Histological changes in retinal detachment: A systematic review for the clinician.

Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the pathophysiological processes that take place before and after repair. Summarizing key concepts using animal studies may allow for a better assessment of common pre- and postoperative microstructural abnormalities in RD. We performed a systematic literature review on Ovid MEDLINE, EMBASE, and Cochrane Controlled Register of Trials from January 1968 to January 2022, searching animal or human studies reporting retinal histologic changes following primary or induced RD. Thirty-two studies were included. Main cellular events were summarized: photoceptor apoptosis occurs as early as 12 hours after RD and, although most cells survive, there is extensive remodeling. Outer segments progressively degenerate, while inner segments are reorganized. Rod and cone opsins are redistributed, and rod axons retract while cones undergo changes in shape. Second- and third-order neurons rearrange their dendritic processes, and Müller cells become hypertrophic, growing into the subretinal space. Finally, retinal pigment epithelium cells undergo a change in their morphology. Acknowledging critical morphologic changes following RD is crucial in understanding why anatomical and functional outcomes can vary. Insights from histological studies, together with high-resolution imaging, may be key in identifying novel biomarkers in RD.

A Meta-Analysis of Neurodevelopmental Outcomes following Intravitreal Bevacizumab for the Treatment of Retinopathy of Prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is the most common cause of preventable blindness in preterm infants. First-line treatments include intravitreal bevacizumab (IVB) or laser photocoagulation (LPC). OBJECTIVES: The aim of the study was to evaluate neurodevelopmental safety of IVB compared to LPC for ROP. METHODS: MEDLINE, Embase, and Cochrane library were searched up to September 2022. Studies were included with at least 12-month follow-up of primary outcomes such as severe neurodevelopmental impairment (sNDI), cerebral palsy (CP), and hearing impairment (HI). Secondary outcomes were moderate-to-severe neurodevelopmental impairment (msNDI), Bayley Scores of Infant Development (BSID-III), and visual impairment. RESULTS: 1,231 patients from 11 comparative studies were included. Quality of evidence was rated low for all outcomes. IVB was associated with a higher risk for sNDI (risk ratio [RR] = 1.25, 95% confidence interval [CI]: [1.01, 1.53], p = 0.04); and CP (RR = 1.40, CI: [1.08, 1.81], p = 0.01) compared to LPC. There was no significant difference between IVB and LPC for msNDI (RR = 1.15, CI: [0.98, 1.35], p = 0.08) and HI (RR = 1.43, CI: [0.86, 2.39], p = 0.17). BSID-III percentile scores were similar between IVB and LPC, with weighted mean differences of 1.51 [CI = -1.25, 4.27], 2.43 [CI = -1.36, 6.22], and 1.97 [CI = -1.06, 5.01] for cognitive, language, and motor domains, respectively (p > 0.05). CONCLUSION: To our knowledge, this is the largest meta-analysis on neurodevelopmental outcomes and the first to rigorously examine IVB monotherapy in ROP treatment. Compared to LPC, there was a marginally increased risk for sNDI and CP with IVB but little or no difference in the risk of msNDI and HI. Further randomized studies are needed to strengthen these findings.

Comparing ProKera With Amniotic Membrane Transplantation: Indications, Outcomes, and Costs.

PURPOSE: The aim of this study was to compare the outcomes of ProKera versus amniotic membrane transplantation (AMT) in managing ocular surface disease. METHODS: This study is a retrospective case series of patients who received either ProKera or sutured AMT for ocular surface disease. Patient demographics, treatment indications, retention time, percentage healed area, changes in visual acuity, and costs to the health care system were analyzed. RESULTS: Fourteen patients were identified and analyzed for each group. The main indications for using ProKera and AMT were similar, including corneal ulcer or epithelial defect due to chemical burns, neurotropic state, or herpes zoster keratitis. The average time to dissolution or removal was 24.8 days in the ProKera group, compared with 50.1 days in the AMT group. The average percentage of healed corneal area was 59% for ProKera and 73% for AMT. There was no significant difference between the initial and the final visual acuity within groups and when comparing both groups. In our expense analysis, ProKera had a total cost of 699.00 Canadian dollars (CAD), whereas the cost of suture AMT was 1561.52 CAD. ProKera priced at 11.85 CAD for each percentage healed surface area and at 21.39 CAD for AMT. CONCLUSIONS: ProKera allowed for a faster corneal healing than sutured AMT, although its total healed area was less than the latter. Moreover, ProKera is more cost-effective than AMT, thus reducing financial burden to our health care system.

Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies.

Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.

Preventing Corneal Calcification Associated With Xylazine for Longitudinal Optical Coherence Tomography in Young Rodents.

