Hark LA, Myers JS, Rahmatnejad K, Wang Q, Zhan T, Hegarty SE, Leiby BE, Udyaver S, Waisbourd M, Leite S, Henderer JD, Pasquale LR, Lee PP, Haller JA, Katz JL. Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Analysis of Unreadable Fundus Images. J Glaucoma 2018;27(11):999-1008.Abstract
PURPOSE: The purpose of this study was to ascertain determinants of unreadable fundus images for participants enrolled in the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. METHODS: Individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening (visit 1) included fundus photography, assessing family history of glaucoma, and intraocular pressure (IOP) measurements. Participants with an unreadable image in at least one eye were deemed unreadable and invited to return for a confirmatory eye examination (visit 2). RESULTS: A total of 906 participants completed the visit 1 eye screening and 17.1% (n=155/906) were "unreadable." In the multivariable logistic regression analysis, older age, male sex, smoking, and worse visual acuity were significantly associated with an unreadable fundus image finding at the eye screening (P<0.05). Of the 89 participants who were invited for the confirmatory eye examination solely for unreadable images and attended visit 2, 58 (65.2%) were diagnosed with at least one ocular pathology. The most frequent diagnoses were cataracts (n=71; 15 visually significant, 56 nonvisually significant), glaucoma suspects (n=27), and anatomical narrow angle (n=10). CONCLUSIONS: Understanding the causes of unreadable fundus images will foster improvements in telemedicine techniques to optimize the predictive accuracy, efficiency, and cost in ophthalmology. A high proportion of participants with unreadable images (65.2%) in our study were diagnosed with some ocular pathology, indicating that the finding of an unreadable fundus image warrants a referral for a comprehensive follow-up eye examination.
Harrar DB, Solomon J, Shah AS, Vaughn J, Durbin AD, Rivkin MJ. Diffusion-Weighted Imaging Changes in a Child With Posterior Ischemic Optic Neuropathy. Pediatr Neurol 2018;84:49-52.Abstract
BACKGROUND: Posterior ischemic optic neuropathy results from ischemia of the retrobulbar aspect of the optic nerve. It presents as acute loss of vision without optic disc swelling. This is rare in children, with only seven cases reported to date. Neuroimaging is frequently used to aid in the diagnosis of acute visual complaints in children; however, none of the cases described to date delineate the neuroimaging findings of this entity in children. METHODS: We retrospectively reviewed the electronic medical record. RESULTS: We describe the MRI findings in a 10-month-old boy with posterior ischemic optic neuropathy after intraophthalmic artery injection of chemotherapy for retinoblastoma. CONCLUSIONS: As targeted therapies for retinoblastoma and other diseases amenable to intravascular treatment delivery are more frequently used, the risk of grave vision-related side effects increases. Posterior ischemic optic neuropathy should be considered in the differential diagnosis of any child presenting with acute loss of vision. Dedicated imaging of the orbits can elucidate specific findings that may aid in the diagnosis of this entity in children.
Harris DL, Yamaguchi T, Hamrah P. A Novel Murine Model of Radiation Keratopathy. Invest Ophthalmol Vis Sci 2018;59(10):3889-3896.Abstract
Purpose: Radiation therapy results in severe chronic keratopathy and dry eye disease. We developed a novel mouse model for radiation keratopathy to allow future mechanistic studies. Methods: Six to 8-week-old BALB/c mice underwent sublethal irradiation to the head only from a Cesium-137 irradiator, 2 × 550 rad, 3-hours apart. Irradiated mice were clinically evaluated by corneal fluorescein staining (CFS) at 1, 2, and 3 months, after which corneas were excised and immunofluorescence histochemistry performed with anti-CD45, anti-MHC class II, and anti-β-tubulin antibodies. Results: The survival rate after irradiation was 100%. Mice demonstrated significant CFS and hair loss around the eyes. Corneal nerve density decreased in the central and peripheral corneas (P < 0.01) at 2 and 3 months, respectively. CD45+ immune cell densities increased in the central and peripheral corneas (P < 0.005, P < 0.001) at 2 and 3 months, respectively. MHC class II, a sign of antigen presenting cell activation, significantly increased after irradiation in the central and peripheral corneas at 2 and 3 months (P = 0.02). A strong inverse correlation was noted between decreased corneal nerves and increase in CD45+ cells in the central cornea at 2 (P = 0.04, r = -0.89) and 3 months (P = 0.03, r = -0.91) after irradiation. Conclusions: We present a model of radiation keratopathy and demonstrate significant nerve loss and increase in immune cell influx and activation within months. This model will enable future investigations to understand the effects of radiation therapy on the eye, and to study mechanisms of neuro-immune crosstalk in the cornea.
