM diagnosis and at the final visit. The patients were divided into subgroups based on their SD-OCT features. The initial best corrected visual acuity (BCVA) and changes in BCVA for each subgroup were compared. A multivariate analysis was performed to assess the factors associated with changes in BCVA. During a mean follow-up period of 20.78 months, the mean change in logMAR visual acuity was 0.052 ± 0.089. Eyes with inner segment/outer segment (IS/OS) junction disruption and cystoid macular edema (CME) had a significantly lower mean initial BCVA than those without disruption and CME (P = 0.036 and P = 0.012, respectively). However, only eyes with CME had significant changes in BCVA (P = .034). Multivariate analysis revealed the presence of CME as the only factor that had a significant correlation with VA changes. In patients with idiopathic ERMs, the presence of CME and IS/OS disruption detected by OCT correlated with a poorer initial BCVA. Most patients’ visual acuity remained stable during follow-up. The presence of CME with OCT represented a predictor of the progression of visual acuity. These results may provide valuable clinical information regarding the management of patients with idiopathic ERMs. We demonstrated that the presence of CME and IS/OS disruption detected with OCT correlated with a poorer BCVA in idiopathic ERMs. The visual acuity of most patients was stable during the follow-up period. The presence of CME in OCT represented a predictor of vision deterioration for patients with idiopathic ERMs.

The m.3243A > G mitochondrial DNA mutation was originally described in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The phenotypic spectrum of the m.3243A > G mutation has since expanded to include a spectrum of neuromuscular and ocular manifestations, including reduced vision with retinal degeneration, the underlying mechanism of which remains unclear. We used dermal fibroblasts, from patients with retinal pathology secondary to the m.3243A > G mutation to generate heteroplasmic induced pluripotent stem cell (hiPSC) clones. RPE cells differentiated from these hiPSCs contained morphologically abnormal mitochondria and melanosomes, and exhibited marked functional defects in phagocytosis of photoreceptor outer segments. These findings have striking similarities to the pathological abnormalities reported in RPE cells studied from post-mortem tissues of affected m.3243A > G mutation carriers. Overall, our results indicate that RPE cells carrying the m.3243A > G mutation have a reduced ability to perform the critical physiological function of phagocytosis. Aberrant melanosomal morphology may potentially have consequences on the ability of the cells to perform another important protective function, namely absorption of stray light. Our in vitro cell model could prove a powerful tool to further dissect the complex pathophysiological mechanisms that underlie the tissue specificity of the m.3243A > G mutation, and importantly, allow the future testing of novel therapeutic agents.

A main requisite in the phagocytosis of ingested material is a coordinated series of maturation steps which lead to the degradation of ingested cargo. Photoreceptor outer segment (POS) renewal involves phagocytosis of the distal disk membranes by the retinal pigment epithelium (RPE). Previously, we identified melanoregulin (MREG) as an intracellular cargo-sorting protein required for the degradation of POS disks. Here, we provide evidence that MREG-dependent processing links both autophagic and phagocytic processes in LC3-associated phagocytosis (LAP). Ingested POS phagosomes are associated with endogenous LC3 and MREG. The LC3 association with POSs exhibited properties of LAP; it was independent of rapamycin pretreatment, but dependent on Atg5. Loss of MREG resulted in a decrease in the extent of LC3-POS association. Studies using DQ™-BSA suggest that loss of MREG does not compromise the association and fusion of LC3-positive phagosomes with lysosomes. Furthermore, the mechanism of MREG action is likely through a protein complex that includes LC3, as determined by colocalization and immunoprecipitation in both RPE cells and macrophages. We posit that MREG participates in coordinating the association of phagosomes with LC3 for content degradation with the loss of MREG leading to phagosome accumulation.

