Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

The mammalian cortex is a multilaminar structure consisting of specialized layer-specific neurons that form complex circuits throughout the brain and spinal cord. These neurons are generated in a defined sequence dictated by their birthdate such that early-born neurons settle in deep cortical layers whereas late-born neurons populate more superficial layers. Cortical neuronal birthdate is partly controlled by an intrinsic clock-type mechanism; however, the role of extrinsic factors in the temporal control of cell-cycle exit is less clear. Here, we show that Gde2, a six-transmembrane protein that induces spinal neuronal differentiation, is expressed in the developing cortex throughout cortical neurogenesis. In the absence of Gde2, cortical progenitors fail to exit the cell cycle on time, remain cycling, accumulate and exit the cell cycle en masse towards the end of the neurogenic period. These dynamic changes in cell-cycle progression cause deficits and delays in deep-layer neuronal differentiation and robust increases in superficial neuronal numbers. Gde2−/− cortices show elevated levels of Notch signaling coincident with when progenitors fail to differentiate, suggesting that abnormal Notch activation retains cells in a proliferative phase that biases them to superficial fates. However, no change in Notch signaling is observed at the time of increased cell-cycle exit. These observations define a key role for Gde2 in controlling cortical neuronal fates by regulating the timing of neurogenesis, and show that loss of Gde2 uncovers additional mechanisms that trigger remaining neuronal progenitors to differentiate at the end of the neurogenic period.</jats:p

Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears

To report a case of filamentary keratitis (FK) successfully treated with autologous serum tears and to review the pathogenesis and management of FK. Case report including high-resolution anterior segment optical coherence tomography and filament histopathology. A 61-year-old Hispanic man presented with pain and photophobia of the right eye. He was found to have a corneal epithelial defect and a small peripheral infiltrate 4 months after Laser Assisted in situ Keratomileusis. After resolution of the epithelial defect, he developed FK. Over a 4-month period, conservative management with aggressive lubrication, lid hygiene, topical corticosteroids, topical cyclosporine, bandage contact lenses, and oral doxycycline failed to resolve the corneal filaments. Notably, treatment with 20% autologous serum tears, four times daily, led to a sustained resolution of the FK within 1 week. This case demonstrates the complexity of FK management and introduces autologous serum tears as a viable management option when conservative approaches to this condition fail

GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

BACKGROUND: Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2’s roles beyond embryonic neurogenesis have yet to be defined. METHOD: Using a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2 (−/−) mouse for evidence of degenerative neuropathology. A conditional deletion of Gde2 was used to study the temporal requirements for GDE2 in neuronal survival. Biochemical approaches identified deficits in the processing of GPI-anchored GDE2 substrates in the SOD1 (G93A) mouse model of familial Amyotrophic Lateral Sclerosis that shows robust motor neuron degeneration. RESULTS: Here we show that GDE2 expression continues postnatally, and adult mice lacking GDE2 exhibit a slow, progressive neuronal degeneration with pathologies similar to human neurodegenerative disease. Early phenotypes include vacuolization, microgliosis, cytoskeletal accumulation, and lipofuscin deposition followed by astrogliosis and cell death. Remaining motor neurons exhibit peripheral motor unit restructuring causing behavioral motor deficits. Genetic ablation of GDE2 after embryonic neurogenesis is complete still elicits degenerative pathology, signifying that GDE2’s requirement for neuronal survival is distinct from its involvement in neuronal differentiation. Unbiased screens identify impaired processing of Glypican 4 and 6 in Gde2 null animals, and Glypican release is markedly reduced in SOD1 (G93A) mice. CONCLUSIONS: This study identifies a novel function for GDE2 in neuronal survival and implicates deregulated GPI-anchored protein activity in pathways mediating neurodegeneration. These findings provide new molecular insight for neuropathologies found in multiple disease settings, and raise the possibility of GDE2 hypofunctionality as a component of neurodegenerative disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0148-1) contains supplementary material, which is available to authorized users

Acute Syphilitic Posterior Placoid Chorioretinitis With Subfoveal Choroidal Neovascularization Managed With Anti-VEGF Therapy

Purpose: We describe the development and management of choroidal neovascularization (CNV) in a patient with acute syphilitic posterior placoid chorioretinitis (ASPPC). Methods: A retrospective case review is presented. Results: A 66-year-old man presented with unilateral blurry vision. He had a history of systemic syphilis infection twice, the last diagnosed 15 years before presentation and treated with intravenous ceftriaxone, resulting in seroreversion of an initially positive rapid plasma reagin (RPR). Examination revealed ASPPC with subfoveal CNV. Repeat testing revealed an RPR titer of 1:16 384. He was treated with 6 monthly intravitreal injections of bevacizumab and systemic antibiotics, resulting in resolution of his ASPPC and regression of his CNV. Conclusions: CNV is a rare complication of ASPPC. Multimodal imaging can be useful to suggest the diagnosis, and prompt treatment with systemic antibiotics and intravitreal anti-vascular endothelial growth factor agents can lead to resolution of ASPPC and regression of CNV, respectively. </jats:sec

