AIBILI Association for Innovation and Biomedical Research on Light and Image

Coimbra, Portugal

AIBILI Association for Innovation and Biomedical Research on Light and Image

Coimbra, Portugal
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Cunha-Vaz J.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Cunha-Vaz J.,University of Coimbra
Ophthalmologica | Year: 2017

Retinal diseases are the main causes of blindness in the Western world. Diabetic retinopathy and age-related macular degeneration continue to increase in prevalence and as main causes of vision loss. Intravitreal anti-VEGF and steroid injections have raised new expectations for their successful treatment. These agents act by stabilizing the blood-retinal barrier (BRB). Our group defined the BRB by identifying for the first time the tight junctions that unite retinal endothelial cells and are the basis for the inner BRB, an observation later confirmed in retinal pigment epithelial cells and in brain vessels. A major role of active transport processes was also identified. Today, the BRB is understood to play a fundamental role in retinal function in both health and disease. Retinal edema, an ubiquitous manifestation of retinal disease, is directly associated with breakdown of the BRB and with vision loss. In its most common form (i.e., vasogenic edema), due to breakdown of the BRB, Starling's law of capillary filtration may be used to interpret the mechanisms of fluid accumulation in the retina. The main factors involved in the development of retinal edema are BRB permeability, capillary hydrostatic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and plasma osmotic pressure. In the clinical environment, breakdown of the BRB has been identified by fluorescein angiography and vitreous fluorometry, requiring the intravenous administration of fluorescein. An OCT-based method, OCT-Leakage, recently introduced by our group is capable of noninvasively identifying and quantifying sites of alteration of the BRB by mapping areas of lower-Than-normal optical reflectivity, thus reflecting changes in the retinal extracellular fluid. We found good correspondence between the location of increased areas of low optical reflectivity identified by OCT-Leakage and the main sites of leakage on fluorescein angiography. Furthermore, with OCT-Leakage the areas of abnormal fluid accumulation can be identified in specific retinal layers, clearly offering more information than previously obtained with fluorescein angiography. OCT angiography has become available, replacing much of the information yielded by fluorescein angiography in a noninvasive manner. However, OCT angiography cannot visualize the leakage, i.e., the alteration of the BRB. OCT-Leakage is able to identify the locations of increases in extracellular fluid in the different layers of the retina. The complementarity of these 2 methods is of potential great interest for the diagnosis and management of several retinal diseases in which the presence and amount of fluid, as a marker of severity and activity, is paramount to treatment and management decisions in clinical practice. 2017 © 2017 S. Karger AG, Basel.


Santos-Carvalho A.,University of Coimbra | Alvaro A.R.,University of Coimbra | Alvaro A.R.,Royal University | Martins J.,University of Coimbra | And 3 more authors.
Progress in Neurobiology | Year: 2014

Neuropeptide Y (NPY) and NPY receptors are widely expressed in the central nervous system, including the retina. Retinal cells, in particular neurons, astrocytes, and Müller, microglial and endothelial cells express this peptide and its receptors (Y1, Y2, Y4 and/or Y5). Several studies have shown that NPY is expressed in the retina of various mammalian and non-mammalian species. However, studies analyzing the distribution of NPY receptors in the retina are still scarce. Although the physiological roles of NPY in the retina have not been completely elucidated, its early expression strongly suggests that NPY may be involved in the development of retinal circuitry. NPY inhibits the increase in [Ca2+]i triggered by elevated KCl in retinal neurons, protects retinal neural cells against toxic insults and induces the proliferation of retinal progenitor cells. In this review, we will focus on the roles of NPY in the retina, specifically proliferation, neuromodulation and neuroprotection. Alterations in the NPY system in the retina might contribute to the pathogenesis of retinal degenerative diseases, such as diabetic retinopathy and glaucoma, and NPY and its receptors might be viewed as potentially novel therapeutic targets. © 2013 Elsevier Ltd.


