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Latremoliere A, Cheng L, DeLisle M, Wu C, Chew S, Hutchinson EB, Sheridan A, Alexandre C, Latremoliere F, Sheu S-H, Golidy S, Omura T, Huebner EA, Fan Y, Whitman MC, Nguyen E, Hermawan C, Pierpaoli C, Tischfield MA, Woolf CJ, Engle EC. Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration. Cell Rep 2018;24(7):1865-1879.e9.Abstract
We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3 mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total β-tubulin levels in Tubb3 and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.
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.
Grundy SJ, Tshering L, Wanjala SW, Diamond MB, Audi MS, Prasad S, Shinohara RT, Rogo D, Wangmo D, Wangdi U, Aarayang A, Tshering T, Burke TF, Mateen FJ. Retinal Parameters as Compared with Head Circumference, Height, Weight, and Body Mass Index in Children in Kenya and Bhutan. Am J Trop Med Hyg 2018;99(2):482-488.Abstract
The retina shares embryological derivation with the brain and may provide a new measurement of overall growth status, especially useful in resource-limited settings. Optical coherence tomography (OCT) provides detailed quantification of retinal structures. We enrolled community-dwelling children ages 3-11 years old in Siaya, Kenya and Thimphu, Bhutan in 2016. We measured head circumference (age < 5 years only), height, and weight, and standardized these by age and gender. Research staff performed OCT (; Optovue, Inc., Fremont, CA), measuring the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) thicknesses. A neuro-ophthalmologist performed quality control for centration, motion artifact, and algorithm-derived quality scores. Generalized estimating equations were used to determine the relationship between anthropometric and retinal measurements. Two hundred and fifty-eight children (139 females, average age 6.4 years) successfully completed at least one retinal scan, totaling 1,048 scans. Nine hundred and twenty-two scans (88.0%) were deemed usable. Fifty-three of the 258 children (20.5%) were able to complete all six scans. Kenyan children had a thinner average GCC ( < 0.001) than Bhutanese children after adjustment for age and gender, but not RNFL ( = 0.70). In models adjusting for age, gender, and study location, none of standardized height, weight, and body mass index (BMI) were statistically significantly associated with RNFL or GCC. We determined that OCT is feasible in some children in resource-limited settings, particularly those > 4 years old, using the device. We found no evidence for GCC or RNFL as a proxy for height-, weight-, or BMI-for-age. The variation in mean GCC thickness in Asian versus African children warrants further investigation.
Chen H, Cho K-S, Vu KTH, Shen C-H, Kaur M, Chen G, Mathew R, McHam LM, Fazelat A, Lashkari K, Au NPB, Tse JKY, Li Y, Yu H, Yang L, Stein-Streilein J, Ma CHE, Woolf CJ, Whary MT, Jager MJ, Fox JG, Chen J, Chen DF. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat Commun 2018;9(1):3209.Abstract
Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.
Stacy R, Huttner K, Watts J, Peace J, Wirta D, Walters T, Sall K, Seaman J, Ni X, Prasanna G, Mogi M, Adams C, Yan J-H, Wald M, He Y, Newton R, Kolega R, Grosskreutz C. A Randomized, Controlled Phase I/II Study to Evaluate the Safety and Efficacy of MGV354 for Ocular Hypertension or Glaucoma. Am J Ophthalmol 2018;192:113-123.Abstract
PURPOSE: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. DESIGN: Double-masked, randomized, and vehicle-controlled study. METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780). RESULTS: There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. CONCLUSIONS: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.