To evaluate the photoreceptor inner and outer segment layer thickness in eyes with MEWDS. Prospective, non-comparative, observational case series. The follow-up duration was 4 months. Four women were diagnosed with unilateral MEWDS. The ages of the patients were 25, 24, 35, and 40 years. The retinal microstructure was assessed by spectral-domain optical coherence tomography (SD-OCT). The thickness of the photoreceptor inner (IS) and outer (OS) segments and sum of them (IS + OS) at the fovea were analyzed. The visual acuity was reduced in three of four eyes at the acute phase. SD-OCT showed that the border of IS and OS (IS/OS) line and the cone outer segment tips (COST) line in the macula area were not detected in all four eyes. The IS + OS thickness was 50.3 ± 5.6 μm and that of the healthy fellow eyes was 73.5 ± 7.0 μm (n = 4 eyes). The thickness of the IS was 27.8 ± 2.6 μm and that of the OS was 45.8 ± 7.3 μm. In all eyes, there was a spontaneous improvement of the visual acuity. SD-OCT showed a recovery of only the IS/OS line in the macular area, but the COST line was not visible in three cases. The mean IS + OS thickness increased to 56.0 ± 7.9 μm (n = 4), IS = 26.0 ± 2.0 μm (n = 3), and OS = 30.1 ± 8.7 μm (n = 3) in the early recovery phase, and to 64.8 ± 9.3 μm (n = 4), IS = 28.5 ± 1.7 μm (n = 4), and OS = 36.3 ± 7.9 μm (n = 4) in the late recovery phase. The mean inner and outer segment thickness remained unchanged in the fellow eyes. Eyes with MEWDS have changes in the photoreceptor microstructures. The change in the IS + OS thickness during the natural recovery course might be due to an increase in the OS length.

To assess the results of perimetry recorded under dark- and light-adapted (DA and LA) conditions in patients with acute zonal occult outer retinopathy (AZOOR) and to compare the results of electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT) in two groups of AZOOR patients.Twelve patients with AZOOR were studied. The diagnosis of AZOOR was based on the results of ophthalmoscopy, Goldmann kinetic perimetry, and multifocal ERGs. In addition, DA and LA perimetry, ERG, and SD-OCT were performed. The patients were followed for 1-9 years.The patients were classified into two types: type A patients (3) had a scotoma detected by both DA and LA perimetry, normal or equally abnormal cone and rod ERGs, atrophy of the outer nuclear layer (ONL), and disruption of the inner segment/outer segment (IS/OS) junction line in the OCT images. Type B patients (7) had a scotoma that was more prominent in LA than in DA perimetry and a continuous IS/OS junction line in the OCT images. Two patients had characteristics of both type A and type B AZOOR.Our findings suggest that eyes with type A AZOOR have focal and severe impairment of both the rods and cones, and eyes with type B AZOOR have focal and specific impairment of the cones.

To obtain a de novo map of outer photoreceptor layer (OPRL) thickness using a semiautomatic segmentation method for commercial spectral-domain optical coherence tomography (SD-OCT) and analyze the features of the resulting OPRL map in normal eyes and eyes with various inactive macular diseases. Forty normal eyes and 50 eyes with various inactive macular diseases such as resolved central serous chorioretinopathy (20 eyes), surgically-repaired macular hole (10 eyes), epiretinal membrane (10 eyes), and reattached rhegmatogenous retinal detachment (10 eyes) were screened. All subjects underwent a 12 radial scan protocol in SD-OCT. The segmentation lines defining the OPRL were modified using built-in software. The diseased eyes were subdivided into two groups (good vision, or intermediate to poor vision) based on a visual acuity better or worse than 20/40. The map of the OPRL thickness was obtained automatically by the embedded software and was presented as the Early Treatment Diabetic Retinopathy Study (ETDRS) style. The mean OPRL thickness in normal eyes in all subfields was 40.37 ± 4.35 μm. The central subfield area showed the greatest mean OPRL thickness in normal eyes. The mean OPRL thickness of diseased eyes with good vision in the central subfield was greater than that of eyes with intermediate to poor vision. The OPRL thickness map showed various patterns according to the type of macular diseases. We suggest that our semiautomated segmentation method using a 12 radial scan protocol is simple, fast, and suitable for producing a reliable OPRL map with ETDRS. This quantitative data could be useful in clinical practice or research of various macular diseases.

