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Dohlman JC, Cestari DM, Freitag SK. Orbital disease in neuro-ophthalmology. Curr Opin Ophthalmol 2020;31(6):469-474.Abstract
PURPOSE OF REVIEW: Orbital disease represents a diverse spectrum of pathology and can result in a variety of neuro-ophthalmic manifestations. The aim of this review is to provide updates on recent advances in our understanding of orbital disease secondary to thyroid eye disease, myositis, IgG4-related disease, sarcoidosis, granulomatosis with polyangiitis and various tumours. RECENT FINDINGS: With regards to thyroid eye disease, there have been recent advances in the development of steroid-sparing therapies, new modalities for objectively monitoring disease activity and increased understanding of the role of environmental risk factors. There has been interest in characterizing the clinical course and underlying mechanism of optic nerve disease secondary to orbital disorders, which has led to advances in how we monitor for and prevent permanent vision loss. Increased knowledge of orbital tumour subtype histopathology and the development of novel classification systems has had prognostic value and aided medical decision-making. SUMMARY: Orbital disease occurs secondary to a wide variety of diseases and can lead to neuro-ophthalmic manifestations with significant morbidity. Advances in our understanding of different subtypes of orbital disease have improved our ability to treat these potentially debilitating conditions.
Hu Z, Riquelme MA, Gu S, Jiang JX. Regulation of Connexin Gap Junctions and Hemichannels by Calcium and Calcium Binding Protein Calmodulin. Int J Mol Sci 2020;21(21)Abstract
Connexins are the structural components of gap junctions and hemichannels that mediate the communication and exchange of small molecules between cells, and between the intracellular and extracellular environment, respectively. Connexin (Cx) 46 is predominately expressed in lens fiber cells, where they function in maintaining the homeostasis and transparency of the lens. Cx46 mutations are associated with impairment of channel function, which results in the development of congenital cataracts. Cx46 gap junctions and hemichannels are closely regulated by multiple mechanisms. Key regulators of Cx46 channel function include Ca and calmodulin (CaM). Ca plays an essential role in lens homeostasis, and its dysregulation causes cataracts. Ca associated CaM is a well-established inhibitor of gap junction coupling. Recent studies suggest that elevated intracellular Ca activates Cx hemichannels in lens fiber cells and Cx46 directly interacts with CaM. A Cx46 site mutation (Cx46-G143R), which is associated with congenital Coppock cataracts, shows an increased Cx46-CaM interaction and this interaction is insensitive to Ca, given that depletion of Ca reduces the interaction between CaM and wild-type Cx46. Moreover, inhibition of CaM function greatly reduces the hemichannel activity in the Cx46 G143R mutant. These research findings suggest a new regulatory mechanism by which enhanced association of Cx46 with CaM leads to the increase in hemichannel activity and dysregulation may lead to cataract development. In this review, we will first discuss the involvement of Ca/CaM in lens homeostasis and pathology, and follow by providing a general overview of Ca/CaM in the regulation of Cx46 gap junctions. We discuss the most recent studies concerning the molecular mechanism of Ca/CaM in regulating Cx46 hemichannels. Finally, we will offer perspectives of the impacts of Ca/CaM and dysregulation on Cx46 channels and vice versa.
