Imaging of Hypoxia in Retinal Vascular Disease

Retinal tissue hypoxia is a key mediator in the pathogenesis of many leading causes of irreversible vision loss, including diabetic retinopathy. Retinal hypoxia in diabetic retinopathy has been shown to drive the production of pro-inflammatory cytokines and pro-angiogenic growth factors. Together, these factors contribute to disease progression by causing unregulated growth of new blood vessels, increased vascular permeability and cell death within the retina. Studies have shown that retinal hypoxia precedes many of the pathologic events that occur during the progression of diabetic retinopathy such as angiopathy, microaneurysms, and capillary dropout. Therefore, early detection of hypoxia in the retinas of diabetic patients could help clinicians identify problems in patients before irreversible damage has occurred. Currently, oxygen sensitive electrodes remain the gold standard for direct measurement of oxygen tension within the retinal tissue; however the procedure is highly invasive and is therefore limited in its applicability towards preclinical models. Less invasive techniques such as retinal oximetry, phosphorescence-lifetime imaging, and hypoxia-sensitive fluorescent probes have shown promising diagnostic value in facilitating detection of oxygen imbalance correlated with neurovascular dysfunction in DR patients. This review highlights the current progress and potential of these minimally invasive hypoxia-imaging techniques in diabetic retinopathy

Enablers and Barriers to Deployment of Smartphone-Based Home Vision Monitoring in Clinical Practice Settings

Importance: Telemedicine is accelerating the remote detection and monitoring of medical conditions, such as vision-threatening diseases. Meaningful deployment of smartphone apps for home vision monitoring should consider the barriers to patient uptake and engagement and address issues around digital exclusion in vulnerable patient populations. Objective: To quantify the associations between patient characteristics and clinical measures with vision monitoring app uptake and engagement. Design, Setting, and Participants: In this cohort and survey study, consecutive adult patients attending Moorfields Eye Hospital receiving intravitreal injections for retinal disease between May 2020 and February 2021 were included. Exposures: Patients were offered the Home Vision Monitor (HVM) smartphone app to self-test their vision. A patient survey was conducted to capture their experience. App data, demographic characteristics, survey results, and clinical data from the electronic health record were analyzed via regression and machine learning. Main Outcomes and Measures: Associations of patient uptake, compliance, and use rate measured in odds ratios (ORs). Results: Of 417 included patients, 236 (56.6%) were female, and the mean (SD) age was 72.8 (12.8) years. A total of 258 patients (61.9%) were active users. Uptake was negatively associated with age (OR, 0.98; 95% CI, 0.97-0.998; P = .02) and positively associated with both visual acuity in the better-seeing eye (OR, 1.02; 95% CI, 1.00-1.03; P = .01) and baseline number of intravitreal injections (OR, 1.01; 95% CI, 1.00-1.02; P = .02). Of 258 active patients, 166 (64.3%) fulfilled the definition of compliance. Compliance was associated with patients diagnosed with neovascular age-related macular degeneration (OR, 1.94; 95% CI, 1.07-3.53; P = .002), White British ethnicity (OR, 1.69; 95% CI, 0.96-3.01; P = .02), and visual acuity in the better-seeing eye at baseline (OR, 1.02; 95% CI, 1.01-1.04; P = .04). Use rate was higher with increasing levels of comfort with use of modern technologies (β = 0.031; 95% CI, 0.007-0.055; P = .02). A total of 119 patients (98.4%) found the app either easy or very easy to use, while 96 (82.1%) experienced increased reassurance from using the app. Conclusions and Relevance: This evaluation of home vision monitoring for patients with common vision-threatening disease within a clinical practice setting revealed demographic, clinical, and patient-related factors associated with patient uptake and engagement. These insights inform targeted interventions to address risks of digital exclusion with smartphone-based medical devices

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy

Modelling Macular Edema:The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro

Purpose: Macular edema (ME) is a leading cause of visual loss in a range of retinal diseases and despite the use of antivascular endothelial growth factor (anti-VEGF) agents, its successful treatment remains a major clinical challenge. Based on the indirect clinical evidence that interleukin-6 (IL-6) is a key additional candidate mediator of ME, we interrogated the effect of IL-6 on blood–retinal barrier (BRB) integrity in vitro. Methods: Human retinal pigment epithelial cell (ARPE-19) and human retinal microvascular endothelial cell (HRMEC) monolayers were used to mimic the outer and inner BRB, respectively. Their paracellular permeability was assessed by measuring the passive permeation of 40 kDa fluorescein isothiocyanate (FITC)-dextran across confluent cells in the presence of IL-6. Transendothelial/epithelial electrical resistance (TEER) then was measured and the distribution of the tight junction protein ZO-1 was assessed by immunofluorescence using confocal microscopy. Results: Treatment with IL-6 for 48 hours significantly increased the diffusion rate of FITC-dextran, decreased TEER, and disrupted the distribution of ZO-1 in ARPE-19 cells, which constitutively express the IL-6 transmembrane receptor, and this was reversed with IL-6R blockade. In contrast, IL-6 did not affect the paracellular permeability, TEER, or ZO-1 distribution in HRMECs. Conclusions: These in vitro data support the hypothesis that IL-6 reversibly disrupts the integrity of ARPE-19 cells, but it does not affect HRMECs. Translational Relevance: IL-6 is a candidate therapeutic target in the treatment of outer BRB driven ME

Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe.

Despite its essential role in the (patho)physiology of several diseases, CB2R tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CB2R agonist probe employing structure-based reverse design. It commences with a highly potent, preclinically validated ligand, which is conjugated to a silicon-rhodamine fluorophore, enabling cell permeability. The probe is the first to preserve interspecies affinity and selectivity for both mouse and human CB2R. Extensive cross-validation (FACS, TR-FRET and confocal microscopy) set the stage for CB2R detection in endogenously expressing living cells along with zebrafish larvae. Together, these findings will benefit clinical translatability of CB2R based drugs

Mitochondrial Function and Dysfunction in Dilated Cardiomyopathy

Cardiac tissue requires a persistent production of energy in order to exert its pumping function. Therefore, the maintenance of this function relies on mitochondria that represent the "powerhouse" of all cardiac activities. Mitochondria being one of the key players for the proper functioning of the mammalian heart suggests continual regulation and organization. Mitochondria adapt to cellular energy demands via fusion-fission events and, as a proof-reading ability, undergo mitophagy in cases of abnormalities. Ca2+ fluxes play a pivotal role in regulating all mitochondrial functions, including ATP production, metabolism, oxidative stress balance and apoptosis. Communication between mitochondria and others organelles, especially the sarcoplasmic reticulum is required for optimal function. Consequently, abnormal mitochondrial activity results in decreased energy production leading to pathological conditions. In this review, we will describe how mitochondrial function or dysfunction impacts cardiac activities and the development of dilated cardiomyopathy

Timothy H. Lim and John H. Collins, eds., The Oxford Handbook of the Dead Sea Scrolls (Oxford: Oxford University Press, 2010, Paperback edition, 2012). Pp. xviii + 785. $ 45. ISBN 978-0-19-966308-8

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Rochberg, Francesca, In the Path of the Moon: Babylonian Celestial Divination and Its Legacy (Studies in Ancient Magic and Divination 6; Leiden: Brill, 2010). Pp. xxii, 445. € 152.00 / US $ 216.00. ISBN 978-90-04-18389-6

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