He M, Lippestad M, Li D, Hodges RR, Utheim TP, Dartt DA. Activation of the EGF Receptor by Histamine Receptor Subtypes Stimulates Mucin Secretion in Conjunctival Goblet Cells. Invest Ophthalmol Vis Sci 2018;59(8):3543-3553.Abstract
Purpose: The purpose of this study was to determine if histamine receptors interact with the epidermal growth factor receptor (EGFR) in cultured rat conjunctival goblet cells. Methods: Goblet cells from rat conjunctiva were grown in organ culture. First-passage goblet cells were used in all experiments. Phosphorylated (active) and total EGFR, AKT, and extracellular signal-regulated kinase (ERK)1/2 were measured by Western blot analysis. Cells were preincubated with the EGFR antagonist AG1478 for 30 minutes or small interfering RNA specific to the EGFR for 3 days prior to stimulation with histamine or agonists specific for histamine receptor subtypes for 2 hours. Goblet cell secretion was measured using an enzyme-linked lectin assay. Goblet cells were incubated for 1 hour with the calcium indicator molecule fura-2/AM, and intracellular [Ca2+] ([Ca2+]i) was determined. Data were collected in real time and presented as the actual [Ca2+]i with time and as the change in peak [Ca2+]i. Results: Histamine increased the phosphorylation of the EGFR. Mucin secretion and increase in [Ca2+]i stimulated by histamine, and agonists specific for each histamine receptor subtype were blocked by inhibition of the EGFR. Increase in [Ca2+]i stimulated by histamine and specific agonists for each histamine receptor was also inhibited by TAPI-1, a matrix metalloproteinase (MMP) inhibitor. The histamine-stimulated increase in activation of AKT, but not ERK1/2, was blocked by AG1478. Conclusions: In conjunctival goblet cells, histamine, using all four receptor subtypes, transactivates the EGFR via an MMP. This in turn phosphorylates AKT to increase [Ca2+]i and stimulate mucin secretion.
Hellgren G, Löfqvist C, Hansen-Pupp I, Gram M, Smith LE, Ley D, Hellström A. Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity. Growth Horm IGF Res 2018;39:19-24.Abstract
OBJECTIVE: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α in relation to IGF-I levels and ROP. DESIGN: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n=33), non-proliferative ROP (stages 1 and 2; n=10), or proliferative ROP (stage 3, all treated for ROP; n=9). Blood samples were collected at birth, 24h after birth, and then weekly until at least 36weeks postmenstrual age (PMA) (i.e., up to 13weeks after birth). Circulating levels of IL-6 and TNF-α were evaluated in relation to circulating IGF-I levels and ROP. RESULTS: IL-6 levels negatively correlated with IGF-I levels between 5 and 8weeks after birth, (p<0.01 to p<0.05). At birth, the IL-6 and TNF-α levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-α levels had increased in infants later treated for ROP (p<0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. CONCLUSIONS: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP.
Homer N, Fay A. Management of Long-Standing Flaccid Facial Palsy: Periocular Considerations. Otolaryngol Clin North Am 2018;51(6):1107-1118.Abstract
Ineffective eyelid closure can pose a serious risk of injury to the ocular surface and eye. In cases of eyelid paresis, systematic examination of the eye and ocular adnexa will direct appropriate interventions. Specifically, 4 distinct periorbital regions should be independently assessed: eyebrow, upper eyelid, ocular surface, and lower eyelid. Corneal exposure can lead to dehydration, thinning, scarring, infection, perforation, and blindness. Long-term sequelae following facial nerve palsy may also include epiphora, gustatory lacrimation, and synkinesis.