Gilmore MS, Salamzade R, Selleck E, Bryan N, Mello SS, Manson AL, Earl AM. Genes Contributing to the Unique Biology and Intrinsic Antibiotic Resistance of Enterococcus faecalis. mBio 2020;11(6)Abstract
The enterococci, which are among the leading causes of multidrug-resistant (MDR) hospital infection, are notable for their environmental ruggedness, which extends to intrinsic antibiotic resistance. To identify genes that confer this unique property, we used Tn-seq to comprehensively explore the genome of MDR strain MMH594 for genes important for growth in nutrient-containing medium and with low-level antibiotic challenge. As expected, a large core of genes for DNA replication, expression, and central metabolism, shared with other bacteria, are intolerant to transposon disruption. However, genes were identified that are important to that are either absent from or unimportant for and fitness when similarly tested. Further, 217 genes were identified that when challenged by sub-MIC antibiotic levels exhibited reduced tolerance to transposon disruption, including those previously shown to contribute to intrinsic resistance, and others not previously ascribed this role. is one of the few Gram-positive bacteria experimentally shown to possess a functional Entner-Doudoroff pathway for carbon metabolism, a pathway that contributes to stress tolerance in other microbes. Through functional genomics and network analysis we defined the unusual structure of this pathway in and assessed its importance. These approaches also identified toxin-antitoxin and related systems that are unique and active in Finally, we identified genes that are absent in the closest nonenterococcal relatives, the vagococci, and that contribute importantly to fitness with and without antibiotic selection, advancing an understanding of the unique biology of enterococci. Enterococci are leading causes of antibiotic-resistant infection transmitted in hospitals. The intrinsic hardiness of these organisms allows them to survive disinfection practices and then proliferate in the gastrointestinal tracts of antibiotic-treated patients. The objective of this study was to identify the underlying genetic basis for its unusual hardiness. Using a functional genomic approach, we identified traits and pathways of general importance for enterococcal survival and growth that distinguish them from closely related pathogens as well as ancestrally related species. We further identified unique traits that enable them to survive antibiotic challenge, revealing a large set of genes that contribute to intrinsic antibiotic resistance and a smaller set of uniquely important genes that are rare outside enterococci.
Charles NC, Jakobiec FA, Sherwood P, Belinsky I. Multicameral Steatocystoma Simplex of the Caruncle. Ophthalmic Plast Reconstr Surg 2020;Abstract
A yellow cyst of the caruncle in a 68-year-old man displayed the characteristic sebaceous glands and sebocytes of steatocystoma within the cyst wall, with a unique configuration of multiple branching compartments. The cyst lining was of trichilemmal character, lacking a keratohyalin granular layer, and replicated the immunohistochemical characteristics of a previously reported caruncular steatocystoma with the exception of a positive trichilemmal marker, calretinin, in the present case. Four previous cases of caruncular steatocystoma have been described, only one of which incorporated immunohistochemical analysis. Steatocystoma develops from a sebaceous gland duct, which displayed in this case multiple chambers subdividing what is usually a single round lumen.
Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T Cells in Angiogenesis. J Immunol 2020;205(10):2557-2565.Abstract
Regulatory T cells (Tregs) are crucial mediators of immune homeostasis. They regulate immune response by suppressing inflammation and promoting self-tolerance. In addition to their immunoregulatory role, a growing body of evidence highlights the dynamic role of Tregs in angiogenesis, the process of forming new blood vessels. Although angiogenesis is critically important for normal tissue regeneration, it is also a hallmark of pathological processes, including malignancy and chronic inflammation. Interestingly, the role of Tregs in angiogenesis has been shown to be highly tissue- and context-specific and as a result can yield either pro- or antiangiogenic effects. For these reasons, there is considerable interest in determining the molecular underpinnings of Treg-mediated modulation of angiogenesis in different disease states. The present review summarizes the role of Tregs in angiogenesis and mechanisms by which Tregs regulate angiogenesis and discusses how these mechanisms differ in homeostatic and pathological settings.
Chirapapaisan C, Muller RT, Sahin A, Cruzat A, Cavalcanti BM, Jamali A, Pavan-Langston D, Hamrah P. Effect of herpes simplex keratitis scar location on bilateral corneal nerve alterations: an in vivo confocal microscopy study. Br J Ophthalmol 2020;Abstract
AIMS: To evaluate the impact of herpes simplex virus (HSV)-induced scar location on bilateral corneal nerve alterations using laser in vivo confocal microscopy (IVCM). METHODS: Central and peripheral corneal subbasal nerve density (CSND) were assessed bilaterally in 39 patients with unilateral HSV-induced corneal scars (21 central scars (CS), 18 peripheral scars (PS)) using IVCM. Results were compared between patients and 24 age-matched controls. CSND was correlated to corneal sensation for all locations. RESULTS: Overall patients revealed significant decrease of CSND in the central and peripheral cornea (9.13±0.98 and 6.26±0.53 mm/mm, p<0.001), compared with controls (22.60±0.77 and 9.88±0.49 mm/mm). CS group showed a decrease in central (8.09±1.30 mm/mm) and total peripheral nerves (5.15±0.62 mm/mm) of the affected eyes, whereas PS group demonstrated a decrease in central (10.34±1.48 mm/mm) and localised peripheral nerves only in the scar area (4.22±0.77 mm/mm) (all p<0.001). In contralateral eyes, CSND decreased in the central cornea of the CS group (16.88±1.27, p=0.004), and in the peripheral area, mirroring the scar area in the affected eyes of the PS group (7.20±0.87, p=0.032). Corneal sensation significantly decreased in the whole cornea of the affected, but not in contralateral eyes (p<0.001). A positive correlation between CSND and corneal sensation was found in all locations (p<0.001). CONCLUSIONS: Patients with HSV scar demonstrate bilateral CSND decrease as shown by IVCM. CSND and corneal sensation decrease in both central and peripheral cornea in affected eyes, although only in the scar area in PS group. Interestingly, diminishment of CSND was found locally in the contralateral eyes, corresponding and mirroring the scar location in the affected eyes.