Cunha-Vaz J.,AIBILI Association for Innovation and Biomedical Research on Light and Image
Developments in Ophthalmology | Year: 2017

Macular edema is the swelling of the central portion of the human retina and it is associated with increased retinal thickness. It can be simply defined as an excess of fluid within the retinal tissue. It must be realized that the normal retina possesses a functional extracellular space. With regard to the extracellular volume of the retina, there have been few physiologic studies, but there are reported values of 24.8% for the cerebrum and 23.6% for the cerebellum. It is accepted that the retinal extracellular space is similar to the brain. It is generally agreed that the proximate cause of macular edema and retinal fluid accumulation is a breakdown of the blood-retinal barrier (BRB). When there is a breakdown of the BRB, retinal edema can be interpreted in terms of basic principles of capillary filtration (Starling's law). Therefore, the main factors influencing retinal edema formation are BRB permeability, capillary hydrostatic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and plasma osmotic pressure. Active transport by the retinal pigment epithelium is necessary to remove water that percolates through the retina from intraocular pressure and is also as a safety mechanism against fluid accumulation in disease. Clinical evaluation of the BRB and retinal edema can be performed noninvasively by using an OCT-based method designated OCT-Leakage, which is capable of identifying and quantifying sites of alteration of the BRB, and by mapping sites of low optical reflectivity, i.e., changes in the retinal extracellular fluid. © 2017 S. Karger AG, Basel.


Santos-Carvalho A.,University of Coimbra | Santos-Carvalho A.,Institute Educacao e Cidadania | Ambrosio A.F.,University of Coimbra | Ambrosio A.F.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Cavadas C.,University of Coimbra
Progress in Retinal and Eye Research | Year: 2015

The retina is a highly complex structure where several types of cells communicate through countless different molecules to codify visual information. Each type of cells plays unique roles in the retina, presenting a singular expression of neurotransmitters. Some neurotransmitter systems in the retina are well understood, while others need to be better explored to unravel the intricate signaling system involved. Neuropeptide Y (NPY), a 36 amino acid peptide, is one of the most common peptide neurotransmitter in the CNS and a highly conserved peptide among species. We review the localization of NPY and NPY receptors (mainly NPY Y1, Y2, Y4 and Y5) in retinal cells. Common features of the expression of NPY and NPY receptors in mammalian and non-mammalian species indicate universal roles of this system in the retina. In the present review, we highlight the putative roles of NPY receptor activation in the retina, discussing, in particular, their involvement in retinal development, neurotransmitter release modulation, neuroprotection, microglia and Muller cells function, retinal pigmented epithelium changes, retinal endothelial physiology and proliferation of retinal progenitor cells. Further studies are needed to confirm that targeting the NPY system might be a potential therapeutic strategy for retinal degenerative diseases. © 2015 Elsevier Ltd.


Oliveira C.M.,Critical Health SA | Cristovao L.M.,University of Coimbra | Ribeiro M.L.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Abreu J.R.F.,AIBILI Association for Innovation and Biomedical Research on Light and Image
Ophthalmologica | Year: 2011

Aim: To assess a two-step automated system (RetmarkerSR) that analyzes retinal photographs to detect diabetic retinopathy for the purpose of reducing the burden of manual grading. Methods: Anonymous images from 5,386 patients screened in 2007 were obtained from a nonmydriatic diabetic retinopathy screening program in Portugal and graded by an experienced ophthalmologist. RetmarkerSR earmarked microaneurysms, generating two outputs: 'disease' or 'no disease'. A second-step analysis, based on coregistration, combining two visits, was subsequently performed in 289 patients who underwent repeated examinations in 2008. The study was extended by analyzing all referrals considered urgent by the ophthalmologist from 2001 to 2007. Results were compared with those obtained by manual grading. Results: The RetmarkerSR classified in a first-step analysis 2,560 patients (47.5%) as having 'no disease' and 2,826 patients (52.5%) as having 'disease', thus requiring manual grading. RetmarkerSR detected all eyes considered urgent referrals. The two-step analysis further reduced the number of false-positive results by 26.3%, indicating an overall sensitivity of 95.8% and a specificity of 63.2%. Conclusion: Automated grading of diabetic retinopathy may safely reduce the burden of grading patients in diabetic retinopathy screening programs. The novel two-step automated analysis system offers improved sensitivity and specificity over published automated analysis systems. © 2011 S. Karger AG, Basel.


