RESUMEN
HbSC disease, a less severe form of sickle cell disease, affects the retina more frequently and patients have higher rates of proliferative retinopathy that can progress to vision loss. This study aimed to identify differences in the expression of endothelial cell-derived molecules associated with the pathophysiology of proliferative sickle cell retinopathy (PSCR). RNAseq was used to compare the gene expression profile of circulating endothelial colony-forming cells from patients with SC hemoglobinopathy and proliferative retinopathy (n = 5), versus SC patients without retinopathy (n = 3). Real-time polymerase chain reaction (qRT-PCR) was used to validate the RNAseq results. A total of 134 differentially expressed genes (DEGs) were found. DEGs were mainly associated with vasodilatation, type I interferon signaling, innate immunity and angiogenesis. Among the DEGs identified, we highlight the most up-regulated genes ROBO1 (log2FoldChange = 4.32, FDR = 1.35E-11) and SLC38A5 (log2FoldChange = 3.36 FDR = 1.59E-07). ROBO1, an axon-guided receptor, promotes endothelial cell migration and contributes to the development of retinal angiogenesis and pathological ocular neovascularization. Endothelial SLC38A5, an amino acid (AA) transporter, regulates developmental and pathological retinal angiogenesis by controlling the uptake of AA nutrient, which may serve as metabolic fuel for the proliferation of endothelial cells (ECs) and consequent promotion of angiogenesis. Our data provide an important step towards elucidating the molecular pathophysiology of PSCR that may explain the differences in ocular manifestations between individuals with hemoglobinopathies and afford insights for new alternative strategies to inhibit pathological angiogenesis.
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Proteínas del Tejido Nervioso , Receptores Inmunológicos , Neovascularización Retiniana , Proteínas Roundabout , Adulto , Femenino , Humanos , Masculino , Angiogénesis , Células Endoteliales/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Neovascularización Retiniana/genética , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patologíaRESUMEN
BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.
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Modelos Animales de Enfermedad , Hidrógeno , Neuroglía , Oxígeno , Neovascularización Retiniana , Retinopatía de la Prematuridad , Animales , Hidrógeno/farmacología , Neovascularización Retiniana/tratamiento farmacológico , Neuroglía/efectos de los fármacos , Ratones , Retinopatía de la Prematuridad/tratamiento farmacológico , Ratones Endogámicos C57BL , Retina/efectos de los fármacos , Animales Recién Nacidos , Regeneración/efectos de los fármacos , Inmunohistoquímica , Vasos Retinianos/efectos de los fármacosRESUMEN
Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They strongly monitor retinal environment and, in response to retinal imbalance, activate neuroprotective mechanisms mainly characterized by the increase of glial fibrillary acidic protein (GFAP). Under these circumstances, if homeostasis is not reestablished, the retina can be severely injured and GFAP contributes to neuronal degeneration, as they occur in several proliferative retinopathies such as diabetic retinopathy, sickle cell retinopathy and retinopathy of prematurity. In addition, MGCs have an active participation in inflammatory responses releasing proinflammatory mediators and metalloproteinases to the extracellular space and vitreous cavity. MGCs are also involved in the retinal neovascularization and matrix extracellular remodeling during the proliferative stage of retinopathies. Interestingly, low-density lipoprotein receptor-related protein 1 (LRP1) and its ligand α2-macroglobulin (α2M) are highly expressed in MGCs and they have been established to participate in multiple cellular and molecular activities with relevance in retinopathies. However, the exact mechanism of regulation of retinal LRP1 in MGCs is still unclear. Thus, the active participation of MGCs and LRP1 in these diseases, strongly supports the potential interest of them for the design of novel therapeutic approaches. In this review, we discuss the role of LRP1 in the multiple MGCs activities involved in the development and progression of proliferative retinopathies, identifying opportunities in the field that beg further research in this topic area.Summary StatementMGCs and LRP1 are active players in injured retinas, participating in key features such as gliosis and neurotoxicity, neovascularization, inflammation, and glucose control homeostasis during the progression of ischemic diseases, such as proliferative retinopathies.