Sohn EH, Mullins RF, Eliott D. Reply. Retina 2020;40(11):e68-e69.
Redler Y, Levy M. Rodent Models of Optic Neuritis. Front Neurol 2020;11:580951.Abstract
Optic neuritis (ON) is an inflammatory attack of the optic nerve that leads to visual disability. It is the most common optic neuropathy affecting healthy young adults, most commonly women aged 20-45 years. It can be idiopathic and monophasic or as part of a neurologic disease such as multiple sclerosis with recurrence and cumulative damage. Currently, there is no therapy to repair the damage from optic neuritis. Animal models are an essential tool for the understanding of the pathogenesis of optic neuritis and for the development of potential treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental rodent model for human autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). In this review, we discuss the latest rodent models regarding optic neuritis, focusing on EAE model, and on its recent achievements and developments.
Duarte D, Bauer CCC, Pinto CB, Saleh Velez FG, Estudillo-Guerra MA, Pacheco-Barrios K, Gunduz ME, Crandell D, Merabet L, Fregni F. Cortical plasticity in phantom limb pain: A fMRI study on the neural correlates of behavioral clinical manifestations. Psychiatry Res Neuroimaging 2020;304:111151.Abstract
The neural mechanism of phantom limb pain (PLP) is related to the intense brain reorganization process implicating plasticity after deafferentation mostly in sensorimotor system. There is a limited understanding of the association between the sensorimotor system and PLP. We used a novel task-based functional magnetic resonance imaging (fMRI) approach to (1) assess neural activation within a-priori selected regions-of-interested (motor cortex [M1], somatosensory cortex [S1], and visual cortex [V1]), (2) quantify the cortical representation shift in the affected M1, and (3) correlate these changes with baseline clinical characteristics. In a sample of 18 participants, we found a significantly increased activity in M1 and S1 as well as a shift in motor cortex representation that was not related to PLP intensity. In an exploratory analyses (not corrected for multiple comparisons), they were directly correlated with time since amputation; and there was an association between increased activity in M1 with a lack of itching sensation and V1 activation was negatively correlated with PLP. Longer periods of amputation lead to compensatory changes in sensory-motor areas; and itching seems to be a protective marker for less signal changes. We confirmed that PLP intensity is not associated with signal changes in M1 and S1 but in V1.
Venkatraman P, Mills-Henry I, Padmanabhan KR, Pascuzzi P, Hassan M, Zhang J, Zhang X, Ma P, Pang CP, Dowling JE, Zhang M, Leung YF. Rods Contribute to Visual Behavior in Larval Zebrafish. Invest Ophthalmol Vis Sci 2020;61(12):11.Abstract
Purpose: Although zebrafish rods begin to develop as early as 2 days postfertilization (dpf), they are not deemed anatomically mature and functional until 15 to 21 dpf. A recent study detected a small electroretinogram (ERG) from rods in a cone mutant called no optokinetic response f (nof) at 5 dpf, suggesting that young rods are functional. Whether they can mediate behavioral responses in larvae is unknown. Methods: We first confirmed rod function by measuring nof ERGs under photopic and scotopic illumination at 6 dpf. We evaluated the role of rods in visual behaviors using two different assays: the visual-motor response (VMR) and optokinetic response (OKR). We measured responses from wild-type (WT) larvae and nof mutants under photopic and scotopic illuminations at 6 dpf. Results: Nof mutants lacked a photopic ERG. However, after prolonged dark adaptation, they displayed scotopic ERGs. Compared with WT larvae, the nof mutants displayed reduced VMRs. The VMR difference during light onset gradually diminished with decreased illumination and became nearly identical at lower light intensities. Additionally, light-adapted nof mutants did not display an OKR, whereas dark-adapted nof mutants displayed scotopic OKRs. Conclusions: Because the nof mutants lacked a photopic ERG but displayed scotopic ERGs after dark adaptation, the mutants clearly had functional rods. WT larvae and the nof mutants displayed comparable scotopic light-On VMRs and scotopic OKRs after dark adaptation, suggesting that these responses were driven primarily by rods. Together, these observations indicate that rods contribute to zebrafish visual behaviors as early as 6 dpf.