Rhiu S, Michalak S, Phanphruk W, Hunter DG. Anomalous Vertical Deviations in Attempted Abduction Occur in the Majority of Patients With Esotropic Duane Syndrome. Am J Ophthalmol 2018;195:171-175.Abstract
PURPOSE: To describe a phenomenon, depression in attempted abduction, not previously recognized as a feature of Duane syndrome (DS). DESIGN: Retrospective, observational case series. METHODS: Setting: Institutional practice. PATIENT POPULATION: Patients diagnosed with esotropic DS at Boston Children's Hospital from 2002 to 2015. Patients with clinical photographs documenting horizontal gaze were included. Patients with prior strabismus surgery were excluded. OBSERVATION PROCEDURES: Patients were classified into 3 groups according to their vertical eye position in attempted abduction: midline group, depression group, and elevation group. Group assignment was performed by 3 independent ophthalmologists. Baseline characteristics, eye movement, and ocular deviation were compared among the 3 groups. MAIN OUTCOME MEASURES: Horizontal and vertical deviation on attempted abduction in the DS eye. RESULTS: Depression in attempted abduction was present in 74 of 113 unilateral patients (66%) and 18 of 42 gradable eyes (43%) of bilateral patients. Abduction limitation was significantly less severe in the midline group (median: -3.0) than in the depression group (median: -4.0) (P = .01). Vertical deviation in attempted abduction was more severe in the elevation group than in the depression group (P = .003). CONCLUSIONS: Depression of the eye in attempted abduction has not been widely described, yet it is present in the majority of DS patients. It is more likely to occur with more severe abduction limitation. This phenomenon is likely another form of dysinnervation in DS, the result either of anomalous vertical rectus muscle activation or asymmetric lateral rectus muscle innervation during attempted abduction. Awareness of vertical deviation in attempted abduction may facilitate surgical planning in affected patients.
Li Z, Cestari DM, Fortin E. Thyroid eye disease: what is new to know?. Curr Opin Ophthalmol 2018;29(6):528-534.Abstract
PURPOSE OF REVIEW: The pathophysiology of thyroid eye disease (TED) is still not fully understood. However, recently described risk factors and molecular findings have brought new insights into the mechanisms of TED and could lead to the emerging use of more targeted therapies. This article aims to review the clinical findings of TED, and the most recent advances in our understanding of the risk factors and therapeutic options for TED. RECENT FINDINGS: Smoking has been recently shown to have an impact on specific gene expression involved in several disease-related pathways, which seems to be reversible with smoking cessation. This finding further emphasizes the importance of smoking cessation in the prevention and treatment of TED. Selenium deficiency and high-serum cholesterol have been described to be potential independent risk factors for TED and their management could decrease the incidence and severity of TED. In terms of therapeutic options, immunomodulatory medications have shown some promising results for disease control in TED over the past years, but further randomized prospective studies with larger sample sizes are still needed to prove their efficacy. A new technique of P brachytherapy was shown to have quick therapeutic effects on TED without significant side effects and could be a promising therapy for selected cases of TED. SUMMARY: TED is one of the most common autoimmune inflammatory disorders of the orbit. Although its pathophysiology remains unclear, newly described genetic findings and risk factors could help in explaining its occurrence and guide future therapies. Immunosuppressant medications are increasingly used in the management of TED, but further studies are needed to confirm their effectiveness.
Costela FM, Saunders DR, Kajtezovic S, Rose DJ, Woods RL. Measuring the Difficulty Watching Video With Hemianopia and an Initial Test of a Rehabilitation Approach. Transl Vis Sci Technol 2018;7(4):13.Abstract
Purpose: If you cannot follow the story when watching a video, then the viewing experience is degraded. We measured the difficulty of following the story, defined as the ability to acquire visual information, which is experienced by people with homonymous hemianopia (HH). Further, we proposed and tested a novel rehabilitation aid. Methods: Participants watched 30-second directed video clips. Following each video clip, subjects described the visual content of the clip. An objective score of information acquisition (IA) was derived by comparing each new response to a control database of descriptions of the same clip using natural language processing. Study 1 compared 60 participants with normal vision (NV) to 24 participants with HH to test the hypothesis that participants with HH would score lower than NV participants, consistent with reports from people with HH that describe difficulties in video watching. In the second study, 21 participants with HH viewed clips with or without a superimposed dynamic cue that we called a content guide. We hypothesized that IA scores would increase using this content guide. Results: The HH group had a significantly lower IA score, with an average of 2.8, compared with 4.3 shared words of the NV group (mixed-effects regression, < 0.001). Presence of the content guide significantly increased the IA score by 0.5 shared words ( = 0.03). Conclusions: Participants with HH had more difficulty acquiring information from a video, which was objectively demonstrated (reduced IA score). The content guide improved information acquisition, but not to the level of people with NV. Translational Relevance: The value as a possible rehabilitation aid of the content guide warrants further study that involves an extended period of content-guide use and a randomized controlled trial.
