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ABSTRACT: There are many reasons to suspect a genetic influence on the development and progression of diabetic retinopathy, including substantial variability in disease severity among patients with similar risk factors. Linkage studies have suggested associations with chromosomes 1, 3, 12 and others. The most studied individual genes are those encoding vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products, all of which have shown statistically significant associations in multiple series from various parts of the world. At this time, no definite genetic associations with diabetic retinopathy have been consistently reported.This may be due to small sample sizes, differences in study design, underlying genetic differences between study populations, or other factors. As we continue to collect data, these relationships may become more clear.
Current diabetes reviews 08/2012;
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Lucia Sobrin,
Stephan Ripke,
Yi Yu,
Jesen Fagerness,
Tushar R Bhangale,
Perciliz L Tan,
Eric H Souied,
Gabriëlle H S Buitendijk,
Joanna E Merriam,
Andrea J Richardson, [......],
Johannes R Vingerling, Milam A Brantley,
Paul N Baird,
Caroline C W Klaver,
Rando Allikmets,
Nicholas Katsanis,
Robert R Graham,
John P A Ioannidis,
Mark J Daly,
Johanna M Seddon
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ABSTRACT: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.
Sibling correlation study and genome-wide association study (GWAS).
For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.
Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).
Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.
Ophthalmology 06/2012; 119(9):1874-85. · 5.45 Impact Factor
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ABSTRACT: To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes.
Prospective case-control study.
Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes.
CySS was elevated in cases compared with controls (P = .013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P = .028) as well as an 8-allele CFH haplotype (P = .029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort.
Our investigation of the gene-environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
American journal of ophthalmology 03/2012; 153(3):460-467.e1. · 3.83 Impact Factor
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ABSTRACT: To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy.
Prospective interventional case series.
Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped 2 weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on study day 2. Blood was drawn on study days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined.
Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet (P = .034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls.
This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.
American journal of ophthalmology 02/2012; 153(6):1104-9.e2. · 3.83 Impact Factor
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The British journal of ophthalmology 08/2011; · 2.92 Impact Factor
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Yi Yu,
Tushar R Bhangale,
Jesen Fagerness,
Stephan Ripke,
Gudmar Thorleifsson,
Perciliz L Tan,
Eric H Souied,
Andrea J Richardson,
Joanna E Merriam,
Gabriëlle H S Buitendijk, [......],
Caroline C W Klaver,
Rando Allikmets, Milam A Brantley,
Paul N Baird,
Nicholas Katsanis,
Unnur Thorsteinsdottir,
John P A Ioannidis,
Mark J Daly,
Robert R Graham,
Johanna M Seddon
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ABSTRACT: Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
Human Molecular Genetics 06/2011; 20(18):3699-709. · 7.64 Impact Factor
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ABSTRACT: OBJECTIVE To determine whether prolonged vascular endothelial growth factor inhibition is toxic to the retina by using pattern electroretinographic imaging in participants with neovascular age-related macular degeneration (AMD). METHODS We performed a prospective, single-arm clinical trial of 17 eyes in 17 treatment-naive participants with subfoveal choroidal neovascularization from AMD. On-label intravitreous ranibizumab was injected monthly for 6 months. Then pattern electroretinographic imaging was performed before and at 1 month, 3 months, and 6 months after first treatment, and results were interpreted by a trained reader masked to the clinical data. The primary outcome measure was the change in pattern electroretinographic imaging (positive wave peaking at 50 milliseconds [P50] and negative wave peaking at 95 milliseconds [N95] values) from baseline at 6 months. The secondary outcome measure was the change in visual acuity at 6 months. RESULTS The mean participant age was 79.6 years (range, 69.5-90.4 years). At baseline, mean (SD) P50 and N95 amplitudes were 1.3 (0.69) μV and 1.5 (0.71) μV, respectively. By 6 months, no decrease in P50 or N95 amplitudes from baseline was observed (1.4 [0.47] μV, P = .46; and 1.8 [0.96] μV, P = .14, respectively). Mean visual acuity before treatment was 20/85 with improvement to a mean of 20/55 (P = .004) at 6 months. CONCLUSIONS This study found no decrease in P50 and N95 amplitudes in participants treated with ranibizumab for neovascular AMD. These findings indicate that vascular endothelial growth factor inhibition with monthly injections of ranibizumab for 6 months likely does not lead to retinal damage. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00500344Arch Ophthalmol. 2011;129(5):580-584-->
Archives of ophthalmology 05/2011; 129(5):580-4. · 3.86 Impact Factor
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ABSTRACT: To determine whether prolonged vascular endothelial growth factor inhibition is toxic to the retina by using pattern electroretinographic imaging in participants with neovascular age-related macular degeneration (AMD).