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Células Ependimogliales , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Neovascularización Retiniana , Humanos , Células Ependimogliales/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Retina/metabolismo , Retina/patología , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patologíaRESUMEN
Diabetes is a disease that leads to proliferative diabetic retinopathy (PDR), which is associated with an increase of new vessels formation due to an overexpression of angiogenic factors, such as angiopoietin 2 (ANGPT2). The aim of this work was to design a siRNA targeting ANGPT2 to decrease the retinal neovascularization associated with PDR. Adult male Wistar rats weighing 325-375 g were used. Diabetes was induced by a single dose of streptozotocin (STZ, 60 mg/kg i.p.). The siRNAs were designed, synthesised, and administered intravitreally at the beginning of diabetes induction (t0), and after 4 weeks of diabetes evolution (t4), subsequently evaluated the retinal neovascularization (junctions and lacunarity) and ANGPT2 expression in the retina by RT-PCR, after 4 weeks of the siRNAs administration. The results showed that the administration of STZ produced significant increases in blood glucose levels, retinal neovascularization (augmented junctions and lower lacunarity), and ANGPT2 expression, while the administration of the ANGPT2-siRNAs at different groups (t0 and t4) reduces the junctions and increases the lacunarity in diabetic rats. Therefore, we conclude that the administration of siRNAs targeting ANGPT2 could be an option to decrease the retinal neovascularization associated with PDR and halt the progression of blindness caused by diabetes.
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Diabetes Mellitus Experimental , Retinopatía Diabética , Neovascularización Retiniana , Angiopoyetina 2/genética , Animales , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/genética , Masculino , Neovascularización Patológica/genética , ARN Interferente Pequeño/farmacología , Ratas , Ratas Wistar , Retina/metabolismo , Neovascularización Retiniana/complicaciones , Neovascularización Retiniana/genética , Neovascularización Retiniana/metabolismo , EstreptozocinaRESUMEN
PURPOSE: To report a rare presentation of ocular von Hippel-Lindau disease associated with a massive epiretinal vascular proliferation over the macula removed by vitrectomy and submitted to histological analysis. METHODS: Interventional case report. RESULTS: A 13-year-old woman with von Hippel-Lindau disease reported progressive visual loss in the right eye over the preceding 6 months. Best-corrected visual acuity was 20/100 in the right eye. Fundoscopy showed retinal neovascularization (RNV) with macular traction and a small superotemporal hemangioblastoma. Spectral-domain optical coherence tomography confirmed increased macular thickness and macular traction secondary to RNV. Bevacizumab was injected intravitreally, resulting in partial regression of RNV. Five days after the injection, the patient underwent complete removal of fibrovascular proliferation via pars plana vitrectomy, followed by peripheral tumor photocoagulation. The specimen was subjected to histopathological and immunohistochemical analyses. At 2 years of follow-up, vision had improved to 20/30, and anatomical improvement was confirmed on both fundoscopy and spectral-domain optical coherence tomography. CONCLUSION: Ocular von Hippel-Lindau disease may be associated with RNV and macular traction. In such cases, RNV is likely responsive to anti-vascular endothelial growth factor and may be removed surgically along a cleavage plane between the tissue proliferation and the inner retina. In the reported case, the procedure was found to be safe and associated with macular anatomical improvement and vision recovery.
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Neovascularización Retiniana , Enfermedad de von Hippel-Lindau , Adolescente , Femenino , Angiografía con Fluoresceína/métodos , Humanos , Inmunohistoquímica , Neovascularización Retiniana/diagnóstico , Neovascularización Retiniana/etiología , Tomografía de Coherencia Óptica , Vitrectomía , Enfermedad de von Hippel-Lindau/complicaciones , Enfermedad de von Hippel-Lindau/cirugíaRESUMEN
Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.
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Aptámeros de Nucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Oxígeno/efectos adversos , Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , Neovascularización Retiniana/tratamiento farmacológico , Animales , Aptámeros de Nucleótidos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inyecciones Intravítreas , Ratones , MicroARNs/genética , Oligodesoxirribonucleótidos/farmacología , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/genética , Fosforilación/efectos de los fármacos , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/genética , Neovascularización Retiniana/inducido químicamente , Neovascularización Retiniana/genética , Neovascularización Retiniana/metabolismo , NucleolinaRESUMEN
Blood leakage from the vessels in the eye is the hallmark of many vascular eye diseases. One of the preclinical mouse models of retinal blood leakage, the very-low-density-lipoprotein receptor deficient mouse (Vldlr-/-), is used for drug screening and mechanistic studies. Vessel leakage is usually examined using Fundus fluorescein angiography (FFA). However, interpreting FFA images of the Vldlr-/- model is challenging as no automated and objective techniques exist for this model. A pipeline has been developed for quantifying leakage intensity and area including three tasks: (i) blood leakage identification, (ii) blood vessel segmentation, and (iii) image registration. Morphological operations followed by log-Gabor quadrature filters were used to identify leakage regions. In addition, a novel optic disk detection algorithm based on graph analysis was developed for registering the images at different timepoints. Blood leakage intensity and area measured by the methodology were compared to ground truth quantifications produced by two annotators. The relative difference between the quantifications from the method and those obtained from ground truth images was around 10% ± 6% for leakage intensity and 17% ± 8% for leakage region. The Pearson correlation coefficient between the method results and the ground truth was around 0.98 for leakage intensity and 0.94 for leakage region. Therefore, we presented a computational method for quantifying retinal vascular leakage and vessels using FFA in a preclinical angiogenesis model, the Vldlr-/- model.
