@article {2070, title = {Liquid Biopsy Proteomics in Ophthalmology.}, journal = {J Proteome Res}, volume = {23}, year = {2024}, month = {2024 Feb 02}, pages = {511-522}, abstract = {

Minimally invasive liquid biopsies from the eye capture locally enriched fluids that contain thousands of proteins from highly specialized ocular cell types, presenting a promising alternative to solid tissue biopsies. The advantages of liquid biopsies include sampling the eye without causing irreversible functional damage, potentially better reflecting tissue heterogeneity, collecting samples in an outpatient setting, monitoring therapeutic response with sequential sampling, and even allowing examination of disease mechanisms at the cell level in living humans, an approach that we refer to as TEMPO (Tracing Expression of Multiple Protein Origins). Liquid biopsy proteomics has the potential to transform molecular diagnostics and prognostics and to assess disease mechanisms and personalized therapeutic strategies in individual patients. This review addresses opportunities, challenges, and future directions of high-resolution liquid biopsy proteomics in ophthalmology, with particular emphasis on the large-scale collection of high-quality samples, cutting edge proteomics technology, and artificial intelligence-supported data analysis.

}, keywords = {Artificial Intelligence, Biopsy, Humans, Liquid Biopsy, Ophthalmology, Proteins, Proteomics}, issn = {1535-3907}, doi = {10.1021/acs.jproteome.3c00756}, author = {Wolf, Julian and Franco, Joel A and Yip, Rui and Dabaja, Mohamed Ziad and Velez, Gabriel and Liu, Fei and Bassuk, Alexander G and Mruthyunjaya, Prithvi and Dufour, Antoine and Mahajan, Vinit B} } @article {2051, title = {Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium.}, journal = {Sci Rep}, volume = {13}, year = {2023}, month = {2023 May 21}, pages = {8205}, abstract = {

Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.

}, keywords = {Animals, Cilia, Ciliopathies, Disease Models, Animal, Humans, Mice, Microtubule-Associated Proteins, Retinal Degeneration, Retinal Pigment Epithelium, Tumor Suppressor Proteins}, issn = {2045-2322}, doi = {10.1038/s41598-023-35099-3}, author = {Ning, Ke and Bhuckory, Mohajeet B and Lo, Chien-Hui and Sendayen, Brent E and Kowal, Tia J and Chen, Ming and Bansal, Ruchi and Chang, Kun-Che and Vollrath, Douglas and Berbari, Nicolas F and Mahajan, Vinit B and Hu, Yang and Sun, Yang} } @article {2068, title = {Cross-Platform Identification and Validation of Uveal Melanoma Vitreous Protein Biomarkers.}, journal = {Invest Ophthalmol Vis Sci}, volume = {64}, year = {2023}, month = {2023 Nov 01}, pages = {14}, abstract = {

PURPOSE: The purpose of this study was to profile protein expression liquid vitreous biopsies from patients with uveal melanoma (UM) using mass spectrometry to identify prognostic biomarkers, signaling pathways, and therapeutic targets.

METHODS: Vitreous biopsies were collected from two cohorts in a pilot study: comparative control eyes with epiretinal membranes (ERM; n = 3) and test eyes with UM (n = 8). Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Identified proteins were compared to data from a targeted multiplex ELISA proteomics platform.

RESULTS: A total of 69 significantly elevated proteins were detected in the UM vitreous, including LYVE-1. LC-MS/MS identified 62 significantly upregulated proteins in UM vitreous that were not previously identified by ELISA. Analysis of differential protein expression by tumor molecular classification (gene expression profiling [GEP] and preferentially expressed antigen in melanoma [PRAME]) further identified proteins that correlated with these classifications. Patients with high-risk GEP tumors displayed elevated vitreous expression of HGFR (fold-change [FC] = 2.66E\ +\ 03, P value = 0.003) and PYGL (FC = 1.02E\ +\ 04, P = 1.72E-08). Patients with PRAME positive tumors displayed elevated vitreous expression of ENPP-2 (FC = 3.21, P = 0.04), NEO1 (FC = 2.65E\ +\ 03, P = 0.002), and LRP1 (FC = 5.59E\ +\ 02, P value = 0.01). IGF regulatory effectors were highly represented (P value = 1.74E-16). Cross-platform analysis validated seven proteins identified by ELISA and LC-MS/MS.

CONCLUSIONS: Proteomic analysis of liquid biopsies may provide prognostic information supporting gene expression of tumor biopsies. The use of multiple protein detection platforms in the same patient samples increases the sensitivity of candidate biomarker detection and allows for precise characterization of the vitreous proteome.

}, keywords = {Antigens, Neoplasm, Biomarkers, Chromatography, Liquid, Humans, Melanoma, Pilot Projects, Proteomics, Tandem Mass Spectrometry, Uveal Neoplasms}, issn = {1552-5783}, doi = {10.1167/iovs.64.14.14}, author = {Velez, Gabriel and Wolf, Julian and Dufour, Antoine and Mruthyunjaya, Prithvi and Mahajan, Vinit B} } @article {2037, title = {Intraoperative Complications With Vitreous Biopsy for Molecular Proteomics.}, journal = {Ophthalmic Surg Lasers Imaging Retina}, volume = {54}, year = {2023}, month = {2023 Jan}, pages = {32-36}, abstract = {

OBJECTIVE: To study the incidence of intraoperative complications while collecting a vitreous sample for proteomic biomarker analyses during small-gauge pars plana vitrectomy (PPV).

METHODS: A retrospective case series was assembled from the surgical logs and charts of patients who underwent 23-, 25-, and 27-gauge PPV along with an undiluted vitreous biopsy. Primary surgical indication and detailed operative reports were reviewed. Complications specific to vitreous biopsy were assessed while complications related to vitrectomy in general without biopsy were not tabulated.

RESULTS: In 1190 eyes that underwent vitreous biopsy, the most common indications for PPV were rhegmatogenous retinal detachment (24.2\%), epiretinal membrane (ERM) (21.7\%), vitreous hemorrhage (11.0\%), uveitis (8.3\%), and macular hole (7.5\%). An adequate sample of 0.5 cc to 1.0 cc was obtained in all cases. There was one sclerotomy break associated with biopsy, but no instances of lens touch, retinal contusion, retinal detachment, or intraocular hemorrhage.

CONCLUSIONS: Undiluted vitreous biopsy obtained at the time of small-gauge vitrectomy is a generally safe procedure and may be considered for collection of samples for proteomic analysis. .

}, keywords = {Biopsy, Humans, Intraoperative Complications, Postoperative Complications, Proteomics, Retinal Detachment, Retrospective Studies, Vitrectomy}, issn = {2325-8179}, doi = {10.3928/23258160-20221214-02}, author = {Mishra, Kapil and Velez, Gabriel and Chemudupati, Teja and Tang, Peter H and Mruthyunjaya, Prithvi and Sanislo, Steven R and Mahajan, Vinit B} } @article {2058, title = {Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in~vivo.}, journal = {Cell}, volume = {186}, year = {2023}, month = {2023 Oct 26}, pages = {4868-4884.e12}, abstract = {

Single-cell analysis in living humans is essential for understanding disease mechanisms, but it is impractical in non-regenerative organs, such as the eye and brain, because tissue biopsies would cause serious damage. We resolve this problem by integrating proteomics of liquid biopsies with single-cell transcriptomics from all known ocular cell types to trace the cellular origin of 5,953 proteins detected in the aqueous humor. We identified hundreds of cell-specific protein markers, including for individual retinal cell types. Surprisingly, our results reveal that retinal degeneration occurs in Parkinson\&$\#$39;s disease, and the cells driving diabetic retinopathy switch with disease stage. Finally, we developed artificial intelligence (AI) models to assess individual cellular aging and found that many eye diseases not associated with chronological age undergo accelerated molecular aging of disease-specific cell types. Our approach, which can be applied to other organ systems, has the potential to transform molecular diagnostics and prognostics while uncovering new cellular disease and aging mechanisms.

