Acute zonal occult outer retinopathy.

Acute zonal occult outer retinopathy (AZOOR) is a rare unilateral or bilateral disease of unknown etiology characterized by focal degeneration of photoreceptors. A total of 131 cases of AZOOR (205 eyes), including the variant known as acute annular outer retinopathy, have been reported in the English language literature. In this group of predominantly white individuals, average age at presentation was 36.7 years, and the male:female ratio was 1:3.2. The majority of patients complained of the acute onset of a scotoma, which was associated with photopsia. Visual acuity was 20/40 or better in 74% of tested eyes, and fundus examination was unremarkable in 76% of eyes. Blind spot enlargement, with or without other field defects, was observed in 75% of the visual fields examined, and electroretinographic abnormalities were recorded in 99% of patients tested. Typically patients retained good visual acuity, although retinal pigment epithelial disturbances commonly developed over time. It was unusual for visual field loss to continue beyond six months. Various treatments have been attempted in patients with AZOOR--including systemic corticosteroids, other systemic immunosuppressive agents, and different antimicrobials--but none have been proven effective.

Clinicopathologic correlation of retinal angiomatous proliferation.

OBJECTIVES: To correlate clinical and histopathologic features of an eye with retinal angiomatous proliferation (RAP) secondary to age-related macular degeneration and to investigate the expression of von Willebrand factor (VWF) and vascular endothelial growth factor (VEGF) in this condition. METHODS: Histopathologic features from serial sections through the globe of an 87-year-old woman with RAP were studied and compared with fluorescein angiography and color fundus photographs obtained 4 months before death. Commercially available anti bodies were used to detect expression of VWF and VEGF in tissue sections. RESULTS: The pathologic correlate of RAP was a circumscribed intraretinal angiomatous complex within the outer part of the neurosensory retina overlying a large pigment epithelial detachment. There were no breaks in the Bruch membrane. No choroidal neovascularization was present. Endothelial cells within the RAP lesion immunostained positively for VWF and VEGF. The Bruch membrane expressed VWF adjacent to the RAP. CONCLUSIONS: Fundus examination and fluorescein angiography images of RAP in a patient with age-related macular degeneration correlated histopathologically with a neovascular intraretinal angiomatous complex, without the presence of sub-retinal pigment epithelial neovascularization. Immunostaining demonstrated that RAP expresses VWF and VEGF.

Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas.

Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, approximately 50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor-selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors.

Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer.

It has previously been shown that the Copenhagen (COP) rat contains several genetic loci that contribute to its mammary tumor-resistant phenotype after 7,12-dimethylbenz(a)anthracene (DMBA) administration. One of these loci, mammary carcinoma susceptibility 1 (Mcs1), is located on the centromeric end of chromosome 2 and appears to act in a semidominant fashion. To confirm the existence and independent action of this locus and also aid in the identification of the physical location of the Mcs1 gene, congenic lines were generated by transferring the Mcs1 COP allele onto a Wistar Furth (WF) genetic background. Male carriers were genotyped using microsatellite markers spanning 20-30 cM of the Mcs1 locus. One of the congenic lines minimally retained the COP allele at D2Mit29 on the centromeric end of chromosome 2 and extended distally to D2Rat201. Heterozygous Mcs1 carrier rats were interbred, and the female offspring were treated with DMBA. The female rats from the Mcs1 congenic line that carried one or two COP alleles of the Mcs1 region had a significantly reduced (65 and 85%, respectively) tumor development (P < 0.001) compared with rats carrying zero COP alleles at this locus. A WF.COP-D2Mit29/D2Rat201 homozygous congenic strain derived at the N10 generation was treated with DMBA, and the COP homozygous rats developed 1.5 +/- 0.3 carcinomas/rat versus 6.3 +/- 0.5 in WF control rats (P < 0.0001). Fine mapping of this congenic interval using several recombinant lines identified three genetic loci within the Mcs1 congenic region that independently supported a tumor resistance phenotype. These genetic loci have been termed Mcs1a, Mcs1b, and Mcs1c. In rats for which each locus was homozygous for the COP allele, tumor development was reduced by approximately 60% compared with littermate controls. The identification of these independent loci within the Mcs1 COP allele provide a model of the genetic complexity of cancer.

Physical evidence of Mcs5, a QTL controlling mammary carcinoma susceptibility, in congenic rats.

Genetic susceptibility to breast cancer is influenced by high- and low-penetrance genes. The low-penetrance genes contributing to increased and decreased risk likely exist at appreciable frequencies in the human population. To identify high-frequency, low-penetrance modifier genes, we are using a rat genetic model. Eight quantitative trait loci, named mammary carcinoma susceptibility (Mcs) loci, have been genetically identified in two rat strains, Wistar-Kyoto (WKy) and Copenhagen. These strains are resistant to developing mammary cancer compared with susceptible Wistar-Furth (WF) female rats. Here we provide physical evidence of the existence of Mcs5 in the resistant WKy rat and further narrow the candidate region defining the QTL. Two congenic rat lines (C and D) containing large segments of the WKy Mcs5 QTL on chromosome 5 were generated on a WF background. The minimal WKy interval from markers D5Wox7 and D5Uwm37 (line C) conferred resistance to developing 7,12-dimethylbenz- [a]anthracene (DMBA)-induced mammary carcinomas. Line C females that were homozygous for the WKy allele at this interval averaged 1.1+/-0.3 carcinomas/rat compared with 6.9+/-0.4 average carcinomas/rat for WF control females (P<0.01). Line D females containing the minimal WKy interval from D5Rat26 to D5Uwm42, were as susceptible to developing mammary carcinomas as WF controls (5.7+/-0.6 versus 6.9+/-0.4, respectively). The WKy region in common to these lines from D5Rat26 to D5Uwm37 is thus not expected to contain Mcs5-associated genes. Based on results presented here, the Mcs5 locus has been physically located within a congenic interval on rat chromosome 5 between markers D5Uwm8 and D5Rat26.