To evaluate the baseline spectral-domain optical coherence tomography (SD-OCT) characteristics of macular edema (ME) due to branch retinal vein occlusion (BRVO) for visual outcome after intravitreal bevacizumab injection.Fifty-nine patients treated in one eye with intravitreal bevacizumab for ME due to BRVO were retrospectively reviewed. Stepwise multiple regression analysis was used to evaluate the relative contribution of several variables, including SD-OCT characteristics such as photoreceptor inner segment/outer segment (IS/OS) integrity and external limiting membrane (ELM status), baseline best-corrected visual acuity (BCVA), and baseline central retinal thickness (CRT) with final visual outcome.Thirty-one patients (52.5 %) had disrupted photoreceptor IS/OS integrity. The mean BCVA improved significantly from 0.50 logMAR (20/63 Snellen equivalent) to 0.10 logMAR (20/25 Snellen equivalent) in the intact photoreceptor group (p = 0.000, paired t-test). However, the mean BCVA was improved in the disrupted photoreceptor group, from 1.10 logMAR (20/252 Snellen equivalent) to 0.94 logMAR (20/174 Snellen equivalent), which was not statistically significant (p = 0.177, paired t-test). ELM was disrupted in 23 patients (39.0 %). The mean BCVA improved significantly from 0.63 logMAR (20/85 Snellen equivalent) to 0.26 logMAR (20/36 Snellen equivalent) in the intact ELM group (p = 0.000, paired t-test), however, not significantly improved in the disrupted ELM group, from 1.09 logMAR (20/246 Snellen equivalent) to 1.01 logMAR (20/205 Snellen equivalent) (p = 0.563, paired t-test). The strongest individual predictor of final BCVA among patients with ME due to BRVO was the integrity of photoreceptor IS/OS layer on SD OCT (r (2) = 0.514, p = 0.000, stepwise multiple regression), but the most efficient model was the combination of the photoreceptor IS/OS integrity, ELM status, and baseline BCVA (r(2) = 0.671, p = 0.000, stepwise multiple regression). The strongest predictor of final BCVA was the status of photoreceptor IS/OS integrity (β = 0.532, p = 0.000, stepwise multiple regression), followed by ELM status (β = 0.325, p = 0.006, stepwise multiple regression), and the baseline BCVA (β = 0.238, p = 0.013, stepwise multiple regression).Our results suggest that baseline SD-OCT characteristics, the status of photoreceptor IS/OS and ELM can be helpful in predicting the final visual outcome after intravitreal bevacizumab injection in these patients.

To study the evolution of lamellar macular holes (LMHs) using spectral domain-optical coherence tomography (SD-OCT). Thirty-four consecutive patients diagnosed with a LMH were followed prospectively at Sacco University Hospital from October 2008 to January 2011. Inclusion criteria were a foveal defect on SD-OCT with residual foveal tissue above the retinal pigment epithelium and corresponding hyperautofluorescence on fundus autofluorescence imaging. Epiretinal membranes (ERMs) were categorized by SD-OCT at baseline as two different types: normal and thicker than normal. Best corrected visual acuity (BCVA) and SD-OCT findings were collected and compared at baseline and every 6 months thereafter. Active eye tracking technology ensured that the same scanning location was identified on follow-up visits. Main outcome measures were visual acuity changes (Early Treatment Diabetic Retinopathy charts) and progression of the lamellar macular defect. The influence of ERM type on disease progression was also evaluated. The patients included 15 males and 19 females with a mean age of 73 years and mean refraction of −0.25 diopters. The mean follow-up period was 18 months (range 6 to 24 months). BCVA at baseline (±standard deviation) was 63 ± 6 letters and did not change significantly during the follow-up period (P = 0.256). Foveal thickness at baseline, 180 ± 29 μm, was also stable (P = 0.592). All eyes had an ERM at baseline. Both thicker and normal ERMs showed similar functional and morphological evolution during follow-up with no significant changes. Two LMHs (5.8 %) developed a full thickness macular hole after 6 and 15 months follow-up respectively. Lamellar macular holes seem to be a stable macular condition. Vitrectomy should be considered only in the presence of progressive thinning of foveal thickness and/or decrease of visual acuity during the follow-up of the disease.