Ashraf M, Sampani K, Rageh A, Silva PS, Aiello LP, Sun JK. Interaction Between the Distribution of Diabetic Retinopathy Lesions and the Association of Optical Coherence Tomography Angiography Scans With Diabetic Retinopathy Severity. JAMA Ophthalmol 2020;138(12):1291-1297.Abstract
Importance: Studies have not yet determined whether the distribution of lesions in the retinal periphery alters the association between the severity of diabetic retinopathy (DR) and macular vessel density. Objective: To evaluate the association of DR lesion distribution with optical coherence tomography angiography (OCTA) metrics and DR severity. Design, Setting, and Participants: This cross-sectional observational study was conducted at a tertiary care center for diabetic eye disease among 225 patients with type 1 or 2 diabetes who had undergone imaging between February 15, 2016, and December 31, 2019. Exposures: Optical coherence tomography angiography 3 × 3-mm macular scans and ultra-widefield color imaging. Main Outcomes and Measures: Optical coherence tomography angiography vessel density in the superficial capillary plexus, intermediate capillary plexus, and deep capillary plexus and choriocapillaris flow density. The severity of DR and the predominantly peripheral lesions (PPL) were evaluated from ultra-widefield color imaging. Results: The study evaluated 352 eyes (225 patients; 125 men [55.6%]; mean [SD] age, 52.1 [15.1] years), of which 183 eyes (52.0%) had mild nonproliferative diabetic retinopathy (NPDR), 71 eyes (20.2%) had moderate NPDR, and 98 eyes (27.8%) had severe NPDR or proliferative diabetic retinopathy (PDR). In eyes with no PPL (209 [59.4%]), the mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 38.1% [4.7%]; moderate NPDR, 36.4% [4.6%]; severe NPDR or PDR, 34.1% [4.1%]; P < .001) and the deep capillary plexus (mild NPDR, 45.8% [3.0%]; moderate NPDR, 45.8% [2.2%]; severe NPDR or PDR, 44.5% [1.9%]; P = .002), as well as the mean (SD) choriocapillaris flow density (mild NPDR, 69.7% [6.2%]; moderate NPDR, 67.6% [5.6%]; severe NPDR or PDR, 67.1% [5.6%]; P = .01), decreased with increasing DR severity. These associations remained statistically significant even after correcting for age, signal strength index, spherical equivalent, duration of diabetes, type of diabetes, and correlation between eyes of the same patient. In eyes with PPL (143 [40.6%]), mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 34.1% [4.1%]; moderate NPDR, 35.2% [4.1%]; severe NPDR or PDR, 36.0% [4.3%]; P = .42) and the deep capillary plexus (mild NPDR, 44.5% [1.7%]; moderate NPDR, 45.4% [1.4%]; severe NPDR or PDR, 44.9% [1.5%]; P = .81), as well as the mean (SD) choriocapillaris flow density (mild NPDR, 67.1% [5.6%]; moderate NPDR, 69.3% [4.6%]; severe NPDR or PDR, 68.3% [5.6%]; P = .49), did not appear to change with increasing DR severity. Conclusions and Relevance: These results suggest that central retinal vessel density is associated with DR severity in eyes without, but not with, PPL. These findings suggest a potential need to stratify future optical coherence tomography angiography studies of eyes with DR by the presence or absence of PPL. If DR onset and worsening are associated with the location of retinal nonperfusion, assessment of global retinal nonperfusion using widefield angiography may improve the ability to evaluate DR severity and risk of DR worsening over time.