Satitpitakul V, Sun Z, Suri K, Amouzegar A, Katikireddy KR, Jurkunas UV, Kheirkhah A, Dana R. Vasoactive Intestinal Peptide Promotes Corneal Allograft Survival. Am J Pathol 2018;188(9):2016-2024.Abstract
Corneal transplantation is the most prevalent form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain graft transparency. CEnC density decreases significantly after corneal transplantation even in the absence of graft rejection. To date, different strategies have been used to enhance CEnC survival. The neuropeptide vasoactive intestinal peptide (VIP) improves CEnC integrity during donor cornea tissue storage and protects CEnCs against oxidative stress-induced apoptosis. However, little is known about the effect of exogenous administration of VIP on corneal transplant outcomes. We found that VIP significantly accelerates endothelial wound closure and suppresses interferon-γ- and tumor necrosis factor-α-induced CEnC apoptosis in vitro in a dose-dependent manner. In addition, we found that intracameral administration of VIP to mice undergoing syngeneic corneal transplantation with endothelial injury increases CEnC density and decreases graft opacity scores. Finally, using a mouse model of allogeneic corneal transplantation, we found for the first time that treatment with VIP significantly suppresses posttransplantation CEnC loss and improves corneal allograft survival.
Raghuram A, Gowrisankaran S, Swanson E, Zurakowski D, Hunter DG, Waber DP. Frequency of Visual Deficits in Children With Developmental Dyslexia. JAMA Ophthalmol 2018;136(10):1089-1095.Abstract
Importance: Developmental dyslexia (DD) is a specific learning disability of neurobiological origin whose core cognitive deficit is widely believed to involve language (phonological) processing. Although reading is also a visual task, the potential role of vision in DD has been controversial, and little is known about the integrity of visual function in individuals with DD. Objective: To assess the frequency of visual deficits (specifically vergence, accommodation, and ocular motor tracking) in children with DD compared with a control group of typically developing readers. Design, Setting, and Participants: A prospective, uncontrolled observational study was conducted from May 28 to October 17, 2016, in an outpatient ophthalmology ambulatory clinic among 29 children with DD and 33 typically developing (TD) children. Main Outcomes and Measures: Primary outcomes were frequencies of deficits in vergence (amplitude, fusional ranges, and facility), accommodation (amplitude, facility, and accuracy), and ocular motor tracking (Developmental Eye Movement test and Visagraph eye tracker). Results: Among the children with DD (10 girls and 19 boys; mean [SD] age, 10.3 [1.2] years) and the TD group (21 girls and 12 boys; mean [SD] age, 9.4 [1.4] years), accommodation deficits were more frequent in the DD group than the TD group (16 [55%] vs 3 [9%]; difference = 46%; 95% CI, 25%-67%; P < .001). For ocular motor tracking, 18 children in the DD group (62%) had scores in the impaired range (in the Developmental Eye Movement test, Visagraph, or both) vs 5 children in the TD group (15%) (difference, 47%; 95% CI, 25%-69%; P < .001). Vergence deficits occurred in 10 children in the DD group (34%) and 5 children in the TD group (15%) (difference, 19%; 95% CI, -2.2% to 41%; P = .08). In all, 23 children in the DD group (79%) and 11 children in the TD group (33%) had deficits in 1 or more domain of visual function (difference, 46%; 95% CI, 23%-69%; P < .001). Conclusions and Relevance: These findings suggest that deficits in visual function are far more prevalent in school-aged children with DD than in TD readers, but the possible cause and clinical relevance of these deficits are uncertain. Further study is needed to determine the extent to which treating these deficits can improve visual symptoms and/or reading parameters.
