Abstract: Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes mellitus (DM), and remains the single greatest cause of blindness in working age adults around the world. In this article, we review the evolution of pharmacotherapies for both diabetic macular edema (DME) and DR such as anti-vascular endothelial growth factor inhibitors and various steroid formulations, as well as other emerging pharmacotherapies currently in late stage clinical testing for this disease.

Abstract: Myopia in children remains a major public health problem worldwide, especially in some Asian countries such as China, Singapore and Japan. Although many interventions have been attempted, few has been proven to be effective in controlling onset and progression of myopia in children. Environmental factors, genetic susceptibility or ethnic differences can affect the efficacy of these interventions. However, many questions remain unclear and even controversial for controlling myopia. China has the biggest population with myopia, especially for children myopia. Thus, it is of importance to present what achievements Chinese scientists have made in the field of myopia control in children. We summarize the current findings on myopia control in children from the Anyang Childhood Eye Study, including epidemiological data, clinical trials, systematic reviews and meta-analyses, and compare them with studies in other countries to find potential clues for controlling myopia in children.

Background: Because of its superficial anatomical localization, the cornea is particularly vulnerable to abrasive forces and various traumas, which can lead to significant visual impairments. Upon injury of the corneal epithelium, there are important changes that occur in the composition of the underlying extracellular matrix (ECM). Those changes are perceived by the integrins that recognize the ECM components as their ligand and activate different intracellular signalling pathways, ultimately leading to reepithelialisation and reorganization of the injured epithelium, both of which are necessary in order to restore the visual properties of the cornea. The goal of this study was to analyse the impact of the pharmacological inhibition of specific signal transduction mediators of integrin-dependant signalling pathways on corneal wound healing using both monolayers of hCECs and tissue-engineered human corneas (hTECs) as in vitro models.

Methods: hTECs were produced by the self-assembly approach and wounded with a 8-mm diameter biopsy punch. Total RNA and proteins were isolated from the wounded and unwounded hTECs to conduct gene profiling analyses and protein kinase arrays. The wounded tissues were then incubated with the WNK1 inhibitor WNK463 and wound healing was monitored over a period of 6 days. Control corneas were incubated with the vehicle alone (DMSO). The impact of WNK1 inhibition on hCECs monolayers was determined using a scratch wound assay.

Results: Gene profiling analyses and protein kinases arrays revealed important alterations in the expression and activity of several mediators from the integrin-dependent signalling pathways in response to the ECM changes taking place during corneal wound healing. Among these, WNK1 is considerably activated through phosphorylation during corneal wound healing. The pharmacological inhibition of WNK1 by WNK463 significantly reduced the dynamic of corneal wound closure in our hTECs and hCECs monolayers compared to their respective negative controls.

Conclusions: These results allowed the identification of WNK1 kinase as an important player for a proper healing of the cornea. Also, these results allowed for a better understanding of the cellular and molecular mechanisms involved in corneal wound healing and they may lead to the identification of new therapeutic targets in the field of corneal wounds.

Background: The goal of the present study was to determine whether exogenous attentional mechanisms involved in motor planning for saccades and reaches are the same for both effectors or are independent for each effector. We compared how eye and arm movement parameters, notably reaction time and amplitude, are affected by modulating exogenous attentional visual cues at different locations relative to a target.

Methods: Thirteen participants (M =22.8, SD =1.5) were asked to perform a task involving exogenous attentional allocation and movement planning. The participants were asked to fixate and maintain their hand at an initial position on a screen in front of them (left or right of screen centre) and then, at the disappearance of the fixation cross, perform an eye or arm movement, or both, to a target square (mirror location of fixation cross). A distractor appeared momentarily just before the appearance of the target at one of seven equidistant locations on the horizontal meridian. Saccade reaction times (SRTs), reach reaction times (RRTs) and amplitudes were calculated.