Coutinho A.M.,University of Coimbra | Silva R.M.,University of Coimbra | Silva R.M.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Nunes S.G.,AIBILI Association for Innovation and Biomedical Research on Light and Image | And 5 more authors.
Retina | Year: 2011

Purpose: To evaluate the long-term safety and efficacy of photodynamic therapy in the treatment of choroidal neovascularization associated with pathologic myopia. Methods: Five-year retrospective study of 43 consecutive eyes of 36 patients with juxtafoveal or subfoveal choroidal neovascularization and pathologic myopia treated with photodynamic therapy. Results: Mean best-corrected visual acuity changed from 20/125 +1 letter (0.78 logarithm of the minimum angle of resolution) at baseline to 20/100 (0.70 logarithm of the minimum angle of resolution) at 5 years (P = 0.122). Final best-corrected visual acuity improved in 53.5% of the eyes, remained stable in 11.6%, and decreased in 34.9%. A visual acuity gain of ≥3 lines occurred in 32.6% of the eyes, and a visual acuity decrease of ≥3 lines was registered in 20.9% of the cases at 5 years. Only patient's age and initial visual acuity showed to have a significant predictive value for the final visual acuity outcome (P = 0.024 and P = 0.002, respectively). Conclusion: Photodynamic therapy with verteporfin may increase the chance of stabilizing and improving vision in patients with choroidal neovascularization from pathologic myopia at 5 years. Better results were found in younger patients (<55 years). Copyright © 2011 Lippincott Williams &Wilkins.


Ribeiro L.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Cunha-Vaz J.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Cunha-Vaz J.,University of Coimbra
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2013

Diabetic retinopathy remains the most frequent cause of new cases of blindness among adults aged 20-74 years. A number of large trials have validated that laser photocoagulation is a useful treatment but the disease continues to progress in approximately 50% of eyes treated by photocoagulation. Current treatment of diabetic retinopathy is only available for advanced stages of the disease and is given independently of the diabetes disease status itself and metabolic status. Other forms of therapy targeted at the earliest stages of retinal disease are needed. Proposals for defining and accepting surrogate outcomes that appropriately evaluate the earlier stages of the retinopathy are presented in this review. The most likely candidates for surrogate outcomes are: mean difference in ETDRS retinopa-thy scale, 2 steps per eye, microaneurysm turnover and reduction in macular thickening. © 2013 Bentham Science Publishers.


Santos-Carvalho A.,University of Coimbra | Elvas F.,University of Coimbra | Elvas F.,AIBILI Association for Innovation and Biomedical Research on Light and Image | Alvaro A.R.,Royal University | And 2 more authors.
Cell Death and Disease | Year: 2013

It has been claimed that glutamate excitotoxicity might have a role in the pathogenesis of several retinal degenerative diseases, including glaucoma and diabetic retinopathy. Neuropeptide Y (NPY) has neuroprotective properties against excitotoxicity in the hippocampus, through the activation of Y 1, Y2 and/or Y5 receptors. The principal objective of this study is to investigate the potential protective role of NPY against glutamate-induced toxicity in rat retinal cells (in vitro and in an animal model), unraveling the NPY receptors and intracellular mechanisms involved. Rat retinal neural cell cultures were prepared from newborn Wistar rats (P3-P5) and exposed to glutamate (500 lM) for 24 h. Necrotic cell death was evaluated by propidium iodide (PI) assay and apoptotic cell death using TUNEL and caspase-3 assays. The cell types present in culture were identified by immunocytochemistry. The involvement of NPY receptors was assessed using selective agonists and antagonists. Pre-treatment of cells with NPY (100 nM) inhibited both necrotic cell death (PI-positive cells) and apoptotic cell death (TUNEL-positive cells and caspase 3-positive cells) triggered by glutamate, with the neurons being the cells most strongly affected. The activation of NPY Y2, Y4 and Y5 receptors inhibited necrotic cell death, while apoptotic cell death was only prevented by the activation of NPY Y5 receptor. Moreover, NPY neuroprotective effect was mediated by the activation of PKA and p38K. In the animal model, NPY (2.35 nmol) was intravitreally injected 2 h before glutamate (500 nmol) injection into the vitreous. The protective role of NPY was assessed 24 h after glutamate (or saline) injection by TUNEL assay and Brn3a (marker of ganglion cells) immunohistochemistry. NPY inhibited the increase in the number of TUNEL-positive cells and the decrease in the number of Brn3a-positive cells induced by glutamate. In conclusion, NPY and NPY receptors can be considered potential targets to treat retinal degenerative diseases, such as glaucoma and diabetic retinopathy. © 2013 Macmillan Publishers Limited. All rights reserved.


