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Purpose: To use the power of knowledge acquisition and machine learning in the development of a collaborative computer classification system based on the features of age-related macular degeneration (AMD)., Methods: A vocabulary was acquired from four AMD experts who examined 100 ophthalmoscopic images. The vocabulary was analyzed, hierarchically structured, and incorporated into a collaborative computer classification system called IDOCS. Using this system, three of the experts examined images from a second set of digital images compiled from more than 1000 patients with AMD. Images were annotated, and features were identified and defined. Decision trees, a machine learning method, were trained on the data collected and used to extract patterns. Interrelationships between the data from the different clinicians were investigated., Results: Six drusen classes in the structured vocabulary were largely sufficient to describe all the identified features. The decision trees classified the data with 76.86% to 88.5% accuracy and distilled patterns in the form of hierarchical trees composed of 5 to 15 nodes. Experts were largely consistent in their characterization of soft, and to a lesser extent, hard drusen, but diverge in definition of other drusen. Size and crystalline morphology were the main determinants of drusen type across all experts., Conclusions: Machine learning is a powerful tool for the characterization of disease phenotypes. The creation of a defined feature set for AMD will facilitate the development of an IDOCS-based classification system.

Objective: To identify the genetic factors associated with familial non-arteritic anterior ischemic optic neuropathy (NA-AION) in a large pedigree., Methods: Eleven family members of a single pedigree, including six affected with NA-AION, underwent detailed clinical examinations. The mitochondrial DNA of the proband was sequenced in its entirety in search of disease-causing mutations associated with NA-AION in the pedigree. A control panel comprising 1488 patients suspected of having Leber hereditary optic neuropathy (LHON) and 97 general-population control subjects was screened for the mitochondrial sequence variant identified in the family., Results: Affected family members were all male and exhibited classic features of NA-AION. Their mean age was 50.2 +/- 5.0 years. A total of 23 sequence variations were detected in the mitochondrial genome of the proband, including one novel sequence variation (G4132A, Ala276Thr) in the NADH dehydrogenase subunit 1 gene (ND1). The G4132A mitochondrial variant was detected in six members of a single pedigree with NA-AION. The G4132A variation was not observed in any of the 1585 subjects in the control panel. Moreover, this variant was not identified in over 2469 ethnically diverse individuals previously evaluated through the Human Mitochondrial Genome Database. None of the three major mutations associated with LHON (G3460A, G11778A, T14484C) were identified in the family., Conclusion: The G4132A mitochondrial variation is associated with familial NA-AION in our pedigree.