We performed a prospective, single-arm clinical trial of 17 eyes in 17 treatment-naive participants with subfoveal choroidal neovascularization from AMD. On-label intravitreous ranibizumab was injected monthly for 6 months. Then pattern electroretinographic imaging was performed before and at 1 month, 3 months, and 6 months after first treatment, and results were interpreted by a trained reader masked to the clinical data. The primary outcome measure was the change in pattern electroretinographic imaging (positive wave peaking at 50 milliseconds [P50] and negative wave peaking at 95 milliseconds [N95] values) from baseline at 6 months. The secondary outcome measure was the change in visual acuity at 6 months.
The mean participant age was 79.6 years (range, 69.5-90.4 years). At baseline, mean (SD) P50 and N95 amplitudes were 1.3 (0.69) μV and 1.5 (0.71) μV, respectively. By 6 months, no decrease in P50 or N95 amplitudes from baseline was observed (1.4 [0.47] μV, P = .46; and 1.8 [0.96] μV, P = .14, respectively). Mean visual acuity before treatment was 20/85 with improvement to a mean of 20/55 (P = .004) at 6 months.
This study found no decrease in P50 and N95 amplitudes in participants treated with ranibizumab for neovascular AMD. These findings indicate that vascular endothelial growth factor inhibition with monthly injections of ranibizumab for 6 months likely does not lead to retinal damage. Trial Registration clinicaltrials.gov Identifier: NCT00500344.
Archives of ophthalmology 05/2011; 129(5):580-4. · 3.86 Impact Factor
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ABSTRACT: Pharmacogenetics seeks to explain interpatient variability in response to medications by investigating genotype-phenotype correlations. There is a small but growing body of data regarding the pharmacogenetics of both nonexudative and exudative age-related macular degeneration. Most reported data concern polymorphisms in the complement factor H and age-related maculopathy susceptibility 2 genes. At this time, the data are not consistent and no definite conclusions may be drawn. As clinical trials data continue to accumulate, these relationships may become more apparent.
Journal of Ophthalmology 01/2011; 2011:252549.
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Benjamin M Neale,
Jesen Fagerness,
Robyn Reynolds,
Lucia Sobrin,
Margaret Parker,
Soumya Raychaudhuri,
Perciliz L Tan,
Edwin C Oh,
Joanna E Merriam,
Eric Souied, [......],
Donald J Zack,
Betsy Campochiaro,
Peter Campochiaro,
Stephan Ripke,
R Theodore Smith,
Gaetano R Barile,
Nicholas Katsanis,
Rando Allikmets,
Mark J Daly,
Johanna M Seddon
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ABSTRACT: Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
Proceedings of the National Academy of Sciences 04/2010; 107(16):7395-400. · 9.68 Impact Factor
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ABSTRACT: Genetic factors influence an individual's risk for developing neovascular age-related macular degeneration (AMD), a leading cause of irreversible blindness. Previous studies on the potential genetic link between AMD and vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability, have yielded conflicting results. In the present case-control association study, we aimed to determine whether VEGF or its main receptor tyrosine kinase VEGFR-2 is genetically associated with neovascular AMD.
A total of 515 Caucasian patients with neovascular AMD and 253 ethically-matched controls were genotyped for polymorphisms in the VEGFA and VEGFR-2 genes. A tagging single nucleotide polymorphism (tSNP) approach was employed to cover each gene plus two kilobases on each side, spanning the promoter and 3' untranslated regions. SNPs with a minimum allele frequency of 10% were covered by seven tSNPs in VEGFA and 20 tSNPs in VEGFR-2. Two VEGFA SNPs previously linked with AMD, rs1413711 and rs3025039, were also analyzed.