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Angiografía con Fluoresceína , Neovascularización Retiniana/diagnóstico por imagen , Neovascularización Retiniana/patología , Vasos Retinianos/patología , Tomografía de Coherencia Óptica , Algoritmos , Animales , Modelos Animales de Enfermedad , Angiografía con Fluoresceína/métodos , Humanos , Procesamiento de Imagen Asistido por Computador , Ratones , Ratones Noqueados , Tomografía de Coherencia Óptica/métodosRESUMEN
We conducted retinal neovascularization under subfoveal fibrotic nodule for Coats disease by using optic coherence tomography-angiography before and after ranibizumab treatment. Our patient was an 8-year-old boy who was referred with suspicious left retinal mass. His visual acuity was 20/400 in the left eye and 20/20 in the right eye at the time of admission. Posterior segment evaluation of the left eye revealed telengiectatic vessels at the inferotemporal region of the peripheral retina with hard exudates around the optic disc and macula typical for Coats disease. His optic coherence tomography revealed a subfoveal fibrotic nodule after ranibizumab injections and laser photocoagulation treatment. The optic coherence tomography-angiography results revealed neovascularization under the subfoveal nodule at the superficial vascular complex layer. After 3 intravitreal ranibizumab injections, his neovascularization regressed on optic coherence tomography-angiography and his visual acuity improved. To the best of our knowledge, this is the first report demonstrating neovascularization under the subfoveal fibrotic nodule in Coats disease on the basis of comparative with the help of optic coherence tomography-angiography before and after the treatment.
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Neovascularización Coroidal , Neovascularización Retiniana , Telangiectasia Retiniana , Inhibidores de la Angiogénesis/uso terapéutico , Niño , Neovascularización Coroidal/tratamiento farmacológico , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Masculino , Ranibizumab/uso terapéutico , Neovascularización Retiniana/diagnóstico por imagen , Neovascularización Retiniana/tratamiento farmacológico , Telangiectasia Retiniana/complicaciones , Telangiectasia Retiniana/diagnóstico por imagen , Telangiectasia Retiniana/tratamiento farmacológico , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE OF REVIEW: Diabetic retinopathy (DR) is one of the leading causes of preventable vision loss in the world and its prevalence continues to increase worldwide. One of the ultimate and visually impairing complications of DR is proliferative diabetic retinopathy (PDR) and subsequent tractional retinal detachment. Treatment modalities, surgical techniques, and a better understanding of the pathophysiology of DR and PDR continue to change the way we approach the disease. The goal of this review is to provide an update on recent treatment modalities and outcomes of proliferative diabetic retinopathy and its complications including tractional retinal detachment. RECENT FINDINGS: Panretinal photocoagulation (PRP), anti-vascular endothelial growth factor (anti-VEGF), and pars plana vitrectomy are the mainstay of PDR treatment. However, PRP and anti-VEGF are associated with significant treatment burden and multiple subsequent treatments. Early vitrectomy is associated with vision preservation, less treatment burden, and less subsequent treatments than therapy with PRP and anti-VEGF. SUMMARY: Concerning costs, high rates of noncompliance in the diabetic population and significant rates of subsequent treatments with initial PRP and anti-VEGF, early vitrectomy for diabetic retinopathy in patients at risk of PDR is a cost-effective long-term stabilizing treatment for diabetics with advanced disease.