The aim of this work is to evaluate the preoperative and postoperative spectral domain optical coherence tomography (SD-OCT) findings as predictors of visual acuity for macular hole (MH) surgery.Fifty eyes of 46 patients diagnosed with MH and that had undergone 25-g vitrectomy with internal limiting membrane peeling were included in this retrospective study. A complete clinical examination and SD-OCT were performed before and after surgery. Three groups were considered on the basis of the postoperative integrity of photoreceptor inner and outer segment (IS-OS) junction and the external limiting membrane (ELM): group A (11 eyes, both lines disrupted), group B (ten eyes, disrupted IS/OS line and complete ELM), and group C (29 eyes, both lines restored).LogMAR BCVA improved significantly after surgery from an average 0.60 ± 0.29 to 0.19 ± 0.19 (p 0.01). No significant differences had been detected preoperatively among these groups (p≥0.18). Postoperative BCVA was significantly better in group C compared to groups A and B (p ≤ 0.01). A significant correlation was found between ELM restoration and postoperative BCVA (r = -0.63, p 0.01), as well as between IS/OS line restoration and postoperative BCVA (r = -0.55, p 0.01).Outer retina restoration seems to be the best determining factor for a good visual rehabilitation after MH surgery.

To evaluate the predictors of visual improvement using spectral-domain optical coherence tomography (SD-OCT) in eyes with resistant diabetic macular edema (DME) treated with pars plana vitrectomy. Thirty-four eyes with resistant DME were evaluated in a retrospective manner. Several SD-OCT variables including photoreceptor inner segment/outer segment (IS/OS) junction, external limiting membrane (ELM) integrity, and central macular thickness (CMT) before and after the surgery, were evaluated by two experienced observers, masked to visual acuity. The visual improvement was used as the outcome measure for a stepwise regression, while the OCT factors were used as predictors. The strongest predictor of vision improvement was pre-operative damage to the ELM (p = 0.0277) compared to IS/OS junction (p = 0.03). Pretreatment central macular thickness was a very weak predictor (p = 0.18) of visual improvement. For each percentage increase of ELM integrity there was a 0.13 letter gain in vision. ELM integrity explained 16% of the visual acuity improvement after treatment, which rose to 21% with the addition of CMT. The addition of IS/OS junction in the model did not add predictive information. Evaluation of ELM preoperatively predicts the vision improvement more accurately than the IS/OS junction and CMT in eyes with DME.

The temporal and spatial characteristics of cone degeneration in the Royal College of Surgeons (RCS) rat were studied to provide information for treatment strategies of retinitis pigmentosa.Nonpigmented dystrophic RCS rats (RCS) and pigmented nondystrophic RCS rats (controls) were used. Cone processes were visualized with peanut agglutinin (PNA).Cone development appears to have been completed by postnatal day 21 (P21) in both the RCS and control rats. Signs of cone degeneration were obvious by P30, with shorter outer segments (OSs) and enlarged inner segments (ISs). At that time, 81.7% of the cones retained stained ISs. The rate of IS density decline was slower in the peripheral, nasal, and superior retina, and only 43.6% of the cones with ISs were present at P45. By P60, PNA-labeled cone ISs were distorted and restricted to the peripheral retina, and by P90, few cone pedicles were detected.Our findings indicate that therapeutic strategies aimed at rescuing cones in the degenerating retina should be applied before P21 and no later than P45 while substantial numbers of cones retain their ISs. Either the middle or peripheral regions of the nasal and superior retina are the best locations for transplantation strategies.

We have previously shown that bevacizumab, but not ranibizumab, is taken up by porcine RPE cells. In this study, the effects of bevacizumab and ranibizumab on proliferation, wound healing and phagocytosis of the RPE were investigated.Primary porcine RPE cell culture were prepared from fresh eyes, cultivated and treated with clinically relevant concentrations of bevacizumab or ranibizumab respectively. Proliferation was investigated in a proliferation assay, wound healing in a wound scratch assay and phagocytosis was investigated by feeding RPE cells photoreceptor outer segment-opsonized FITC-labeled latex beads.Bevacizumab, and to a lesser extend ranibizumab, impair the proliferation of RPE cells but do not affect wound healing. Bevacizumab, but not ranibizumab, reduces the phagocytotic function of RPE cells.The uptake of bevacizumab reduces phagocytosis in RPE cells, which indicates possible long-term effects of repeated bevacizumab treatment.

