TY - JOUR T1 - Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence. JF - Mol Genet Genomic Med Y1 - 2022 A1 - Kolesnikova, Masha A1 - Lima de Carvalho, Jose Ronaldo A1 - Parmann, Rait A1 - Kim, Angela H A1 - Mahajan, Vinit B A1 - Tsang, Stephen H A1 - Sparrow, Janet R KW - Atrophy KW - Child KW - cis-trans-Isomerases KW - Female KW - Humans KW - Leber Congenital Amaurosis KW - Mutation KW - Retinal Degeneration AB -

INTRODUCTION: Leber congenital amaurosis (LCA) type 2, due to disease-causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec-rzyl (VN) for RPE65-associated LCA. Herein, we present the long-term follow-up of a patient treated with VN using quantitative autofluorescence (488 nm excitation).

CASE REPORT: A 9-year-old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6- and 8-year follow-up revealed a central area of fundus autofluorescence.

DISCUSSION: This case report demonstrates acquisition of fundus autofluorescence at 6- and 8-year follow-up despite the development of chorioretinal atrophy.

VL - 10 IS - 11 ER - TY - JOUR T1 - REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies. JF - Retina Y1 - 2022 A1 - Park, Jong G A1 - Xu, Christine L A1 - Boyd, Allison A1 - Aghajanova, Lusine A1 - Mahajan, Vinit B A1 - Wood, Edward H KW - Child KW - Eye Diseases, Hereditary KW - Female KW - Fertilization in Vitro KW - Humans KW - Ophthalmology KW - Pregnancy KW - Preimplantation Diagnosis KW - Retrospective Studies AB -

PURPOSE: To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing.

METHODS: Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children.

RESULTS: Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children.

CONCLUSION: A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

VL - 42 IS - 11 ER - TY - JOUR T1 - Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). JF - PLoS One Y1 - 2017 A1 - Cox, Allison J A1 - Darbro, Benjamin W A1 - Laxer, Ronald M A1 - Velez, Gabriel A1 - Bing, Xinyu A1 - Finer, Alexis L A1 - Erives, Albert A1 - Mahajan, Vinit B A1 - Bassuk, Alexander G A1 - Ferguson, Polly J KW - Amino Acid Sequence KW - Animals KW - Cell Adhesion Molecules KW - Cell Line, Tumor KW - Child KW - Cytoskeletal Proteins KW - Female KW - Genes, Recessive KW - Humans KW - Interleukin-10 KW - Mice KW - Mutation KW - Osteomyelitis KW - Promoter Regions, Genetic KW - Sequence Homology, Amino Acid AB -

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.

VL - 12 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28301468?dopt=Abstract ER - TY - JOUR T1 - Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate. JF - PLoS One Y1 - 2016 A1 - Darbro, Benjamin W A1 - Singh, Rohini A1 - Zimmerman, M Bridget A1 - Mahajan, Vinit B A1 - Bassuk, Alexander G KW - Adolescent KW - Adult KW - Autism Spectrum Disorder KW - Child KW - Child, Preschool KW - Female KW - Genes, Tumor Suppressor KW - Genetic Predisposition to Disease KW - Humans KW - Infant KW - Male KW - Middle Aged KW - Mutation KW - Neoplasms KW - Oncogenes KW - Prevalence KW - Young Adult AB -

Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0 x 10(-8)). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26934580?dopt=Abstract ER - TY - JOUR T1 - Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses. JF - Invest Ophthalmol Vis Sci Y1 - 2016 A1 - Schaefer, Kellie A A1 - Toral, Marcus A A1 - Velez, Gabriel A1 - Cox, Allison J A1 - Baker, Sheila A A1 - Borcherding, Nicholas C A1 - Colgan, Diana F A1 - Bondada, Vimala A1 - Mashburn, Charles B A1 - Yu, Chen-Guang A1 - Geddes, James W A1 - Tsang, Stephen H A1 - Bassuk, Alexander G A1 - Mahajan, Vinit B KW - Animals KW - Blotting, Western KW - Calpain KW - Cattle KW - Female KW - Gene Expression Regulation, Neoplastic KW - Humans KW - Immunohistochemistry KW - Male KW - Mice KW - Neoplasms, Experimental KW - Photoreceptor Cells KW - Retina KW - Retinal Neoplasms KW - Retinoblastoma KW - RNA, Neoplasm KW - Synapses KW - Tumor Cells, Cultured AB -

PURPOSE: We characterize calpain-5 (CAPN5) expression in retinal and neuronal subcellular compartments.

METHODS: CAPN5 gene variants were classified using the exome variant server, and RNA-sequencing was used to compare expression of CAPN5 mRNA in the mouse and human retina and in retinoblastoma cells. Expression of CAPN5 protein was ascertained in humans and mice in silico, in mouse retina by immunohistochemistry, and in neuronal cancer cell lines and fractionated central nervous system tissue extracts by Western analysis with eight antibodies targeting different CAPN5 regions.

RESULTS: Most CAPN5 genetic variation occurs outside its protease core; and searches of cancer and epilepsy/autism genetic databases found no variants similar to hyperactivating retinal disease alleles. The mouse retina expressed one transcript for CAPN5 plus those of nine other calpains, similar to the human retina. In Y79 retinoblastoma cells, the level of CAPN5 transcript was very low. Immunohistochemistry detected CAPN5 expression in the inner and outer nuclear layers and at synapses in the outer plexiform layer. Western analysis of fractionated retinal extracts confirmed CAPN5 synapse localization. Western blots of fractionated brain neuronal extracts revealed distinct subcellular patterns and the potential presence of autoproteolytic CAPN5 domains.

CONCLUSIONS: CAPN5 is moderately expressed in the retina and, despite higher expression in other tissues, hyperactive disease mutants of CAPN5 only manifest as eye disease. At the cellular level, CAPN5 is expressed in several different functional compartments. CAPN5 localization at the photoreceptor synapse and with mitochondria explains the neural circuitry phenotype in human CAPN5 disease alleles.

VL - 57 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27152965?dopt=Abstract ER - TY - JOUR T1 - Chronic Recurrent Pseudophakic Endophthalmitis. JF - JAMA Ophthalmol Y1 - 2016 A1 - Chin, Eric K A1 - Almeida, David R P A1 - Mahajan, Vinit B KW - Aged, 80 and over KW - Chronic Disease KW - Combined Modality Therapy KW - Drug Therapy, Combination KW - Endophthalmitis KW - Female KW - Follow-Up Studies KW - Humans KW - Mycobacterium chelonae KW - Mycobacterium Infections, Nontuberculous KW - Recurrence KW - Risk Assessment KW - Slit Lamp KW - Treatment Outcome KW - Vancomycin KW - Vitrectomy VL - 134 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26868359?dopt=Abstract ER - TY - JOUR T1 - COMBINED VITRECTOMY AND INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT. JF - Retina Y1 - 2016 A1 - Zheng, Andrew A1 - Chin, Eric K A1 - Almeida, David R P A1 - Tsang, Stephen H A1 - Mahajan, Vinit B KW - Adult KW - Aged KW - Aged, 80 and over KW - Combined Modality Therapy KW - Dexamethasone KW - Drug Implants KW - Female KW - Glucocorticoids KW - Humans KW - Intraocular Pressure KW - Intravitreal Injections KW - Macular Edema KW - Male KW - Middle Aged KW - Retinal Vein Occlusion KW - Retrospective Studies KW - Tomography, Optical Coherence KW - Uveitis, Posterior KW - Visual Acuity KW - Vitrectomy KW - Wet Macular Degeneration AB -

PURPOSE: To evaluate the safety and efficacy of combining intravitreal dexamethasone implantation (Ozurdex) with pars plana vitrectomy (PPV).