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Retinopatía Diabética/cirugía , Desprendimiento de Retina/cirugía , Neovascularización Retiniana/cirugía , Vitrectomía/métodos , Inhibidores de la Angiogénesis/uso terapéutico , Retinopatía Diabética/complicaciones , Retinopatía Diabética/tratamiento farmacológico , Humanos , Coagulación con Láser/métodos , Desprendimiento de Retina/tratamiento farmacológico , Desprendimiento de Retina/etiología , Neovascularización Retiniana/complicaciones , Neovascularización Retiniana/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Background: The great diversity of molecules found in spider venoms include amino acids, polyamines, proteins and peptides, among others. Some of these compounds can interact with different neuronal receptors and ion channels including those present in the ocular system. To study potential toxicity and safety of intravitreal injection in rabbits of LyeTx I b, a synthetic peptide derived from the toxin LyeTx I found in venom from the spider Lycosa eritrognatha and to evaluate the angiogenic activity on a CAM model. Methods: ARPE-19 cells were treated with LyeTx I b (0.36; 0.54; 0.72; 2.89; 4.34 or 9.06 M). In this study, New Zealand rabbits were used. LyeTx I b (2.89 M) labeled with FITC dissolved in PBS, or only PBS, were injected into vitreous humor. Electroretinogram (ERG) was recorded 1 day before injection and at 7,14 and 28 days post-injection. Clinical examination of the retina was conducted through tonometer and eye fundus after ERG. Eyes were enucleated and retinas were prepared for histology in order to assess retinal structure. CAMs were exposed to LyeTx I b (0.54; 0.72; 2.17 or 2.89 M). Results: ARPE-19 cells exposed to LyeTx I b showed cell viability at the same levels of the control. The fluorescence of LyeTx I b labeled with FITC indicated its retinal localization. Our findings indicate ERG responses from rats injected in the eye with LyeTx I b were very similar to the corresponding responses of those animals injected only with vehicle. Clinical examination found no alterations of intraocular pressure or retinal integrity. No histological damage in retinal layers was observed. CAM presented reduced neovascularization when exposed to LyeTx I b. Conclusions: Intravitreal injection of LyeTx I b is safe for use in the rabbit eye and prevents neovascularization in the CAM model, at Bevacizumab levels... (AU)
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Animales , Conejos , Inyecciones Intravítreas/veterinaria , Péptidos/uso terapéutico , Venenos de Araña/química , Venenos de Araña/uso terapéutico , Neovascularización Retiniana/prevención & control , Membrana Corioalantoides , Arañas , Toxinas BiológicasRESUMEN
PURPOSE: To compare retinal function changes in eyes with proliferative diabetic retinopathy (PDR) after intravitreal ranibizumab (IVR), combined or not with conventional (ETDRS) or multispot laser panretinal (PASCAL) photocoagulation (PRP). METHODS: This study included laser-naive PDR patients that required PRP. Eyes were randomly and prospectively assigned to receive IVR or IVR combined with PASCAL or EDTRS. PRP was performed at baseline in 1 (PASCAL) or 2 (ETDRS) sessions. In eyes with macular edema, macular short pulse grid laser was associated with IVR at baseline and IVR was repeated monthly or quarterly if neovascularization was detected on angiography. Comprehensive ophthalmological evaluations, including SD-OCT, were performed at baseline and every 4 weeks after treatment. Full-field electroretinography (ERG: extended ISCEV standard) was performed at baseline and at 12, 24 and 48 weeks. RESULTS: IVR = 13, PASCAL = 15 and ETDRS = 15 eyes finished 48-week follow-up. There was a statistically significant BCVA improvement of 0.1-0.3 logMAR in all groups, and fluorescein angiography leakage area (FLA) reduced in 56%, 73%, and 73% from baseline for ETDRS, IVR and PASCAL, respectively, up to 48 weeks without significant differences between groups (p > 0.05). A significant a- and b-wave amplitudes reduction was observed for dark- and light-adapted ERG for ETDRS and PASCAL, but only minor dark-adapted b-wave reduction was found for IVR, up to 48 weeks. As an example, at week 48, combined response b-wave amplitude reduced in 181.5 ± 31.4 µV, 128.0 ± 27.9 µV and 82.4 ± 15.2 µV for ETDRS, PASCAL and IVR (p < 0.05 each group), respectively. No significant difference was observed between ETDRS and PASCAL for any ERG parameter. CONCLUSIONS: IVR combined with single or multiple spot PRP causes similar retinal function impairment during 48 weeks of observation, while IVR alone seems to be similarly effective controlling FLA without changing retinal function.