}, keywords = {Aging, Artificial Intelligence, Biopsy, Humans, Liquid Biopsy, Proteomics}, issn = {1097-4172}, doi = {10.1016/j.cell.2023.09.012}, author = {Wolf, Julian and Rasmussen, Ditte K and Sun, Young Joo and Vu, Jennifer T and Wang, Elena and Espinosa, Camilo and Bigini, Fabio and Chang, Robert T and Montague, Artis A and Tang, Peter H and Mruthyunjaya, Prithvi and Aghaeepour, Nima and Dufour, Antoine and Bassuk, Alexander G and Mahajan, Vinit B} } @article {2018, title = {Bacillary Layer Detachment after Photodynamic Therapy.}, journal = {Ophthalmol Retina}, volume = {6}, year = {2022}, month = {2022 06}, pages = {500}, keywords = {Fluorescein Angiography, Humans, Photochemotherapy, Verteporfin}, issn = {2468-6530}, doi = {10.1016/j.oret.2022.02.012}, author = {Mishra, Kapil and Mahajan, Vinit B} } @article {2019, title = {Calpains as mechanistic drivers and therapeutic targets for ocular disease.}, journal = {Trends Mol Med}, volume = {28}, year = {2022}, month = {2022 08}, pages = {644-661}, abstract = {

Ophthalmic neurodegenerative diseases encompass a wide array of molecular pathologies unified by calpain dysregulation. Calpains are calcium-dependent proteases that perpetuate cellular death and inflammation when hyperactivated. Calpain inhibition trials in other organs have faced pharmacological challenges, but the eye offers many advantages for the development and testing of targeted molecular therapeutics, including small molecules, peptides, engineered proteins, drug implants, and gene-based therapies. This review highlights structural mechanisms underlying calpain activation, distinct cellular expression patterns, and in vivo models that link calpain hyperactivity to human retinal and developmental disease. Optimizing therapeutic approaches for calpain-mediated eye diseases can help accelerate clinically feasible strategies for treating calpain dysregulation in other diseased tissues.

}, keywords = {Calcium, Calpain, Cell Death, Humans, Retina}, issn = {1471-499X}, doi = {10.1016/j.molmed.2022.05.007}, author = {Vu, Jennifer T and Wang, Elena and Wu, Jolan and Sun, Young Joo and Velez, Gabriel and Bassuk, Alexander G and Lee, Soo Hyeon and Mahajan, Vinit B} } @article {2043, title = {Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence.}, journal = {Mol Genet Genomic Med}, volume = {10}, year = {2022}, month = {2022 Nov}, pages = {e2038}, abstract = {

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.

}, keywords = {Atrophy, Child, cis-trans-Isomerases, Female, Humans, Leber Congenital Amaurosis, Mutation, Retinal Degeneration}, issn = {2324-9269}, doi = {10.1002/mgg3.2038}, author = {Kolesnikova, Masha and Lima de Carvalho, Jose Ronaldo and Parmann, Rait and Kim, Angela H and Mahajan, Vinit B and Tsang, Stephen H and Sparrow, Janet R} } @article {2020, title = {Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series.}, journal = {Orphanet J Rare Dis}, volume = {17}, year = {2022}, month = {2022 04 01}, pages = {146}, abstract = {

BACKGROUND: Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations.

RESULTS: Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients.

CONCLUSIONS: The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.

}, keywords = {Carrier Proteins, Electroretinography, Genetic Association Studies, Humans, Mutation, Phenotype, Retinal Dystrophies}, issn = {1750-1172}, doi = {10.1186/s13023-022-02295-9}, author = {Oh, Jin Kyun and Vargas Del Valle, Jos{\'e} G and Lima de Carvalho, Jose Ronaldo and Sun, Young Joo and Levi, Sarah R and Ryu, Joseph and Yang, Jing and Nagasaki, Takayuki and Emanuelli, Andres and Rasool, Nailyn and Allikmets, Rando and Sparrow, Janet R and Izquierdo, Natalio J and Duncan, Jacque L and Mahajan, Vinit B and Tsang, Stephen H} } @article {1896, title = {Investigation of Cas9 antibodies in the human eye.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 02 25}, pages = {1053}, abstract = {

Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR-Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR-Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than systemically.

}, keywords = {Animals, Antibodies, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Humans, Mice, Streptococcus pyogenes, T-Lymphocytes}, issn = {2041-1723}, doi = {10.1038/s41467-022-28674-1}, author = {Toral, Marcus A and Charlesworth, Carsten T and Ng, Benjamin and Chemudupati, Teja and Homma, Shota and Nakauchi, Hiromitsu and Bassuk, Alexander G and Porteus, Matthew H and Mahajan, Vinit B} } @article {1921, title = {New COL6A6 Variant Causes Autosomal Dominant Retinitis Pigmentosa in a Four-Generation Family.}, journal = {Invest Ophthalmol Vis Sci}, volume = {63}, year = {2022}, month = {2022 Mar 02}, pages = {23}, abstract = {

Purpose: To report that variants in the gene for a large lamina basal component protein, COL6A6 (collagen type VI alpha 6 chain, Col6α6), linked to chromosome 3p22.1 causes retinitis pigmentosa (RP) in patients with autosomal dominant transmission (adRP).

Methods: A positional-cloning approach, whole exome sequencing, and modeling were used. The proband and several affected family members have been phenotyped and followed for over 12 years.

Results: A heterozygous missense variant, c.509C\>G (p. Ser170Cys) in exon 2 of COL6A6 (comprised of 36 exons and 2236 amino acids), was observed in a four- generation family and is likely to cause the adRP phenotype. It was identified in 10 affected members. All affected family members had a distinct phenotype: late-onset rod cone dystrophy, with good retained visual acuity, until their late 70s. Immunohistochemistry of human retina showed a dot-like signal at the base of the inner segments of photoreceptors and outer plexiform layer (OPL). The structural modeling of the N7 domain of Col6α6 suggests that the mutant might result in the abnormal cellular localization of collagen VI or malformation of collagen fibers resulting in the loss of its unique filament structure.

Conclusions: COL6A6 is widely expressed in human tissues and evolutionary conserved. It is thought to interact with a range of extracellular matrix components. Our findings suggest that this form of RP has long-term useful central visual acuity and a mild progression, which are important considerations for patient counseling.

}, keywords = {Collagen Type VI, Cone-Rod Dystrophies, Exons, Humans, Mutation, Missense, Pedigree, Retinitis Pigmentosa}, issn = {1552-5783}, doi = {10.1167/iovs.63.3.23}, author = {Vaclavik, Veronika and Tiab, Leila and Sun, Young Joo and Mahajan, Vinit B and Moulin, Alexandre and Allaman-Pillet, Nathalie and Munier, Francis L and Schorderet, Daniel F} } @article {2021, title = {REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.}, journal = {Retina}, volume = {42}, year = {2022}, month = {2022 11 01}, pages = {2025-2030}, abstract = {

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.

}, keywords = {Child, Eye Diseases, Hereditary, Female, Fertilization in Vitro, Humans, Ophthalmology, Pregnancy, Preimplantation Diagnosis, Retrospective Studies}, issn = {1539-2864}, doi = {10.1097/IAE.0000000000003591}, author = {Park, Jong G and Xu, Christine L and Boyd, Allison and Aghajanova, Lusine and Mahajan, Vinit B and Wood, Edward H} } @article {1861, title = {Molecular Characterization of a Rare Case of Bilateral Vitreoretinal T Cell Lymphoma through Vitreous Liquid Biopsy.}, journal = {Int J Mol Sci}, volume = {22}, year = {2021}, month = {2021 Jun 05}, abstract = {

Vitreoretinal lymphoma (VRL) is an uncommon eye malignancy, and VRLs of T cell origin are rare. They are difficult to treat, and their molecular underpinnings, including actionable genomic alterations, remain to be elucidated. At present, vitreous fluid liquid biopsies represent a valuable VRL sample for molecular analysis to study VRLs. In this study, we report the molecular diagnostic workup of a rare case of bilateral T cell VRL and characterize its genomic landscape, including identification of potentially targetable alterations. Using next-generation sequencing of vitreous-derived DNA with a pan-cancer 126-gene panel, we found a copy number gain of and copy number loss of tumor suppressor . To the best of our knowledge, this represents the first exploration of the T cell VRL cancer genome and supports vitreous liquid biopsy as a suitable approach for precision oncology treatments.

}, keywords = {Biomarkers, Tumor, DNA (Cytosine-5-)-Methyltransferases, DNA Copy Number Variations, DNA Methyltransferase 3A, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Liquid Biopsy, Lymphoma, T-Cell, Male, Middle Aged, Neoplasm Proteins, Proto-Oncogene Proteins B-raf, Retinal Neoplasms, Vitreous Body}, issn = {1422-0067}, doi = {10.3390/ijms22116099}, author = {Cani, Andi K and Toral, Marcus A and Balikov, Daniel A and Betz, Bryan L and Hu, Kevin and Liu, Chia-Jen and Prifti, Matthew V and Chinnaiyan, Arul M and Tomlins, Scott A and Mahajan, Vinit B and Rao, Rajesh C} } @article {1856, title = {The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease.}, journal = {Transl Vis Sci Technol}, volume = {10}, year = {2021}, month = {2021 07 01}, pages = {4}, abstract = {

Translational Relevance: Mitochondria are viable therapeutic targets for a broad spectrum of ocular diseases.