PubMed | Carl Zeiss GmbH and AIBILI Association for Innovation and Biomedical Research on Light and Image
Type: Journal Article | Journal: The British journal of ophthalmology | Year: 2016

To analyse and compare the classification of eyes with diabetic retinopathy using fluorescein angiography (FA) and optical coherence tomography angiography (OCTA) performed either with AngioPlex or AngioVue.This was an observational cross-sectional study of 50 eyes from 26 diabetic subjects. Two independent graders classified the FA angiograms, to assess the presence and severity of several characteristics according to the ETDRS Report 11, and a similar evaluation was performed for each 33 mm OCTA image from the superficial retinal layer and for the full retina slab.Percentages of non-gradable images for the outline of foveal avascular zone (FAZ) in the central subfield (CSF) were 29.0% for FA, 12.0% for AngioVue and 3.0% for AngioPlex. For capillary loss, percentages of non-gradable images in the CSF were 25.0% for FA, 11% for AngioVue and 0.0% for AngioPlex. For the inner ring (IR), percentages of non-gradable images were 12.5% for FA, 11.5% for AngioVue and 0.5% for AngioPlex. Agreement between graders was substantial for outline of FAZ. For capillary loss, the agreement was fair for the CSF, and moderate for the IR.The OCTA allows better discrimination of the CSF and parafoveal macular microvasculature than FA, especially for FAZ disruption and capillary dropout, without the need of an intravenous injection of fluorescein. In addition, FA had also a higher number of non-gradable images. The OCTA can replace with advantage the FA, as a non-invasive and more sensitive procedure for detailed morphological evaluation of central macular vascular changes.NCT02391558, Pre-results.


PubMed | University Hospitals Leuven, AIBILI Association for Innovation and Biomedical Research on Light and Image, Glaucoma Research Unit, Imperial College London and 3 more.
Type: Journal Article | Journal: Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | Year: 2016

The aim of this study was to investigate the efficacy and safety of Bimatoprost Unit Dose Preservative Free (BUDPF) and Latanoprost Unit Dose Preservative Free (LUDPF).A prospective, randomized, investigator-masked, cross-over comparison was used. Inclusion criteria were ocular hypertension (OHT) or open-angle glaucoma (OAG) with a maximum intraocular pressure (IOP) of 21mmHg on a preserved prostaglandin monotherapy. After 6weeks washout, patients were randomized to BUDPF or LUDPF for 3months and then switched to the other treatment for 3months. IOP curves were performed at baseline and after each treatment period. Statistical analysis was performed in a R programming environment. Linear mixed modeling was used to account for repeated measures on the same subject and clustering of observations from the same center. Safety outcomes included visual acuity, adverse events, slit-lamp biomicroscopy, ocular tolerability, and optic nerve assessment.Analysis at 6months (primary outcome) showed a 1.60.5-mmHg difference in IOP values between LUDPF and BUDPF (p<0.01). A mean intra-subject IOP difference of 0.90.2mmHg (LUDPF - BUDPF) was observed (p<0.01).. Significant differences in IOP were observed for both drugs at 3 and at 6months compared to baseline: -4,00.5mmHg for both BUDPF and LUDPF at 3months (p<0.01 for both drugs; p=0.32 between the two drugs); -5.20.5 and -3.40.5mmHg for BUDPF and LUDPF, respectively (both p<0.01), at 6months. Both drugs were tolerated well, the only statistically significant difference being lower hyperemia scores for LUDPF (albeit low for both drugs).This study demonstrates a superior efficacy of BUDPF over LUDPF in lowering IOP. The results are consistent both in the parallel comparison between the two treatment groups at 6months as well as in the intra-subject pressure comparison.

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