PURPOSE: To study morphologically and functionally the prognosis of damaged outer segments of the foveal photoreceptor layer in eyes with resolved central serous chorioretinopathy (CSC). METHODS: We studied retrospectively the medical records of 70 patients (74 eyes) with resolved CSC. Optical coherence tomography was used to detect the junctions between inner and outer segments of the photoreceptors (IS/OS) as a hallmark of the integrity of the outer photoreceptor layer. RESULTS: In 53 eyes (71.6%), the IS/OS line was clearly detected beneath the fovea immediately after resolution of the retinal detachment, with good visual acuity (VA). In the remaining 21 eyes (28.4%), however, the foveal IS/OS line could not be detected shortly after resolution of CSC, and VA was variable, ranging from 0.1 to 1.5 (median, 0.9). Of these 21 eyes, 15 had a follow-up examination with OCT, and in four the foveal IS/OS line was not detected at the follow-up and vision in these eyes remained poor. However, nine eyes showed recovery of the foveal IS/OS line during follow-up, and these eyes had substantial visual recovery. CONCLUSIONS: Immediately after resolution of active CSC, although the IS/OS line cannot be detected beneath the fovea, it often shows restoration over time, with visual recovery, though in some eyes no restoration takes place and the prognosis remains poor.

Targeted deletion of membrane guanylate cyclases (GCs) has yielded new information concerning their function. Here, we summarize briefly recent results of laboratory generated non-photoreceptor GC knockouts characterized by complex phenotypes affecting the vasculature, heart, brain, kidney, and other tissues. The main emphasis of the review, however, addresses the two GCs expressed in retinal photoreceptors, termed GC-E and GC-F. Naturally occurring GC-E (GUCY2D) null alleles in human and chicken are associated with an early onset blinding disorder, termed "Leber congenital amaurosis type 1" (LCA-1), characterized by extinguished scotopic and photopic ERGs, and retina degeneration. In mouse, a GC-E null genotype produces a recessive cone dystrophy, while rods remain functional. Rod function is supported by the presence of GC-F (Gucy2f), a close relative of GC-E. Deletion of Gucy2f has very little effect on rod and cone physiology and survival. However, a GC-E/GC-F double knockout (GCdko) phenotypically resembles human LCA-1 with extinguished ERGs and rod/cone degeneration. In GCdko rods, PDE6 and GCAPs are absent in outer segments. In contrast, GC-E(-/-) cones lack proteins of the entire phototransduction cascade. These results suggest that GC-E may participate in transport of peripheral membrane proteins from the endoplasmic reticulum (ER) to the outer segments.

Diabetic retinopathy (DR) is one of the leading causes of blindness, affecting over 90% of diabetics. Exendin-4 (E4) is a potent and long-acting agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an insulinotropic gut peptide, which normalizes blood glucose level and is now being tested in clinical trials as a treatment for diabetes. The purpose of our study was to explore the protective effect of subcutaneous (sc.) exendin-4 analogue (E4a) on early DR.Expression of GLP-1R was detected at both mRNA and protein levels and verified by immunohistochemistry. Thirty-six Sprague-Dawley (SD) rats were included in the experiment. Diabetes was induced by intraperitoneal injection (ip) of streptozotocin (STZ). The rats were divided into three groups: normal control (N), diabetic control (D) and E4a-treated diabetic (E4a) group. For the E4a group, the rats were treated with E4a (sc.0.05 microg/g BW/day); for the N and D groups, the rats were treated with normal saline (NS, sc). Blood glucose levels and body weight were measured weekly. Electroretinogram (ERG) was performed 1 and 3 months after diabetes onset. The retinal thickness and cell counts in each layer were evaluated under light microscopy after ERG examination.GLP-1R was expressed at both mRNA and protein levels in the retina of SD rats. Immunostaining of the rat retina revealed that GLP-1R was predominantly expressed in the inner layer of the retina. E4a can reduce the blood glucose level of diabetic rats to the normal control level. B-wave amplitudes and OPs decreased with the progress of diabetes, and E4a prevents the loss of b-wave amplitude and OPs caused by diabetes. The retinal thickness was reduced in a diabetes-duration-dependent fashion. The cell counts of both ONL and INL were reduced accordingly in the diabetic rats. E4a prevented cell loss and maintained a normal thickness.GLP-1R is expressed in rat retina. Apoptosis is an important constituent of retinal cell death in early DR. E4a administration can reverse the changes of ERG, prevent the retinal cell death and maintain normal retinal thickness in diabetic rats. Therefore, this is a potent approach for treatment of early DR.