Results: Compared to the neutral condition (where no distractor was presented), distractors overall did not result in a facilitation of SRTs at any location (shorter SRTs), rather only a strong inhibition (longer SRTs) as a function of distractor target distance. In contrast, RRTs showed strong facilitation at the target location and less inhibition at further distances. However, both SRTs and RRTs followed a similar pattern in that RTs were shortest closer to the target position and were increasingly longer as a function of distractor target distance. In terms of amplitude, there was no effect of the distractor on reach endpoints, whereas, for saccades, there was an averaging effect of distractor position on saccade endpoints, but only for saccades with short SRTs. These effects were similar when either effector movement was performed alone or together.

Conclusions: These findings suggest that attentional selection mechanisms have both similar and differential effects on motor planning depending on the effectors used, providing evidence for both effector independent and effector dependent attentional selection mechanisms. This study furthers understanding of the operating mechanisms of exogenous attention on eye and arm movements and the interaction between sensory and motor systems.

Background: Overexpression of inducible nitric oxide synthase (iNOS) has been reported in diabetic retinopathy (DR). The kinin B1 receptor (B1R) is also overexpressed in DR, and can stimulate iNOS via Gαi/ERK/MAPK pathway. We previously showed that the topical administration of a B1R antagonist, LF22-0542, significantly reduces leukocyte infiltration, increased vascular permeability and overexpression of several inflammatory mediators, including iNOS in DR. Thus, the aim of this study was to determine whether the pro-inflammatory effects of B1R are attributed to oxidative stress caused by the activation of iNOS pathway in order to identify new therapeutic targets for the treatment of DR. iNOS and B1R being absent in the normal retina, their inhibition is unlikely to result in undesirable side effects. The approach will be no invasive by eye application of drops.

Methods: Diabetes was induced in male Wistar rats (200–230 g) by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg b.w). One week later, rats were randomly divided into four groups (N=5) and treated for one week as follows: Gr 1: control rats treated with the selective iNOS inhibitor (1,400 W, 0.06 μM twice a day by eye-drops ×7 days), Gr 2, STZ-diabetic rats treated with 1,400 W, Gr 3: control rats received a selective B1R agonist [Sar (D-Phe8)-des-Arg9-BK, 100 μg twice a week] by intravitreal injections (itrv) and treated with 1,400 W, Gr 4: STZ-diabetic rats + B1R agonist +1,400 W. At the end of treatment and two weeks post-STZ, three series of experiments were carried out to measure vascular permeability (by Evans blue dye method) and the expression of vasoactive and inflammatory mediators, including iNOS, VEGF-A, VEGF-R2, IL-1β, Cox-2, TNF-α, bradykinin 1 and 2 receptors and carboxypeptidase M/kininase 1 (by Western Blotting and qRT-PCR). The nitrosative stress (nitrosylation of proteins) was also assessed by Western Blotting. One-way Anova test with Bonferroni post hoc was used for statistical analysis.

Results: STZ-diabetic rats showed a significant increase in retinal vascular permeability (22.8 μg/g Evans blue dye per g of fresh retinas, P=0.016) compared with control rats and control treated rats (17.2 and 16.8 μg/g respectively). The injections of B1R agonist amplified the increase of vascular permeability which was normalized by the 1,400 W. The overexpression of inflammatory markers was also normalized by the 1,400 W in STZ-diabetic rats received or not the B1R agonist.

Conclusions: These results support a contribution of iNOS in the deleterious effects of B1R in this model of diabetic retinopathy. Hence, iNOS inhibition by ocular application of 1,400 W may represent a promising and non-invasive therapeutic approach in the treatment of diabetic retinopathy.

Background: Sight-threatening diabetic macular edema (DME) is caused by increased microvascular permeability. While few direct vascular targeting strategies are available, VEGF pathway inhibition has shown to be effective in reducing retinal vascular leakage but is associated with non-negligible side effects. Thus, more options are needed. Vascular specific Activin-like kinase receptor type I (ALK1) pathway and its circulating ligand Bone morphogenetic protein-9 (BMP9) is known for its potent quiescent and stabilizing effect on the vasculature. However, little is known about this pathway in the context of microvascular permeability associated with diabetes. We hypothesize that BMP9/ALK1 pathway is inhibited in diabetic (DB) retinas leading to vascular destabilization and leakage and that its activation could re-establish proper vascular endothelial barrier functions (EBF).