METHODS: A retrospective review was conducted on cases where Ozurdex injection was performed in the operating room in conjunction with pars plana vitrectomy. Our primary outcome measure was the presence of surgical complications in the perioperative and 3-month postoperative window. We also measured visual acuity, intraocular pressure (IOP), and macular edema at baseline, one, and 3 months after surgery.

RESULTS: Fifteen eyes in 14 cases were reviewed. There were no complications intraoperatively or at 1-month postoperatively. Two patients (2 eyes) with prior retinal detachment developed proliferative vitreoretinopathy and redetachment at 3 months. Visual acuity improved in 7 of 15 eyes, and an average improvement of 2 lines was achieved for the entire cohort. There was no overall change in intraocular pressure although 1 patient developed an increase in intraocular pressure >5 mmHg. Five of 9 patients with baseline macular edema experienced improvement or resolution at 3 months.

CONCLUSION: Intraoperative Ozurdex in combination with PPV may be safe and effective in treating macular edema caused by many different underlying diseases.

VL - 36 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27148836?dopt=Abstract ER - TY - JOUR T1 - ELEVATED INTRAOCULAR PRESSURE FOLLOWING PARS PLANA VITRECTOMY DUE TO TRAPPED GAS IN THE POSTERIOR CHAMBER. JF - Retin Cases Brief Rep Y1 - 2016 A1 - Chin, Eric K A1 - Almeida, David R P A1 - Strohbehn, Austin L A1 - Mahajan, Vinit B A1 - Russell, Stephen R A1 - Folk, James C KW - Aged KW - Endotamponade KW - Female KW - Gases KW - Humans KW - Intraocular Pressure KW - Male KW - Middle Aged KW - Ocular Hypertension KW - Posterior Eye Segment KW - Vitrectomy AB -

PURPOSE: Elevated intraocular pressure is relatively common following pars plana vitrectomy and intraocular gas tamponade. We discuss a series of patients who experienced elevated intraocular pressure from pupillary block and angle closure secondary to trapped gas in the posterior chamber.

METHODS: Case series.

RESULTS: Case 1 is a patient who underwent pars plana vitrectomy for retinal detachment repair. The intraocular pressure was elevated on postoperative Day 3 because of trapped gas in the posterior chamber, and it did not lower with prone positioning, maximal medical therapy, and laser peripheral iridotomies. Aspiration of the trapped gas was done with the patient sitting upright using a 27-gauge needle at the limbus, which was curative. Case 2 provides anterior-segment optical coherence tomography images that confirmed the location of the trapped gas resulting in angle closure. Case 3 demonstrates the unfortunate sequelae of a central retinal artery occlusion following delayed recognition of this entity. Case 4 highlights the challenges encountered when migratory gas is also seen elsewhere in the eye.

CONCLUSION: Clinicians should be aware of elevated intraocular pressure secondary to trapped gas in the posterior chamber, which may be recalcitrant to medical therapy. Aspiration of the trapped gas can alleviate both pupillary block and angle closure without compromising the gas tamponade.

VL - 10 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26630244?dopt=Abstract ER - TY - JOUR T1 - Management of Pediatric Aphakic Glaucoma With Vitrectomy and Tube Shunts. JF - J Pediatr Ophthalmol Strabismus Y1 - 2016 A1 - Elshatory, Yasser M A1 - Gauger, Elizabeth H A1 - Kwon, Young H A1 - Alward, Wallace L M A1 - Boldt, H Culver A1 - Russell, Stephen R A1 - Mahajan, Vinit B KW - Adolescent KW - Aphakia, Postcataract KW - Cataract KW - Cataract Extraction KW - Child KW - Child, Preschool KW - Female KW - Glaucoma KW - Glaucoma Drainage Implants KW - Humans KW - Infant KW - Intraocular Pressure KW - Male KW - Retrospective Studies KW - Visual Acuity KW - Vitrectomy AB -

PURPOSE: To review the impact of vitrectomy and tube shunts on mean intraocular pressure (IOP) and number of glaucoma medications in pediatric aphakic glaucoma.

METHODS: A retrospective review of pediatric patients who underwent combined vitrectomy and glaucoma tube shunt surgery for aphakic glaucoma was conducted. Inclusion criteria were: age 18 years or younger, diagnosis of aphakic glaucoma, preoperative IOP data, and postoperative IOP data for at least 6 months. Mean IOP lowering at 1 year, number of glaucoma medications at 1 year, and surgical complications, including tube occlusion in the postoperative period, were noted.

RESULTS: The mean ± standard deviation preoperative IOP was 33.9 ± 10.6 mm Hg (range: 18 to 57 mm Hg) with a mean of three topical IOP-lowering medications. A total of 5 (36%) Ahmed and 9 (64%) Baerveldt tube shunts were placed. One of the Baerveldt tube shunt procedures was combined with revision of a traumatically dislocated tube. The mean IOP at 12 months postoperatively was 16.6 ± 5.8 mm Hg (range: 6 to 28 mm Hg; P < .01, t = 3.74, df = 13) with a mean of 2.3 glaucoma medications. There were no cases of tube occlusion, corneal decompensation, endophthalmitis, or retinal detachment over the 12 months of follow-up.

CONCLUSIONS: Combined vitrectomy and placement of a glaucoma tube shunt can be safe and effective in lowering IOP based on mean IOP values and number of glaucoma medications at 1 year. [J Pediatr Ophthalmol Strabismus. 2016;53(6):339-343.].

VL - 53 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27668871?dopt=Abstract ER - TY - JOUR T1 - Response to Sandford et al.: PRICKLE2 Variants in Epilepsy: A Call for Precision Medicine. JF - Am J Hum Genet Y1 - 2016 A1 - Mahajan, Vinit B A1 - Bassuk, Alexander G KW - Animals KW - Carrier Proteins KW - DNA-Binding Proteins KW - Drosophila Proteins KW - Female KW - Humans KW - Male KW - Mutation KW - Nerve Tissue Proteins KW - Seizures KW - Tumor Suppressor Proteins KW - Zebrafish Proteins VL - 98 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26942292?dopt=Abstract ER - TY - JOUR T1 - Intravitreal Anti-VEGF Injections in Pregnancy: Case Series and Review of Literature. JF - J Ocul Pharmacol Ther Y1 - 2015 A1 - Polizzi, Silvio A1 - Mahajan, Vinit B KW - Adult KW - Angiogenesis Inhibitors KW - Bevacizumab KW - Female KW - Humans KW - Infant, Newborn KW - Intravitreal Injections KW - Pregnancy KW - Pregnancy Complications KW - Pregnancy Outcome KW - Risk Factors KW - Vascular Endothelial Growth Factor A AB -

The use of intravitreal antivascular endothelial growth factor (anti-VEGF) injection is gaining wide acceptance as an off-label therapy for diseases that may affect pregnant women. However, these drugs may cause systemic side effects in the mother and fetal harm. This could lead specialists to not administer the drug or women to abort the fetus or to refuse treatment during pregnancy. We report the course of pregnancy in 3 women treated with intravitreal bevacizumab and provide a review of the literature on the use of intravitreal anti-VEGF in pregnancy. Our patients did not have any drug-related adverse event and delivered healthy full-term infants, although one of the women had risk factors for miscarriage. Infants reached all developmental milestones appropriately during infancy. A literature search on the use of intravitreal anti-VEGF injection in pregnancy was undertaken. Data for this review were identified by searches of PubMed and references from relevant articles using the search terms "pegaptanib," "bevacizumab," "ranibizumab," "aflibercept," "anti-VEGF," "intravitreal injection," "pregnant," "pregnancy," "abortion," "miscarriage," "preeclampsia," "embryo-fetal toxicity," "fetal malformations," "teratogenesis," "adverse events," and "maternofetal complications" in multiple combinations. We believe that intravitreal anti-VEGF can be given during pregnancy only when potential benefit to the woman justifies the potential risks to the fetus. When making a decision about whether to give drugs during pregnancy, it is important to consider the timing of exposure and its relationship to windows of developmental sensitivity. We believe that this review will be useful to specialists to inform and possibly treat their pregnant patients.