}, keywords = {Eye Diseases, Humans, Mitochondria}, issn = {2164-2591}, doi = {10.1167/tvst.10.8.4}, author = {Ji, Marco H and Kreymerman, Alexander and Belle, Kinsley and Ghiam, Benjamin K and Muscat, Stephanie P and Mahajan, Vinit B and Enns, Gregory M and Mercola, Mark and Wood, Edward H} } @article {1091, title = {Optical Coherence Tomography Angiography of RPGR-Associated Retinitis Pigmentosa Suggests Foveal Avascular Zone is a Biomarker for Vision Loss.}, journal = {Ophthalmic Surg Lasers Imaging Retina}, volume = {50}, year = {2019}, month = {2019 02 01}, pages = {e44-e48}, abstract = {

RPGR-associated retinitis pigmentosa (RP) is a progressive disease with retina degeneration. Optical coherence tomography angiography (OCTA) is an imaging technique that provides novel insights. The authors report two affected male siblings who underwent OCTA imaging. The area of the foveal avascular zone (FAZ) was measured. Although the younger sibling exhibited more advanced clinical disease, his visual acuity was superior to his older sibling. OCTA imaging revealed a better preserved FAZ in the younger sibling as the reason for this. It also highlighted attenuation of choriocapillaris / choroid layers as biomarkers for disease severity. This provides new insights into retinal degeneration in RPGR-associated RP. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e44-e48.].

}, keywords = {Biomarkers, Capillaries, Choroid, Eye Proteins, Fluorescein Angiography, Fovea Centralis, Humans, Male, Middle Aged, Retinitis Pigmentosa, Tomography, Optical Coherence, Vision Disorders}, issn = {2325-8179}, doi = {10.3928/23258160-20190129-18}, author = {Tang, Peter H and Jauregui, Ruben and Tsang, Stephen H and Bassuk, Alexander G and Mahajan, Vinit B} } @article {2047, title = {Therapeutic Window for Phosphodiesterase 6-Related Retinitis Pigmentosa.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 Jun 01}, pages = {679-680}, keywords = {Cone-Rod Dystrophies, Cyclic Nucleotide Phosphodiesterases, Type 6, Eye Proteins, Follow-Up Studies, Humans, Mutation, Retinitis Pigmentosa}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.6381}, author = {Wang, Nan-Kai and Mahajan, Vinit B and Tsang, Stephen H} } @article {978, title = {CRISPR GENOME SURGERY IN THE RETINA IN LIGHT OF OFF-TARGETING.}, journal = {Retina}, volume = {38}, year = {2018}, month = {2018 08}, pages = {1443-1455}, abstract = {

PURPOSE: Recent concerns regarding the clinical utilization of clustered regularly interspaced short palindromic repeats (CRISPR) involve uncertainties about the potential detrimental effects that many arise due to unintended genetic changes, as in off-target mutagenesis, during CRISPR genome surgery. This review gives an overview of off-targeting detection methods and CRISPR{\textquoteright}s place in the clinical setting, specifically in the field of ophthalmology.

RESULTS: As CRISPR utilization in the laboratory setting has increased, knowledge regarding CRISPR mechanisms including its off-target effects has also increased. Although a perfect method for achieving 100\% specificity is yet to be determined, the past few years have seen many developments in off-targeting detection and in increasing efficacy of CRISPR tools.

CONCLUSION: The CRISPR system has high potential to be an invaluable therapeutic tool as it has the ability to modify and repair pathogenic retinal lesions. Although it is not yet a perfect system, with further efforts to improve its specificity and efficacy along with careful screening of off-target mutations, CRISPR-mediated genome surgery potential can become maximized and applied to patients.

}, keywords = {Clustered Regularly Interspaced Short Palindromic Repeats, Gene Editing, Genetic Therapy, Humans, Ophthalmology, Retinal Diseases}, issn = {1539-2864}, doi = {10.1097/IAE.0000000000002197}, author = {Cho, Galaxy Y and Schaefer, Kellie A and Bassuk, Alexander G and Tsang, Stephen H and Mahajan, Vinit B} } @article {635, title = {Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0169687}, abstract = {

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.

}, keywords = {Amino Acid Sequence, Animals, Cell Adhesion Molecules, Cell Line, Tumor, Child, Cytoskeletal Proteins, Female, Genes, Recessive, Humans, Interleukin-10, Mice, Mutation, Osteomyelitis, Promoter Regions, Genetic, Sequence Homology, Amino Acid}, issn = {1932-6203}, doi = {10.1371/journal.pone.0169687}, author = {Cox, Allison J and Darbro, Benjamin W and Laxer, Ronald M and Velez, Gabriel and Bing, Xinyu and Finer, Alexis L and Erives, Albert and Mahajan, Vinit B and Bassuk, Alexander G and Ferguson, Polly J} } @article {671, title = {Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0149041}, abstract = {

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.

}, keywords = {Adolescent, Adult, Autism Spectrum Disorder, Child, Child, Preschool, Female, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Humans, Infant, Male, Middle Aged, Mutation, Neoplasms, Oncogenes, Prevalence, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0149041}, author = {Darbro, Benjamin W and Singh, Rohini and Zimmerman, M Bridget and Mahajan, Vinit B and Bassuk, Alexander G} } @article {659, title = {BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 07 01}, pages = {2672-2680}, abstract = {

Bestrophin1 (BEST1) is expressed in human retinal pigment epithelium (RPE) and mutations in the BEST1 gene commonly cause retinal dysfunction and macular degeneration. BEST1 is presumed to assemble into a calcium-activated chloride channel and be involved in chloride transport but there is no direct evidence in live human RPE cells to support this idea. To test whether BEST1 functions as a chloride channel in living tissue, BEST1-mutant RPE (R218H, L234P, A243T) were generated from patient-derived induced pluripotent stem cells and compared with wild-type RPE in a retinal environment, using a biosensor that visualizes calcium-induced chloride ion flux in the cell. Calcium stimulation elicited chloride ion export in normal RPE but not in RPE derived from three patients with BEST1 mutations. These data, along with three-dimensional modeling, provide evidence that BEST1 assembles into a key calcium-sensing chloride channel in human RPE.

}, keywords = {Bestrophins, Calcium Signaling, Chloride Channels, Chlorides, Eye Proteins, Humans, Induced Pluripotent Stem Cells, Mutation, Retinal Pigment Epithelium, Vitelliform Macular Dystrophy}, issn = {1460-2083}, doi = {10.1093/hmg/ddw126}, author = {Moshfegh, Yasmin and Velez, Gabriel and Li, Yao and Bassuk, Alexander G and Mahajan, Vinit B and Tsang, Stephen H} } @article {663, title = {Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses.}, journal = {Invest Ophthalmol Vis Sci}, volume = {57}, year = {2016}, month = {2016 05 01}, pages = {2509-21}, abstract = {

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.

}, keywords = {Animals, Blotting, Western, Calpain, Cattle, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Male, Mice, Neoplasms, Experimental, Photoreceptor Cells, Retina, Retinal Neoplasms, Retinoblastoma, RNA, Neoplasm, Synapses, Tumor Cells, Cultured}, issn = {1552-5783}, doi = {10.1167/iovs.15-18680}, author = {Schaefer, Kellie A and Toral, Marcus A and Velez, Gabriel and Cox, Allison J and Baker, Sheila A and Borcherding, Nicholas C and Colgan, Diana F and Bondada, Vimala and Mashburn, Charles B and Yu, Chen-Guang and Geddes, James W and Tsang, Stephen H and Bassuk, Alexander G and Mahajan, Vinit B} } @article {673, title = {Chronic Recurrent Pseudophakic Endophthalmitis.}, journal = {JAMA Ophthalmol}, volume = {134}, year = {2016}, month = {2016 Apr}, pages = {455-6}, keywords = {Aged, 80 and over, Chronic Disease, Combined Modality Therapy, Drug Therapy, Combination, Endophthalmitis, Female, Follow-Up Studies, Humans, Mycobacterium chelonae, Mycobacterium Infections, Nontuberculous, Recurrence, Risk Assessment, Slit Lamp, Treatment Outcome, Vancomycin, Vitrectomy}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.3638}, author = {Chin, Eric K and Almeida, David R P and Mahajan, Vinit B} } @article {645, title = {COMBINED VITRECTOMY AND INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT.}, journal = {Retina}, volume = {36}, year = {2016}, month = {2016 Nov}, pages = {2087-2092}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Dexamethasone, Drug Implants, Female, Glucocorticoids, Humans, Intraocular Pressure, Intravitreal Injections, Macular Edema, Male, Middle Aged, Retinal Vein Occlusion, Retrospective Studies, Tomography, Optical Coherence, Uveitis, Posterior, Visual Acuity, Vitrectomy, Wet Macular Degeneration}, issn = {1539-2864}, doi = {10.1097/IAE.0000000000001063}, author = {Zheng, Andrew and Chin, Eric K and Almeida, David R P and Tsang, Stephen H and Mahajan, Vinit B} } @article {683, title = {ELEVATED INTRAOCULAR PRESSURE FOLLOWING PARS PLANA VITRECTOMY DUE TO TRAPPED GAS IN THE POSTERIOR CHAMBER.}, journal = {Retin Cases Brief Rep}, volume = {10}, year = {2016}, month = {2016 Fall}, pages = {334-7}, abstract = {

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.