Objective: To determine the histidine frequency in patients with the cuticular drusen phenotype of age-related macular degeneration (AMD)., Methods: Fifty individuals were identified who met the criteria for the cuticular drusen phenotype using a standard threshold photograph. We genotyped DNA samples using a polymerase chain reaction-based restriction digest assay. Seven hundred individuals with typical AMD and 252 controls were also genotyped. Fisher exact test was used to analyze the significance of allele frequency differences., Results: The histidine variant was present in 70% (frequency +/- SE, 0.70 +/- 0.05) of the cuticular cohort, 55% (frequency +/- SE, 0.55 +/- 0.01) of the more typical AMD cases, and 34% (frequency +/- SE, 0.34 +/- 0.02) of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = .003; odds ratio, 2.0; 95% confidence interval, 1.21-3.07; vs AMD cases P<.001; odds ratio 4.54; 95% confidence interval, 2.79-7.50; vs controls). Genotype distribution between the 3 groups was similarly significant (P<.001)., Conclusion: The cuticular drusen phenotype is highly associated with the Tyr402His variant of the complement factor H (CFH) gene. The significantly higher histidine allele frequency in this group compared with the typical AMD cohort suggests that the complement cascade may play a greater role in the pathogenesis of the cuticular drusen subtype than in AMD as a whole., Clinical Relevance: The c.1204T>C, p.Tyr402His allelic variant in the CFH gene is associated with a 3-fold increased risk for AMD. A high frequency of the histidine allele has also been noted in patients with membranoproliferative glomerulonephritis type II.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. Previous studies have demonstrated that the c.1204T>C, p.Tyr402His allelic variant in the complement factor H (CFH) gene is associated with an approximately three-fold increased risk for AMD in Caucasians of predominantly European descent. Both the prevalence as well as the phenotypic spectrum of AMD varies widely among persons of different ethnicities. We hypothesized that populations with a lower prevalence of AMD might also have a lower prevalence of the CFH risk allele. In this study we sought to determine the frequency of this sequence variant in control populations of Caucasians, African Americans, Hispanics, Somalis, and Japanese. Normal control populations were assembled for each ethnic group: Caucasian (n=148), Somali (n=128), African American (n=75), Hispanic (n=81), and Japanese (n=82). Individuals were genotyped using a restriction digest assay and the frequency of the C allele at nucleotide position 1204 of the CFH gene was determined. A bioinformatic approach was used to identify SNPs in linkage disequilibrium with rs1061170 (c.1204T>C, p.Tyr402His) from the human haplotype map project database (HapMap) in order to validate the findings. We found widely discordant frequencies of the risk allele between some of the different ethnic groups: Japanese 0.07+/-0.02, Hispanics 0.17+/-0.03, African-Americans 0.35+/-0.04, Caucasians 0.34+/-0.03, and Somalis 0.34+/-0.03. Allele frequencies generated by analysis of the HapMap database were consistent with these findings. This study suggests that there are other yet unidentified genetic factors important in the pathogenesis of AMD that may mitigate the effects of c.1204T>C, p.Tyr402His variant., ((c) 2006 Wiley-Liss, Inc.)

Purpose: Choroidal neovascularization (CNV) is a complication of multiple eye diseases, including age-related macular degeneration, that usually results in irreversible vision loss. It is characterized by proliferation and growth of choroidal blood vessels through Bruch's membrane into the subpigment epithelial and/or subretinal space. The purpose of this study was to characterize the carbohydrate groups associated with CNV by lectin histochemistry., Methods: Frozen sections from three human eyes with CNV (two fixed eyes and one unfixed eye) were prepared. Sections containing choroidal neovascular membranes were incubated with a battery of biotinylated lectins directed against a number of distinct oligosaccharide moieties. Lectin labeling of the vessels in CNV was visualized with avidin-Texas red., Results: Several carbohydrate groups were preferentially associated with the vascular elements in CNV. Glycoconjugates that react with lectins derived from wheat germ, soybean, and hairy vetch seed (sWGA, SBA, and VVA, respectively) all showed reactivity with CNV vessels that was higher than the labeling of the surrounding matrix. SBA and sWGA also reacted with CNV vessels at low concentrations at which normal retinal and choroidal vessels were largely unlabeled., Conclusions: Choroidal neovascular membranes possess a distinct set of carbohydrate moieties. These data may be valuable in understanding endothelial cell biology in CNV.

Purpose: To elucidate the phenotypic and biochemical characteristics of a novel mutation associated with autosomal dominant cone-rod dystrophy (adCORD)., Methods: Twenty-three family members of a CORD pedigree underwent clinical examinations, including visual acuity tests, standardized full-field ERG, and fundus photography. Genomic DNA was screened for mutations in GCAP1 exons using DNA sequencing and single-strand conformational polymorphism (SSCP) analysis. Function and stability of recombinant GCAP1-L151F were tested as a function of [Ca(2+)], and its structure was probed by molecular dynamics., Results: Affected family members experienced dyschromatopsia, hemeralopia, and reduced visual acuity by the second to third decade of life. Electrophysiology revealed a nonrecordable photopic response with later attenuation of the scotopic response. Affected family members harbored a C-->T transition in exon 4 of the GCAP1 gene, resulting in an L151F missense mutation affecting the EF hand motif 4 (EF4). This change was absent in 11 unaffected family members and in 100 unrelated normal subjects. GCAP1-L151F stimulation of photoreceptor guanylate cyclase was not completely inhibited at high physiological [Ca(2+)], consistent with a lowered affinity for Ca(2+)-binding to EF4., Conclusions: A novel L151F mutation in the EF4 hand domain of GCAP1 is associated with adCORD. The clinical phenotype is characterized by early cone dysfunction and a progressive loss of rod function. The biochemical phenotype is best described as persistent stimulation of photoreceptor guanylate cyclase, representing a gain of function of mutant GCAP1. Although a conservative substitution, molecular dynamics suggests a significant change in Ca(2+)-binding to EF4 and EF2 and changes in the shape of L151F-GCAP1.