Hoshi S, Okamoto F, Arai M, Hirose T, Sugiura Y, Murakami T, Oshika T. Patching retinal breaks with polyethylene glycol-based synthetic hydrogel sealant for retinal detachment in rabbits. Exp Eye Res 2018;177:117-121.Abstract
The purpose of this study was to evaluate absorbable polyethylene glycol (PEG)-based synthetic hydrogel as a sealant for retinal breaks in rhegmatogenous retinal detachment (RD). A three-port, 25-gauge vitrectomy was performed on nine Dutch pigmented rabbit eyes. Subsequently, RD was induced by creating a retinal break. The retina was then reattached by fluid-air exchange. In six of nine eyes (RD-PEG group), PEG sealant was applied to completely cover the retinal breaks, and then photopolymerized with light; thereafter, intravitreous air was replaced with balanced salt solution (BSS). In the remaining three eyes (RD group), PEG sealant was not applied, but the intravitreous air was replaced with BSS. Ophthalmological examinations and intraocular pressure measurements were conducted preoperatively, and at 1 and 7 days, and 1, 3, and 6 months postoperatively. Histological examinations of the eyes were performed after 6 postoperative months. At surgery, retinal reattachment with PEG sealant was achieved in all eyes in the RD-PEG group. Fundoscopic and optical coherence tomographic examinations revealed that the retina remained attached in all the eyes of the RD-PEG group throughout the 6-month observation period. Histological examination revealed no signs of damage in the retinal layers at the edges of the retinal breaks that were in contact with the sealant. In the RD group, the retinas detached in all eyes within 7 days postoperatively. The PEG sealant closed the retinal breaks and maintained retinal reattachment. Intraocular tamponade was not necessary.
Houston KE, Bowers AR, Peli E, Woods RL. Peripheral Prisms Improve Obstacle Detection during Simulated Walking for Patients with Left Hemispatial Neglect and Hemianopia. Optom Vis Sci 2018;95(9):795-804.Abstract
SIGNIFICANCE: The first report on the use of peripheral prisms (p-prisms) for patients with left neglect and homonymous visual field defects (HVFDs). PURPOSE: The purpose of this study was to investigate if patients with left hemispatial neglect and HVFDs benefit from p-prisms to expand the visual field and improve obstacle detection. METHODS: Patients (24 with HVFDs, 10 of whom had left neglect) viewed an animated, virtual, shopping mall corridor and reported if they would have collided with a human obstacle that appeared at various offsets up to 13.5° from their simulated walking path. There were 40 obstacle presentations on each side, with and without p-prisms. No training with p-prisms was provided, and gaze was fixed at the center of expansion. RESULTS: Detection on the side of the HVFD improved significantly with p-prisms in both groups, from 26 to 92% in the left-neglect group and 43 to 98% in the non-neglect group (both P < .001). There was a tendency for greater improvement in the neglect patients with p-prisms. For collision judgments, both groups exhibited a large increase in perceived collisions on the side of the HVFD with the prisms (P < .001), with no difference between the groups (P = .93). Increased perceived collisions represent a wider perceived safety margin on the side of the HVFD. CONCLUSIONS: Within the controlled conditions of this simulated, collision judgment task, patients with left neglect responded well to initial application of p-prisms exhibiting improved detection and wider safety margins on the side of the HVFD that did not differ from non-neglect patients. Further study of p-prisms for neglect patients in free-gaze conditions after extended wear and in real-world mobility tasks is clearly warranted.
Houston KE, Peli E, Goldstein RB, Bowers AR. Driving With Hemianopia VI: Peripheral Prisms and Perceptual-Motor Training Improve Detection in a Driving Simulator. Transl Vis Sci Technol 2018;7(1):5.Abstract
Purpose: Drivers with homonymous hemianopia (HH) were previously found to have impaired detection of blind-side hazards, yet in many jurisdictions they may obtain a license. We evaluated whether oblique 57Δ peripheral prisms (p-prisms) and perceptual-motor training improved blind-side detection rates. Methods: Patients with HH (n = 11) wore p-prisms for 2 weeks and then received perceptual-motor training (six visits) detecting and touching stimuli in the prism-expanded vision. In a driving simulator, patients drove and pressed the horn upon detection of pedestrians who ran toward the roadway (26 from each side): (1) without p-prisms at baseline; (2) with p-prisms after 2 weeks acclimation but before training; (3) with p-prisms after training; and (4) 3 months later. Results: P-prisms improved blind-side detection from 42% to 56%, which further improved after training to 72% (all P < 0.001). Blind-side timely responses (adequate time to have stopped) improved from 31% without to 44% with p-prisms (P < 0.001) and further improved with training to 55% (P = 0.02). At the 3-month follow-up, improvements from training were maintained for detection (65%; P = 0.02) but not timely responses (P = 0.725). There was wide between-subject variability in baseline detection performance and response to p-prisms. There were no negative effects of p-prisms on vehicle control or seeing-side performance. Conclusions: P-prisms improved detection with no negative effects, and training may provide additional benefit. Translational Relevance: In jurisdictions where people with HH are legally driving, these data aid in clinical decision making by providing evidence that p-prisms improve performance without negative effects.