}, keywords = {Aged, Endotamponade, Female, Gases, Humans, Intraocular Pressure, Male, Middle Aged, Ocular Hypertension, Posterior Eye Segment, Vitrectomy}, issn = {1937-1578}, doi = {10.1097/ICB.0000000000000256}, author = {Chin, Eric K and Almeida, David R P and Strohbehn, Austin L and Mahajan, Vinit B and Russell, Stephen R and Folk, James C} } @article {643, title = {Intravitreal Foscarnet With Concurrent Silicone Oil Tamponade for Rhegmatogenous Retinal Detachment Secondary to Viral Retinitis.}, journal = {Retina}, volume = {36}, year = {2016}, month = {2016 Nov}, pages = {2236-2238}, keywords = {Antiviral Agents, Combined Modality Therapy, Endotamponade, Eye Infections, Viral, Foscarnet, Humans, Intravitreal Injections, Retinal Detachment, Retinitis, Silicone Oils, Vitrectomy}, issn = {1539-2864}, doi = {10.1097/IAE.0000000000001174}, author = {Xu, Kunyong and Chin, Eric K and Mahajan, Vinit B and Almeida, David R P} } @article {647, title = {Management of Pediatric Aphakic Glaucoma With Vitrectomy and Tube Shunts.}, journal = {J Pediatr Ophthalmol Strabismus}, volume = {53}, year = {2016}, month = {2016 Nov 01}, pages = {339-343}, abstract = {

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.].

}, keywords = {Adolescent, Aphakia, Postcataract, Cataract, Cataract Extraction, Child, Child, Preschool, Female, Glaucoma, Glaucoma Drainage Implants, Humans, Infant, Intraocular Pressure, Male, Retrospective Studies, Visual Acuity, Vitrectomy}, issn = {1938-2405}, doi = {10.3928/01913913-20160818-01}, author = {Elshatory, Yasser M and Gauger, Elizabeth H and Kwon, Young H and Alward, Wallace L M and Boldt, H Culver and Russell, Stephen R and Mahajan, Vinit B} } @article {677, title = {Precision Medicine: Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease.}, journal = {JAMA Ophthalmol}, volume = {134}, year = {2016}, month = {2016 Apr}, pages = {444-8}, abstract = {

IMPORTANCE: To better characterize posterior uveitis, vitreous samples from 15 patients were subjected to antibody arrays, and the expression levels of 200 human cytokines were evaluated. Expression was analyzed by 1-way analysis of variance (significance at P < .01), unsupervised cluster algorithm, and pathway analysis.

OBSERVATIONS: Unbiased clustering of patients, based on their cytokine expression profile, suggested that particular protein networks and molecular pathways are altered in various forms of uveitis. Expression of interleukin 23 (IL-23), IL-1 receptor I (IL-1RI), IL-17R, tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2), insulinlike growth factor-binding protein 2 (IGFBP-2), nerve growth factor (b-NGF), platelet-derived growth factor receptor β polypeptide (PDGFRb), bone morphogenic protein 4 (BMP-4), and stem cell factor (SCF) constituted a common cytokine signature in the vitreous of patients with uveitis. In 1 patient with progressive, idiopathic visual loss, this last-line analysis implicated retinal autoimmunity, a diagnosis that was validated when her serum sample was found to contain antibodies to S-arrestin, a retinal protein and potent cause of autoimmune retinal degeneration.

CONCLUSIONS AND RELEVANCE: The analysis identifies a common cytokine signature for posterior uveitis and guides the diagnosis of a patient with idiopathic uveitis. Personalized treatment reversed the visual loss, illustrating how proteomic tools may individualize therapy.

}, keywords = {Adrenal Cortex Hormones, Adult, Analysis of Variance, Case-Control Studies, Cytokines, Follow-Up Studies, Humans, Immunosuppressive Agents, Male, Middle Aged, Precision Medicine, Proteomics, Reference Values, Risk Assessment, Severity of Illness Index, Treatment Outcome, Uveitis, Visual Acuity}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.5934}, author = {Velez, Gabriel and Roybal, C Nathaniel and Colgan, Diana and Tsang, Stephen H and Bassuk, Alexander G and Mahajan, Vinit B} } @article {641, title = {Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 10 01}, pages = {4244-4255}, abstract = {

Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-gene-specific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6bpreclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing anabolism promoted neuronal survival and function and could potentially benefit a number of photoreceptor and other degenerative conditions.

}, keywords = {Animals, Cell Death, Cellular Reprogramming, Cone-Rod Dystrophies, Disease Models, Animal, Humans, Macular Degeneration, Metabolism, Mice, Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddw256}, author = {Zhang, Lijuan and Justus, Sally and Xu, Yu and Pluchenik, Tamara and Hsu, Chun-Wei and Yang, Jin and Duong, Jimmy K and Lin, Chyuan-Sheng and Jia, Yading and Bassuk, Alexander G and Mahajan, Vinit B and Tsang, Stephen H} } @article {669, title = {Response to Sandford et~al.: PRICKLE2 Variants in Epilepsy: A Call for Precision Medicine.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {590-591}, keywords = {Animals, Carrier Proteins, DNA-Binding Proteins, Drosophila Proteins, Female, Humans, Male, Mutation, Nerve Tissue Proteins, Seizures, Tumor Suppressor Proteins, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.02.002}, author = {Mahajan, Vinit B and Bassuk, Alexander G} } @article {681, title = {SURGICAL EMBOLECTOMY FOR FOVEA-THREATENING ACUTE RETINAL ARTERY OCCLUSION.}, journal = {Retin Cases Brief Rep}, volume = {10}, year = {2016}, month = {2016 Fall}, pages = {331-3}, abstract = {

PURPOSE: To describe a technique of surgical intraocular embolectomy in patients with acute fovea-threatening branch retinal artery occlusion.

METHODS: Pars plana vitrectomy with embolectomy involving embolus isolation, dissection, and removal in patients with an acute fovea-threatening arterial occlusion without a patent cilioretinal artery.

RESULTS: The surgical technique involves a core vitrectomy. The blocked artery is incised using a microvitreoretinal blade, and microsurgical forceps are used to retrieve the embolus. No significant complications were noted. The study technique offers an excellent safety profile and minimizes the risk of vitreous hemorrhage by carefully dissecting the vascular adventitial sheath and isolating the embolus.

CONCLUSION: Surgical embolectomy is a viable technique for patients with acute fovea-threatening arterial occlusions without patent cilioretinal artery. Careful dissection and retrieval of the embolus minimizes the risk of vitreous hemorrhage, which is an important improvement in previous techniques for management of acute retinal arterial occlusions.

}, keywords = {Acute Disease, Embolectomy, Humans, Retinal Artery Occlusion, Treatment Outcome, Vitrectomy}, issn = {1937-1578}, doi = {10.1097/ICB.0000000000000257}, author = {Almeida, David R P and Mammo, Zaid and Chin, Eric K and Mahajan, Vinit B} } @article {687, title = {Intravitreal Anti-VEGF Injections in Pregnancy: Case Series and Review of Literature.}, journal = {J Ocul Pharmacol Ther}, volume = {31}, year = {2015}, month = {2015 Dec}, pages = {605-10}, abstract = {

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.

}, keywords = {Adult, Angiogenesis Inhibitors, Bevacizumab, Female, Humans, Infant, Newborn, Intravitreal Injections, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Risk Factors, Vascular Endothelial Growth Factor A}, issn = {1557-7732}, doi = {10.1089/jop.2015.0056}, author = {Polizzi, Silvio and Mahajan, Vinit B} } @article {701, title = {Macular Hole Closure With Internal Limiting Membrane Abrasion Technique.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Jun}, pages = {635-41}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Basement Membrane, Endotamponade, Female, Fluorocarbons, Humans, Male, Middle Aged, Ophthalmologic Surgical Procedures, Prone Position, Retinal Perforations, Retrospective Studies, Sulfur Hexafluoride, Tomography, Optical Coherence, Visual Acuity, Vitrectomy}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.204}, author = {Mahajan, Vinit B and Chin, Eric K and Tarantola, Ryan M and Almeida, David R P and Somani, Riz and Boldt, H Culver and Folk, James C and Gehrs, Karen M and Russell, Stephen R} } @article {685, title = {Management of Choroidal Granulomas Involving the Macula in Corticosteroid-Intolerant Patients.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Nov}, pages = {1351-2}, keywords = {Adult, Choroid Diseases, Combined Modality Therapy, Dexamethasone, Drug Therapy, Combination, Drug Tolerance, Folic Acid Antagonists, Glucocorticoids, Granuloma, Humans, Interferon-gamma Release Tests, Intravitreal Injections, Macula Lutea, Male, Methotrexate, Tuberculoma, Tuberculosis, Ocular, Vitrectomy}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.1951}, author = {Chin, Eric K and Almeida, David R P and Mahajan, Vinit B} } @article {693, title = {Proteomic insight into the molecular function of the vitreous.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0127567}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Eye Proteins, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Proteome, Proteomics, Vitreous Body}, issn = {1932-6203}, doi = {10.1371/journal.pone.0127567}, author = {Skeie, Jessica M and Roybal, C Nathaniel and Mahajan, Vinit B} } @article {713, title = {Quantitative autofluorescence as a clinical tool for expedited differential diagnosis of retinal degeneration.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Feb}, pages = {219-20}, keywords = {Adult, ATP-Binding Cassette Transporters, Diagnosis, Differential, DNA, DNA Mutational Analysis, Fluorescein Angiography, Fundus Oculi, Humans, Male, Mutation, Optical Imaging, Retina, Retinal Degeneration, Retinitis Pigmentosa}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2014.4507}, author = {Marsiglia, Marcela and Lee, Winston and Mahajan, Vinit B and Zernant, Jana and Delori, Fran{\c c}ois C and Tsang, Stephen H and Sparrow, Janet R} } @article {711, title = {Spontaneous dislocation of a fluocinolone acetonide implant (Retisert) into the anterior chamber and its successful extraction in sympathetic ophthalmia.}, journal = {Retin Cases Brief Rep}, volume = {9}, year = {2015}, month = {2015 Spring}, pages = {142-4}, abstract = {

PURPOSE: To report a case of spontaneous fluocinolone acetonide (Retisert) implant dislocation and migration into the anterior chamber.

METHODS: Retrospective case report.

PATIENTS: One patient with sympathetic ophthalmia uveitis was well controlled by fluocinolone acetonide implants.

RESULTS: The fluocinolone acetonide implant spontaneously migrated into the anterior chamber causing corneal edema and anterior chamber reaction. The implant was subsequently successfully removed through a temporal corneal wound.

CONCLUSION: Clinicians should be aware of the spontaneous dislocation and migration of an intact fluocinolone implant as a potential surgical complication, particularly in pseudophakic eyes with iridectomy.

}, keywords = {Anterior Chamber, Device Removal, Drug Implants, Fluocinolone Acetonide, Glucocorticoids, Humans, Male, Middle Aged, Ophthalmia, Sympathetic, Visual Acuity}, issn = {1937-1578}, doi = {10.1097/ICB.0000000000000119}, author = {Almeida, David R P and Chin, Eric K and Mears, Katrina and Russell, Stephen R and Mahajan, Vinit B} } @article {699, title = {Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0122352}, abstract = {

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.

}, keywords = {Base Sequence, Calpain, Computational Biology, DNA Primers, Female, Fluorescein Angiography, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Retinal Detachment, Sequence Analysis, DNA, Tomography, Optical Coherence, Uveitis, Vitreoretinopathy, Proliferative}, issn = {1932-6203}, doi = {10.1371/journal.pone.0122352}, author = {Bassuk, Alexander G and Yeh, Steven and Wu, Shu and Martin, Daniel F and Tsang, Stephen H and Gakhar, Lokesh and Mahajan, Vinit B} } @article {725, title = {Decreased macular thickness in nonproliferative macular telangiectasia type 2 with oral carbonic anhydrase inhibitors.}, journal = {Retina}, volume = {34}, year = {2014}, month = {2014 Jul}, pages = {1400-6}, abstract = {

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.

}, keywords = {Acetazolamide, Administration, Oral, Adult, Aged, Carbonic Anhydrase Inhibitors, Female, Fluorescein Angiography, Humans, Male, Methazolamide, Middle Aged, Organ Size, Retina, Retinal Telangiectasis, Retrospective Studies, Tomography, Optical Coherence, Visual Acuity}, issn = {1539-2864}, doi = {10.1097/IAE.0000000000000093}, author = {Chen, John J and Sohn, Elliott H and Folk, James C and Mahajan, Vinit B and Kay, Christine N and Boldt, H Culver and Russell, Stephen R} } @article {719, title = {Proteomic landscape of the human choroid-retinal pigment epithelial complex.}, journal = {JAMA Ophthalmol}, volume = {132}, year = {2014}, month = {2014 Nov}, pages = {1271-81}, abstract = {

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.

}, keywords = {Aged, 80 and over, Choroid, Chromatography, Liquid, Computational Biology, Eye Proteins, Female, Gene Expression Regulation, Gene Ontology, Humans, Male, Proteome, Proteomics, Retinal Pigment Epithelium, Tandem Mass Spectrometry}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2014.2065}, author = {Skeie, Jessica M and Mahajan, Vinit B} } @article {745, title = {Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab.}, journal = {Am J Ophthalmol}, volume = {156}, year = {2013}, month = {2013 Jul}, pages = {15-22.e1}, abstract = {

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~{\texttimes} 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.

}, keywords = {Aged, Aged, 80 and over, Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized, Bevacizumab, Drug Resistance, Drug Substitution, Exudates and Transudates, Female, Humans, Intravitreal Injections, Male, Middle Aged, Postoperative Complications, Ranibizumab, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Retina, Retreatment, Retrospective Studies, Subretinal Fluid, Tomography, Optical Coherence, Treatment Outcome, Vascular Endothelial Growth Factor A, Visual Acuity, Wet Macular Degeneration}, issn = {1879-1891}, doi = {10.1016/j.ajo.2013.02.017}, author = {Bakall, Benjamin and Folk, James C and Boldt, H Culver and Sohn, Elliott H and Stone, Edwin M and Russell, Stephen R and Mahajan, Vinit B} } @article {755, title = {Elimination of infusion bubbles and uncontrolled reflux in the alcon constellation vitrectomy vision system.}, journal = {Retina}, volume = {33}, year = {2013}, month = {2013 Apr}, pages = {803-6}, abstract = {

PURPOSE: To identify the sources and management of 2 problems associated with the Alcon Constellation Vitrectomy (Alcon Laboratories, Inc) System: 1) infusion bubbles and 2) uncontrolled reflux.

METHODS: Surgical and analytical videos were evaluated to identify the source of intraoperative bubbles, which localized to the duckbill valve (DV). Intraoperatively, the authors modified the infusion tubing and its control by removing the DV. The DV was repurposed as a one-way valve to block reflux originating from the vitrectomy console.

RESULTS: Twenty consecutive 23-gauge vitrectomies in 20 eyes of 20 subjects from 2 surgeons (S.R.R. and E.H.S.) were reviewed. Infusion bubbles at the DV developed with each transitory tubing pressure drop upon opening of the infusion clamp. Removal of the DV from the infusion line eliminated infusion bubbles in 20 consecutive 23-gauge cases. Adding a one-way valve, which was fashioned from the DV, to the aspiration tubing, resulted in elimination of infusion bubbles and console-originated reflux in 20 eyes. Placement of the DV to block reflux eliminated both uncontrolled and purposeful console-originated reflux.

CONCLUSION: Intraoperative modification of Constellation tubing may eliminate two potentially harmful problems until manufacturer correction is instituted. Because the authors{\textquoteright} modified connections represent off-label connectivity, the manufacturer cannot contact potentially affected surgeons or suggest temporary alternative connectivity improvements.

}, keywords = {Gases, Humans, Intraoperative Complications, Microbubbles, Retinal Perforations, Video Recording, Vitrectomy, Vitreoretinal Surgery}, issn = {1539-2864}, doi = {10.1097/IAE.0b013e31826c20c6}, author = {Russell, Stephen R and Sohn, Elliott H and Boldt, H Culver and Folk, James C and Tarantola, Ryan M and Kay, Christine N and Mahajan, Vinit B} } @article {767, title = {Intraoperative sclerotomy-related retinal breaks during 23-gauge pars plana vitrectomy.}, journal = {Retina}, volume = {33}, year = {2013}, month = {2013 Jan}, pages = {136-42}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Incidence, Intraoperative Complications, Male, Microsurgery, Middle Aged, Postoperative Complications, Retinal Detachment, Retinal Perforations, Retrospective Studies, Sclerostomy, Tomography, Optical Coherence, Visual Acuity, Vitrectomy}, issn = {1539-2864}, doi = {10.1097/IAE.0b013e31825e1d62}, author = {Tarantola, Ryan M and Tsui, Janet Y and Graff, Jordan M and Russell, Stephen R and Boldt, H Culver and Folk, James C and Mahajan, Vinit B} } @article {113, title = {23-gauge pediatric vitrectomy using limbus-based trocar-cannulas.}, journal = {Retina (Philadelphia, Pa.)}, volume = {32}, year = {2012}, month = {2012 May}, pages = {1023-7}, keywords = {Catheters, Child, Child, Preschool, Female, Glaucoma Drainage Implants, Humans, Infant, Male, Microsurgery, Retinal Detachment, Retrospective Studies, Vitrectomy, Vitreous Hemorrhage}, author = {Kay, Christine N and Quiram, Polly H and Mahajan, Vinit B} } @article {115, title = {Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003001}, abstract = {

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.

}, keywords = {Amino Acid Sequence, Base Sequence, Calpain, Cell Line, Cells, Cultured, Choroid Diseases, Exome, Exons, Eye Diseases, Hereditary, Female, Gene Expression, Genetic Linkage, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Photoreceptor Cells, Vertebrate, Protein Conformation, Protein Transport, Retinal Degeneration, Sequence Alignment}, author = {Mahajan, Vinit B and Skeie, Jessica M and Bassuk, Alexander G and Fingert, John H and Braun, Terry A and Daggett, Heather T and Folk, James C and Sheffield, Val C and Stone, Edwin M} } @article {775, title = {Infrared imaging and optical coherence tomography reveal early-stage astrocytic hamartomas not detectable by fundoscopy.}, journal = {Am J Ophthalmol}, volume = {153}, year = {2012}, month = {2012 May}, pages = {883-889.e2}, abstract = {

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.

}, keywords = {Adolescent, Astrocytes, Child, Diagnostic Imaging, Female, Fluorescein Angiography, Humans, Infrared Rays, Male, Ophthalmoscopes, Prospective Studies, Retinal Neoplasms, Tomography, Optical Coherence, Tuberous Sclerosis}, issn = {1879-1891}, doi = {10.1016/j.ajo.2011.10.033}, author = {Xu, Luna and Burke, Tomas R and Greenberg, Jonathan P and Mahajan, Vinit B and Tsang, Stephen H} } @article {765, title = {Intravitreal bevacizumab for peripapillary choroidal neovascular membranes.}, journal = {Arch Ophthalmol}, volume = {130}, year = {2012}, month = {2012 Aug}, pages = {1073-5}, keywords = {Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized, Bevacizumab, Choroidal Neovascularization, Female, Fluorescein Angiography, Humans, Intravitreal Injections, Macular Degeneration, Male, Middle Aged, Retreatment, Subretinal Fluid, Tomography, Optical Coherence, Treatment Outcome, Vascular Endothelial Growth Factor A, Visual Acuity}, issn = {1538-3601}, doi = {10.1001/archophthalmol.2012.465}, author = {Davis, Andrew S and Folk, James C and Russell, Stephen R and Sohn, Elliott H and Sohn, Elliot H and Boldt, H Culver and Stone, Edwin M and Mahajan, Vinit B} } @article {129, title = {Proteomic analysis of vitreous biopsy techniques.}, journal = {Retina}, volume = {32}, year = {2012}, month = {2012 Nov-Dec}, pages = {2141-9}, abstract = {

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.

}, keywords = {Adolescent, Aged, Biological Markers, Biopsy, Chromatography, Liquid, Electrophoresis, Polyacrylamide Gel, Eye Diseases, Eye Proteins, Female, Humans, Male, Middle Aged, Proteomics, Spectrophotometry, Ultraviolet, Tandem Mass Spectrometry, Vitrectomy, Vitreous Body, Young Adult}, author = {Skeie, Jessica M and Brown, Eric N and Martinez, Harryl D and Russell, Stephen R and Birkholz, Emily S and Folk, James C and Boldt, H Culver and Gehrs, Karen M and Stone, Edwin M and Wright, Michael E and Mahajan, Vinit B} } @article {777, title = {Re: Intraoperative choroidal detachment during 23-gauge vitrectomy.}, journal = {Retina}, volume = {32}, year = {2012}, month = {2012 Feb}, pages = {411}, keywords = {Choroid Diseases, Drainage, Humans, Incidence, Intraoperative Complications, Microsurgery, Retinal Detachment, Retinal Perforations, Risk Factors, Vitrectomy}, issn = {1539-2864}, doi = {10.1097/IAE.0b013e3182398122}, author = {Tarantola, Ryan M and Mahajan, Vinit B} } @article {781, title = {Automated discovery and quantification of image-based complex phenotypes: a twin study of drusen phenotypes in age-related macular degeneration.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Nov 25}, pages = {9195-206}, abstract = {

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.

}, keywords = {Aged, 80 and over, Diseases in Twins, Female, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Phenotype, Registries, Retinal Drusen, Twins, Dizygotic, Twins, Monozygotic}, issn = {1552-5783}, doi = {10.1167/iovs.10-6793}, author = {Quellec, Gw{\'e}nol{\'e} and Russell, Stephen R and Seddon, Johanna M and Reynolds, Robyn and Scheetz, Todd and Mahajan, Vinit B and Stone, Edwin M and Abr{\`a}moff, Michael D} } @article {137, title = {Bilateral intravitreal injection of antivascular endothelial growth factor therapy.}, journal = {Retina (Philadelphia, Pa.)}, volume = {31}, year = {2011}, month = {2011 Jan}, pages = {31-5}, abstract = {

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

}, keywords = {Aged, Aged, 80 and over, Antibodies, Monoclonal, Case-Control Studies, Drug Administration Schedule, Drug Combinations, Female, Follow-Up Studies, Humans, Incidence, Injections, Intraocular, Macular Degeneration, Male, Middle Aged, Myocardial Infarction, Patient Preference, Retrospective Studies, Vascular Endothelial Growth Factor A, Vitreous Body}, author = {Mahajan, Vinit B and Elkins, Kori A and Russell, Stephen R and Boldt, H Culver and Gehrs, Karen M and Weingeist, Thomas A and Stone, Edwin M and Abr{\`a}moff, Michael D and Liu, Dawei and Folk, James C} } @article {139, title = {Dissection of human vitreous body elements for proteomic analysis.}, journal = {Journal of visualized experiments : JoVE}, year = {2011}, month = {2011}, abstract = {

The vitreous is an optically clear, collagenous extracellular matrix that fills the inside of the eye and overlies the retina. (1,2) Abnormal interactions between vitreous substructures and the retina underlie several vitreoretinal diseases, including retinal tear and detachment, macular pucker, macular hole, age-related macular degeneration, vitreomacular traction, proliferative vitreoretinopathy, proliferative diabetic retinopathy, and inherited vitreoretinopathies. (1,2) The molecular composition of the vitreous substructures is not known. Since the vitreous body is transparent with limited surgical access, it has been difficult to study its substructures at the molecular level. We developed a method to separate and preserve these tissues for proteomic and biochemical analysis. The dissection technique in this experimental video shows how to isolate vitreous base, anterior hyaloid, vitreous core, and vitreous cortex from postmortem human eyes. One-dimensional SDS-PAGE analyses of each vitreous component showed that our dissection technique resulted in four unique protein profiles corresponding to each substructure of the human vitreous body. Identification of differentially compartmentalized proteins will reveal candidate molecules underlying various vitreoretinal diseases.

}, keywords = {Dissection, Electrophoresis, Polyacrylamide Gel, Humans, Proteomics, Vitreous Body}, author = {Skeie, Jessica M and Mahajan, Vinit B} } @article {149, title = {Mutations in prickle orthologs cause seizures in flies, mice, and humans.}, journal = {American journal of human genetics}, volume = {88}, year = {2011}, month = {2011 Feb 11}, pages = {138-49}, abstract = {

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.

}, keywords = {Animals, Blotting, Western, Brain, Calcium, Carrier Proteins, DNA-Binding Proteins, Drosophila melanogaster, Drosophila Proteins, Embryo, Nonmammalian, Epilepsies, Myoclonic, Female, Heterozygote, Humans, Immunoenzyme Techniques, In Situ Hybridization, Male, Mice, Mice, Knockout, Mutation, Nerve Tissue Proteins, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Seizures, Tumor Suppressor Proteins, Zebrafish, Zebrafish Proteins}, author = {Tao, Hirotaka and Manak, J Robert and Sowers, Levi and Mei, Xue and Kiyonari, Hiroshi and Abe, Takaya and Dahdaleh, Nader S and Yang, Tian and Wu, Shu and Chen, Shan and Fox, Mark H and Gurnett, Christina and Montine, Thomas and Bird, Thomas and Shaffer, Lisa G and Rosenfeld, Jill A and McConnell, Juliann and Madan-Khetarpal, Suneeta and Berry-Kravis, Elizabeth and Griesbach, Hilary and Saneto, Russell P and Scott, Matthew P and Antic, Dragana and Reed, Jordan and Boland, Riley and Ehaideb, Salleh N and El-Shanti, Hatem and Mahajan, Vinit B and Ferguson, Polly J and Axelrod, Jeffrey D and Lehesjoki, Anna-Elina and Fritzsch, Bernd and Slusarski, Diane C and Wemmie, John and Ueno, Naoto and Bassuk, Alexander G} } @article {151, title = {Seroreactivity against aqueous-soluble and detergent-soluble retinal proteins in posterior uveitis.}, journal = {Archives of ophthalmology}, volume = {129}, year = {2011}, month = {2011 Apr}, pages = {415-20}, abstract = {

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

}, keywords = {Adolescent, Adult, Autoantibodies, Autoantigens, Blotting, Western, Electrophoresis, Polyacrylamide Gel, Eye Proteins, Female, Humans, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M, Male, Middle Aged, Retina, Retinal Degeneration, Solubility, Uveitis, Posterior, Young Adult}, author = {Ko, Audrey C and Brinton, Jason P and Mahajan, Vinit B and Zimmerman, Bridget and Brinton, Gregory S and Stone, Edwin M and Folk, James C and Mullins, Robert F} } @article {783, title = {Uveitis following intravitreal bevacizumab: a non-infectious cluster.}, journal = {Ophthalmic Surg Lasers Imaging}, volume = {42}, year = {2011}, month = {2011 Jul-Aug}, pages = {292-6}, abstract = {

BACKGROUND AND OBJECTIVE: In this retrospective case series, the authors report seven cases of bevacizumab-related uveitis that occurred within a 4-month period.

PATIENTS AND METHODS: Seven eyes of six patients developed non-infectious uveitis following bevacizumab intravitreal injections in a cohort of 978 consecutive bevacizumab injections.

RESULTS: The mean age of patients was 74.6 years (range: 26 to 92). All patients developed symptom onset within 1 day of injection. Shared signs and symptoms included corneal edema, anterior chamber and vitreous cell, conjunctival injection, ocular pain, and lack of hypopyon. In all patients, visual acuity returned to within one line of baseline acuity. All seven eyes had been previously injected with bevacizumab, with a mean number of antecedent injections of 6.1 (range: 3 to 12).

CONCLUSION: A cluster of sterile bevacizumab-related uveitic reactions was described in this case series. Acute onset of symptoms, absence of hypopyon, a predominant anterior segment reaction, and prompt improvement on topical steroid therapy are useful clinical features distinguishing this uveitic syndrome from infectious endophthalmitis.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Bevacizumab, Humans, Immunosuppressive Agents, Intravitreal Injections, Middle Aged, Retrospective Studies, Uveitis, Anterior, Vascular Endothelial Growth Factor A, Visual Acuity}, issn = {1938-2375}, doi = {10.3928/15428877-20110603-04}, author = {Kay, Christine N and Tarantola, Ryan M and Gehrs, Karen M and Folk, James C and Mahajan, Vinit B and Boldt, H Culver and Syed, Nasreen A and Russell, Stephen R} } @article {155, title = {Automated early detection of diabetic retinopathy.}, journal = {Ophthalmology}, volume = {117}, year = {2010}, month = {2010 Jun}, pages = {1147-54}, abstract = {

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.

}, keywords = {Aged, Algorithms, Area Under Curve, Diabetic Retinopathy, Diagnosis, Computer-Assisted, Diagnostic Techniques, Ophthalmological, Female, Humans, Male, Observer Variation, ROC Curve, Sensitivity and Specificity}, author = {Abr{\`a}moff, Michael D and Reinhardt, Joseph M and Russell, Stephen R and Folk, James C and Mahajan, Vinit B and Niemeijer, Meindert and Quellec, Gw{\'e}nol{\'e}} } @article {157, title = {Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.}, journal = {American journal of medical genetics. Part A}, volume = {152A}, year = {2010}, month = {2010 Nov}, pages = {2875-9}, abstract = {

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.

}, keywords = {Base Sequence, Child, Child, Preschool, Collagen Type XVIII, DNA Mutational Analysis, Encephalocele, Eye Abnormalities, Family, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Retinal Detachment}, author = {Mahajan, Vinit B and Olney, Ann Haskins and Garrett, Penny and Chary, Ajit and Dragan, Ecaterina and Lerner, Gary and Murray, Jeffrey and Bassuk, Alexander G} } @article {159, title = {Effects of vitrectomy on age-related macular degeneration.}, journal = {Ophthalmology}, volume = {117}, year = {2010}, month = {2010 Jul}, pages = {1381-6}, abstract = {

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

}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Choroidal Neovascularization, Disease Progression, Epiretinal Membrane, Female, Follow-Up Studies, Geographic Atrophy, Humans, Macular Degeneration, Male, Middle Aged, Pilot Projects, Retinal Perforations, Retrospective Studies, Visual Acuity, Vitrectomy}, author = {Roller, A Brock and Mahajan, Vinit B and Boldt, H Culver and Abr{\`a}moff, Michael D and Russell, Stephen R and Folk, James C} } @article {161, title = {Intravitreal bevacizumab during pregnancy.}, journal = {Retina (Philadelphia, Pa.)}, volume = {30}, year = {2010}, month = {2010 Oct}, pages = {1405-11}, abstract = {

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

}, keywords = {Adult, Angiogenesis Inhibitors, Antibodies, Monoclonal, Choroidal Neovascularization, Eye Infections, Fungal, Female, Follow-Up Studies, Gestational Age, Histoplasmosis, Humans, Intravitreal Injections, Off-Label Use, Pregnancy, Pregnancy Complications, Sarcoidosis, Tomography, Optical Coherence, Uveitis, Vascular Endothelial Growth Factor A, Visual Acuity}, author = {Tarantola, Ryan M and Folk, James C and Boldt, H Culver and Mahajan, Vinit B} } @article {163, title = {Patients with an acute zonal occult outer retinopathy-like illness rapidly improve with valacyclovir treatment.}, journal = {American journal of ophthalmology}, volume = {150}, year = {2010}, month = {2010 Oct}, pages = {511-8}, abstract = {

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

}, keywords = {Acute Disease, Acyclovir, Adolescent, Adult, Antiviral Agents, Electroretinography, Eye Infections, Viral, Female, Herpesviridae Infections, Humans, Male, Retinal Diseases, Retrospective Studies, Scotoma, Tomography, Optical Coherence, Valine, Visual Field Tests, Visual Fields}, author = {Mahajan, Vinit B and Stone, Edwin M} } @article {165, title = {T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy.}, journal = {Molecular vision}, volume = {16}, year = {2010}, month = {2010}, pages = {1034-40}, abstract = {

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.

}, keywords = {Aged, 80 and over, Antigens, CD4, Antigens, CD8, Autoantibodies, B-Lymphocytes, Eye Diseases, Female, Genes, Dominant, Humans, Immunoglobulin G, Immunologic Techniques, Neovascularization, Pathologic, Retina, Retinal Diseases, Staining and Labeling, T-Lymphocytes, Vitreous Body}, author = {Mahajan, Vinit B and Vallone, John G and Lin, Jonathan H and Mullins, Robert F and Ko, Audrey C and Folk, James C and Stone, Edwin M} } @article {169, title = {A head-tilt test for hypopyon after intravitreal triamcinolone.}, journal = {Retina (Philadelphia, Pa.)}, volume = {29}, year = {2009}, month = {2009 Apr}, pages = {560-1}, keywords = {Adult, Anterior Chamber, Diagnosis, Differential, Diagnostic Techniques, Ophthalmological, Endophthalmitis, Eye Infections, Female, Glucocorticoids, Head, Humans, Inflammation, Injections, Posture, Triamcinolone Acetonide, Vitreous Body}, author = {Mahajan, Vinit B and Folk, James C and Boldt, H Culver} } @article {171, title = {Management of sympathetic ophthalmia with the fluocinolone acetonide implant.}, journal = {Ophthalmology}, volume = {116}, year = {2009}, month = {2009 Mar}, pages = {552-557.e1}, abstract = {

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).