VL - 31 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26302032?dopt=Abstract ER - TY - JOUR T1 - Macular Hole Closure With Internal Limiting Membrane Abrasion Technique. JF - JAMA Ophthalmol Y1 - 2015 A1 - Mahajan, Vinit B A1 - Chin, Eric K A1 - Tarantola, Ryan M A1 - Almeida, David R P A1 - Somani, Riz A1 - Boldt, H Culver A1 - Folk, James C A1 - Gehrs, Karen M A1 - Russell, Stephen R KW - Adult KW - Aged KW - Aged, 80 and over KW - Basement Membrane KW - Endotamponade KW - Female KW - Fluorocarbons KW - Humans KW - Male KW - Middle Aged KW - Ophthalmologic Surgical Procedures KW - Prone Position KW - Retinal Perforations KW - Retrospective Studies KW - Sulfur Hexafluoride KW - Tomography, Optical Coherence KW - Visual Acuity KW - Vitrectomy AB -

IMPORTANCE: Internal limiting membrane (ILM) abrasion is an alternative surgical technique for successful full-thickness macular hole (MH) repair.

OBJECTIVE: To study the effects of ILM abrasion as an alternative method of MH repair.

DESIGN, SETTING, AND PARTICIPANTS: Retrospective consecutive case series from January 2006 to December 2008. Demographic data and preoperative, intraoperative, and postoperative examination records of all patients were reviewed for patients who underwent ILM abrasion with a diamond-dusted membrane scraper during vitrectomy for MH repair. A total of 100 eyes underwent ILM abrasion as an alternative to traditional ILM peeling.

MAIN OUTCOMES AND MEASURES: Rate of MH closure and visual acuity (VA) outcomes at 3 months after surgery.

RESULTS: Macular hole closure was achieved with a single surgical procedure in 94 of 100 eyes (94.0%; 95% CI, 87.4%-97.8%). Among all patients, the median preoperative VA was 20/100 (range, 20/30 to hand motions; 25th quartile, 20/60; and 75th quartile, 20/160), and the median postoperative VA at 3 months after surgery was 20/60 (range, 20/20 to hand motions; 25th quartile, 20/40; and 75th quartile, 20/100). Among all patients with stage 2 MHs, 30 of 38 patients (78.9%) had at least 2 lines of VA gain: 15 of 23 (65.2%) were phakic, and 15 of 15 (100%) were pseudophakic. Four of 38 patients (10.5%) with stage 2 MHs had at least 2 lines of VA loss, and all were phakic. Among all patients with stage 3 or 4 MHs, 42 of 62 (67.7%) had at least 2 lines of VA gain, of which 30 of 38 (78.9%) were phakic and 22 of 24 (91.7%) were pseudophakic. Six of 62 patients (9.7%) with stage 3 or 4 MHs had at least 2 lines of VA loss: 4 were phakic, and 2 were pseudophakic. In total, 35.0% (95% CI, 25.7%-44.3%) of patients achieved 20/40 vision or better, and 52.0% (95% CI, 42.2%-61.8%) of patients achieved 20/50 vision or better.

CONCLUSIONS AND RELEVANCE: Abrasion of the ILM with a diamond-dusted membrane scraper at the time of vitrectomy achieves high rates of MH closure. This technique avoids complete removal of the retinal ILM basement membrane and subjacent tissues and appears to provide MH closure rates similar to those of traditional ILM peeling.

VL - 133 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25764352?dopt=Abstract ER - TY - JOUR T1 - Proteomic insight into the molecular function of the vitreous. JF - PLoS One Y1 - 2015 A1 - Skeie, Jessica M A1 - Roybal, C Nathaniel A1 - Mahajan, Vinit B KW - Aged KW - Aged, 80 and over KW - Eye Proteins KW - Female KW - Gene Expression Regulation KW - Humans KW - Male KW - Middle Aged KW - Proteome KW - Proteomics KW - Vitreous Body AB -

The human vitreous contains primarily water, but also contains proteins which have yet to be fully characterized. To gain insight into the four vitreous substructures and their potential functions, we isolated and analyzed the vitreous protein profiles of three non-diseased human eyes. The four analyzed substructures were the anterior hyaloid, the vitreous cortex, the vitreous core, and the vitreous base. Proteins were separated by multidimensional liquid chromatography and identified by tandem mass spectrometry. Bioinformatics tools then extracted the expression profiles, signaling pathways, and interactomes unique to each tissue. From each substructure, a mean of 2,062 unique proteins were identified, with many being differentially expressed in a specific substructure: 278 proteins were unique to the anterior hyaloid, 322 to the vitreous cortex, 128 to the vitreous base, and 136 to the vitreous core. When the identified proteins were organized according to relevant functional pathways and networks, key patterns appeared. The blood coagulation pathway and extracellular matrix turnover networks were highly represented. Oxidative stress regulation and energy metabolism proteins were distributed throughout the vitreous. Immune functions were represented by high levels of immunoglobulin, the complement pathway, damage-associated molecular patterns (DAMPs), and evolutionarily conserved antimicrobial proteins. The majority of vitreous proteins detected were intracellular proteins, some of which originate from the retina, including rhodopsin (RHO), phosphodiesterase 6 (PDE6), and glial fibrillary acidic protein (GFAP). This comprehensive analysis uncovers a picture of the vitreous as a biologically active tissue, where proteins localize to distinct substructures to protect the intraocular tissues from infection, oxidative stress, and energy disequilibrium. It also reveals the retina as a potential source of inflammatory mediators. The vitreous proteome catalogues the dynamic interactions between the vitreous and surrounding tissues. It therefore could be an indirect and effective method for surveying vitreoretinal disease for specific biomarkers.

VL - 10 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26020955?dopt=Abstract ER - TY - JOUR T1 - Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment. JF - PLoS One Y1 - 2015 A1 - Bassuk, Alexander G A1 - Yeh, Steven A1 - Wu, Shu A1 - Martin, Daniel F A1 - Tsang, Stephen H A1 - Gakhar, Lokesh A1 - Mahajan, Vinit B KW - Base Sequence KW - Calpain KW - Computational Biology KW - DNA Primers KW - Female KW - Fluorescein Angiography KW - Humans KW - Models, Molecular KW - Molecular Sequence Data KW - Mutation, Missense KW - Pedigree KW - Phenotype KW - Protein Conformation KW - Retinal Detachment KW - Sequence Analysis, DNA KW - Tomography, Optical Coherence KW - Uveitis KW - Vitreoretinopathy, Proliferative AB -

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

VL - 10 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25856303?dopt=Abstract ER - TY - JOUR T1 - Decreased macular thickness in nonproliferative macular telangiectasia type 2 with oral carbonic anhydrase inhibitors. JF - Retina Y1 - 2014 A1 - Chen, John J A1 - Sohn, Elliott H A1 - Folk, James C A1 - Mahajan, Vinit B A1 - Kay, Christine N A1 - Boldt, H Culver A1 - Russell, Stephen R KW - Acetazolamide KW - Administration, Oral KW - Adult KW - Aged KW - Carbonic Anhydrase Inhibitors KW - Female KW - Fluorescein Angiography KW - Humans KW - Male KW - Methazolamide KW - Middle Aged KW - Organ Size KW - Retina KW - Retinal Telangiectasis KW - Retrospective Studies KW - Tomography, Optical Coherence KW - Visual Acuity AB -

PURPOSE: To evaluate whether carbonic anhydrase inhibitors reduce the macular thickness and/or cystic spaces in patients with macular telangiectasia (MacTel) Type 2.