Hua J, Inomata T, Chen Y, Foulsham W, Stevenson W, Shiang T, Bluestone JA, Dana R. Pathological conversion of regulatory T cells is associated with loss of allotolerance. Sci Rep 2018;8(1):7059.Abstract
CD4CD25Foxp3 Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3 Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17 or IFNγ 'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1 peripherally-derived Tregs are particularly susceptible to conversion to IL-17/IFNγ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
Huang C-C, Yang W, Guo C, Jiang H, Li F, Xiao M, Davidson S, Yu G, Duan B, Huang T, Huang AJW, Liu Q. Anatomical and functional dichotomy of ocular itch and pain. Nat Med 2018;Abstract
Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.
Hudry E, Andres-Mateos E, Lerner EP, Volak A, Cohen O, Hyman BT, Maguire CA, Vandenberghe LH. Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65. Mol Ther Methods Clin Dev 2018;10:197-209.Abstract
Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from reconstruction of the viral evolutionary lineage, has previously demonstrated robust transduction capabilities after local delivery in various tissues such as liver, retina, or cochlea, compared with conventional AAVs. Here, we compared the transduction efficacy of Anc80L65 with conventional AAV9 in the CNS after intravenous, intracerebroventricular (i.c.v.), or intraparenchymal injections. Anc80L65 was more potent at targeting the brain and spinal cord after intravenous injection than AAV9, and mostly transduced astrocytes and a wide range of neuronal subpopulations. Although the efficacy of Anc80L65 and AAV9 is similar after direct intraparenchymal injection in the striatum, Anc80L65's diffusion throughout the CNS was more extensive than AAV9 after i.c.v. infusion, leading to widespread expression in the cerebellum. These findings demonstrate that Anc80L65 is a highly efficient gene transfer vector for the murine CNS. Systemic injection of Anc80L65 leads to notable expression in the CNS that does not rely on a self-complementary genome. These data warrant further testing in larger animal models.
Hunter DG. Improving Access-but Not Outcomes-With Iris Optical Coherence Tomography Angiography. JAMA Ophthalmol 2018;136(9):1045-1046.
Hwang AD, Tuccar-Burak M, Goldstein R, Peli E. Impact of Oncoming Headlight Glare With Cataracts: A Pilot Study. Front Psychol 2018;9:164.Abstract
Oncoming headlight glare (HLG) reduces the visibility of objects on the road and may affect the safety of nighttime driving. With cataracts, the impact of oncoming HLG is expected to be more severe. We used our custom HLG simulator in a driving simulator to measure the impact of HLG on pedestrian detection by normal vision subjects with simulated mild cataracts and by patients with real cataracts.Five normal vision subjects drove nighttime scenarios under two HLG conditions (with and without HLG: HLGY and HLGN, respectively), and three vision conditions (with plano lens, simulated mild cataract, and optically blurred clip-on). Mild cataract was simulated by applying a 0.8 Bangerter diffusion foil to clip-on plano lenses. The visual acuity with the optically blurred lenses was individually chosen to match the visual acuity with the simulated cataract clip-ons under HLGN. Each nighttime driving scenario contains 24 pedestrian encounters, encompassing four pedestrian types; walking along the left side of the road, walking along the right side of the road, crossing the road from left to right, and crossing the road from right to left. Pedestrian detection performances of five patients with mild real cataracts were measured using the same setup. The cataract patients were tested only in HLGY and HLGN conditions. Participants' visual acuity and contrast sensitivity were also measured in the simulator with and without stationary HLG.For normal vision subjects, both the presence of oncoming HLG and wearing the simulated cataract clip-on reduced pedestrian detection performance. The subjects performed worst in events where the pedestrian crossed from the left, followed by events where the pedestrian crossed from the right. Significant interactions between HLG condition and other factors were also found: (1) the impact of oncoming HLG with the simulated cataract clip-on was larger than with the plano lens clip-on, (2) the impact of oncoming HLG was larger with the optically blurred clip-on than with the plano lens clip-on, but smaller than with the simulated cataract clip-on, and (3) the impact was larger for the pedestrians that crossed from the left than those that crossed from the right, and for the pedestrians walking along the left side of the road than walking along the right side of the road, suggesting that the pedestrian proximity to the glare source contributed to the performance reduction. Under HLGN, almost no pedestrians were missed with the plano lens or the simulated cataract clip-on (0 and 0.5%, respectively), but under HLGY, the rate of pedestrian misses increased to 0.5 and 6%, respectively. With the optically blurred clip-on, the percent of missed pedestrians under HLGN and HLGY did not change much (5% and 6%, respectively). Untimely response rate increased under HLGY with the plano lens and simulated cataract clip-ons, but the increase with the simulated cataract clip-on was significantly larger than with the plano lens clip-on. The contrast sensitivity with the simulated cataract clip-on was significantly degraded under HLGY. The visual acuity with the plano lens clip-on was significantly improved under HLGY, possibly due to pupil myosis. The impact of HLG measured for real cataract patients was similar to the impact on performance of normal vision subjects with simulated cataract clip-ons.Even with mild (simulated or real) cataracts, a substantial negative effect of oncoming HLG was measurable in the detection of crossing and walking-along pedestrians. The lowered pedestrian detection rates and longer response times with HLGY demonstrate a possible risk that oncoming HLG poses to patients driving with cataracts.
