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The ARMS2 A69S Polymorphism Is Associated with Delayed Rod-Mediated Dark Adaptation in Eyes at Risk for Incident Age-Related Macular Degeneration.

Thu, 2018-11-08 13:21
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The ARMS2 A69S Polymorphism Is Associated with Delayed Rod-Mediated Dark Adaptation in Eyes at Risk for Incident Age-Related Macular Degeneration.

Ophthalmology. 2018 Oct 30;:

Authors: Mullins RF, McGwin G, Searcey K, Clark ME, Kennedy EL, Curcio CA, Stone EM, Owsley C

Abstract
OBJECTIVE: To examine the association between sequence variants in genetic risk factors for age-related macular degeneration (AMD), and delayed rod-mediated dark adaptation (RMDA), the first functional biomarker for incident AMD, in older adults with normal macular health and early AMD.
DESIGN: Cross-sectional SUBJECTS: Older adults aged ≥60 years in normal macular health (defined as both eyes at step 1 on the Age-Related Eye Disease 9-step AMD classification system) and those with AMD in one or both eyes (defined as steps 2-9).
METHODS: Single nucleotide polymorphisms were genotyped in the CFH and ARMS2 genes using a Taqman assay. RMDA was assessed in one eye after photobleach with targets centered at 5° on the inferior vertical meridian. Rate of dark adaptation was defined by rod intercept time (RIT), duration (minutes) required for sensitivity to reach a criterion sensitivity level in the latter half of the second component of rod recovery. Associations between CFH and ARMS2 polymorphisms and RMDA were adjusted for age and smoking.
MAIN OUTCOME MEASURE: RIT.
RESULTS: The sample consisted of 543 participants having both genotype and RIT determination; 408 were in normal macular health and 135 had AMD, most having early AMD (124 of 135). For the combined sample, higher RIT (slower RMDA) was observed for both the A69S variant in ARMS2 and the Y402H variant in CFH (adjusted p=0.0001 and p=0.0023 respectively). For normal subjects the A69S variant in ARMS2 was associated with higher RIT (adjusted p=0.0011), whereas CFH Y402H was not (adjusted p=0.2175). For AMD cases, the A69S variant of ARMS2 and CFH Y402H were associated with higher RIT (adjusted p=0.0182 and p=0.0222 respectively). Those with a greater number of high-risk ARMS2 and CFH alleles had higher RIT, in both normal and AMD groups (adjusted p=0.0002 and p<0.0001 respectively).
CONCLUSIONS: We report a novel association wherein older adults with high risk ARMS2 and CFH genotypes are more likely to have delayed RMDA, the first functional biomarker for incident early AMD. Before the AMD clinical phenotype is present, those in normal macular health with the ARMS2 A69S allele have delayed RMDA. Understanding ARMS2 function is a research priority.

PMID: 30389424 [PubMed - as supplied by publisher]

Autoimmune retinopathy and optic neuropathy associated with enolase-positive renal oncocytoma.

Wed, 2018-09-26 22:42
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Autoimmune retinopathy and optic neuropathy associated with enolase-positive renal oncocytoma.

Am J Ophthalmol Case Rep. 2018 Dec;12:55-60

Authors: Cheng JL, Beebe JD, Nepple KG, Zakharia Y, Mullins RF, Flamme-Wiese MJ, Thurtell MJ, Han IC

Abstract
Purpose: To report a case of autoimmune retinopathy and optic neuropathy associated with an enolase-positive renal oncocytoma.
Observations: A 41-year-old man presented with subacute, painless, bilateral vision loss. On initial examination, visual acuity measured 20/125 OD and 20/1250 OS, and telangiectatic vessels were noted on the optic nerves and in the maculae. Goldmann perimetry showed bilateral, cecocentral scotomas, and electroretinography demonstrated reduced photopic and scotopic signals, concerning for autoimmune retinopathy. Serum testing showed multiple positive anti-optic nerve and anti-retinal antibodies, including to alpha-enolase. Extensive systemic workup was negative except for a large, exophytic, right renal mass. Biopsy was consistent with a benign oncocytoma, and immunohistochemical staining showed diffusely positive alpha-enolase staining. The patient was treated with a five-day course of intravenous methylprednisolone and plasmapheresis with minimal improvement. Surgical excision of the oncocytoma was performed. At 9-months post-operatively, visual acuity had improved to 20/40 OU, with corresponding improvement on visual field and electroretinography testing.
Conclusions and importance: To our knowledge, this is the first report of autoimmune retinopathy and optic neuropathy associated with a renal oncocytoma. The case highlights the importance of a thorough systemic workup in cases of suspected autoimmune retinopathy and reminds clinicians that even tumors considered benign can have distal effects on other organs.