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Inhibidores de la Angiogénesis/uso terapéutico , Retinopatía Diabética/fisiopatología , Coagulación con Láser , Ranibizumab/uso terapéutico , Retina/fisiopatología , Neovascularización Retiniana/fisiopatología , Terapia Combinada , Retinopatía Diabética/terapia , Electrorretinografía , Femenino , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Neovascularización Retiniana/terapia , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
Resumo Objetivo: O objetivo desse trabalho é avaliar o perfil de aplicações intravítreas do Ranibizumab em uma população de adultos atendidos no Instituto Benjamin Constant, no ano de 2015, levando em consideração o efeito sobre a acuidade visual e a espessura macular após tratamento. O objetivo secundário é apresentar as principais indicações desse tipo tratamento no serviço de olhos acima citado. Métodos: Foi realizado um estudo retrospectivo seccional, em indivíduos acima de 20 anos entre os meses de março a agosto de 2015, para analisar a acuidade visual e espessura foveal pré e pós tratamento. A dose do anti-VEGF utilizada foi de 0,05ml por aplicação com intervalo de quatro semanas entre elas. A aferição da acuidade visual assim como o OCT pós tratamento foram realizados em torno de trinta dias após a última aplicação. As análises estatísticas foram feitas com uso do software SPSS versão 21 e o nível de significância estatística foi de 95% com um valor de p <0,05. Resultado: O estudo mostrou que a principal afecção relacionada a esse tratamento foi a retinopatia diabética não proliferativa associada ao edema macular (32,8%). Após o tratamento indicado com Ranibizumab, houve uma melhora da acuidade visual média de 0,70 para 0,59 (logMAR) e uma regressão da espessura macular, visto no OCT, de 408,1µm para 337,2 µm (valor de p <0,05). Conclusão: Pode-se concluir portanto, que o tratamento com Ranibizumab na população estudada contribuiu para uma melhor qualidade de vida dos pacientes, pois a maioria dele apresentou uma melhora estatisticamente significativa na acuidade visual após as aplicações.
Abstract The objective of this work is to evaluate the profile of intravitreal applications of Ranibizumab in a population of adults attended at the Benjamin Constant Institute in the year of 2015, taking into account the effect on visual acuity and macular thickness after the treatment. The secondary objective is to present the main indications of this type of treatment in the eye care mentioned above. A retrospective cross-sectional study was performed in individuals over 20 years of age between March and August of 2015 to analyze visual acuity and foveal thickness before and after treatment. The dose of anti-VEGF used was 0.05 ml per application with an interval of four weeks between them. Visual acuity assessment as well as OCT post treatment were performed around 30 days after the last application. Statistical analyses were performed using SPSS software version 21 and the level of statistical significance was of 95% with a value of p <0.05. The study showed that the main condition related to this treatment was non-proliferative diabetic retinopathy associated with macular edema (32.8%). After treatment indicated with Ranibizumab, there was an improvement in the average visual acuity from 0.70 to 0.59 (logMAR) and a regression of the macular thickness, seen in the OCT, from 408.1μm to 337.2μm (p < 0.05). It can be concluded, therefore, that treatment with Ranibizumab in the studied population contributed to a better quality of life of the patients, since most of them presented a statistically significant improvement in the visual acuity after the applications.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Edema Macular/tratamiento farmacológico , Edema Macular/diagnóstico por imagen , Inyecciones Intravítreas , Ranibizumab/administración & dosificación , Retina/diagnóstico por imagen , Angiografía con Fluoresceína , Agudeza Visual , Neovascularización Retiniana , Estudios Retrospectivos , Neovascularización Coroidal , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tomografía de Coherencia Óptica , Retinopatía Diabética , Ranibizumab/uso terapéutico , Ranibizumab/farmacología , Fóvea Central/diagnóstico por imagen , Mácula Lútea/diagnóstico por imagen , Degeneración MacularRESUMEN
In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.
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Metaloproteinasa 2 de la Matriz/metabolismo , Receptor IGF Tipo 1/metabolismo , Retina/metabolismo , Neovascularización Retiniana/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Glutamato-Amoníaco Ligasa/metabolismo , Humanos , Ratones , Oxígeno , Retina/patología , Neovascularización Retiniana/etiología , Neovascularización Retiniana/patologíaRESUMEN
Age-related macular disease (AMD) and diabetic retinopathy (DR) are prevalent diseases. Vascular endothelial growth factor (VEGF) related retinal neovascularization is a common feature in both. Consequently, both pathologies are treated with anti-VEGF therapy. We have previously reported a lower incidence of AMD in patients with DR compared to controls. The present study hypothesizes that DR in stages in which the concentration of intravitreal VEGF is increased, might have a protective role for both the onset and development of AMD.