Ibrahim AS, Elmasry K, Wan M, Abdulmoneim S, Still A, Khan F, Khalil A, Saul A, Hoda MN, Al-Shabrawey M. A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse. Invest Ophthalmol Vis Sci 2018;59(13):5548-5557.Abstract
Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.
Ichhpujani P, Thakur S, Kumar S, Singh RB. Juvenile Open Angle Glaucoma With Nonbullous Congenital Ichthyosiform Erythroderma. J Glaucoma 2018;27(11):e180-e182.Abstract
INTRODUCTION: Glaucoma in patients with nonbullous congenital ichthyosiform erythroderma (NBCIE) is a rare entity that has not been described in a histologically confirmed case. We present a unique case of coexisting glaucoma, ichthyosis, and dwarfism that has not been previously described. METHODS: We present a case of NBCIE with glaucoma and dwarfism that presented to our outpatient department. The patient was referred for watering and photophobia that were due to an epithelial defect that was subsequently managed conservatively. Investigations revealed the existence of a constellation of findings that are presented here. RESULTS: NBCIE, glaucoma, and dwarfism represent a spectrum of diseases that seem to have a syndromic association. More gene linkage-based analysis are, however, needed to further confirm our observations. CONCLUSIONS: NBCIE, glaucoma, and dwarfism can often occur together and need to be assessed and managed individually. Early diagnosis of this spectrum can help improve patient management and quality of life. Dermatologists must get an ocular examination conducted for icthyoses patients.
Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Höhn R, Springelkamp H, Cuellar-Partida G, Gharahkhani P, Bailey JCN, Willoughby CE, Li X, Yazar S, Nag A, Khawaja AP, Polašek O, Siscovick D, Mitchell P, Tham YC, Haines JL, Kearns LS, Hayward C, Shi Y, van Leeuwen EM, Taylor KD, Taylor KD, Bonnemaijer P, Rotter JI, Martin NG, Zeller T, Mills RA, Staffieri SE, Jonas JB, Schmidtmann I, Boutin T, Kang JH, Lucas SEM, Wong TY, Beutel ME, Wilson JF, Wilson JF, Wilson JF, Uitterlinden AG, Vithana EN, Foster PJ, Hysi PG, Hewitt AW, Khor CC, Pasquale LR, Montgomery GW, Klaver CCW, Aung T, Pfeiffer N, Mackey DA, Hammond CJ, Cheng C-Y, Craig JE, Rabinowitz YS, Wiggs JL, Burdon KP, van Duijn CM, Macgregor S. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nat Commun 2018;9(1):1864.Abstract
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Ikeda Y, Sun Z, Ru X, Vandenberghe LH, Humphreys BD. Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno-Associated Viral Vector. J Am Soc Nephrol 2018;29(9):2287-2297.Abstract
BACKGROUND: After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets ; however, protocols for transduction of kidney mesenchymal cells have not been established. METHODS: We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids. RESULTS: Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by injection of Anc80-Cre virus into either homozygous or heterozygous Gli2-floxed mice. After unilateral ureteral obstruction, the homozygous Gli2-floxed mice had less fibrosis than the Gli2 heterozygotes had. We observed the same antifibrotic effect in -catenin-floxed mice injected with Anc80-Cre virus before obstructive injury, strongly supporting a central role for canonical Wnt signaling in kidney myofibroblast activation. Finally, we showed that the Anc80 synthetic virus can transduce the mesenchymal lineage in human kidney organoids. CONCLUSIONS: These studies establish a novel method for inducible knockout of floxed genes in mouse mesangium, pericytes, and perivascular fibroblasts and are the foundation for future gene therapy approaches to treat kidney fibrosis.
