Clinical and Molecular Aspects of C2orf71/PCARE in Retinal Diseases

Ciliopathies; Photoreceptors; RetinaCiliopatías; Fotorreceptores; RetinaCiliopaties; Fotoreceptors; RetinaMutations in the photoreceptor-specific C2orf71 gene (also known as photoreceptor cilium actin regulator protein PCARE) cause autosomal recessive retinitis pigmentosa type 54 and cone-rod dystrophy. No treatments are available for patients with C2orf71 retinal ciliopathies exhibiting a severe clinical phenotype. Our understanding of the disease process and the role of PCARE in the healthy retina significantly limits our capacity to transfer recent technical developments into viable therapy choices. This study summarizes the current understanding of C2orf71-related retinal diseases, including their clinical manifestations and an unclear genotype-phenotype correlation. It discusses molecular and functional studies on the photoreceptor-specific ciliary PCARE, focusing on the photoreceptor cell and its ciliary axoneme. It is proposed that PCARE is an actin-associated protein that interacts with WASF3 to regulate the actin-driven expansion of the ciliary membrane during the development of a new outer segment disk in photoreceptor cells. This review also introduces various cellular and animal models used to model these diseases and provides an overview of potential treatments.This research project was funded by Instituto de Salud Carlos III, grant number PI22/01747

Tractional Retinal Detachment Related to Hemoglobin C Trait Retinopathy: A Case Report

Hemoglobin C (HbC) disease is an uncommon disease that is generally considered benign, causing only occasionally painless hematuria, osteomyelitis, and dental abnormalities. Ocular manifestations have rarely been described in these patients. Here we report a novel ophthalmological manifestation of the disease. A 20-year-old woman presented with progressive visual loss in her right eye due to tractional retinal detachment. The left eye was apparently normal, but wide-field fluorescence angiography showed mild peripheral ischemia with multiple vascular abnormalities. Vitrectomy was performed and the systemic workup revealed the presence of hemoglobinopathy C in heterozygous form. HbC disease can be sight-threating due to retinal proliferation, similar to sickle cell retinopathy. Patients affected with this disease should undergo regular surveillance. Ultra-wide angiography is a helpful examination to detect peripheral ischemia in the earlier stages

CD4-CD8 and CD28 expression in T cells infiltrating the vitreous fluid in patients with proliferative diabetic retinopathy : a flow cytometric analysis

OBJECTIVES: To investigate CD4-CD8 and CD28 expression in T cells infiltrating the vitreous fluid in patients with proliferative diabetic retinopathy and to evaluate the relationship between the infiltrating T cells and both the activity of proliferative diabetic retinopathy and the clinical outcome. METHODS: Both vitreous and peripheral blood samples were obtained simultaneously from 20 consecutive diabetic patients and analyzed by flow cytometry. Three diabetic patients were excluded because there were no viable cells in the vitreous fluid. Six nondiabetic patients requiring vitrectomy were also studied. RESULTS:T lymphocytes were detected in all 6 diabetic patients with vitreous hemorrhage and in 6 (55%) of the 11 diabetic patients without vitreous hemorrhage, but in none of the nondiabetic patients. The percentages of T cells (CD3+), TCD4+ (CD3+ CD4+), and TCD8+ (CD3+ CD8+) subsets, as well as the expression of CD28, were similar in the vitreous fluid and in the peripheral blood in patients with vitreous hemorrhage. However, in patients without vitreous hemorrhage, the percentage of CD4+ CD28-T cells in the vitreous fluid was significantly higher than in the peripheral blood (33.34% [20.75%-100.00%] vs 8.45% [2.43%-56.59%]; P =.02). In addition, all of these patients showed quiescent retinopathy and their outcome was better than that of patients with vitreous hemorrhage and patients in whom intravitreous T cells were undetectable. CONCLUSION: T cells infiltrating the vitreous of diabetic patients without vitreous hemorrhage not only show a different pattern than in the peripheral blood but also seem to improve the prognosis of proliferative diabetic retinopathy. CLINICAL RELEVANCE: Our results provide further understanding of events involved in the autoimmune response in diabetic retinopathy and may aid in the research for new treatment approaches

Efficacy and safety of an aflibercept treat-and-extend regimen in treatment-naïve patients with macular oedema secondary to Central Retinal Vein Occlusion (CRVO) : A Prospective 12-Month, Single-Arm, Multicentre Trial

To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). Design, Setting, and Patients. Phase IV, prospective, open-label, single-arm trial in 11 Spanish hospitals. Treatment-naïve patients with <6 month diagnosis of MO secondary to CRVO and best-corrected visual acuity (BCVA) of 73-24 ETDRS letters were included between 23 January 2015 and 17 March 2016. Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. Mean change in BCVA after 12 months. 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P = 0.0001. Twelve (50.0%) patients gained ≥15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) μm) and Month 12 (mean 257.4 (48.4) μm); P < 0.0001. At Month 12, 8.3% patients had MO. & The mean (SD) number of injections: 8.3 (3.0). No treatmentrelated AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability

Comparative study of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC) as a treatment for retinal dystrophies

