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1.  Diagnostic Sensitivity and Specificity of Dark Adaptometry for Detection of Age-Related Macular Degeneration 
Purpose.
Difficulty with night vision is a common complaint of patients with age-related macular degeneration (AMD). Consistent with this complaint, dark adaptation (DA) is substantially impaired in these patients. Because of the severity of the deficit, measurement of DA has been suggested as a means for the diagnosis of AMD. Previous methods for measurement of DA were time intensive (>30 minutes), which made them unsuitable for clinical use. This study evaluated a rapid DA test (≤6.5 minutes) for the detection of AMD.
Methods.
Dark adaptation was measured by using the AdaptDx dark adaptometer in two groups: subjects with normal retinal health and subjects with AMD. Subjects were assigned to their group by clinical examination and grading of fundus photographs. Subjects were classified as having DA consistent with normal retinal health (rod intercept ≤ 6.5 minutes) or having dark adaptation consistent with AMD (rod intercept > 6.5 minutes).
Results.
The eligible sample for analysis included 21 normal adults and 127 AMD patients. The rapid test was found to have a diagnostic sensitivity of 90.6% (P < 0.001) and specificity of 90.5% (P < 0.027). Thus, abnormal DA was detected in 115 of 127 AMD patients, and normal DA was found in 19 of 21 normal adults.
Conclusions.
The high diagnostic sensitivity and specificity compared favorably to long-duration research methods for the measurement of DA, and slit lamp biomicroscopy performed by a retina specialist. These results suggest that a rapid DA test is useful for the detection of AMD.
The AdaptDx exhibited greater than 90% sensitivity and specificity indicating its usefulness for the detection of abnormal dark adaptation associated with age-related macular degeneration.
doi:10.1167/iovs.13-13745
PMCID: PMC3954002  PMID: 24550363
age-related macular degeneration; dark adaptation; human; diagnostic
2.  Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing 
Journal of medical genetics  2013;50(10):674-688.
Background
Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments.
Methods
We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.
Results
Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients.
Conclusions
We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.
doi:10.1136/jmedgenet-2013-101558
PMCID: PMC3932025  PMID: 23847139
3.  Modulation of Wolframin Expression in Human Placenta during Pregnancy: Comparison among Physiological and Pathological States 
BioMed Research International  2014;2014:985478.
The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ.
doi:10.1155/2014/985478
PMCID: PMC3920918  PMID: 24588001
4.  Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative Disease 
Purpose.
To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2.
Methods.
Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA.
Results.
We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region).
Conclusions.
This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration.
Identification of mutations in 15% of the screened patients has important implications for guiding clinicians who are ordering genetic testing and provides a strong argument for screening the RPGR gene in simplex cases of retinal degenerative diseases.
doi:10.1167/iovs.12-11025
PMCID: PMC3522443  PMID: 23150612
5.  Gene Therapy for Leber Congenital Amaurosis caused by RPE65 mutations: Safety and Efficacy in Fifteen Children and Adults Followed up to Three Years 
Archives of ophthalmology  2011;130(1):9-24.
Objective
To determine safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying human RPE65 gene.
Design
Open-label, dose-escalation Phase I study of 15 patients (11-30 years) evaluated after subretinal injection of rAAV2-hRPE65 to the worse-functioning eye. Five cohorts represented four dose levels and two different injection strategies.
Main Outcome Measures
Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and ETDRS visual acuity. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance and OCT.
Results
No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in study eyes but not control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections.
Conclusions
RPE65-LCA gene therapy is sufficiently safe and substantially efficacious to the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases.
Application to Clinical Practice
Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice.
doi:10.1001/archophthalmol.2011.298
PMCID: PMC3600816  PMID: 21911650
6.  Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in the ABCA4 Gene 
Purpose.
We evaluated the pathogenicity of the G1961E mutation in the ABCA4 gene, and present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes.
Methods.
Patients were enrolled from the ABCA4 disease database at Columbia University or by inquiry from collaborating physicians. Only patients homozygous for the G1961E mutation were enrolled. The entire ABCA4 gene open reading frame, including all exons and flanking intronic sequences, was sequenced in all patients. Phenotype data were obtained from clinical history and examination, fundus photography, infrared imaging, fundus autofluorescence, fluorescein angiography, and spectral domain-optical coherence tomography. Additional functional data were obtained using the full-field electroretinogram, and static or kinetic perimetry.