METHODS: Retrospective review of patients with nonproliferative cystoid changes associated with MacTel seen at the University of Iowa between 2009 and 2012. Carbonic anhydrase inhibitors were used in 8 patients with MacTel Type 2. Five patients with MacTel Type 2 were observed during this period. Initial and final visual acuities were documented. The presence of cystic spaces and the retinal thickness were measured with spectral-domain optical coherence tomography.

RESULTS: Patients treated with oral carbonic anhydrase inhibitors showed significant reduction in both the cystoid cavities and central macular thickness when compared with the patients who were observed (-12.2 μm; P = 0.020). The reduction in retinal thickness was more pronounced in patients receiving acetazolamide (-20.13 μm; P = 0.007) compared with methazolamide (-6.25 μm; P = 0.177). There was no significant change in visual acuity in patients receiving carbonic anhydrase inhibitors. Five patients with MacTel Type 2 did not receive treatment and demonstrated no change in visual acuity, cystoid cavities, or central macular thickness.

CONCLUSION: Oral carbonic anhydrase inhibitors, particularly acetazolamide, may decrease macular cystic cavities and reduce central macular thickness but does not appear to improve visual acuity. These findings have yet to be confirmed with a prospective treatment trial.

VL - 34 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24451922?dopt=Abstract ER - TY - JOUR T1 - Proteomic landscape of the human choroid-retinal pigment epithelial complex. JF - JAMA Ophthalmol Y1 - 2014 A1 - Skeie, Jessica M A1 - Mahajan, Vinit B KW - Aged, 80 and over KW - Choroid KW - Chromatography, Liquid KW - Computational Biology KW - Eye Proteins KW - Female KW - Gene Expression Regulation KW - Gene Ontology KW - Humans KW - Male KW - Proteome KW - Proteomics KW - Retinal Pigment Epithelium KW - Tandem Mass Spectrometry AB -

IMPORTANCE: Differences in geographical protein expression in the human choroid-retinal pigment epithelial (RPE) complex may explain molecular predisposition of regions to ophthalmic diseases such as age-related macular degeneration.

OBJECTIVE: To characterize the proteome of the human choroid-RPE complex and to identify differentially expressed proteins in specific anatomic regions.

DESIGN, SETTING, AND PARTICIPANTS: Experimental study of choroid-RPE tissue from 3 nondiseased eyes. The choroid-RPE complex underwent biopsy from beneath the foveal, macular, and peripheral retina. Protein fractions were isolated and subjected to multidimensional liquid chromatography and tandem mass spectrometry. A bioinformatic pipeline matched peptide spectra to the human proteome, assigned gene ontology classification, and identified protein signaling pathways unique to each of the choroid-RPE regions.

MAIN OUTCOMES AND MEASURES: Mean number of mass spectra, statistically significant differentially expressed proteins, gene ontology classification, and pathway representation.

RESULTS: We identified a mean of 4403 unique proteins in each of the foveal, macular, and peripheral choroid-RPE tissues. Six hundred seventy-one differentially expressed proteins included previously known risk factors for retinal diseases related to oxidative stress, inflammation, and the complement cascade. Gene ontology analysis showed that unique categories in the foveal and macular regions included immune process proteins as well as protein complexes and plasma membrane proteins. The peripheral region contained unique antioxidant activity proteins. Many proteins had the highest expression in the foveal or macular regions, including inflammation-related proteins HLA-A, HLA-B, and HLA-C antigens; intercellular adhesion molecule 1 (ICAM-1); S100; transcription factor ERG; antioxidant superoxide dismutase 1 (SOD1); chloride intracellular channel 6 ion (CLIC6); activators of the complement cascade C1q, C6, and C8; and complement factor H. Proteins with higher expression in the periphery included bestrophin 1 (BEST1), transcription factor RNA binding motif protein 39 (RBM39), inflammatory mediator macrophage migration inhibitory factor, antioxidant SOD3, ion channel voltage-dependent anion-selective channel protein 3 (VDAC3), and complement inhibitor CD55. The complement activation was among the highest represented pathways (P < 7.5e-13).

CONCLUSIONS AND RELEVANCE: This proteomic data set identifies novel molecular signatures in anatomically sensitive regions of the choroid-RPE complex. The findings give mechanistic insight into choroid-RPE function, reveal important choroid-RPE processes, and prioritize new pathways for therapeutic targeting.

VL - 132 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25058583?dopt=Abstract ER - TY - JOUR T1 - Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. JF - Am J Ophthalmol Y1 - 2013 A1 - Bakall, Benjamin A1 - Folk, James C A1 - Boldt, H Culver A1 - Sohn, Elliott H A1 - Stone, Edwin M A1 - Russell, Stephen R A1 - Mahajan, Vinit B KW - Aged KW - Aged, 80 and over KW - Angiogenesis Inhibitors KW - Antibodies, Monoclonal, Humanized KW - Bevacizumab KW - Drug Resistance KW - Drug Substitution KW - Exudates and Transudates KW - Female KW - Humans KW - Intravitreal Injections KW - Male KW - Middle Aged KW - Postoperative Complications KW - Ranibizumab KW - Receptors, Vascular Endothelial Growth Factor KW - Recombinant Fusion Proteins KW - Retina KW - Retreatment KW - Retrospective Studies KW - Subretinal Fluid KW - Tomography, Optical Coherence KW - Treatment Outcome KW - Vascular Endothelial Growth Factor A KW - Visual Acuity KW - Wet Macular Degeneration AB -

PURPOSE: To evaluate the outcome of intravitreal injection of aflibercept in cases with exudative age-related macular degeneration, (AMD) resistant to injections of bevacizumab or ranibizumab.

DESIGN: Retrospective observational case series.

METHODS: A retrospective chart review at a single institution was conducted to identify patients with exudative AMD and choroidal neovascularization (CNV) in 1 or both eyes resistant to treatment with ranibizumab or bevacizumab who were switched to treatment with at least 3 monthly injections of aflibercept. In total, 36 eyes from 31 patients were included. The demographic data, visual acuities, central macular thickness on optical coherence tomography (OCT), complications, and number of injections were reviewed.

RESULTS: The mean patient age was 79 years (range 60-88). There were 13 male and 18 female patients. The number of prior injections with either bevacizumab or ranibizumab ranged from 6-74. After 3 monthly injections of aflibercept, there was a reduction of either subretinal or intraretinal fluid in 18 of 36 (50.0%) of the treated eyes; the amount of fluid remained stable in 15 eyes (41.7%) and worsened in 3 eyes (8.3%). A significant average decrease was observed for the central macular thickness after 3 injections of 65 μm (P = 2.9 × 10(-6)), with no significant change in visual acuity.

CONCLUSIONS: Aflibercept therapy appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intraretinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab.