The 29 VEGFA and VEGFR-2 SNPs analyzed in our cohort demonstrated no significant association with neovascular AMD. A single rare haplotype in the VEGFR-2 gene was associated with the presence of neovascular AMD (p=0.034).
This study is the first to investigate the association of VEGFR-2 polymorphisms with AMD and evaluates VEGFA genetic variants in the largest neovascular AMD cohort to date. Despite the angiogenic and permeability-enhancing effects of VEGF/VEGFR-2 signaling, we found minimal evidence of a significant link between polymorphisms in the VEGFA and VEGFR-2 genes and neovascular AMD.
Molecular vision 01/2009; 15:2710-9. · 2.20 Impact Factor
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ABSTRACT: To determine whether complement factor H (CFH) genotypes have a pharmacogenetic effect on the treatment of exudative age-related macular degeneration (AMD) with ranibizumab.
A retrospective study of 156 patients with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. AMD phenotypes were characterised by clinical examination, visual acuity, fundus photography, fluorescein angiography and injection timing. Patients received intravitreal ranibizumab injections as part of routine ophthalmological care and were followed for a minimum of 9 months. Each patient was genotyped for the single nucleotide polymorphism rs1061170 (Y402H) in the CFH gene.
Baseline lesion size and angiographic type, as well as mean visual acuities at baseline, 6 months, and 9 months were similar among the three CFH genotypes. Over 9 months, patients with both risk alleles received approximately one more injection (p = 0.09). In a recurrent event analysis, patients homozygous for the CFH Y402H risk allele had a 37% significantly higher risk of requiring additional ranibizumab injections (p = 0.04).
In this study cohort, the response to treatment of AMD with ranibizumab differed according to CFH genotype, suggesting that determining patients' CFH genotype may be helpful in the future in tailoring treatment for exudative AMD with intravitreal ranibizumab.
The British journal of ophthalmology 01/2009; 93(5):610-3. · 2.92 Impact Factor
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ABSTRACT: EVALUATION OF: Klein ML, Francis PJ, Rosner B et al.: CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115(6), 1019-1025 (2008). The late form of age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, with a complex etiology involving genetic and environmental factors. Recently, multiple distinct genetic susceptibility loci for AMD have been identified. Specifically, variations in the Complement Factor H (CFH) gene as well as the LOC387715/ARMS2 gene have been shown to be strongly associated with AMD. The Age-Related Eye Disease Study (AREDS) is a large multicenter, placebo-controlled, randomized clinical trial that showed that a combination of zinc and antioxidants reduced progression to late-stage AMD. In the present study, the authors found that within AREDS there was a significant interaction between zinc and CFH genotypes, indicating that CFH genotypes may be predictive of treatment response to zinc supplementation.
Pharmacogenomics 11/2008; 9(10):1547-50. · 3.97 Impact Factor
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ABSTRACT: The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) [GDNF, NRTN (neurturin), ARTN (artemin), and PSPN (persephin)] interact with GDNF family receptors (GFRalphas) and activate intracellular signaling through the Ret receptor tyrosine kinase. To characterize the role of Ret signaling in retinal activity, we examined Ret hypomorphic and Ret conditional mice using electroretinography. We found that aberrant Ret function resulted in markedly diminished scotopic and photopic responses. Using mice deficient in individual GFLs, we found that only NRTN deficiency led to reduced retinal activity. To determine the potential target cell type for NRTN, we examined the retinal expression of its coreceptors (GFRalpha1 and GFRalpha2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFRalpha1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFRalpha2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFRalpha1, GFRalpha2, or Ret was detected in photoreceptors or Müller cells, suggesting that these cells are not directly affected by Ret. Finally, detailed morphologic analyses of retinas from NRTN- and Ret-deficient mice demonstrated a reduction in normal horizontal cell dendrites and axons, abnormal extensions of horizontal cell and bipolar cell processes into the outer nuclear layer, and mislocalized synaptic complexes. These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice.
Journal of Neuroscience 05/2008; 28(16):4123-35. · 7.11 Impact Factor
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ABSTRACT: To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD).
Retrospective cohort study.
The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone.
Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active.
CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment.
For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype.
The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered.