Results.
We evaluated 12 patients homozygous for the G1961E mutation. All patients had evidence of retinal pathology consistent with the range of phenotypes observed in ABCA4 disease. The latest age of onset was recorded at 64 years, in a patient diagnosed initially with age-related macular degeneration (AMD). Of 6 patients in whom severe structural (with/without functional) fundus changes were detected, 5 had additional, heterozygous or homozygous, variants detected in the ABCA4 gene.
Conclusions.
Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. The phenotype usually is at the milder end of the disease spectrum, with severe phenotypes linked to the presence of additional ABCA4 variants. Our report also highlights that milder, late-onset Stargardt disease may be confused with AMD.
There is still debate as to the pathogenicity of homozygous G1961E mutation in the ABCA4 gene. We present 12 patients, homozygous for G1961E mutation, with retinal disease. In 6 cases, additional mutations were detected in ABCA4 and tended to yield more severe disease phenotypes.
doi:10.1167/iovs.11-9166
PMCID: PMC3394687  PMID: 22661473
7.  Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss 
We report a 77-year-old Caucasian man with a 1-year complaint of unexplained visual loss and a 4-year history of prostate cancer. A complete ophthalmologic exam, Goldmann visual fields (GVFs), intravenous fluorescein angiography (IVFA), macular and disc optical coherence tomography (OCT), pattern-reversal visual evoked potentials (PVEPs), and flash electroretinograms (ERGs) were performed. On examination, visual acuity was reduced bilaterally. Fundus exam showed juxtapapillary changes (OS > OD) and, in OS, disc pallor, peripheral RPE dropout and whitish retinal discoloration along the arcades. OCTs were normal OU. Cancer-associated retinopathy (CAR) was suspected. A flash ERG was normal OD and markedly reduced and electronegative OS. An IVFA showed bilateral juxtapapillary staining and changes highly suggestive of sequelae of central retinal artery occlusion (CRAO) OS, in which a cilioretinal artery existed along the papillomacular bundle. GVFs showed bilateral blind spot enlargement and centrocecal scotomas, and PVEPs were delayed. These findings suggested cancer-associated optic neuropathy (CAON), confirmed by presence of anti-optic nerve autoantibodies (auto-Abs). No anti-retinal auto-Abs were found. CAON is a less common paraneoplastic manifestation than CAR and it is rarely observed in association with prostate cancer. A combination of visual function testing methods permitted the recognition, in this highly unusual case, of the concurrent presence of unilateral ERG changes most likely attributable to CRAO complications in OS, in all likelihood unrelated to CAON, and not to be confused with unilateral CAR. Auto-Ab testing in combination with visual function tests helps achieve a better understanding of the pathophysiology of vision loss in paraneoplastic visual syndromes.
doi:10.1007/s10633-012-9327-0
PMCID: PMC3491897  PMID: 22569848
Electroretinogram; Visual evoked potentials; Visual field; Central retinal artery occlusion; Paraneoplastic optic neuropathy; Autoimmunity
8.  The Association of Cataract With Leukocyte Telomere Length in Older Adults: Defining a New Marker of Aging 
Lens transparency, or the magnitude of cataract severity, is a potential in vivo marker of aging distinguishable from diagnosed cataract. To explore lens transparency as a marker of aging, we determined its association with leukocyte telomere length (LTL) measured with quantitative polymerase chain reaction. Cataract severity was directly measured in 259 participants, and prevalent cataract and incident cataract surgery were ascertained in 2,750 participants of the Health, Aging, and Body Composition Study. LTL was unassociated with clinical cataract outcomes. Six of 259 had successfully aged lenses and a mean LTL of 5,700 bp, whereas 253/259 with poorly aged lenses had a mean LTL of 4,770 bp. Participants with a 1,000 bp greater mean LTL had nearly half the odds of any cataract (odds ratio = 0.47, 95% confidence interval 0.22–1.02) after adjustment. Lens transparency might be associated with longer LTL in community-dwelling older adults and should be investigated further as a possible biomarker of aging.