VL - 156 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23706500?dopt=Abstract ER - TY - JOUR T1 - Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. JF - Cell Y1 - 2013 A1 - White, Jacqueline K A1 - Gerdin, Anna-Karin A1 - Karp, Natasha A A1 - Ryder, Ed A1 - Buljan, Marija A1 - Bussell, James N A1 - Salisbury, Jennifer A1 - Clare, Simon A1 - Ingham, Neil J A1 - Podrini, Christine A1 - Houghton, Richard A1 - Estabel, Jeanne A1 - Bottomley, Joanna R A1 - Melvin, David G A1 - Sunter, David A1 - Adams, Niels C A1 - Tannahill, David A1 - Logan, Darren W A1 - Macarthur, Daniel G A1 - Flint, Jonathan A1 - Mahajan, Vinit B A1 - Tsang, Stephen H A1 - Smyth, Ian A1 - Watt, Fiona M A1 - Skarnes, William C A1 - Dougan, Gordon A1 - Adams, David J A1 - Ramirez-Solis, Ramiro A1 - Bradley, Allan A1 - Steel, Karen P KW - Animals KW - Disease KW - Disease Models, Animal KW - Female KW - Genes, Essential KW - Genetic Techniques KW - Genome-Wide Association Study KW - Male KW - Mice KW - Mice, Knockout KW - Phenotype AB -

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PAPERCLIP:

VL - 154 IS - 2 ER - TY - JOUR T1 - Intraoperative sclerotomy-related retinal breaks during 23-gauge pars plana vitrectomy. JF - Retina Y1 - 2013 A1 - Tarantola, Ryan M A1 - Tsui, Janet Y A1 - Graff, Jordan M A1 - Russell, Stephen R A1 - Boldt, H Culver A1 - Folk, James C A1 - Mahajan, Vinit B KW - Aged KW - Aged, 80 and over KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Intraoperative Complications KW - Male KW - Microsurgery KW - Middle Aged KW - Postoperative Complications KW - Retinal Detachment KW - Retinal Perforations KW - Retrospective Studies KW - Sclerostomy KW - Tomography, Optical Coherence KW - Visual Acuity KW - Vitrectomy AB -

PURPOSE: To study the incidence and characteristics of intraoperative sclerotomy-related retinal breaks encountered during 23-gauge pars plana vitrectomy.

METHODS: A retrospective consecutive case series was assembled from the surgical logs and charts of patients who underwent 23-gauge pars plana vitrectomy. Demographic data and preoperative, intraoperative, and postoperative records were examined.

RESULTS: A total 548 eyes met the inclusion criteria. Of them, 145 eyes underwent pars plana vitrectomy for repair of a rhegmatogenous retinal detachment (RRD) and 403 eyes for other indications. Sclerotomy-related retinal breaks were found in 8 of 548 (1.45%) eyes. No breaks were found in the 145 RRD eyes. In non-RRD cases, 8 of 403 (1.98%) eyes had sclerotomy-related breaks. All breaks were adjacent to the superior sclerotomies. The incidence of postoperative retinal detachment was 0% (0 of 403) in the non-RRD group. In eyes with breaks, the primary surgical indication was vitreomacular traction in six of eight eyes and epiretinal membrane in two of eight eyes. Posterior vitreous detachment was absent in six of eight eyes, and six of eight eyes were phakic. Eyes with vitreomacular traction had a significantly higher incidence of breaks (P < 0.0001). Eyes with a surgical indication other than RRD had a higher incidence of breaks, but this was not statistically significant when compared with eyes with RRD (P = 0.087).

CONCLUSION: Pars plana vitrectomy (23-gauge) is associated with a low incidence of sclerotomy-related retinal breaks and postoperative retinal detachments. Eyes with breaks are more likely to be phakic and without a preoperative posterior vitreous detachment. The presence of vitreomacular traction may be a risk factor for the development of intraoperative sclerotomy-related breaks.

VL - 33 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22791174?dopt=Abstract ER - TY - JOUR T1 - 23-gauge pediatric vitrectomy using limbus-based trocar-cannulas. JF - Retina (Philadelphia, Pa.) Y1 - 2012 A1 - Kay, Christine N A1 - Quiram, Polly H A1 - Mahajan, Vinit B KW - Catheters KW - Child KW - Child, Preschool KW - Female KW - Glaucoma Drainage Implants KW - Humans KW - Infant KW - Male KW - Microsurgery KW - Retinal Detachment KW - Retrospective Studies KW - Vitrectomy KW - Vitreous Hemorrhage VL - 32 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22466464?dopt=Abstract ER - TY - JOUR T1 - Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. JF - PLoS Genet Y1 - 2012 A1 - Mahajan, Vinit B A1 - Skeie, Jessica M A1 - Bassuk, Alexander G A1 - Fingert, John H A1 - Braun, Terry A A1 - Daggett, Heather T A1 - Folk, James C A1 - Sheffield, Val C A1 - Stone, Edwin M KW - Amino Acid Sequence KW - Base Sequence KW - Calpain KW - Cell Line KW - Cells, Cultured KW - Choroid Diseases KW - Exome KW - Exons KW - Eye Diseases, Hereditary KW - Female KW - Gene Expression KW - Genetic Linkage KW - Humans KW - Male KW - Models, Molecular KW - Molecular Sequence Data KW - Mutation KW - Pedigree KW - Phenotype KW - Photoreceptor Cells, Vertebrate KW - Protein Conformation KW - Protein Transport KW - Retinal Degeneration KW - Sequence Alignment AB -

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. We identified two different missense mutations in the CAPN5 gene in three ADNIV kindreds. CAPN5 encodes calpain-5, a calcium-activated cysteine protease that is expressed in retinal photoreceptor cells. Both mutations cause mislocalization from the cell membrane to the cytosol, and structural modeling reveals that both mutations lie within a calcium-sensitive domain near the active site. CAPN5 is only the second member of the large calpain gene family to cause a human Mendelian disorder, and this is the first report of a specific molecular cause for autoimmune eye disease. Further investigation of these mutations is likely to provide insight into the pathophysiologic mechanisms of common diseases ranging from autoimmune disorders to diabetic retinopathy.

VL - 8 IS - 10 ER - TY - JOUR T1 - Infrared imaging and optical coherence tomography reveal early-stage astrocytic hamartomas not detectable by fundoscopy. JF - Am J Ophthalmol Y1 - 2012 A1 - Xu, Luna A1 - Burke, Tomas R A1 - Greenberg, Jonathan P A1 - Mahajan, Vinit B A1 - Tsang, Stephen H KW - Adolescent KW - Astrocytes KW - Child KW - Diagnostic Imaging KW - Female KW - Fluorescein Angiography KW - Humans KW - Infrared Rays KW - Male KW - Ophthalmoscopes KW - Prospective Studies KW - Retinal Neoplasms KW - Tomography, Optical Coherence KW - Tuberous Sclerosis AB -

PURPOSE: To describe and correlate the features of astrocytic hamartomas using multimodal imaging.

DESIGN: Prospective, noncomparative, observational case series.

METHODS: This was a single-center study of 4 patients (8 eyes) with tuberous sclerosis complex. A complete ophthalmologic examination, fundus photography, fundus autofluorescence (FAF), infrared imaging, and spectral-domain optical coherence tomography (SD-OCT) were performed for each patient. Images from each modality were analyzed and compared.

RESULTS: In 2 patients, infrared imaging and SD-OCT detected occult retinal astrocytic hamartomas that were not observed on clinical examination or color fundus photography. FAF demonstrated the greatest contrast between lesions and surrounding retina but failed to identify 1 occult lesion that was detected with infrared imaging and SD-OCT. SD-OCT revealed lesions arising from the retinal nerve fiber layer with overlying vitreous adhesions, hyperreflective dots, and optically empty spaces at all depths of the tumor. Hamartomas were hyporeflective on infrared imaging and hypoautofluorescent on FAF. FAF of some lesions demonstrated hyperautofluorescent spots.

CONCLUSIONS: Infrared imaging and SD-OCT aid in the detection of astrocytic hamartomas that are not visible on clinical examination or color fundus photography. SD-OCT enhances visualization of structural details. FAF is a useful adjunctive test to obtain greater contrast between lesions and surrounding retina. The ability to monitor structural changes over time in astrocytic hamartomas using SD-OCT may be beneficial for monitoring the success of systemic chemotherapy in the treatment of various tuberous sclerosis tumors.