Moos WH, Faller DV, Glavas IP, Harpp DN, Irwin MH, Kanara I, Pinkert CA, Powers WR, Steliou K, Vavvas DG, Kodukula K. A New Approach to Treating Neurodegenerative Otologic Disorders. Biores Open Access 2018;7(1):107-115.Abstract
Hearing loss, the most common neurological disorder and the fourth leading cause of years lived with disability, can have profound effects on quality of life. The impact of this "invisible disability," with significant consequences, economic and personal, is most substantial in low- and middle-income countries, where >80% of affected people live. Given the importance of hearing for communication, enjoyment, and safety, with up to 500 million affected globally at a cost of nearly $800 billion/year, research on new approaches toward prevention and treatment is attracting increased attention. The consequences of noise pollution are largely preventable, but irreversible hearing loss can result from aging, disease, or drug side effects. Once damage occurs, treatment relies on hearing aids and cochlear implants. Preventing, delaying, or reducing some degree of hearing loss may be possible by avoiding excessive noise and addressing major contributory factors such as cardiovascular risk. However, given the magnitude of the problem, these interventions alone are unlikely to be sufficient. Recent advances in understanding principal mechanisms that govern hearing function, together with new drug discovery paradigms designed to identify efficacious therapies, bode well for pharmaceutical intervention. This review surveys various causes of loss of auditory function and discusses potential neurological underpinnings, including mitochondrial dysfunction. Mitochondria mitigate cell protection, survival, and function and may succumb to cumulative degradation of energy production and performance; the end result is cell death. Energy-demanding neurons and vestibulocochlear hair cells are vulnerable to mitochondrial dysfunction, and hearing impairment and deafness are characteristic of neurodegenerative mitochondrial disease phenotypes. Beyond acting as cellular powerhouses, mitochondria regulate immune responses to infections, and studies of this phenomenon have aided in identifying nuclear factor kappa B and nuclear factor erythroid 2-related factor 2/antioxidant response element signaling as targets for discovery of otologic drugs, respectively, suppressing or upregulating these pathways. Treatment with free radical scavenging antioxidants is one therapeutic approach, with lipoic acid and corresponding carnitine esters exhibiting improved biodistribution and other features showing promise. These compounds are also histone deacetylase (HDAC) inhibitors, adding epigenetic modulation to the mechanistic milieu through which they act. These data suggest that new drugs targeting mitochondrial dysfunction and modulating epigenetic pathways via HDAC inhibition or other mechanisms hold great promise.
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.
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.
Cestari DM, Freire MV, Chun BY. Vertical rectus muscle recession versus combined vertical and horizontal rectus muscle recession in patients with thyroid eye disease and hypotropia. J AAPOS 2018;Abstract
PURPOSE: To compare the postoperative vertical drift in patients with thyroid eye disease (TED) with hypotropia who underwent vertical rectus recession alone versus recession combined with horizontal rectus recession. METHODS: The medical records of patients with TED who underwent strabismus surgery for hypotropia between 2006 and 2015 were reviewed retrospectively. Patients were divided into two groups: group 1 underwent vertical rectus recession only; group 2 underwent vertical rectus recession plus horizontal rectus recession. Data collection included pre- and postoperative deviation measurements and amount of surgical recession performed. The amount of postoperative vertical drift between groups was compared. RESULTS: Of 67 patients who underwent surgery during the study period, 18 met inclusion criteria, 9 in each group. Mean postoperative hypotropia was 24.2 in group 1 and 24.5 in group 2 (P = 0.82). Mean vertical deviations were 0.3 and -2.2 (P = 0.134) on postoperative day 1 -0.9 and -8.0 (P = 0.043) at final follow-up for groups 1 and 2. Mean postoperative vertical drift toward hypertropia was 1.2 in group 1 and 6.8 in group 2 (P = 0.048). The surgical success rate for group 1 was superior to that for group 2 (89% vs 67% [P = 0.024]). CONCLUSIONS: There was a significantly larger postoperative vertical drift in TED patients with hypotropia who had combined vertical rectus and horizontal rectus recessions compared with those who underwent vertical rectus recession alone.

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