Purpose: Spectral-domain optical coherence tomography (SD-OCT) is widely used in clinical ophthalmology and recently gained popularity in laboratory research involving small rodents. Its noninvasive nature allows repeated measurements, thereby decreasing the number of animals required. However, when used at a conventional dosage, xylazine (an α2-adrenoceptor) can cause irreversible corneal calcification, especially among young rodents. In the present study, we test whether corneal calcification associated with xylazine is mediated by the α2-adrenoceptor. Methods: Our study tested Sprague-Dawley rats, Long-Evans rats, and CD-1 mice (postnatal day [P]14). Retinal images were captured by SD-OCT. Quantitative PCR (qPCR) was used to study gene expression, whereas receptor localization was examined by immunofluorescent staining followed by confocal microscopy. Calcium deposits were detected via von Kossa staining. Results: When used at dosages appropriate for adult animals, ketamine-xylazine anesthetics led to a high rate of respiratory failure, increased apoptotic activity in the corneal epithelium, and irreversible corneal calcification in P14 rat pups. Meanwhile, OCT image quality decreased drastically as a result of corneal calcification among animals recovering from anesthesia. α2-Adrenoceptor subtypes were highly expressed on P14, in line with rodents' age-specific sensitivity to xylazine. Clonidine, a potent α2-adrenoceptor agonist, dose-dependently induced corneal calcification, which could be prevented by an α2-adrenoceptor antagonist. Conclusions: These data suggest that α2-adrenoceptors contribute to corneal calcification in young rodents. Therefore, we developed a suitable OCT imaging protocol for this cohort, including a carefully tailored ketamine-xylazine dosage (60 mg/kg and 2.5 kg/mg, respectively).

Scientific Overview: CSCI-CITAC Annual General Meeting and Young Investigators' Forum 2015.

The 2015 Annual General Meeting of The Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Toronto November 23-25, 2015, in conjunction with The University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "It takes a village" and the focus was the various support systems necessary to train a successful clinician scientist. The meeting featured an opening presentation by Dr. Vincent Dumez and workshops by Dr. Peter Nickerson, Dr. Jane Aubin, Dr. Kelly Warmington and Dr. Norman Rosenblum, and MD/PhD trainees Nardin Samuel, Kevin Wang and Kirill Zaslavsky. The keynote speakers were Dr. David Malkin (Hospital for Sick Children) who received the CSCI-RCPSC Henry Friesen Award, Dr. Brent Richards (McGill University) who received the Joe Doupe Award and Ernesto Shiffrin (Lady Davis Institute) who received the Distinguished Scientist Award. As always, the conference showcased outstanding scientific presentations from clinician investigator trainees from across the country at the Young Investigators' Forum. The research topics, which ranged from basic sciences to clinical medicine and translational work, are summarized in this review. Over 90 abstracts were presented at this year's meeting during two poster sessions, with several of the outstanding abstracts selected for oral presentations.

Erratum: Nuclear localization of platelet-activating factor receptor controls retinal neovascularization.

[This corrects the article DOI: 10.1038/celldisc.2016.17.].

Review of the mechanisms and therapeutic avenues for retinal and choroidal vascular dysfunctions in retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a multifactorial disease and the main cause of visual impairment and blindness in premature neonates. The inner retina has been considered the primary region affected in ROP, but choroidal vascular degeneration and progressive outer retinal dysfunctions have also been observed. This review focuses on observations regarding neurovascular dysfunctions in both the inner and outer immature retina, the mechanisms and the neuronal-derived factors implicated in the development of ROP, as well potential therapeutic avenues for this disorder. CONCLUSION: Alterations in the neurovascular integrity of the inner and outer retina contribute to the development of ROP.

Nuclear localization of platelet-activating factor receptor controls retinal neovascularization.

Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly understood. We hereby identify the importance of C-terminal motif of the receptor and uncover novel roles of Rab11a GTPase and importin-5 in nuclear translocation of Ptafr in primary human retinal microvascular endothelial cells. Nuclear localization of Ptafr is independent of exogenous PAF stimulation as well as intracellular PAF biosynthesis. Moreover, nuclear Ptafr is responsible for the upregulation of unique set of growth factors, including vascular endothelial growth factor, in vitro and ex vivo. We further corroborate the intracrine PAF signaling, resulting in angiogenesis in vivo, using Ptafr antagonists with distinct plasma membrane permeability. Collectively, our findings show that nuclear Ptafr translocates in an agonist-independent manner, and distinctive functions of Ptafr based on its cellular localization point to another dimension needed for pharmacologic selectivity of drugs.