Association of drusen deposition with choroidal intercapillary pillars in the aging human eye

PURPOSE. To determine the pattern of drusen accumulation with age and to investigate the initial sites of deposition and their relationship to choroidal capillaries in human donor eyes from the eye bank of Moorfields Eye Hospital.METHODS. Wholemounted, hydrated preparations of the choriocapillaris and Bruch's membrane from donor eyes ranging from 42 to 95 years, with or without retinal pigment epithelium (RPE), were examined by conventional and confocal microscopy. Drusen were visualized by their autofluorescence.RESULTS. In all age groups studied autofluorescent drusen were present at the equator but were not found centrally where the vascular architecture is different, being tubular rather than a honeycomb pattern. Autofluorescing drusen were strongly associated with the lateral walls of the choriocapillaris (an area commonly known as the intercapillary pillars of the choriocapillaris (P = 0.028; Wilcoxon signed ranks test). Nonfluorescing drusen were occasionally seen centrally, but were not easily identified, and because of their large size, their localization with respect to capillary walls was not possible.CONCLUSIONS. These results strongly support the notion that autofluorescent drusen are not randomly distributed and have a specific spatial relationship to choroidal vessel walls. That equatorial drusen fluoresce, whereas central drusen do not, suggests that they may have different chemical compositions at the two sites and possibly different significance in age-related macular disease

Primary orbital melanoma: presentation, treatment and long-term outcomes for 13 patients

Background: Periocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest origin), conjunctiva or orbit (rarest primary site). Melanoma accounts for 5–10% of metastatic/secondary orbital malignancies, but only a tiny proportion of primary orbital neoplasia. Primary orbital melanoma (POM) is exceedingly rare, with approximately 50 cases reported to date. Methods: All patients seen in the orbital unit at a tertiary referral hospital (1991–2016) with a biopsy-proven diagnosis of POM were identified from a diagnostic database and were studied. The case notes, imaging, surgical approach, and histology were reviewed. Results: Thirteen patients (five male; 38%) presented with isolated malignant melanoma of the orbit, for which no other primary site was identified at presentation or during an average follow-up of 44 months (median 22; range 0–13 years). The patients presented between the ages of 40 and 84 years (mean 55.5; median 48 years) and typically gave a short history of rapidly increasing proptosis and eyelid swelling. On the basis of history, a malignant lesion was suspected in most patients and all underwent incisional biopsy, with debulking of the mass in 10 (77%) patients, and skin-sparing exenteration in 3/13 (23%). Ten patients underwent orbital radiotherapy and the survival to date ranged from 9 months to 14 years (mean 55 months; median 23 months); two patients received solely palliative care for widespread disease and one patient refused orbital radiotherapy. Five of the 13 (38%) patients died from the disease. Discussion: POM is a very rare malignancy, but clinical analysis of this cohort gives insight into disease presentation and prognosis. The tumor typically presents with a rapidly progressive, well-defined mass that is, in some cases, amenable to macroscopically intact excision. Unusual for malignant melanoma, some of these patients can show an unusually long period of quiescent disease after surgical debulking and radiotherapy

Increased Epithelial Expression of CTGF and S100A7 with Elevated Subepithelial Expression of IL-1 beta in Trachomatous Trichiasis

Purpose: To characterize the histological appearance and expression of pro-inflammatory mediators, growth factors, matrix metalloproteinases and biomarkers of epithelial-mesenchymal transition (EMT) in healthy control and trachomatous trichiasis (TT) conjunctival tissue. Methods: Conjunctival biopsies were taken from 20 individuals with TT and from 16 individuals with healthy conjunctiva, which served as controls. Study participants were of varying ethnicity and were living in a trachoma-endemic region of northern Tanzania. Formalin-fixed paraffin-embedded tissue sections were stained using hematoxylin and eosin or by immunohistochemistry using antibodies against: IL-1β, IL-6, IL-17A, IL-22, CXCL5, S100A7, cleaved caspase 1 (CC1), PDGF, CTGF, TGFβ2, MMP7, MMP9, E-cadherin, vimentin, and αSMA. Results: Tissue from TT cases had a greater inflammatory cell infiltrate relative to controls and greater disruption of collagen structure. CTGF and S100A7 were more highly expressed in the epithelium and IL-1β was more highly expressed in the substantia propria of TT cases relative to controls. Latent TGFβ2 was slightly more abundant in the substantia propria of control tissue. No differences were detected between TT cases and controls in the degree of epithelial atrophy, the number of myofibroblasts or expression of EMT biomarkers. Conclusions: These data indicate that the innate immune system is active in the immunopathology of trachoma, even in the absence of clinical inflammation. CTGF might provide a direct link between inflammation and fibrosis and could be a suitable target for therapeutic treatment to halt the progression of trachomatous scarring

Predictive mathematical models for the spread and treatment of hyperoxia-induced photoreceptor degeneration in retinitis pigmentosa

Purpose: To determine whether the oxygen toxicity hypothesis can explain the distinctive spatio-temporal patterns of retinal degeneration associated with human retinitis pigmentosa (RP) and to predict the effects of antioxidant and trophic factor treatments under this hypothesis. Methods: Three mathematical models were derived to describe the evolution of the retinal oxygen concentration and photoreceptor density over time. The first model considers only hyperoxia-induced degeneration, while the second and third models include mutation-induced rod and cone loss respectively. The models were formulated as systems of partial differential equations, defined on a two-dimensional domain spanning the region between the foveal center and the ora serrata, and were solved numerically using the finite element method. Results: The mathematical models recapitulate patterns of retinal degeneration which involve preferential loss of photoreceptors in the parafoveal/perifoveal and far-peripheral retina, while those which involve a preferential loss of midperipheral photoreceptors cannot be reproduced. Treatment with antioxidants or trophic factors is predicted to delay, halt, or partially reverse retinal degeneration, depending upon the strength and timing of treatment and disease severity. Conclusions: The model simulations indicate that while the oxygen toxicity hypothesis is sufficient to explain some of the patterns of retinal degeneration observed in human RP, additional mechanisms are necessary to explain the full range of behaviors. The models further suggest that antioxidant and trophic factor treatments have the potential to reduce hyperoxia-induced disease severity and that, where possible, these treatments should be targeted at retinal regions with low photoreceptor density to maximize their efficacy

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents

Pathways and patterns of cell loss in verified Alzheimer's disease: a factor and cluster analysis of clinico-pathological subgroups

Thirty-seven patients with neuropathologicaUy verified Alzheimer's disease (AD) have been studied prospectively. A principal components analysis of neuron numbers in cortical and subcortical areas revealed two variables: Variable I with high loadings for the hippocampo-parahippocampo-parietal neuron counts and Variable n with high loadings for coeruleo-frontal cell numbers. Both may reflect functional neuroanatomical connections which may act as pathways of neurodegeneration in AD. A cluster analysis based on these neuron numbers yielded three groups of patients: Cluster A with low hippocampoparahippocampo-parietal cell counts, Cluster B with well-preserved neuron numbers, and Cluster C with low coeruleo-frontal neuron numbers. Differences in clinical features between these patient groups indicated the potential clinical relevance of these clusters

Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial

Introduction Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. Methods and analysis This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52�weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52�weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52�weeks. Ethics and dissemination The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects� regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR

Automated quantification of retinal vessel morphometry in the UK Biobank Cohort

The following topics are dealt with: feature extraction; learning (artificial intelligence); image classification; image segmentation; computer vision; object detection; feedforward neural nets; image colour analysis; image representation; medical image processing

Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer’s disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease