Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age-related retinal degenerative disorders particularly age-related macular degeneration. During aging RPE cells decline in number, suggesting an age-dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose-dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted 'postmitotic' status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long-standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age-related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.

Targeting the complement system for the management of retinal inflammatory and degenerative diseases

The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states.

Adaptation and Evaluation of the Neighborhood Environment Walkability Scale in India (NEWS-India)

Physical inactivity is the fourth leading risk factor for global mortality, with most of these deaths occurring in low and middle-income countries (LMICs) like India. Research from developed countries has consistently demonstrated associations between built environment features and physical activity levels of populations. The development of culturally sensitive and reliable measures of the built environment is a necessary first step for accurate analysis of environmental correlates of physical activity in LMICs. This study systematically adapted the Neighborhood Environment Walkability Scale (NEWS) for India and evaluated aspects of test-retest reliability of the adapted version among Indian adults. Cultural adaptation of the NEWS was conducted by Indian and international experts. Semi-structured interviews were conducted with local residents and key informants in the city of Chennai, India. At baseline, participants (N = 370; female = 47.2%) from Chennai completed the adapted NEWS-India surveys on perceived residential density, land use mix-diversity, land use mix-access, street connectivity, infrastructure and safety for walking and cycling, aesthetics, traffic safety, and safety from crime. NEWS-India was administered for a second time to consenting participants (N = 62; female = 53.2%) with a gap of 2–3 weeks between successive administrations. Qualitative findings demonstrated that built environment barriers and constraints to active commuting and physical activity behaviors intersected with social ecological systems. The adapted NEWS subscales had moderate to high test-retest reliability (ICC range 0.48–0.99). The NEWS-India demonstrated acceptable measurement properties among Indian adults and may be a useful tool for evaluation of built environment attributes in India. Further adaptation and evaluation in rural and suburban settings in India is essential to create a version that could be used throughout India.

The duration compression effect is mediated by adaptation of both retinotopic and spatiotopic mechanisms

The duration compression effect is a phenomenon in which prior adaptation to a spatially circumscribed dynamic stimulus results in the duration of subsequent subsecond stimuli presented in the adapted region being underestimated. There is disagreement over the frame of reference within which the duration compression phenomenon occurs. One view holds that the effect is driven by retinotopic-tuned mechanisms located at early stages of visual processing, and an alternate position is that the mechanisms are spatiotopic and occur at later stages of visual processing (MT+). We addressed the retinotopic-spatiotopic question by using adapting stimuli – drifting plaids - that are known to activate global-motion mechanisms in area MT. If spatiotopic mechanisms contribute to the duration compression effect, drifting plaid adaptors should be well suited to revealing them. Following adaptation participants were tasked with estimating the duration of a 600ms random dot stimulus, whose direction was identical to the pattern direction of the adapting plaid, presented at either the same retinotopic or the same spatiotopic location as the adaptor. Our results reveal significant duration compression in both conditions, pointing to the involvement of both retinotopic-tuned and spatiotopic-tuned mechanisms in the duration compression effect.

Increasing fruit and vegetable intake has no effect on retinal vessel caliber in adults at high risk of developing cardiovascular disease

BACKGROUND AND AIM: Retinal vessel abnormalities are associated with cardiovascular disease (CVD) risk. To date, there are no trials investigating the effect of dietary factors on the retinal microvasculature. This study examined the dose response effect of fruit and vegetable (FV) intake on retinal vessel caliber in overweight adults at high CVD risk.

METHODS AND RESULTS: Following a 4 week washout period, participants were randomized to consume either 2 or 4 or 7 portions of FV daily for 12 weeks. Retinal vessel caliber was measured at baseline and post-intervention. A total of 62 participants completed the study. Self-reported FV intake indicated good compliance with the intervention, with serum concentrations of zeaxanthin and lutein increasing significantly across the groups in a dose-dependent manner (P for trend < 0.05). There were no significant changes in body composition, 24-h ambulatory blood pressure or fasting blood lipid profiles in response to the FV intervention. Increasing age was a significant determinant of wider retinal venules (P = 0.004) whereas baseline systolic blood pressure was a significant determinant of narrower retinal arterioles (P = 0.03). Overall, there was no evidence of any short-term dose-response effect of FV intake on retinal vessel caliber (CRAE (P = 0.92) or CRVE (P = 0.42)).

CONCLUSIONS: This study demonstrated no effect of increasing FV intake on retinal vessel caliber in overweight adults at high risk of developing primary CVD.

Beneficial Effects of Berberine on Oxidized LDL-induced Cytotoxicity in Human Retinal Müller Cells

PURPOSE. Limited mechanistic understanding of diabetic retinopathy (DR) has hindered therapeutic advances. Berberine, an isoquinolone alkaloid, has shown favorable effects on glucose and lipid metabolism in animal and human studies, but effects on DR are unknown. We previously demonstrated intraretinal extravasation and modification of LDL in human diabetes, and toxicity of modified LDL to human retinal M¨uller cells. We now explore pathogenic effects of modified LDL on M¨uller cells, and the efficacy of berberine in mitigating this cytotoxicity. METHODS. Confluent human M¨uller cells were exposed to in vitro–modified ‘highly oxidized, glycated (HOG-) LDL versus native-LDL (N-LDL; 200 mg protein/L) for 6 or 24 hours, with/ without pretreatment with berberine (5 lM, 1 hour) and/or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, Compound C (5 lM, 1 hour). Using techniques including Western blots, reactive oxygen species (ROS) detection assay, and quantitative real-time PCR, the following outcomes were assessed: cell viability (CCK-8 assay), autophagy (LC3, Beclin-1, ATG-5), apoptosis (cleaved caspase 3, cleaved poly-ADP ribose polymerase), oxidative stress (ROS, nuclear factor erythroid 2-related factor 2, glutathione peroxidase 1, NADPH oxidase 4), angiogenesis (VEGF, pigment epithelium-derived factor), inflammation (inducible nitric oxide synthase, intercellular adhesion molecule 1, IL-6, IL-8, TNF-a), and glial cell activation (glial fibrillary acidic protein). RESULTS. Native-LDL had no effect on cultured human M¨uller cells, but HOG-LDL exhibited marked toxicity, significantly decreasing viability and inducing autophagy, apoptosis, oxidative stress, expression of angiogenic factors, inflammation, and glial cell activation. Berberine attenuated all the effects of HOG-LDL (all P < 0.05), and its effects were mitigated by AMPK inhibition (P < 0.05). CONCLUSIONS. Berberine inhibits modified LDL-induced M¨uller cell injury by activating the AMPK pathway, and merits further study as an agent for preventing and/or treating DR.

Adaptable housing design for climate change adaptation

It is predicted that climate change will result in rising sea levels, more frequent and extreme weather events, hotter and drier summers and warmer and wetter winters. This will have a significant impact on the design of buildings, how they are kept cool and how they are weathered against more extreme climatic conditions. The residential sector is already a significant environmental burden with high associated operational energy. Climate change, and a growing population requiring residence, has the potential to exacerbate this problem seriously. New paradigms for residential building design are required to enable low-carbon dioxide operation to mitigate climate change. They must also face the reality of inevitable climate change and adopt climate change adaptation strategies to cope with future scenarios. However, any climate adaptation strategy for dwellings must also be cognisant of adapting occupant needs, influenced by ageing populations and new technologies. This paper presents concepts and priorities for changing how society designs residential buildings by designing for adaptation. A case study home is analysed in the context of its stated aims of low energy and adaptability. A post-occupancy evaluation of the house is presented, and future-proofing strategies are evaluated using climate projection data for future climate change scenarios.

Automated retinal image quality assessment on the UK Biobank dataset for epidemiological studies

Morphological changes in the retinal vascular network are associated with future risk of many systemic and vascular diseases. However, uncertainty over the presence and nature of some of these associations exists. Analysis of data from large population based studies will help to resolve these uncertainties. The QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) retinal image analysis system allows automated processing of large numbers of retinal images. However, an image quality assessment module is needed to achieve full automation. In this paper, we propose such an algorithm, which uses the segmented vessel map to determine the suitability of retinal images for use in the creation of vessel morphometric data suitable for epidemiological studies. This includes an effective 3-dimensional feature set and support vector machine classification. A random subset of 800 retinal images from UK Biobank (a large prospective study of 500,000 middle aged adults; where 68,151 underwent retinal imaging) was used to examine the performance of the image quality algorithm. The algorithm achieved a sensitivity of 95.33% and a specificity of 91.13% for the detection of inadequate images. The strong performance of this image quality algorithm will make rapid automated analysis of vascular morphometry feasible on the entire UK Biobank dataset (and other large retinal datasets), with minimal operator involvement, and at low cost.