Asunto(s)
Neovascularización Coroidal , Retinopatía Diabética/metabolismo , Degeneración Macular/metabolismo , Oxígeno/metabolismo , Neovascularización Retiniana , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Retinopatía Diabética/complicaciones , Humanos , Degeneración Macular/complicaciones , Persona de Mediana Edad , Modelos Teóricos , Neovascularización Patológica , Epitelio Pigmentado de la Retina/metabolismo , Degeneración Macular Húmeda/complicaciones , Degeneración Macular Húmeda/metabolismoRESUMEN
PURPOSE:: To evaluate the retinal vascularization process after intravitreal ranibizumab was administered to infants with aggressive posterior retinopathy of prematurity (AP-ROP). METHODS:: Twenty-six eyes of 13 infants with AP-ROP who received 0.25 mg intravitreal ranibizumab were retrospectively investigated. The patients were evaluated at weekly follow-up visits, and the findings were analyzed after retinal vascularization was complete. RESULTS:: The results showed regression in the AP-ROP of all the patients within the first 48-72 h. Average time for complete vascularization of the nasal quadrant (zone II) was postmenstrual week 45 (range 41-56), and vascularization of the temporal quadrant (zone III) was completed in the postmenstrual week 56 (range 50-65). Reactivation was observed in seven patients, on average at postmenstrual week 42; two of these patients underwent additional treatment. Two patients presented with avascular areas in the peripheral retina despite being 1 year old. CONCLUSION:: These results showed that retinal vascularization following intravitreal ranibizumab was completed after a delay in patients with AP-ROP. Further studies are necessary to evaluate when and how vascularization occurs after intravitreal anti-vascular endothelial growth factor treatments.
Asunto(s)
Ranibizumab/uso terapéutico , Neovascularización Retiniana/tratamiento farmacológico , Retinopatía de la Prematuridad/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Estudios de Seguimiento , Edad Gestacional , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Inyecciones Intravítreas , Masculino , Recurrencia , Estudios RetrospectivosRESUMEN
ABSTRACT Purpose: To evaluate the retinal vascularization process after intravitreal ranibizumab was administered to infants with aggressive posterior retinopathy of prematurity (AP-ROP). Methods: Twenty-six eyes of 13 infants with AP-ROP who received 0.25 mg intravitreal ranibizumab were retrospectively investigated. The patients were evaluated at weekly follow-up visits, and the findings were analyzed after retinal vascularization was complete. Results: The results showed regression in the AP-ROP of all the patients within the first 48-72 h. Average time for complete vascularization of the nasal quadrant (zone II) was postmenstrual week 45 (range 41-56), and vascularization of the temporal quadrant (zone III) was completed in the postmenstrual week 56 (range 50-65). Reactivation was observed in seven patients, on average at postmenstrual week 42; two of these patients underwent additional treatment. Two patients presented with avascular areas in the peripheral retina despite being 1 year old. Conclusion: These results showed that retinal vascularization following intravitreal ranibizumab was completed after a delay in patients with AP-ROP. Further studies are necessary to evaluate when and how vascularization occurs after intravitreal anti-vascular endothelial growth factor treatments.
RESUMO Objetivo: Avaliar o processo de vascularização da retina após injeção intravítrea de ranibizumab aplicada em crianças com retinopatia da prematuridade posterior agressiva (AP-ROP). Métodos: Vinte e seis olhos de 13 crianças com AP-ROP que receberam 0,25 mg de ranibizumab intravítreo foram investigados retrospectivamente. Os resultados foram avaliados após a completa vascularização da retina, observada em acompanhamentos semanais. Resultados: Verificou-se que houve regressão na AP-ROP de todos os pacientes durante as primeiras 48 a 72 horas. Na média, a vascularização do quadrante nasal (zona II) foi concluída na semana 45 pós-menstrual (variação 41-56), enquanto a vascularização do quadrante temporal (zona III) foi concluída na semana 56 pós-menstrual (variação 50-65). Sete pacientes (7/13) apresentaram reativação, que aconteceram em média a 42,14 semanas pós-menstruais, dois pacientes receberam tratamento adicional. Dois pacientes apresentaram áreas avasculares na retina periférica apesar de terem um ano de idade. Conclusões: O presente estudo mostrou que a vascularização da retina após a injeção intravítrea de ranibizumab foi concluída com atraso na AP-ROP. Ensaios clínicos randomizados são necessários para avaliar quando e como a vascularização acontece após tratamentos com injeções intravítreas de anti-VEGF.
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Retinopatía de la Prematuridad/tratamiento farmacológico , Neovascularización Retiniana/tratamiento farmacológico , Ranibizumab/uso terapéutico , Recurrencia , Recien Nacido Prematuro , Estudios Retrospectivos , Estudios de Seguimiento , Edad Gestacional , Inhibidores de la Angiogénesis/uso terapéutico , Inyecciones IntravítreasRESUMEN
Receptor tyrosine kinases (RTKs) are key molecules in numerous cellular processes, the inhibitors of which play an important role in the clinic. Among them are the vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR), which are essential in the formation of new blood vessels by angiogenesis. Anti-VEGF therapy has already shown promising results in oncology and ophthalmology, but one of the challenges in the field is the design of specific small-molecule inhibitors for these receptors. We show the identification and characterization of small 6-mer peptides that target the extracellular ligand-binding domain of all three VEGF receptors. These peptides specifically prevent the binding of VEGF family members to all three receptors and downstream signaling but do not affect other angiogenic RTKs and their ligands. One of the selected peptides was also very effective at preventing pathological angiogenesis in a mouse model of retinopathy, normalizing the vasculature to levels similar to those of a normal developing retina. Collectively, our results suggest that these peptides are pan-VEGF inhibitors directed at a common binding pocket shared by all three VEGFRs. These peptides and the druggable binding site they target might be important for the development of novel and selective small-molecule, extracellular ligand-binding inhibitors of RTKs (eTKIs) for angiogenic-dependent diseases.
Asunto(s)
Inhibidores de la Angiogénesis , Células Endoteliales/metabolismo , Biblioteca de Péptidos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/genética , Inhibidores de la Angiogénesis/farmacología , Animales , Células Endoteliales/citología , Humanos , Ratones , Dominios Proteicos , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Factor A de Crecimiento Endotelial Vascular/química , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Problema de investigación: Realizar el análisis de costo-efectividad del uso de ranibizumab comparado con \r\naflibercept y bevacizumab para pacientes con degeneración macular relacionada con la edad en Colombia. Tipo de evaluación económica: Evaluación económica descriptiva de tipo costo-efectividad. Población objetivo: \r\nPoblación con la condición de degeneración macular relacionada a la edad mayor de 50 años en Colombia. Intervención y comparadores: Intervención: ranibizumab.Comparadores: aflibercept y bevacizumab. Horizonte\r\ntemporal: 24 años. Perspectiva: La del Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: Es de 5% tanto para los costos como para los desenlaces de efectividad. Estructura del modelo: \r\nModelo de Markov de 6 estados con ciclos de 6 meses. Fuentes de datos de efectividad y seguridad: Ensayos clínicos. Desenlaces y valoración: Años de vida ajustados por calidad (AVAC). Costos incluidos: Costos de medicamentos, Costos de procedimientos e insumos. Fuentes de datos de costos: Consulta a proveedores, SISMED, Manual tarifario ISS 2001. Resultados del caso base: La razón de costo-efectividad de una cohorte con pacientes de 50 años de edad sometidos a un tratamiento durante 24 años para cada uno de los medicamentos es: bevacizumab Pro Re Nata $46.8millones/AVAC, bevacizumab mensual $46.1 Millones/AVAC, ranibizumab Pro Re Nata $64.7 millones/AVAC, ranibizumab mensual $64.4 Millones/AVAC, aflibercept Pro Re nata $64.3 Millones/AVAC y aflibercept mensual $63.3Millones/AVAC. Análisis de sensibilidad: Los análisis de sensibilidad llevados a cabo sobre la tasa de descuento evidencian que ninguno de estos parámetros modifica los resultados encontrados. dominancia del bevacizumab en un esquema de \r\ntratamiento mensual es dominante en todos los escenarios planteados demostrando ser un resultado robusto. Conclusiones y discusión: Los resultados de la evaluación indican que el ranibizumab no es costo-\r\nefectivo comparado con bevacizumab y con aflibercept mensual. El ranibizumab es costo-efectivo comparado \r\ncon aflibercept con tratamiento Pro Re nata.(AU)