VL - 153 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22310082?dopt=Abstract ER - TY - JOUR T1 - Intravitreal bevacizumab for peripapillary choroidal neovascular membranes. JF - Arch Ophthalmol Y1 - 2012 A1 - Davis, Andrew S A1 - Folk, James C A1 - Russell, Stephen R A1 - Sohn, Elliott H A1 - Sohn, Elliot H A1 - Boldt, H Culver A1 - Stone, Edwin M A1 - Mahajan, Vinit B KW - Adult KW - Aged KW - Aged, 80 and over KW - Angiogenesis Inhibitors KW - Antibodies, Monoclonal, Humanized KW - Bevacizumab KW - Choroidal Neovascularization KW - Female KW - Fluorescein Angiography KW - Humans KW - Intravitreal Injections KW - Macular Degeneration KW - Male KW - Middle Aged KW - Retreatment KW - Subretinal Fluid KW - Tomography, Optical Coherence KW - Treatment Outcome KW - Vascular Endothelial Growth Factor A KW - Visual Acuity VL - 130 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22893085?dopt=Abstract ER - TY - JOUR T1 - Proteomic analysis of vitreous biopsy techniques. JF - Retina Y1 - 2012 A1 - Skeie, Jessica M A1 - Brown, Eric N A1 - Martinez, Harryl D A1 - Russell, Stephen R A1 - Birkholz, Emily S A1 - Folk, James C A1 - Boldt, H Culver A1 - Gehrs, Karen M A1 - Stone, Edwin M A1 - Wright, Michael E A1 - Mahajan, Vinit B KW - Adolescent KW - Aged KW - Biological Markers KW - Biopsy KW - Chromatography, Liquid KW - Electrophoresis, Polyacrylamide Gel KW - Eye Diseases KW - Eye Proteins KW - Female KW - Humans KW - Male KW - Middle Aged KW - Proteomics KW - Spectrophotometry, Ultraviolet KW - Tandem Mass Spectrometry KW - Vitrectomy KW - Vitreous Body KW - Young Adult AB -

PURPOSE: To compare vitreous biopsy methods using analysis platforms used in proteomics biomarker discovery.

METHODS: Vitreous biopsies from 10 eyes were collected sequentially using a 23-gauge needle and a 23-gauge vitreous cutter instrument. Paired specimens were evaluated by UV absorbance spectroscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and liquid chromatography tandem mass spectrometry (LC-MS/MS).

RESULTS: The total protein concentration obtained with a needle and vitrectomy instrument biopsy averaged 1.10 mg/mL (standard error of the mean = 0.35) and 1.13 mg/mL (standard error of the mean = 0.25), respectively. In eight eyes with low or medium viscidity, there was a very high correlation (R = 0.934) between the biopsy methods. When data from 2 eyes with high viscidity vitreous were included, the correlation was reduced (R = 0.704). The molecular weight protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of paired needle and vitreous cutter samples were similar, except for a minority of pairs with single band intensity variance. Using LC-MS/MS, equivalent peptides were identified with similar frequencies (R ≥ 0.90) in paired samples.

CONCLUSION: Proteins and peptides collected from vitreous needle biopsies are nearly equivalent to those obtained from a vitreous cutter instrument. This study suggests both techniques may be used for most proteomic and biomarker discovery studies of vitreoretinal diseases, although a minority of proteins and peptides may differ in concentration.

VL - 32 IS - 10 ER - TY - JOUR T1 - Automated discovery and quantification of image-based complex phenotypes: a twin study of drusen phenotypes in age-related macular degeneration. JF - Invest Ophthalmol Vis Sci Y1 - 2011 A1 - Quellec, Gwénolé A1 - Russell, Stephen R A1 - Seddon, Johanna M A1 - Reynolds, Robyn A1 - Scheetz, Todd A1 - Mahajan, Vinit B A1 - Stone, Edwin M A1 - Abràmoff, Michael D KW - Aged, 80 and over KW - Diseases in Twins KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Macular Degeneration KW - Male KW - Phenotype KW - Registries KW - Retinal Drusen KW - Twins, Dizygotic KW - Twins, Monozygotic AB -

PURPOSE: Determining the relationships between phenotype and genotype of many disorders can improve clinical diagnoses, identify disease mechanisms, and enhance therapy. Most genetic disorders result from interaction of many genes that obscure the discovery of such relationships. The hypothesis for this study was that image analysis has the potential to enable formalized discovery of new visible phenotypes. It was tested in twins affected with age-related macular degeneration (AMD).

METHODS: Fundus images from 43 monozygotic (MZ) and 32 dizygotic (DZ) twin pairs with AMD were examined. First, soft and hard drusen were segmented. Then newly defined phenotypes were identified by using drusen distribution statistics that significantly separate MZ from DZ twins. The ACE model was used to identify the contributions of additive genetic (A), common environmental (C), and nonshared environmental (E) effects on drusen distribution phenotypes.

RESULTS: Four drusen distribution characteristics significantly separated MZ from DZ twin pairs. One encoded the quantity, and the remaining three encoded the spatial distribution of drusen, achieving a zygosity prediction accuracy of 76%, 74%, 68%, and 68%. Three of the four phenotypes had a 55% to 77% genetic effect in an AE model, and the fourth phenotype showed a nonshared environmental effect (E model).

CONCLUSIONS: Computational discovery of genetically determined features can reveal quantifiable AMD phenotypes that are genetically determined without explicitly linking them to specific genes. In addition, it can identify phenotypes that appear to result predominantly from environmental exposure. The approach is rapid and unbiased, suitable for large datasets, and can be used to reveal unknown phenotype-genotype relationships.

VL - 52 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22039249?dopt=Abstract ER - TY - JOUR T1 - Bilateral intravitreal injection of antivascular endothelial growth factor therapy. JF - Retina (Philadelphia, Pa.) Y1 - 2011 A1 - Mahajan, Vinit B A1 - Elkins, Kori A A1 - Russell, Stephen R A1 - Boldt, H Culver A1 - Gehrs, Karen M A1 - Weingeist, Thomas A A1 - Stone, Edwin M A1 - Abràmoff, Michael D A1 - Liu, Dawei A1 - Folk, James C KW - Aged KW - Aged, 80 and over KW - Antibodies, Monoclonal KW - Case-Control Studies KW - Drug Administration Schedule KW - Drug Combinations KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Injections, Intraocular KW - Macular Degeneration KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Patient Preference KW - Retrospective Studies KW - Vascular Endothelial Growth Factor A KW - Vitreous Body AB -

The purpose of this study was to review adverse events and patient preference after bilateral intravitreal injection of antibodies to vascular endothelial growth factor.

VL - 31 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21187731?dopt=Abstract ER - TY - JOUR T1 - Mutations in prickle orthologs cause seizures in flies, mice, and humans. JF - American journal of human genetics Y1 - 2011 A1 - Tao, Hirotaka A1 - Manak, J Robert A1 - Sowers, Levi A1 - Mei, Xue A1 - Kiyonari, Hiroshi A1 - Abe, Takaya A1 - Dahdaleh, Nader S A1 - Yang, Tian A1 - Wu, Shu A1 - Chen, Shan A1 - Fox, Mark H A1 - Gurnett, Christina A1 - Montine, Thomas A1 - Bird, Thomas A1 - Shaffer, Lisa G A1 - Rosenfeld, Jill A A1 - McConnell, Juliann A1 - Madan-Khetarpal, Suneeta A1 - Berry-Kravis, Elizabeth A1 - Griesbach, Hilary A1 - Saneto, Russell P A1 - Scott, Matthew P A1 - Antic, Dragana A1 - Reed, Jordan A1 - Boland, Riley A1 - Ehaideb, Salleh N A1 - El-Shanti, Hatem A1 - Mahajan, Vinit B A1 - Ferguson, Polly J A1 - Axelrod, Jeffrey D A1 - Lehesjoki, Anna-Elina A1 - Fritzsch, Bernd A1 - Slusarski, Diane C A1 - Wemmie, John A1 - Ueno, Naoto A1 - Bassuk, Alexander G KW - Animals KW - Blotting, Western KW - Brain KW - Calcium KW - Carrier Proteins KW - DNA-Binding Proteins KW - Drosophila melanogaster KW - Drosophila Proteins KW - Embryo, Nonmammalian KW - Epilepsies, Myoclonic KW - Female KW - Heterozygote KW - Humans KW - Immunoenzyme Techniques KW - In Situ Hybridization KW - Male KW - Mice KW - Mice, Knockout KW - Mutation KW - Nerve Tissue Proteins KW - Phenotype KW - Reverse Transcriptase Polymerase Chain Reaction KW - RNA, Messenger KW - Seizures KW - Tumor Suppressor Proteins KW - Zebrafish KW - Zebrafish Proteins AB -