Purpose: To describe the features of atypical pigment dispersion in a child., Design: Observational case report., Methods: Retrospective chart review., Results: An 8-year-old boy presented with midperipheral iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure. He also had several atypical features including emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae., Conclusion: Pigment dispersion in childhood is unusual and may have different features from those classically described in adults.

A 37-year-old man presented with fever and a red, painful right eye. He had proptosis, conjunctival chemosis, and ophthalmoplegia OD. The patient had extremely poor dentition and had self decompressed a dental abscess prior to admission. Magnetic resonance imaging of the brain and orbital revealed extraocular muscle engorgement and a dilated superior ophthalmic vein OD. Orbital echography revealed a lack of flow in the right superior ophthalmic vein. An extensive hematologic evaluation for infection and inflammation was negative. A chest radiograph showed a lung abscess for which he received intravenous antibiotics. Over time, the periorbital erythema, ophthalmoplegia, proptosis, and pain resolved. Repeat MRI showed resolution of the orbital findings and repeat chest x-ray showed resolution of the left upper lobe abscess.

Purpose: To describe diplopia as the initial manifestation of the Burkitt lymphoma., Design: Observational case report., Methods: Retrospective chart review., Results: A 53-year-old human immunodeficiency virus (HIV)-positive man presented with a severe headache associated with binocular diplopia. Flow cytometric analysis of the cerebrospinal fluid demonstrated a monoclonal B-lymphoid cell population consistent with the Burkitt lymphoma., Conclusion: Ophthalmologists should be aware that diplopia may be the presenting manifestation of Burkitt lymphoma in an immunocompromised patient.

Background: Abdominal aortic aneurysms (AAA) are characterized by both increases in proteolysis and changes in the biosynthesis of the extracellular matrix (ECM) proteins. Proteoglycans are important components of the ECM, particularly the small proteoglycans, biglycan and decorin. Biglycan and decorin regulate cell proliferation and collagen assembly. Therefore, the purpose of this study is to quantify the levels of mRNA for biglycan and decorin in normal aorta (Na) and AAA., Materials and Methods: Northern blot hybridization and competitive polymerase chain reaction using gene-specific external standards were used to quantify mRNA levels of bigylcan and decorin in RNA derived from AAA and NA. Results are expressed as a percentage of glyceraldehyde-3-phosphate dehydrogenase or normalized to ribosomal RNA content and compared using the unpaired t test., Results: A statistically significant 15-fold decrease in biglycan mRNA expression was observed in AAA compared to NA (176.9% vs 11.8%, P < 0.001). In contrast to biglycan, the decorin mRNA expression is unchanged in AAA compared to NA., Conclusions: The marked decrease in biglycan mRNA levels is unique to aneurysmal disease of the aorta. In atherosclerosis and restenosis, biglycan expression is increased in comparison with normal artery. This decrease in biglycan expression may reflect important regulatory changes specific for the AAA. Furthermore, a decrease in biglycan gene expression and biosynthesis could have a broad impact on the physiology and matrix architecture of the aorta.

A modification of Lerke enzymic method for histamine determination has been realized. We have observed a modification of the optimum wavelength depending on incubation time at constant temperature of 37°C. A wavelength of 580 nm is recommended, with a incubation time of 15 min. At these conditions the linearity was observed among 1 and 25 ppm (μg/g) of histamine. This technique is a reliable method of screening in food samples and bacterial strains, with low sample preparations requirements, a short incubation time and a low cost.