Retinal dystrophies (RD) are major causes of familial blindness and are characterized by progressive dysfunction of photoreceptor and/or retinal pigment epithelium (RPE) cells. In this study, we aimed to evaluate and compare the therapeutic effects of two pluripotent stem cell (PSC)-based therapies. We differentiated RPE from human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs) and transplanted them into the subretinal space of the Royal College of Surgeons (RCS) rat. Once differentiated, cells from either source of PSC resembled mature RPE in their morphology and gene expression profile. Following transplantation, both hESC- and hiPSC-derived cells maintained the expression of specific RPE markers, lost their proliferative capacity, established tight junctions, and were able to perform phagocytosis of photoreceptor outer segments. Remarkably, grafted areas showed increased numbers of photoreceptor nuclei and outer segment disk membranes. Regardless of the cell source, human transplants protected retina from cell apoptosis, glial stress and accumulation of autofluorescence, and responded better to light stimuli. Altogether, our results show that hESC- and hiPSC-derived cells survived, migrated, integrated, and functioned as RPE in the RCS rat retina, providing preclinical evidence that either PSC source could be of potential benefit for treating RD

Leigh syndrome associated with TRMU gene mutations

tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease

Forest hydrology in Chile: Past, present, and future

This paper reviews the current knowledge of hydrological processes in Chilean temperate forests which extend along western South America from latitude 29° S to 56 ° S. This geographic region includes a diverse range of natural and planted forests and a broad sweep of vegetation, edaphic, topographic, geologic, and climatic settings which create a unique natural laboratory. Many local communities, endangered freshwater ecosystems, and downstream economic activities in Chile rely on water flows from forested catchments. This review aims to (i) provide a comprehensive overview of Chilean forest hydrology, to (ii) review prior research in forest hydrology in Chile, and to (iii) identify knowledge gaps and provide a vision for future research on forest hydrology in Chile. We reviewed the relation between native forests, commercial plantations, and other land uses on water yield and water quality from the plot to the catchment scale. Much of the global understanding of forests and their relationship with the water cycle is in line with the findings of the studies reviewed here. Streamflow from forested catchments increases after timber harvesting, native forests appear to use less water than plantations, and streams draining native forest yield less sediment than streams draining plantations or grassland/shrublands. We identified 20 key knowledge gaps such as forest groundwater systems, soil–plant-atmosphere interactions, native forest hydrology, and the effect of forest management and restoration on hydrology. Also, we found a paucity of research in the northern geographic areas and forest types (35-36 ° S); most forest hydrology studies in Chile (56 %) have been conducted in the southern area (Los Rios Region around 39-40 ° S). There is limited knowledge of the geology and soils in many forested areas and how surface and groundwater are affected by changes in land cover. There is an opportunity to advance our understanding using process-based investigations linking field studies and modeling. Through the establishment of a forest hydrology science “society” to coordinate efforts, regional and national-scale land use planning might be supported. Our review ends with a vision to advance a cross-scale collaborative effort to use new nation-wide catchment-scale networks Long-term Ecosystem Research (LTER) sites, to promote common and complementary techniques in these studies, and to conduct transdisciplinary research to advance sound and integrated planning of forest lands in Chile

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit

Comparison of Anatomical and Visual Outcomes between Idiopathic and Myopic Macular Holes Using the Internal Limiting Membrane or Inverted Internal Limiting Membrane Flap Technique

Purpose. To compare the results of vitrectomy with those of internal limiting membrane (ILM) peeling or inverted ILM flap for treating myopic or idiopathic macular hole. Methods. Thirty-nine eyes of 39 patients undergoing vitrectomy with ILM peeling for macular hole (25 idiopathic and 14 myopic) and 27 eyes of 27 patients undergoing vitrectomy with inverted ILM flap (15 idiopathic and 12 myopic) were included. Outcome measures were macular hole closure by optical coherence tomography and visual acuity at 6 months. Results. Closure was achieved in 25 (100%) idiopathic and 12 (86%) myopic macular holes in the ILM peeling group and in 14 (93%) idiopathic and 11 (91.77%) macular holes in the inverted ILM flap group. There were no statistically significant differences in restoration of the external limiting membrane and ellipsoid zone between the groups. Median best-corrected visual acuity (logarithm of minimal angle of resolution) at the end of follow-up was 0.22 (20/32 Snellen) in idiopathic and 0.4 (20/50) in myopic (P=0.042) patients in the ILM peeling group and 0.4 (20/50) in idiopathic and 0.4 (20/50) in myopic (P=0.652) patients in the inverted ILM flap group. Conclusion. Both techniques were associated with high closure rates in myopic and idiopathic macular holes, with somewhat better visual outcomes in idiopathic cases. The small sample size may have provided insufficient power to support the superiority of one technique over the other in the two groups

Combination of Anti-VEGF and Laser Photocoagulation for Diabetic Macular Edema: A Review

Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. Thirty years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid laser photocoagulation reduces moderate vision loss from DME by 50% or more; thus, macular photocoagulation became the gold standard treatment for DME. However, with the development of anti-VEGF drugs (bevacizumab, ranibizumab, and aflibercept), better outcomes were obtained in terms of visual acuity gain and decrease in macular thickness in some studies when antiangiogenic drugs were administered in monotherapy. Macular laser therapy may still play an important role as an adjuvant treatment because it is able to improve macular thickness outcomes and reduce the number of injections needed. Here, we review some of the clinical trials that have assessed the efficacy of macular laser treatment, either as part of the treatment protocol or as rescue therapy