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

VL - 88 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21276947?dopt=Abstract ER - TY - JOUR T1 - Seroreactivity against aqueous-soluble and detergent-soluble retinal proteins in posterior uveitis. JF - Archives of ophthalmology Y1 - 2011 A1 - Ko, Audrey C A1 - Brinton, Jason P A1 - Mahajan, Vinit B A1 - Zimmerman, Bridget A1 - Brinton, Gregory S A1 - Stone, Edwin M A1 - Folk, James C A1 - Mullins, Robert F KW - Adolescent KW - Adult KW - Autoantibodies KW - Autoantigens KW - Blotting, Western KW - Electrophoresis, Polyacrylamide Gel KW - Eye Proteins KW - Female KW - Humans KW - Immunoglobulin A KW - Immunoglobulin G KW - Immunoglobulin M KW - Male KW - Middle Aged KW - Retina KW - Retinal Degeneration KW - Solubility KW - Uveitis, Posterior KW - Young Adult AB -

To characterize the seroreactivity against retinal proteins in patients with posterior uveitis, retinal disease of noninflammatory origin, and healthy controls.

VL - 129 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21482867?dopt=Abstract ER - TY - JOUR T1 - Automated early detection of diabetic retinopathy. JF - Ophthalmology Y1 - 2010 A1 - Abràmoff, Michael D A1 - Reinhardt, Joseph M A1 - Russell, Stephen R A1 - Folk, James C A1 - Mahajan, Vinit B A1 - Niemeijer, Meindert A1 - Quellec, Gwénolé KW - Aged KW - Algorithms KW - Area Under Curve KW - Diabetic Retinopathy KW - Diagnosis, Computer-Assisted KW - Diagnostic Techniques, Ophthalmological KW - Female KW - Humans KW - Male KW - Observer Variation KW - ROC Curve KW - Sensitivity and Specificity AB -

To compare the performance of automated diabetic retinopathy (DR) detection, using the algorithm that won the 2009 Retinopathy Online Challenge Competition in 2009, the Challenge2009, against that of the one currently used in EyeCheck, a large computer-aided early DR detection project.

VL - 117 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20399502?dopt=Abstract ER - TY - JOUR T1 - Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia. JF - American journal of medical genetics. Part A Y1 - 2010 A1 - Mahajan, Vinit B A1 - Olney, Ann Haskins A1 - Garrett, Penny A1 - Chary, Ajit A1 - Dragan, Ecaterina A1 - Lerner, Gary A1 - Murray, Jeffrey A1 - Bassuk, Alexander G KW - Base Sequence KW - Child KW - Child, Preschool KW - Collagen Type XVIII KW - DNA Mutational Analysis KW - Encephalocele KW - Eye Abnormalities KW - Family KW - Female KW - Humans KW - Infant KW - Magnetic Resonance Imaging KW - Male KW - Molecular Sequence Data KW - Mutation KW - Pedigree KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Retinal Detachment AB -

Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy.

VL - 152A IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20799329?dopt=Abstract ER - TY - JOUR T1 - Effects of vitrectomy on age-related macular degeneration. JF - Ophthalmology Y1 - 2010 A1 - Roller, A Brock A1 - Mahajan, Vinit B A1 - Boldt, H Culver A1 - Abràmoff, Michael D A1 - Russell, Stephen R A1 - Folk, James C KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Choroidal Neovascularization KW - Disease Progression KW - Epiretinal Membrane KW - Female KW - Follow-Up Studies KW - Geographic Atrophy KW - Humans KW - Macular Degeneration KW - Male KW - Middle Aged KW - Pilot Projects KW - Retinal Perforations KW - Retrospective Studies KW - Visual Acuity KW - Vitrectomy AB -

To determine whether vitrectomy alters the long-term progression of age-related macular degeneration (AMD).

VL - 117 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20176401?dopt=Abstract ER - TY - JOUR T1 - Intravitreal bevacizumab during pregnancy. JF - Retina (Philadelphia, Pa.) Y1 - 2010 A1 - Tarantola, Ryan M A1 - Folk, James C A1 - Boldt, H Culver A1 - Mahajan, Vinit B KW - Adult KW - Angiogenesis Inhibitors KW - Antibodies, Monoclonal KW - Choroidal Neovascularization KW - Eye Infections, Fungal KW - Female KW - Follow-Up Studies KW - Gestational Age KW - Histoplasmosis KW - Humans KW - Intravitreal Injections KW - Off-Label Use KW - Pregnancy KW - Pregnancy Complications KW - Sarcoidosis KW - Tomography, Optical Coherence KW - Uveitis KW - Vascular Endothelial Growth Factor A KW - Visual Acuity AB -

To report the clinical course of four women treated with intravitreal bevacizumab during pregnancy.

VL - 30 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20924262?dopt=Abstract ER - TY - JOUR T1 - Patients with an acute zonal occult outer retinopathy-like illness rapidly improve with valacyclovir treatment. JF - American journal of ophthalmology Y1 - 2010 A1 - Mahajan, Vinit B A1 - Stone, Edwin M KW - Acute Disease KW - Acyclovir KW - Adolescent KW - Adult KW - Antiviral Agents KW - Electroretinography KW - Eye Infections, Viral KW - Female KW - Herpesviridae Infections KW - Humans KW - Male KW - Retinal Diseases KW - Retrospective Studies KW - Scotoma KW - Tomography, Optical Coherence KW - Valine KW - Visual Field Tests KW - Visual Fields AB -

To describe 3 cases of an acute zonal occult outer retinopathy-like illness responsive to valacyclovir hydrochloride.

VL - 150 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20691421?dopt=Abstract ER - TY - JOUR T1 - T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy. JF - Molecular vision Y1 - 2010 A1 - Mahajan, Vinit B A1 - Vallone, John G A1 - Lin, Jonathan H A1 - Mullins, Robert F A1 - Ko, Audrey C A1 - Folk, James C A1 - Stone, Edwin M KW - Aged, 80 and over KW - Antigens, CD4 KW - Antigens, CD8 KW - Autoantibodies KW - B-Lymphocytes KW - Eye Diseases KW - Female KW - Genes, Dominant KW - Humans KW - Immunoglobulin G KW - Immunologic Techniques KW - Neovascularization, Pathologic KW - Retina KW - Retinal Diseases KW - Staining and Labeling KW - T-Lymphocytes KW - Vitreous Body AB -

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a familial blinding disease of unknown pathophysiology. The eyes and sera from patients with ADNIV were studied to understand the immune response in this condition.