doi:10.1093/gerona/glr034
PMCID: PMC3110909  PMID: 21382885
Lens transparency; Cataract; Leukocyte telomere length; Aging; Biomarker
9.  Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy 
Purpose
Autoimmune retinopathies and optic neuropathies are complex disorders of the retina and the optic nerve, in which patients develop autoantibodies (AAbs) against retinal and optic nerve proteins. Autoimmunity might significantly influence the outcome of retinal and optic nerve degenerative process but the pathogenic process is not fully elucidated. To better understand the role of AAbs in pathogenicity of these suspected autoimmune visual disorders, we focused on unique AAbs specificities associated with the syndrome to identify their antigenic targets in the optic nerve and retina.
Methods
Serum samples were obtained from patients, whose visual disorders were potentially autoimmune in nature, including patients with cancer with possible paraneoplastic syndrome. Autoantibodies were tested against human optic nerve and retinal antigens for specificity by Western blotting and immunofluorescence.
Results
Out of 209 tested for anti-optic nerve autoantibodies, 55% showed specific neuronal autoantibodies. The repertoire of anti-optic nerve autoantibodies often differed from anti-retinal antibodies. The major antigenic targets for these antibodies could be divided into four groups. Autoantibodies specific to classical glycolytic enzymes involved in energy production (α and γ enolases, glyceraldehyde 3-phosphate dehydrogenase) also reacted with retinal antigens. Autoantibodies targeted neuronal-specific myelin proteins (MBP, MOG), aquaporin 4, and collapsing response mediator protein 5 reacted with optic nerve antigens. They showed immunostaining of axons and myelin in the optic nerve as determined by double immunofluorescence.
Conclusion
We identified novel neuronal autoantigens not previously known to be associated with acquired autoimmune retinopathy and optic neuropathy. Knowledge of the full autoantibody repertoire perpetuating this syndrome is an important first requirement in increasing our understanding of the autoimmune process to facilitate better diagnosis, prognosis, and treatment.
doi:10.1007/s12348-011-0028-8
PMCID: PMC3168374  PMID: 21744285
Autoimmunity; Retinopathy; Optic nerve; Neuropathy; Autoantibodies; Retina; Immunofluorescence; Western blotting; Retinal degeneration
10.  Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy 
Purpose
Autoimmune retinopathies and optic neuropathies are complex disorders of the retina and the optic nerve, in which patients develop autoantibodies (AAbs) against retinal and optic nerve proteins. Autoimmunity might significantly influence the outcome of retinal and optic nerve degenerative process but the pathogenic process is not fully elucidated. To better understand the role of AAbs in pathogenicity of these suspected autoimmune visual disorders, we focused on unique AAbs specificities associated with the syndrome to identify their antigenic targets in the optic nerve and retina.
Methods
Serum samples were obtained from patients, whose visual disorders were potentially autoimmune in nature, including patients with cancer with possible paraneoplastic syndrome. Autoantibodies were tested against human optic nerve and retinal antigens for specificity by Western blotting and immunofluorescence.
Results
Out of 209 tested for anti-optic nerve autoantibodies, 55% showed specific neuronal autoantibodies. The repertoire of anti-optic nerve autoantibodies often differed from anti-retinal antibodies. The major antigenic targets for these antibodies could be divided into four groups. Autoantibodies specific to classical glycolytic enzymes involved in energy production (α and γ enolases, glyceraldehyde 3-phosphate dehydrogenase) also reacted with retinal antigens. Autoantibodies targeted neuronal-specific myelin proteins (MBP, MOG), aquaporin 4, and collapsing response mediator protein 5 reacted with optic nerve antigens. They showed immunostaining of axons and myelin in the optic nerve as determined by double immunofluorescence.
Conclusion
We identified novel neuronal autoantigens not previously known to be associated with acquired autoimmune retinopathy and optic neuropathy. Knowledge of the full autoantibody repertoire perpetuating this syndrome is an important first requirement in increasing our understanding of the autoimmune process to facilitate better diagnosis, prognosis, and treatment.
doi:10.1007/s12348-011-0028-8
PMCID: PMC3168374  PMID: 21744285
Autoimmunity; Retinopathy; Optic nerve; Neuropathy; Autoantibodies; Retina; Immunofluorescence; Western blotting; Retinal degeneration
11.  Using Genetic Variation and Environmental Risk Factor Data to Identify Individuals at High Risk for Age-Related Macular Degeneration 
PLoS ONE  2011;6(3):e17784.
A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.
doi:10.1371/journal.pone.0017784
PMCID: PMC3063776  PMID: 21455292
12.  Treatment of Adult-Onset Acute Macular Retinoschisis in Enhanced-S Cone Syndrome with Oral Acetazolamide 
American journal of ophthalmology  2008;147(2):307-312.e2.
Purpose
To report on the efficacy of the oral carbonic anhydrase inhibitor (CAI), acetazolamide, in treating macular retinoschisis (RS) in the rare vitreoretinal dystrophy best known as the enhanced S-cone syndrome (ESCS).
Design
Interventional case report.
Methods
Setting: University-based practice. Patient: A 48-year old Jewish Italian male with clinically, functionally and molecularly confirmed ESCS, due to homozygosity for the R311Q mutation in the NR2E3 gene, presented with sudden visual acuity loss (20/200) and metamorphopsia in the left eye resulting from acute, late-onset, asymmetric macular RS. Intervention: Open-label, off-label treatment with the oral CAI acetazolamide. Main Outcome Measure(s): Best corrected visual acuity, retinal thickness and retinal microanatomy, assessed by Stratus optical coherence tomography (OCT) criteria.
Results
Following treatment, instituted one month after the acute-onset visual acuity loss, retinal thickness and microanatomic profile normalized in the affected eye, with restoration of 20/20 corrected visual acuity. The fellow eye, which had remained asymptomatic at 20/16 vision, had experienced mild paracentral macular RS evident by OCT criteria, which also resolved completely following oral CAI treatment. The outcome was maintained throughout the follow up period at a low maintenance dose.
Conclusions
Taken together with other recent reported benefits of topical and oral CAIs in the treatment of macular RS in X-linked retinoschisis, this interventional case report shows that CAIs can be used to treat effectively macular RS in general, and also specifically in ESCS.
doi:10.1016/j.ajo.2008.08.003
PMCID: PMC2677970  PMID: 18835469
13.  Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane’s retraction syndrome 
Science (New York, N.Y.)  2008;321(5890):839-843.
The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.
doi:10.1126/science.1156121
PMCID: PMC2593867  PMID: 18653847
14.  Macular Pigment Optical Density in the Elderly: Findings in a Large Biracial Midsouth Population Sample 
Purpose
To report the macular pigment optical density (MPOD) findings at 0.5° of eccentricity from the fovea in elderly subjects participating in ARMA, a study of aging and age-related maculopathy (ARM) ancillary to the Health, Aging, and Body Composition (Health ABC) Study.
Methods
MPOD was estimated with a heterochromatic flicker photometry (HFP) method in a large biracial population sample of normal 79.1 ± 3.2-year-old adults living in the Midsouth (n = 222; 52% female; 23% black, 34% users of lutein-containing supplements). Within a modified testing protocol, subjects identified the lowest and the highest target intensity at which the flicker sensation disappeared, and the exact middle of this “no-flicker zone” was interpolated by the examiner.
Results
An MPOD estimate was obtained successfully in 82% of the participants. The mean MPOD in our sample was 0.34 ± 0.21 (SD). The interocular correlation was high (Pearson’s r = 0.82). Compared with lutein supplement users, mean MPOD was 21% lower in nonusers (P = 0.013). MPOD was also 41% lower in blacks than in whites (P = 0.0002), even after adjustment for lutein supplement use. There were no differences in MPOD by gender, iris color, or history of smoking.
Conclusions
Older adults in the Midsouth appear to have average MPOD and interocular correlation comparable to those in previous studies. Lutein supplement use and white race correlated with higher MPOD. No evidence of an age-related decline in MPOD was seen in the sample. The HFP method for the measurement of MPOD is feasible in epidemiologic investigations of the elderly, the group at highest risk of ARM.
doi:10.1167/iovs.06-0438
PMCID: PMC2279193  PMID: 17389471
15.  Estimation of macular pigment optical density in the elderly: Test–retest variability and effect of optical blur in pseudophakic subjects 
Vision research  2007;47(9):1253-1259.