Giant retinal tears: clinical features and outcomes of vitreoretinal surgery at a university teaching hospital (2011-2017)

The purpose of this study was to report clinical features and outcomes in patients with giant retinal tears (GRTs) undergoing vitreoretinal surgery and to compare data from this contemporary series to a previous study from the same institution. A retrospective, interventional, consecutive case series was conducted for all patients diagnosed with GRTs who underwent vitreoretinal surgery between January 2011 and August 2017. Intraoperative data including the use of scleral buckling, perfluorocarbon liquid, and intraocular tamponade were collected and compared according to GRT size. These parameters, along with postoperative anatomic success and best-corrected visual acuity (BCVA), were compared with the previous series. The study included 80 eyes of 79 patients with a presentation of retinal detachment with a GRT. Management approach for repair of GRT-associated retinal detachments included scleral buckle (SB) alone (three eyes, 4%), pars plana vitrectomy (PPV) (16 eyes, 20%), and combined SB/PPV (61 eyes, 76%). Perfluorocarbon liquids were used in 60/77 eyes (78%) undergoing PPV, and silicone oil was used in 54/77 eyes (70%). Single surgery success rate was in 69/80 eyes (86%). Eyes managed with SB (including SB alone and SB/PPV) or PPV without SB had similar rates of recurrent retinal detachment (16% vs 6%; =0.33). Anatomic success was achieved in 76/80 eyes (95%) with one or more surgical procedures, and 54/80 eyes (68%) achieved postoperative BCVA of ≥20/400. In the current series, repairs of retinal detachment due to GRTs were most commonly managed with combined PPV/SB and perfluorocarbon liquid, resulting in reasonably generally favorable anatomic and visual outcomes

Additional file 1: Figure S1. of GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Sensory neurons exhibit neurodegenerative pathology without impaired nerve conduction in the absence of Gde2. This figure illustrates the presence of neuropathology in the primary sensory neurons of the Gde2 KO, including vacuolization, lipid accrual, and cytoskeletal accumulation; and the maintenance of peripheral sensory nerve conduction. Figure S2-related to Fig. 9. Conditional ablation of Gde2 in the postnatal spinal cord prevents the developmental loss of motor neurons. This figure confirms the effective conditional ablation of Gde2 following neurogenesis. In the constitutive KO, GDE2’s absence during embryonic neurogenesis causes a reduction of alpha motor neurons in the lateral motor column; however, in the Gde2lox/-; ROSA:CreER animals, this loss is avoided by injecting 4-OHT at E17.5. Further, competitive PCR analysis shows a near complete deletion of the conditional Gde2 allele following 4-OHT delivery. Figure S3. Gde2 deletion does not perturb neuromuscular junction morphology. This figure uses wholemount immunohistochemistry to assess the integrity of the neuromuscular junction (NMJ) in aged Gde2 KO hindlimb muscle. At 19 months, no discernible pathology is present in the Gde2 KO NMJ. (DOCX 6586 kb

Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD

Adipose tissue-derived "stem cells" have been increasingly used by "stem-cell clinics" in the United States and elsewhere to treat a variety of disorders. We evaluated three patients in whom severe bilateral visual loss developed after they received intravitreal injections of autologous adipose tissue-derived "stem cells" at one such clinic in the United States. In these three patients, the last documented visual acuity on the Snellen eye chart before the injection ranged from 20/30 to 20/200. The patients' severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation. After 1 year, the patients' visual acuity ranged from 20/200 to no light perception

Impact of contact versus non-contact wide-angle viewing systems on outcomes of primary retinal detachment repair (PRO study report number 5)

Background/aimsVitrectomy to repair retinal detachment is often performed with either non-contact wide-angle viewing systems or wide-angle contact viewing systems. The purpose of this study is to assess whether the viewing system used is associated with any differences in surgical outcomes of vitrectomy for primary non-complex retinal detachment repair.MethodsThis is a multicenter, interventional, retrospective, comparative study. Eyes that underwent non-complex primary retinal detachment repair by either pars plana vitrectomy (PPV) alone or in combination with scleral buckle/PPV in 2015 were evaluated. The viewing system at the time of the retinal detachment repair was identified and preoperative patient characteristics, intraoperative findings and postoperative outcomes were recorded.ResultsA total of 2256 eyes were included in our analysis. Of those, 1893 surgeries used a non-contact viewing system, while 363 used a contact lens system. There was no statistically significant difference in single surgery anatomic success at 3 months (p=0.72), or final anatomic success (p=0.40). Average postoperative visual acuity for the contact-based cases was logMAR 0.345 (20/44 Snellen equivalent) compared with 0.475 (20/60 Snellen equivalent) for non-contact (p=0.001). After controlling for numerous confounding variables in multivariable analysis, viewing system choice was no longer statistically significant (p=0.097).ConclusionThere was no statistically significant difference in anatomic success achieved for primary retinal detachment repair when comparing non-contact viewing systems to contact lens systems. Postoperative visual acuity was better in the contact-based group but this was not statistically significant when confounding factors were controlled for.</jats:sec