Methods: The effect of hyperglycemia (i.e., HG >10 mM of D-glucose) on Alk1 signaling was evaluated in vitro by subjecting endothelial cells (EC) to increasing concentrations of D-glucose (5, 11, 25 mM) and in vivo using DB mice (Streptozotocin-induced diabetes). The contribution of Alk1 signaling on EBF was evaluated using Evans Blue permeation in inducible endothelial specific Alk1 KO mice. To evaluate the potential protective effects of BMP9/Alk1 signaling on EBF, BMP9 overexpression was achieved using adenoviral delivery in DB mice. Statistical-One-Way ANOVA or Student’s t-test was used.

Results: Endothelial tissue from DB mice showed a significant inhibition of BMP9/ALK1-canonical Smad1,5,8 quiescence signaling (DB n=5; CTL n=4; P<0.01), which was associated with reduced expression of target genes (JAG1, Id1,3, Hey1,2 & HES). Moreover, we showed that retinal hyperpermeability associated with diabetes was exacerbated in Alk1 heterozygote mice (n=4–9/group; P<0.0001). Finally, we demonstrated that activation of Alk1 signaling in ECs prevented vascular permeability induced by HG, both in vitro (n=3; P=0.009) and in vivo (n=4–9/group; P<0.0001).

Conclusions: Consistent with our hypothesis, vascular stability and quiescence induced by BMP9-ALK1 signaling is inhibited in the DB/HG endothelium which could be an important factor in vascular leakage leading to DME. Our results show that activation of this pathway could offer a therapeutically interesting future option to slow down the onset of DME.

Abstract: Corneal blindness represents one of the world’s three major causes of blindness, and the fundamental problem of corneal transplantation is a severe shortage of donor tissues worldwide, resulting in approximately 1.5 million new cases of blindness annually. To address the growing need for corneal transplants two main approaches are being pursued: allogenic and bioengineering cornea. Bioengineering corneas are constructed by naturally generating an extracellular matrix (ECM) component as the scaffold structure with or without corneal cells. It is well established that the scaffold structure directs the fate of cells, therefore, the fabrication of the correct scaffold structure components could produce an ideal corneal substitute, able to mimic the native corneal function. Another key factor in the construction of tissue engineering cornea is seed cells. However, unlike the epithelium and stroma cells, human cornea endothelium cells (HCECs) are notorious for having a limited proliferative capacity in vivo because of the mitotic block at the G1 phase of the cell cycle due to “contact-inhibition”. This review will focus on the main concepts of recent progress towards the scaffold and seed cells, especially endothelial cells for bioengineering cornea, along with future perspectives.

Abstract: The biological mechanisms of eye growth and refractive development are increasingly well characterised, a result of many careful studies that have been carried out over many years. As the outer coat of the eye, the sclera has the ultimate impact on the restraint or facilitation of eye growth, thus any changes in its biochemistry, ultrastructure, gross morphology and/or biomechanical properties are critical in refractive error development and, in particular, the development of myopia. The current review briefly revisits our basic understanding of the structure and biomechanics of the sclera and how these are regulated and modified during eye growth and myopia development. The review then applies this knowledge in considering recent advances in our understanding of how the mechanisms of scleral remodelling may be manipulated or controlled, in order to constrain eye growth and limit the development of myopia, in particular the higher degrees of myopia that lead to vision loss and blindness. In doing so, the review specifically considers recent approaches to the strengthening of the sclera, through collagen cross-linking, scleral transplantation, implantation or injection of biomaterials, or the direct therapeutic targeting and manipulation of the biochemical mechanisms known to be involved in myopia development. These latest approaches to the control of scleral changes in myopia are, where possible, placed in the context of our understanding of scleral biology, in order to bring a more complete understanding of current and future therapeutic interventions in myopia, and their consequences.