To evaluate the ability of spectral-domain optical coherence tomography (SD-OCT) images of the inner/outer segment (IS/OS) junction to predict macular hole surgery outcomes.Fifty-four eyes in 53 patients with idiopathic macular holes were studied. Postoperative visual acuity and SD-OCT images of the fovea were examined before and 12 months after surgery. The total area and the maximum length of the IS/OS junction defect were measured.The macular holes were successfully closed in all the eyes included in this series. The mean log MAR visual acuity improved significantly from 0.67 +/- 0.25 preoperatively to 0.16 +/- 0.22 postoperatively (p0.001). The mean total area and maximum length of the IS/OS junction defect at 12 months after surgery were 10,185 +/- 1,537 microm(2) and 100.5 +/- 10.4 microm respectively; these values were significantly negatively correlated with the postoperative visual acuity.SD-OCT is useful for quantitatively measuring IS/OS junction defects. The postoperative IS/OS junction may play an important role in visual recovery after macular hole surgery.

To determine whether a significant correlation exists between the visual acuity or foveal thickness and the status of the inner and outer segment junction (IS/OS) of the photoreceptor in patients with retinitis pigmentosa (RP). Three hundred eyes of 163 patients with RP were examined with the optical coherence tomography (OCT). The IS/OS appeared as a distinct, highly reflective line just vitread of the retinal pigment epithelium in the OCT3 images. The IS/OS line was graded into three groups. The correlations between the grade of the IS/OS and age, best-corrected visual acuity (BCVA), and central foveal thickness (CFT) were determined. Grade 1 included 93 eyes (31.0%) in which an IS/OS line was not seen, Grade 2 included 67 eyes (22.3%) with an abnormal IS/OS, and Grade 3 included 140 eyes (46.7%) with a normal IS/OS. The correlation between the IS/OS grade and age was not significant (P=0.5536). The IS/OS grade was significantly correlated with BCVA and CFT (both P

Background: Multiple evanescent white dot syndrome (MEWDS) is an acute and usually unilateral retinopathy that occurs predominantly in young adults. This report presents the outcomes of ganglion cell analysis (GCA) in MEWDS. Case presentation: A 41-year-old woman was diagnosed as MEWDS in right eye. At her initial visit, the deviation map of the ganglion cell analysis showed there was a decrease of the ganglion cell layer (GCL) + inner plexiform layer (IPL) thickness in both eyes, even though her left eye was not affected. A 29-year-old woman was also diagnosed as MEWDS in right eye. Although the deviation map of ganglion cell analysis showed there was a decrease of the GCL + IPL thickness in both eyes at her initial visit, her right eye was not affected. Conclusion: GCA indicated there was a decrease (

'Poppers' is a slang term referring to recreational substances of abuse belonging to the alkyl nitrite family of compounds. Inhalation of the fumes from these volatile nitric oxide (NO) donors may provide a brief sense of euphoria and sexual arousal. Language: en

The m.3243A > G mitochondrial DNA mutation was originally described in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The phenotypic spectrum of the m.3243A > G mutation has since expanded to include a spectrum of neuromuscular and ocular manifestations, including reduced vision with retinal degeneration, the underlying mechanism of which remains unclear. We used dermal fibroblasts, from patients with retinal pathology secondary to the m.3243A > G mutation to generate heteroplasmic induced pluripotent stem cell (hiPSC) clones. RPE cells differentiated from these hiPSCs contained morphologically abnormal mitochondria and melanosomes, and exhibited marked functional defects in phagocytosis of photoreceptor outer segments. These findings have striking similarities to the pathological abnormalities reported in RPE cells studied from post-mortem tissues of affected m.3243A > G mutation carriers. Overall, our results indicate that RPE cells carrying the m.3243A > G mutation have a reduced ability to perform the critical physiological function of phagocytosis. Aberrant melanosomal morphology may potentially have consequences on the ability of the cells to perform another important protective function, namely absorption of stray light. Our in vitro cell model could prove a powerful tool to further dissect the complex pathophysiological mechanisms that underlie the tissue specificity of the m.3243A > G mutation, and importantly, allow the future testing of novel therapeutic agents.