VL - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20596252?dopt=Abstract ER - TY - JOUR T1 - A head-tilt test for hypopyon after intravitreal triamcinolone. JF - Retina (Philadelphia, Pa.) Y1 - 2009 A1 - Mahajan, Vinit B A1 - Folk, James C A1 - Boldt, H Culver KW - Adult KW - Anterior Chamber KW - Diagnosis, Differential KW - Diagnostic Techniques, Ophthalmological KW - Endophthalmitis KW - Eye Infections KW - Female KW - Glucocorticoids KW - Head KW - Humans KW - Inflammation KW - Injections KW - Posture KW - Triamcinolone Acetonide KW - Vitreous Body VL - 29 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19092731?dopt=Abstract ER - TY - JOUR T1 - Management of sympathetic ophthalmia with the fluocinolone acetonide implant. JF - Ophthalmology Y1 - 2009 A1 - Mahajan, Vinit B A1 - Gehrs, Karen M A1 - Goldstein, Debra A A1 - Fischer, David H A1 - Lopez, Juan S A1 - Folk, James C KW - Adult KW - Aged KW - Drug Implants KW - Female KW - Fluocinolone Acetonide KW - Follow-Up Studies KW - Glucocorticoids KW - Humans KW - Immunosuppressive Agents KW - Intraocular Pressure KW - Male KW - Middle Aged KW - Ophthalmia, Sympathetic KW - Retrospective Studies KW - Treatment Outcome KW - Visual Acuity AB -

We examined whether implantation of the fluocinolone acetonide (Retisert) implant achieved control of inflammation and a reduced need for oral corticosteroids or immunosuppressives in patients with sympathetic ophthalmia (SO).

VL - 116 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19147232?dopt=Abstract ER - TY - JOUR T1 - A new macular dystrophy with anomalous vascular development, pigment spots, cystic spaces, and neovascularization. JF - Archives of ophthalmology Y1 - 2009 A1 - Mahajan, Vinit B A1 - Russell, Stephen R A1 - Stone, Edwin M KW - Adolescent KW - Adult KW - Amblyopia KW - Child KW - Child, Preschool KW - Cysts KW - Electroretinography KW - Female KW - Fluorescein Angiography KW - Humans KW - Macular Degeneration KW - Male KW - Middle Aged KW - Pedigree KW - Phenotype KW - Retinal Hemorrhage KW - Retinal Neovascularization KW - Retinal Pigment Epithelium KW - Retinal Vessels KW - Strabismus KW - Tomography, Optical Coherence KW - Visual Acuity KW - Young Adult AB -

To clinically phenotype an inherited macular dystrophy with peculiar intraretinal pigment spots, cysts, and hemorrhage in a 24-year-old female proband and her family.

VL - 127 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19901210?dopt=Abstract ER - TY - JOUR T1 - Estrogen receptor alpha and matrix metalloproteinase 2 polymorphisms and age-related maculopathy in older women. JF - American journal of epidemiology Y1 - 2008 A1 - Seitzman, Robin L A1 - Mahajan, Vinit B A1 - Mangione, Carol A1 - Cauley, Jane A A1 - Ensrud, Kristine E A1 - Stone, Katie L A1 - Cummings, Steven R A1 - Hochberg, Marc C A1 - Hillier, Teresa A A1 - Sinsheimer, Janet S A1 - Yu, Fei A1 - Coleman, Anne L KW - Aged KW - Aged, 80 and over KW - Confounding Factors (Epidemiology) KW - Estrogen Receptor alpha KW - Estrogen Replacement Therapy KW - Female KW - Gene Frequency KW - Genetic Linkage KW - Genotype KW - Humans KW - Logistic Models KW - Macular Degeneration KW - Matrix Metalloproteinase 2 KW - Osteoporosis, Postmenopausal KW - Pigment Epithelium of Eye KW - Polymerase Chain Reaction KW - Polymorphism, Single Nucleotide KW - Severity of Illness Index AB -

In this study, the authors sought to determine whether single nucleotide polymorphisms in the estrogen receptor alpha (ESR1) and matrix metalloproteinase 2 (MMP2) genes are associated with age-related maculopathy (ARM) in older women. Subjects comprised a random sample of Caucasian women aged > or =74 years participating in the Study of Osteoporotic Fractures year 10 follow-up (n = 906) in 1997-1998. Fundus photographs were graded for ARM using a modification of the Wisconsin Age-Related Maculopathy Grading System. The prevalences of early ARM and late ARM were 46% and 4%, respectively. The MMP2 rs2287074 single nucleotide polymorphism (G-->A) was associated with ARM. The A allele was present in 47%, 43%, and 30% of subjects with no, early, and late ARM, respectively (p = 0.01), and was associated with lower odds of any ARM (for AG vs. GG, odds ratio = 0.80, 95% confidence interval: 0.65, 0.99; for AA vs. GG, odds ratio = 0.64, 95% confidence interval: 0.42, 0.98). An interaction with use of postmenopausal hormone therapy was significant (p = 0.02). The MMP2 rs2287074 A allele may be associated with a lower likelihood of ARM in older Caucasian women, particularly those who have never used hormone therapy. The role of MMP2 rs2287074 in ARM should be further elucidated.

VL - 167 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/18359774?dopt=Abstract ER - TY - JOUR T1 - Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness. JF - Human mutation Y1 - 2007 A1 - Tsang, Stephen H A1 - Woodruff, Michael L A1 - Jun, Lin A1 - Mahajan, Vinit A1 - Yamashita, Clyde K A1 - Pedersen, Robert A1 - Lin, Chyuan-Sheng A1 - Goff, Stephen P A1 - Rosenberg, Thomas A1 - Larsen, Michael A1 - Farber, Debora B A1 - Nusinowitz, Steven KW - Adult KW - Animals KW - Cyclic Nucleotide Phosphodiesterases, Type 6 KW - Disease Models, Animal KW - DNA Mutational Analysis KW - Electroretinography KW - Female KW - Humans KW - Male KW - Mice KW - Mice, Inbred DBA KW - Mice, Transgenic KW - Mutation KW - Night Blindness KW - Phosphoric Diester Hydrolases KW - Retinal Degeneration KW - Transgenes AB -

Mutations in the beta-subunit of cGMP-phosphodiesterase (PDE6beta) can lead to either progressive retinal disease, such as human retinitis pigmentosa (RP), or stationary disease, such as congenital stationary night blindness (CSNB). Individuals with CSNB in the Rambusch pedigree were found to carry the H258N allele of PDE6B (MIM# 180072); a similar mutation was not found in RP patients. This report describes an individual carrying the H258N allele, who presented with generalized retinal dysfunction affecting the rod system and a locus of dysfunction at the rod-bipolar interface. Also described are preclinical studies in which transgenic mice with the H258N allele were generated to study the pathophysiological mechanisms of CSNB. While Pde6b(rd1)/Pde6b(rd1) mice have severe photoreceptor degeneration, as in human RP, the H258N transgene rescued these cells. The cGMP-PDE6 activity of dark-adapted H258N mice showed an approximate three-fold increase in the rate of retinal cGMP hydrolysis: from 130.1 nmol x min(-1) x nmol(-1) rhodopsin in wild-type controls to 319.2 nmol x min(-1) x nmol(-1) rhodopsin in mutants, consistent with the hypothesis that inhibition of the PDE6beta activity by the regulatory PDE6gamma subunit is blocked by this mutation. In the albino (B6CBA x FVB) F2 hybrid background, electroretinograms (ERG) from H258N mice were similar to those obtained from affected Rambusch family members, as well as humans with the most common form of CSNB (X-linked), demonstrating a selective loss of the b-wave with relatively normal a-waves. When the H258N allele was introduced into the DBA background, there was no evidence of selective reduction in b-wave amplitudes; rather a- and b-wave amplitudes were both reduced. Thus, factors other than the PDE6B mutation itself could contribute to the variance of an electrophysiological response. Therefore, caution is advisable when interpreting physiological phenotypes associated with the same allele on different genetic backgrounds. Nevertheless, such animals should be of considerable value in further studies of the molecular pathology of CSNB.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/17044014?dopt=Abstract ER -