The reproducibility of macular pigment optical density (MPOD) estimates in the elderly was assessed in 40 subjects (age: 79.1 ± 3.5). Test–retest variability was good (Pearson’s r coefficient: 0.734), with an average coefficient of variation (CV) of 18.4% and an intraclass correlation coefficient (ICC) of 0.96. The effect of optical blur on MPOD estimates was investigated in 22 elderly pseudophakic subjects (age: 79.9 ± 3.6) by comparing the baseline MPOD, obtained with an optimal correction, with MPODs obtained with a ±1.00-diopter optical blur. This optical blur did not cause differences in the MPOD estimates, its accuracy, or test duration.
doi:10.1016/j.visres.2007.01.013
PMCID: PMC2271149  PMID: 17376502
Macular pigment optical density; Heterochromatic flicker photometry; Reliability; Optical blur; Aging
16.  Age-Related Decline in VIP-Positive Parasympathetic Nerve Fibers in the Human Submacular Choroid 
Purpose
An age-related decline in macular choroidal blood flow (ChBF) occurs in humans. Vasodilatory nerve fibers containing vasoactive intestinal polypeptide (VIP) innervate choroidal blood vessels. The current study was conducted to examine the possibility that an age-related loss of these fibers might occur in the submacular choroid in humans, and thus contribute to a decline in ChBF.
Methods
Macular choroid punches were collected from 35 healthy human donors ranging from 21 to 93 years of age. Choroidal samples were immunolabeled using anti-VIP and the peroxidase–antiperoxidase method. VIP-positive nerve fiber abundance was quantified in up to 12 fields per punch. Fifty macular punches were analyzed, and results for eye pairs were averaged. Choroidal vessel diameter (ChVD) was measured for these same fields. The relationship between age and vessel diameter or VIP-positive fiber abundance was analyzed. Multivariate statistical models were generated correcting for gender, variables related to the tissue specimens, and potential procedural sources of variability.
Results
The fully adjusted multivariate models showed a significant age-related reduction in both the VIP-positive fiber abundance (P = 0.0003, adjusted R2 = 0.51) and ChVD (P < 0.0001, adjusted R2 = 0.63), with slopes of −0.45 and −0.19, respectively. Adjusting for the same variables, VIP-positive fiber abundance showed a significant direct correlation with ChVD.
Conclusions
The results indicate a significant age-related decline in VIP-positive nerve fibers and vessel diameter in the submacular choroid in disease-free human donor eyes. These findings suggest that a decline in the neural control of ChBF and vessel diameter may explain the reductions in ChBF and its adaptive control observed clinically with aging.
doi:10.1167/iovs.06-0972
PMCID: PMC1810355  PMID: 17251439
17.  Contribution of Müller cells toward the regulation of photoreceptor outer segment assembly 
Neuron glia biology  2005;1:1-6.
The assembly of photoreceptor outer segments into stacked discs is a complicated process, the precise regulation of which remains a mystery. It is known that the integrity of the outer segment is heavily dependent upon surrounding cell types including the retinal pigment epithelium and Müller cells; however the role played by Müller cells within this photoreceptor-specific process has not been fully explored. Using an RPE-deprived but otherwise intact Xenopus laevis eye rudiment preparation, we reveal that Müller cell involvement in outer segment assembly is dependent upon the stimulus provided to the retina. Pigment epithelium-derived factor is able to support proper membrane folding after inhibition of Müller cell metabolism by alpha-aminoadipic acid, while isopropyl beta-D-thiogalactoside, a permissive glycan, requires intact Müller cell function. These results demonstrate that both intrinsic and extrinsic redundant mechanisms exist to support the ability of photoreceptors to properly assemble their outer segments. Our study further suggests that the receptor for pigment epithelium-derived factor resides in photoreceptors themselves while that for permissive glycans is likely localized to Müller cells, which in turn communicate with photoreceptors to promote proper membrane assembly.
doi:10.1017/s1740925x05000049
PMCID: PMC1397706  PMID: 16528406
retina; membrane assembly; pigment epithelium-derived factor; sugar; glycan

Results 1-17 (17)