Mathematical Model of Macromolecular Drug Transport in a Partially Liquefied Vitreous Humor

The purpose of this study is to investigate the effect of partial liquefaction (due to ageing) of the vitreous humor on the transport of ocular drugs. In our model, the gel part of the vitreous is treated as a Darcy-type porous medium. A spherical region within the porous part of vitreous is in a liquid state which, for computational purposes, is also treated as a porous medium but with a much higher permeability. Using the finite element method, a time-dependent, three-dimensional model has been developed to computationally simulate (using the Petrov-Galerkin method) the transport of intravitreally injected macromolecules where both convection and diffusion are present. From a fluid physics and transport phenomena perspective, the results show many interesting features. For pressure-driven flow across the vitreous, the flow streamlines converge into the liquefied region as the flow seeks the fastest path of travel. Furthermore, as expected, with increased level of liquefaction, the overall flow rate increases for a given pressure drop. We have quantified this effect for various geometrical considerations. The flow convergence into the liquefied region has important implication for convective transport. One effect is the clear diversion of the drug as it reaches the liquefied region. In some instances, the entry point of the drug in the retinal region gets slightly shifted due to liquefaction. While the model has many approximations and assumptions, the focus is illustrating the effect of liquefaction as one of the building blocks towards a fully comprehensive model.

Seeing the world through the eyes of a butterfly: visual ecology of the territorial males of Pararge aegeria (Lepidoptera: Nymphalidae)

Combining studies of animal visual systems with exact imaging of their visual environment can get us a step closer to understand how animals see their “Umwelt”. Here, we have combined both methods to better understand how males of the speckled wood butterfly, Pararge aegeria, see the surroundings of their perches. These males are well known to sit and wait for a chance to mate with a passing females, in sunspot territories in European forests. We provide a detailed description of the males' body and head posture, viewing direction, visual field and spatial resolution, as well as the visual environment. Pararge aegeria has sexually dimorphic eyes, the smallest interommatidial angles of males are around 1°, those of females 1.5°. Perching males face the antisolar direction with their retinal region of the highest resolution pointing at an angle of about 45° above the horizon; thus, looking at a rather even and dark background in front of which they likely have the best chance to detect a sunlit female passing through the sunspot.

Differential Response of Müller Cells and Microglia in a Mouse Retinal Detachment Model and Its Implications in Detached and Non-Detached Regions

Retinal detachment (RD) is a sight-threatening condition, leading to photoreceptor cell death; however, only a few studies provide insight into its effects on the entire retinal region. We examined the spatiotemporal changes in glial responses in a mouse RD model. In electroretinography, a- and b-waves were reduced in a time-dependent manner. Hematoxylin and eosin staining revealed a gradual decrease in the outer nuclear layer throughout the retinal region. Terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay showed that TUNEL-positive photoreceptors increased 5 days after RD and decreased by 14 days. Glial response was evaluated by immunohistochemistry using antibodies against glial fibrillary acidic protein (GFAP, Müller glial marker) and Iba-1 (microglial marker) and osteopontin (OPN, activated microglial marker). GFAP immunoreactivity increased after 7 days in complete RD, and was retained for 14 days. OPN expression increased in microglial cells 3–7 days after RD, and decreased by 14 days in the detached and border regions. Although OPN was not expressed in the intact region, morphologically activated microglial cells were observed. These retinal glial cell responses and photoreceptor degeneration in the border and intact regions suggest that the effects of RD in the border and intact retinal regions need to be understood further.