Maidana DE, Notomi S, Ueta T, Zhou T, Joseph D, Kosmidou C, Caminal-Mitjana JM, Miller JW, Vavvas DG. ThicknessTool: automated ImageJ retinal layer thickness and profile in digital images. Sci Rep 2020;10(1):18459.Abstract
To develop an automated retina layer thickness measurement tool for the ImageJ platform, to quantitate nuclear layers following the retina contour. We developed the ThicknessTool (TT), an automated thickness measurement plugin for the ImageJ platform. To calibrate TT, we created a calibration dataset of mock binary skeletonized mask images with increasing thickness masks and different rotations. Following, we created a training dataset and performed an agreement analysis of thickness measurements between TT and two masked manual observers. Finally, we tested the performance of TT measurements in a validation dataset of retinal detachment images. In the calibration dataset, there were no differences in layer thickness between measured and known thickness masks, with an overall coefficient of variation of 0.00%. Training dataset measurements of immunofluorescence retina nuclear layers disclosed no significant differences between TT and any observer's average outer nuclear layer (ONL) (p = 0.998), inner nuclear layer (INL) (p = 0.807), and ONL/INL ratio (p = 0.944) measurements. Agreement analysis showed that bias between TT vs. observers' mean was lower than between any observers' mean against each other in the ONL (0.77 ± 0.34 µm vs 3.25 ± 0.33 µm) and INL (1.59 ± 0.28 µm vs 2.82 ± 0.36 µm). Validation dataset showed that TT can detect significant and true ONL thinning (p = 0.006), more sensitive than manual measurement capabilities (p = 0.069). ThicknessTool can measure retina nuclear layers thickness in a fast, accurate, and precise manner with multi-platform capabilities. In addition, the TT can be customized to user preferences and is freely available to download.
Sun Y, Smith LEH. Notice of Withdrawal: Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 2020;Abstract
This article was withdrawn on October 15, 2020, at the request of the journal editors, with agreement from the authors, owing to a substantial amount of unattributed or improperly cited text overlap with other sources. In accordance with Annual Reviews' commitment to transparency, the original PDF of the article remains available for download at .
Ramier A, Eltony AM, Chen YT, Clouser F, Birkenfeld JS, Watts A, Yun S-H. In vivo measurement of shear modulus of the human cornea using optical coherence elastography. Sci Rep 2020;10(1):17366.Abstract
Corneal stiffness plays a critical role in shaping the cornea with respect to intraocular pressure and physical interventions. However, it remains difficult to measure the mechanical properties noninvasively. Here, we report the first measurement of shear modulus in human corneas in vivo using optical coherence elastography (OCE) based on surface elastic waves. In a pilot study of 12 healthy subjects aged between 25 and 67, the Rayleigh-wave speed was 7.86 ± 0.75 m/s, corresponding to a shear modulus of 72 ± 14 kPa. Our data reveal two unexpected trends: no correlation was found between the wave speed and IOP between 13-18 mmHg, and shear modulus decreases with age (- 0.32 ± 0.17 m/s per decade). We propose that shear stiffness is governed by the interfibrillar matrix, whereas tensile strength is dominated by collagen fibrils. Rayleigh-wave OCE may prove useful for clinical diagnosis, refractive surgeries, and treatment monitoring.
Wang J, He X, Meng H, Li Y, Dmitriev P, Tian F, Page JC, Lu RQ, He Z. Robust Myelination of Regenerated Axons Induced by Combined Manipulations of GPR17 and Microglia. Neuron 2020;108(5):876-886.e4.Abstract
Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously, we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated, and the underlying mechanisms are elusive. In this study, we found that, in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient proliferation but fail to differentiate into mature myelination-competent oligodendrocytes, reminiscent of what is observed in human progressive multiple sclerosis. Mechanistically, we showed that OPC-intrinsic GPR17 signaling and sustained activation of microglia inhibit different stages of OPC differentiation. Importantly, co-manipulation of GPR17 and microglia led to extensive myelination of regenerated axons. The regulatory mechanisms of stage-dependent OPC differentiation uncovered here suggest a translatable strategy for efficient de novo myelination after CNS injury.

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