Publications

2017

The function of the meibomian gland in the upper and lower eyelids is critical to maintaining homeostasis at the ocular surface. Highly specialized meibocytes within the gland must differentiate and accumulate intracellular lipid droplets that are released into the tear film following rupture of the cell membrane. Proteases and their inhibitors have been recognized as key players in remodeling extracellular matrices and promoting the normal integrity of glandular tissue. They modulate a wide range of biological processes, such as cell proliferation and differentiation, and can contribute to disease when aberrantly expressed. Deciphering the role of proteolytic activity in the meibomian gland offers an opportunity to gain a more comprehensive and fundamental understanding of the developmental, physiological, and pathological processes associated with this gland.
Bouffard MA, Caplan L, Torun N. Divergence Palsy due to Divalproex and Oxcarbazepine. Clin Neuropharmacol. 2017;

OBJECTIVE: This case series is the first to describe divergence palsy as an adverse effect of antiepileptic drug use. Diplopia is a common adverse effect of antiepileptic drugs, but no explanatory motility deficit has ever been reported. METHODS: We present 2 patients, 1 on oxcarbazepine and 1 on divalproex, each with a normal examination result between spells and divergency palsy when symptomatic. RESULTS: Discontinuation of the antiepileptic medication led to resolution of the episodes in both cases. Rechallenge with the offending agent after washout in one patient resulted in recurrence of diplopia and divergence palsy, both resolving after subsequent withdrawal of the antiepileptic. CONCLUSIONS: Antiepileptic drugs may cause divergence palsy.

Bujakowska K, Liu Q, Pierce E. Photoreceptor Cilia and Retinal Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9(10).
Photoreceptors are sensory neurons designed to convert light stimuli into neurological responses. This process, called phototransduction, takes place in the outer segments (OS) of rod and cone photoreceptors. OS are specialized sensory cilia, with analogous structures to those present in other nonmotile cilia. Deficient morphogenesis and/or dysfunction of photoreceptor sensory cilia (PSC) caused by mutations in a variety of photoreceptor-specific and common cilia genes can lead to inherited retinal degenerations (IRDs). IRDs can manifest as isolated retinal diseases or syndromic diseases. In this review, we describe the structure and composition of PSC and different forms of ciliopathies with retinal involvement. We review the genetics of the IRDs, which are monogenic disorders but genetically diverse with regard to causality.
Chen Q, Qiu F, Zhou K, Matlock G, Takahashi Y, Rajala R, Yang Y, Moran E, Ma JX. Pathogenic Role of MicroRNA-21 in Diabetic Retinopathy Through Down-Regulation of PPARα. Diabetes. 2017;

Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in type 2 diabetic patients. Our recent studies have shown that PPARα is down-regulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced down-regulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. MiR-21 was over-expressed, while PPARα levels were decreased in the retina of db/db mice, a type 2 diabetic model. Such alterations were also observed in palmitate-treated retinal endothelial cells. MiR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα down-regulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα down-regulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for PPARα down-regulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.

Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian A, Jodelka F, Hastings M, Lentz J, Vandenberghe L, Holt J, Géléoc G. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017;35(3):264–272.

Because there are currently no biological treatments for hearing loss, we sought to advance gene therapy approaches to treat genetic deafness. We focused on Usher syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and studied a knock-in mouse model, Ush1c c.216G>A, for Usher syndrome type IC (USH1C). As restoration of complex auditory and balance function is likely to require gene delivery systems that target auditory and vestibular sensory cells with high efficiency, we delivered wild-type Ush1c into the inner ear of Ush1c c.216G>A mice using a synthetic adeno-associated viral vector, Anc80L65, shown to transduce 80-90% of sensory hair cells. We demonstrate recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders.

Sadaka A, Durand M, Sisk R, Gilmore M. Staphylococcus aureus and its Bearing on Ophthalmic Disease. Ocul Immunol Inflamm. 2017;25(1):111–121.

PURPOSE: To review antibiotic resistance associated with S. aureus endophthalmitis and the virulence of S. aureus. METHODS: Review of the current and prospective approaches for treating S. aureus endophthalmitis. RESULTS: Bacterial endophthalmitis remains to be a major threat for vision. S. aureus endophthalmitis specifically, carries a poor visual prognosis making early diagnosis and treatment crucial. Methicillin resistant Staphylococcus aureus (MRSA) endophthalmitis represents a significant number of S. aureus endophthalmitis cases. MRSA with reduced susceptibility to glycopeptide antibiotics such as vancomycin (vancomycin intermediate S. aureus, VISA) have also emerged in the ocular infections, and there has been a rise in S. aureus resistance to new and old generation fluoroquinolones that are commonly used for prophylaxis after intravitreal injections and intraocular surgeries. CONCLUSIONS: With the rise in the number of penetrating procedures in the ophthalmology practice and the parallel rise in antibiotic resistance, prophylaxis and awareness of the antimicrobial resistance profiles remain crucial and the identification of novel antimicrobials is essential.