Functional regulation of an outer retina hyporeflective band on optical coherence tomography images

Human and animal retinal optical coherence tomography (OCT) images show a hyporeflective band (HB) between the photoreceptor tip and retinal pigment epithelium layers whose mechanisms are unclear. In mice, HB magnitude and the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness appear to be dependent on light exposure, which is known to alter photoreceptor mitochondria respiration. Here, we test the hypothesis that these two OCT biomarkers are linked to metabolic activity of the retina. Acetazolamide, which acidifies the subretinal space, had no significant impact on HB magnitude but produced ELM-RPE thinning. Mitochondrial stimulation with 2,4-dinitrophenol reduced both HB magnitude and ELM-RPE thickness in parallel, and also reduced F-actin expression in the same retinal region, but without altering ERG responses. For mice strains with relatively lower (C57BL/6J) or higher (129S6/ev) rod mitochondrial efficacy, light-induced changes in HB magnitude and ELM-RPE thickness were correlated. Humans, analyzed from published data captured with a different protocol, showed a similar light–dark change pattern in HB magnitude as in the mice. Our results indicate that mitochondrial respiration underlies changes in HB magnitude upstream of the pH-sensitive ELM-RPE thickness response. These two distinct OCT biomarkers could be useful indices for non-invasively evaluating photoreceptor mitochondrial metabolic activity.

A connectomics approach to understanding a retinal disease

Macular telangiectasia type 2 (MacTel), a late-onset macular degeneration, has been linked to a loss in the retina of Müller glial cells and the amino acid serine, synthesized by the Müller cells. The disease is confined mainly to a central retinal region called the MacTel zone. We have used electron microscopic connectomics techniques, optimized for disease analysis, to study the retina from a 48-y-old woman suffering from MacTel. The major observations made were specific changes in mitochondrial structure within and outside the MacTel zone that were present in all retinal cell types. We also identified an abrupt boundary of the MacTel zone that coincides with the loss of Müller cells and macular pigment. Since Müller cells synthesize retinal serine, we propose that a deficiency of serine, required for mitochondrial maintenance, causes mitochondrial changes that underlie MacTel development.

The Use of Texture Features to Extract and Analyze Useful Information from Retinal Images

Background: The analysis of retinal images can help to detect retinal abnormalities that are caused by cardiovascular and retinal disorders. Objective: In this paper, we propose methods based on texture features for mining and analyzing information from retinal images. Methods: The recognition of the retinal mask region is a prerequisite for retinal image processing. However, there is no way to automatically recognize the retinal region. By quantifying and analyzing texture features, a method is proposed to automatically identify the retinal region. The boundary of the circular retinal region is detected based on the image texture contrast feature, followed by the filling of the closed circular area, and then the detected circular retinal mask region can be obtained. Results: The experimental results show that the method based on the image contrast feature can be used to detect the retinal region automatically. The average accuracy of retinal mask region detection of images from the Digital Retinal Images for Vessel Extraction (DRIVE) database was 99.34%. Conclusion: This is the first time these texture features of retinal images are analyzed, and texture features are used to recognize the circular retinal region automatically.

A Teleophthalmology Support System Based on the Visibility of Retinal Elements Using the CNNs

This paper proposes a teleophthalmology support system in which we use algorithms of object detection and semantic segmentation, such as faster region-based CNN (FR-CNN) and SegNet, based on several CNN architectures such as: Vgg16, MobileNet, AlexNet, etc. These are used to segment and analyze the principal anatomical elements, such as optic disc (OD), region of interest (ROI) composed by the macular region, real retinal region, and vessels. Unlike the conventional retinal image quality assessment system, the proposed system provides some possible reasons about the low-quality image to support the operator of an ophthalmoscope and patient to acquire and transmit a better-quality image to central eye hospital for its diagnosis. The proposed system consists of four steps: OD detection, OD quality analysis, obstruction detection of the region of interest (ROI), and vessel segmentation. For the OD detection, artefacts and vessel segmentation, the FR-CNN and SegNet are used, while for the OD quality analysis, we use transfer learning. The proposed system provides accuracies of 0.93 for the OD detection, 0.86 for OD image quality, 1.0 for artefact detection, and 0.98 for vessel segmentation. As the global performance metric, the kappa-based agreement score between ophthalmologist and the proposed system is calculated, which is higher than the score between ophthalmologist and general practitioner.

Large Animal Models of Inherited Retinal Degenerations: A Review

Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

ABSTRACTHigh acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible model organisms lack a fovea, its specialized function and dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate and validate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >65 cell types match between the two regions, but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved, but that projection neuron types and programs diverge, despite conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 6 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.