Ing E, Pagnoux C, Tyndel F, Sundaram A, Hershenfeld S, Ranalli P, Chow S, Le T, Lutchman C, Rutherford S, Lam K, Bedi H, Torun N. Lower ocular pulse amplitude with dynamic contour tonometry is associated with biopsy-proven giant cell arteritis. Can J Ophthalmol 2018;53(3):215-221.Abstract
OBJECTIVES: To determine the role of the ocular pulse amplitude (OPA) from Pascal dynamic contour tonometry in predicting the temporal artery biopsy (TABx) result in patients with suspected giant cell arteritis (GCA). DESIGN: Prospective validation study. PARTICIPANTS: Adults aged 50 years or older who underwent TABx from March 2015 to April 2017. METHODS: Subjects on high-dose glucocorticoids more than 14 days or without serology before glucocorticoid initiation were excluded. The OPA from both eyes was obtained and averaged just before TABx of the predominantly symptomatic side. The variables chosen for the a priori prediction model were age, average OPA, and C-reactive protein (CRP). Erythrocyte sedimentation rate (ESR), platelets, jaw claudication, and eye findings were also recorded. In this study, subjects with a negative biopsy were considered not to have GCA, and contralateral biopsy was performed if the clinical suspicion for GCA remained high. An external validation set (XVAL) was obtained. RESULTS: Of 109 TABx, 19 were positive and 90 were negative. On univariate logistic regression, the average OPA had 0.60 odds for positive TABx (p = 0.03), with no statistically significant difference in age, sex, CRP, ESR, or jaw claudication. In suspected GCA, an OPA of 1 mm Hg had positive likelihood ratio 4.74 and negative likelihood ratio 0.87 for positive TABx. Multivariate regression of the prediction model using optimal mathematical transforms (inverse OPA, log CRP, age >65 years) had area under the receiver operating characteristic curve (AUROC) = 0.85 and AUROC = 0.81. CONCLUSIONS: OPA is lower in subjects with biopsy-proven GCA and is a statistically significant predictor of GCA.
Inomata T, Hua J, Nakao T, Shiang T, Chiang H, Amouzegar A, Dana R. Corneal Tissue From Dry Eye Donors Leads to Enhanced Graft Rejection. Cornea 2018;37(1):95-101.Abstract
PURPOSE: To assess the effect of dry eye disease (DED) in graft donors on dendritic cell (DC) maturation, host T-cell sensitization, and corneal allograft rejection. METHODS: Corneas of control (healthy donor) and DED mice (C57BL/6) were transplanted onto fully allogeneic naive BALB/c recipients (n = 10 mice/group). Long-term allograft survival was evaluated for 8 weeks. Corneas and draining lymph nodes (dLNs) were harvested at posttransplantation day 14 (n = 5 mice/group). The frequencies of MHCII CD11c DCs in the donor corneas and host dLNs and the frequencies of interferon (IFN)-γ and IL-17 CD4 T cells and Foxp3 expression by Tregs in host dLNs were investigated using flow cytometry. The enzyme-linked immunospot assay was used to assess host T-cell allosensitization through direct and indirect pathways (n = 3/group). RESULTS: Recipients of DED donor corneas showed significantly reduced graft survival (10%) compared with control mice (50% survival, P = 0.022), and had significantly increased frequencies of mature DCs in the grafted cornea (DED donor 44.0% ± 0.36% vs. healthy donor 35.4 ± 0.5%; P < 0.0001) and host dLNs (DED donor 25.1% ± 0.66% vs. healthy donor 13.7% ± 1.6%; P = 0.005). Frequencies of IFN-γ and IL-17 T cells were increased in the dLNs of recipients of DED corneas, whereas the expression (mean fluorescence intensity) of Foxp3 in Tregs was decreased significantly in these mice (DED donor 6004 ± 193 vs. healthy donor 6806 ± 81; P = 0.0002). Enzyme-linked immunospot analysis showed that the direct pathway of allosensitization was significantly amplified in recipients of grafts with DED (P = 0.0146). CONCLUSIONS: Our results indicate that DED in the donor is a significant risk factor for subsequent corneal allograft rejection.