}, keywords = {Adult, Aged, Drug Implants, Female, Fluocinolone Acetonide, Follow-Up Studies, Glucocorticoids, Humans, Immunosuppressive Agents, Intraocular Pressure, Male, Middle Aged, Ophthalmia, Sympathetic, Retrospective Studies, Treatment Outcome, Visual Acuity}, author = {Mahajan, Vinit B and Gehrs, Karen M and Goldstein, Debra A and Fischer, David H and Lopez, Juan S and Folk, James C} } @article {173, title = {A new macular dystrophy with anomalous vascular development, pigment spots, cystic spaces, and neovascularization.}, journal = {Archives of ophthalmology}, volume = {127}, year = {2009}, month = {2009 Nov}, pages = {1449-57}, abstract = {

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.

}, keywords = {Adolescent, Adult, Amblyopia, Child, Child, Preschool, Cysts, Electroretinography, Female, Fluorescein Angiography, Humans, Macular Degeneration, Male, Middle Aged, Pedigree, Phenotype, Retinal Hemorrhage, Retinal Neovascularization, Retinal Pigment Epithelium, Retinal Vessels, Strabismus, Tomography, Optical Coherence, Visual Acuity, Young Adult}, author = {Mahajan, Vinit B and Russell, Stephen R and Stone, Edwin M} } @article {175, title = {Estrogen receptor alpha and matrix metalloproteinase 2 polymorphisms and age-related maculopathy in older women.}, journal = {American journal of epidemiology}, volume = {167}, year = {2008}, month = {2008 May 15}, pages = {1217-25}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Confounding Factors (Epidemiology), Estrogen Receptor alpha, Estrogen Replacement Therapy, Female, Gene Frequency, Genetic Linkage, Genotype, Humans, Logistic Models, Macular Degeneration, Matrix Metalloproteinase 2, Osteoporosis, Postmenopausal, Pigment Epithelium of Eye, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Severity of Illness Index}, author = {Seitzman, Robin L and Mahajan, Vinit B and Mangione, Carol and Cauley, Jane A and Ensrud, Kristine E and Stone, Katie L and Cummings, Steven R and Hochberg, Marc C and Hillier, Teresa A and Sinsheimer, Janet S and Yu, Fei and Coleman, Anne L} } @article {177, title = {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.}, journal = {Human mutation}, volume = {28}, year = {2007}, month = {2007 Mar}, pages = {243-54}, abstract = {

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.

}, keywords = {Adult, Animals, Cyclic Nucleotide Phosphodiesterases, Type 6, Disease Models, Animal, DNA Mutational Analysis, Electroretinography, Female, Humans, Male, Mice, Mice, Inbred DBA, Mice, Transgenic, Mutation, Night Blindness, Phosphoric Diester Hydrolases, Retinal Degeneration, Transgenes}, author = {Tsang, Stephen H and Woodruff, Michael L and Jun, Lin and Mahajan, Vinit and Yamashita, Clyde K and Pedersen, Robert and Lin, Chyuan-Sheng and Goff, Stephen P and Rosenberg, Thomas and Larsen, Michael and Farber, Debora B and Nusinowitz, Steven} } @article {823, title = {Tissue-specific gene expression of head and neck squamous cell carcinoma in vivo by complementary DNA microarray analysis.}, journal = {Arch Otolaryngol Head Neck Surg}, volume = {129}, year = {2003}, month = {2003 Jul}, pages = {760-70}, abstract = {

OBJECTIVES: To identify distinct gene expression profiles of human head and neck squamous cell carcinomas (HNSCCAs) using complementary DNA (cDNA) microarray analysis and to create a preliminary, comprehensive database of HNSCCA gene expression.

PATIENTS AND METHODS: Nine patients with histologically confirmed HNSCCAs, staged according to the American Joint Committee on Cancer, were enrolled. The HNSCCA tumor tissue and normal mucosal tissue were harvested at the time of surgery. A cDNA library was constructed from the paired fresh-frozen human surgical specimens of HNSCCAs and nonmalignant epithelial tissues. Biotinylated RNA was transcribed from the cDNA library and hybridized to high-density microarrays containing approximately 12 000 human genes. Altered gene expression of HNSCCAs was identified by comparison to corresponding normal mucosal tissues after a bayesian statistical analysis of variance. Results were analyzed using the gene database of the National Institutes of Health. Hierarchical clustering of the genomic data sets was determined by similarity metrics based on Pearson correlation.

RESULTS: Hierarchical clustering analysis revealed that the gene expression profiles obtained from the nonselected panel of 12 000 genes could distinguish the tumors from nonmalignant tissues. Gene expression changes were reproducibly observed in 227 genes representing previously identified chemokines, tumor suppressors, differentiation markers, matrix molecules, membrane receptors, and transcription factors that correlated with neoplasia, including 46 previously uncharacterized genes. Moreover, significant expression of the collagen type XI alpha1 gene and a novel gene was reproducibly observed in all 9 tumors, whereas these genes were virtually undetectable in their corresponding, adjacent nonmalignant tissues.

CONCLUSIONS: Complementary DNA microarray analysis of human HNSCCAs has produced a preliminary, comprehensive database of tumor-specific gene expression profiles and provided important insights into modeling gene expression changes implicated in carcinogenesis. A large-scale analysis of gene expression carries the future potential of identifying sensitive molecular markers for early tumor detection, prognosis, and novel targets for interceptive therapeutics.

}, keywords = {Bayes Theorem, Carcinoma, Squamous Cell, DNA, Complementary, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Humans, Hypopharyngeal Neoplasms, Laryngeal Neoplasms, Maxillary Neoplasms, Mouth Neoplasms, Oligonucleotide Array Sequence Analysis}, issn = {0886-4470}, doi = {10.1001/archotol.129.7.760}, author = {Sok, John C and Kuriakose, M Abraham and Mahajan, Vinit B and Pearlman, Aaron N and DeLacure, Mark D and Chen, Fang-An} } @article {181, title = {Microarray analysis of corneal fibroblast gene expression after interleukin-1 treatment.}, journal = {Investigative ophthalmology \& visual science}, volume = {43}, year = {2002}, month = {2002 Jul}, pages = {2143-51}, abstract = {

To identify changes in gene expression in human corneal fibroblasts after exposure to interleukin-1alpha.

}, keywords = {Cells, Cultured, Computational Biology, Cornea, Eye Proteins, Fibroblasts, Gene Expression, Gene Expression Profiling, Humans, Interleukin-1, Oligonucleotide Array Sequence Analysis, RNA}, author = {Mahajan, Vinit B and Wei, Cui and McDonnell, Peter J} } @article {827, title = {Thrombin receptor signaling to cytoskeleton requires Hsp90.}, journal = {J Biol Chem}, volume = {276}, year = {2001}, month = {2001 Aug 31}, pages = {32642-7}, abstract = {

Thrombin is a serine protease that evokes various cellular responses involved in injury and repair of the nervous system through the activation of protease-activated receptor-1 (PAR-1). Signals that modulate cell morphology precede most PAR-1 effects, but the initial signal transduction molecules are not known. Using the yeast two-hybrid system, we identified Hsp90, a chaperone with known signaling properties, as a binding partner of PAR-1. The interaction was confirmed by glutathione S-transferase pull-down, overlay, and co-immunoprecipitation assays. Morphological assays in mouse astrocytes were carried out to evaluate the importance of Hsp90 during cytoskeletal signaling. Reducing Hsp90 levels by antisense treatment or disruption of the Hsp90.PAR-1 complex by the Hsp90-specific drug geldanamycin attenuated thrombin-mediated astrocyte shape changes. Furthermore, overexpression of the PAR-1 cytoplasmic tail abrogated thrombin-induced cytoskeletal changes in neuronal cells. Treatment with geldanamycin specifically inhibited activation of RhoA without affecting thrombin-mediated intracellular calcium release, revealing the regulation of a distinct signaling pathway by Hsp90. Taken together, these studies demonstrate that Hsp90 may be essential for PAR-1-mediated signaling to the cytoskeleton.

}, keywords = {Animals, Animals, Newborn, Astrocytes, Cells, Cultured, Cerebral Cortex, Cloning, Molecular, Cytoskeleton, HSP90 Heat-Shock Proteins, Humans, Neurons, Oligodeoxyribonucleotides, Antisense, Rats, Rats, Sprague-Dawley, Receptor, PAR-1, Receptors, Thrombin, Recombinant Fusion Proteins, rhoA GTP-Binding Protein, Saccharomyces cerevisiae, Signal Transduction, Thrombin}, issn = {0021-9258}, doi = {10.1074/jbc.M104212200}, author = {Pai, K S and Mahajan, V B and Lau, A and Cunningham, D D} }