PMID: 30229140 [PubMed]

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury.

Wed, 2018-09-12 22:21
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Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury.

Sci Rep. 2018 Sep 06;8(1):13387

Authors: Zeng S, Wen KK, Workalemahu G, Sohn EH, Wu M, Chirco KR, Flamme-Wiese MJ, Liu X, Stone EM, Tucker BA, Mullins RF

Abstract
Age-related macular degeneration (AMD) is a common, blinding disease associated with increased complement system activity. Eyes with AMD show elevated accumulation of the membrane attack complex (MAC) in the choriocapillaris and degeneration of macular choriocapillaris endothelial cells (ECs). Thus, one could reasonably conclude that the endothelial cell death that occurs in AMD is due to injury by the MAC. We therefore sought to identify strategies for protecting ECs against MAC lysis. RF/6A endothelial cells were pre-incubated with a library of FDA-approved small molecules, followed by incubation with complement intact human serum quantification of cell death. Two closely related molecules identified in the screen, econazole nitrate and miconazole nitrate, were followed in validation and mechanistic studies. Both compounds reduced lysis of choroidal ECs treated with complement-intact serum, across a range of doses from 1 to 100 µM. Cell rescue was confirmed in mouse primary choroidal ECs. Both exosome release and cell surface roughness (assessed using a Holomonitor system) were reduced by drug pretreatment in RF/6A cells, whereas endosome formation increased with both drugs, consistent with imidazole-mediated alterations of cell surface dynamics. The results in the current study provide further proof of principle that small molecules can protect choroidal ECs from MAC-induced cell death and suggest that FDA approved compounds may be beneficial in reducing vascular loss and progression of AMD.

PMID: 30190604 [PubMed - in process]

Effect of Molecular Weight and Functionality on Acrylated Poly(caprolactone) for Stereolithography and Biomedical Applications.

Wed, 2018-08-01 11:24
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Effect of Molecular Weight and Functionality on Acrylated Poly(caprolactone) for Stereolithography and Biomedical Applications.

Biomacromolecules. 2018 Jul 25;:

Authors: Green BJ, Worthington KS, Thompson JR, Bunn SJ, Rethwisch M, Kaalberg EE, Jiao C, Wiley LA, Mullins RF, Stone EM, Sohn EH, Tucker BA, Guymon CA

Abstract
Degradable polymers are integral components in many biomedical polymer applications. The ability of these materials to decompose in situ has become a critical component for tissue engineering, allowing scaffolds to guide cell and tissue growth while facilitating gradual regeneration of native tissue. The objective of this work is to understand the role of prepolymer molecular weight and functionality of photocurable poly(caprolactone) (PCL) in determining reaction kinetics, mechanical properties, polymer degradation, biocompatibility, and suitability for stereolithography. PCL, a degradable polymer used in a number of biomedical applications, was functionalized with acrylate groups to enable photopolymerization and 3D printing via stereolithography. PCL prepolymers with different molecular weight and functionality were studied to understand the role of molecular structure on reaction kinetics, mechanical properties and degradation rates. The mechanical properties of photocured PCL were dependent on cross-link density and directly related to the molecular weight and functionality of the prepolymers. High molecular weight, low functionality PCLDA prepolymers exhibited lower modulus and higher strain at break while low molecular weight, high functionality PCLTA prepolymers exhibited lower strain at break and higher modulus. Additionally, degradation profiles of cross-linked PCL followed a similar trend, with low cross-link density leading to degradation times up to 2.5 times shorter than more highly cross-linked polymers. Furthermore, photopolymerized PCL showed biocompatibility both in vitro and in vivo, causing no observed detrimental effects on seeded murine induced pluripotent stem cells or when implanted into pig retinas. Finally, the ability to create 3-dimensional PCL structures is shown by fabrication of simple structures using digital light projection stereolithography. Low molecular weight, high functionality PCLTA prepolymers printed objects with feature sizes near the hardware resolution limit of 50 μm. This work lays the foundation for future work in fabricating micro-scale PCL structures for a wide range of tissue regeneration applications.

PMID: 30044915 [PubMed - as supplied by publisher]