Ophthalmology 01/2008; 114(12):2168-73. · 5.45 Impact Factor
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ABSTRACT: To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes.
Retrospective, case-control study.
One hundred and eighty-eight white subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon 9 of the CFH gene by restriction-fragment length analysis and deoxyribonucleic acid (DNA) sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography.
Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% confidence interval [CI], 1.3 to 3.3), whereas homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI, 3.4 to 12.5) in our population. The C allele was associated significantly with predominantly classic choroidal neovascularization (odds ratio [OR], 2.01; 95% CI, 1.34 to 3.30). Neovascular lesion size was similar among the three genotypes (P = .67).
The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype and phenotype correlations regarding choroidal neovascular lesion type were observed.
American Journal of Ophthalmology 10/2007; 144(3):404-408. · 4.22 Impact Factor
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ABSTRACT: To determine whether the duration of ischemic tolerance in the retina could be extended by repetitive presentations of the preconditioning stimulus and to begin to elucidate the mechanistic underpinnings of the resultant novel phenotype.
Adult male Swiss-Webster ND4 mice were repeatedly preconditioned with systemic hypoxia (RHP) over 12 days; 4 weeks later, the mice were subjected to 30 minutes of unilateral retinal ischemia. Protection was quantified morphologically and functionally 1 week after ischemia by histologic analyses and scotopic electroretinography, respectively. Temporal expression patterns of hypoxia-inducible factor (HIF)-1alpha and heme oxygenase (HO)-1 were measured in response to RHP and after retinal ischemia by immunoblot analysis and immunohistochemistry.
Morphologic and functional protection against ischemia-induced reductions in retinal layer thicknesses and layer cell counts, and a- and b-wave amplitudes, was documented for at least 4 weeks after RHP. There was no evidence of tissue injury or dysfunction by RHP alone. Temporally associated with this period of long-term tolerance (LTT) to retinal ischemia were sustained increases in retinal levels of HIF-1alpha and HO-1 protein lasting at least 1 and 4 weeks, respectively, after the last RHP stimulus.
A novel form of sustained retinal ischemic tolerance is described, wherein endogenous adaptive responses triggered by repeated hypoxia afford protection against injury many weeks after the preconditioning stimulus. HIF-1alpha-mediated, long-lasting increases in retinal HO-1 expression may contribute to the LTT phenotype. Further elucidation of the genetic and molecular basis of such adaptive plasticity could provide therapeutic targets for preventing and/or treating a variety of ischemic retinopathies.
Investigative Ophthalmology & Visual Science 04/2007; 48(4):1735-43. · 3.60 Impact Factor
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ABSTRACT: To evaluate the safety of intravitreal injection of bevacizumab in rabbits using electrophysiological testing and histopathologic analysis.
New Zealand albino rabbits were injected in one eye with control antibody (n = 2), 0.05 mL of bevacizumab (n = 3), or 0.2 mL of bevacizumab (n = 3). Electroretinograms were obtained 1 week and 4 weeks after injection. Histologic analysis was performed after completion of the electroretinographic studies.
No statistical differences were seen in scotopic and photopic a- and b-wave amplitudes between untreated control and bevacizumab-injected eyes. No histopathologic differences were identified between untreated control and bevacizumab-injected eyes.
Our study did not find evidence of retinal toxicity from a single intravitreal injection of bevacizumab in rabbits.
Retina 11/2006; 26(8):882-8. · 2.81 Impact Factor
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ABSTRACT: To examine the expression of proteins in the Rb and p53 tumor suppressor pathways in uveal melanomas following plaque radiotherapy.
Immunohistochemistry and cell culture studies. Immunohistochemistry for Rb, p16, cyclin D1, p53, HDM2, and Bcl-2 was performed on twelve eyes containing posterior uveal melanomas that were enucleated following plaque radiotherapy. Cell culture studies were performed in three cases.
The irradiated eyes were enucleated for radiation complications (five cases), local tumor recurrence (three cases), and other reasons (four cases). On histopathologic examination, all cases showed evidence of tumor cell loss. However, residual tumor cells were present in all cases, including those that were clinically regressed. Residual cells from three of the clinically regressed cases were cultured and demonstrated minimal cell division, marked cell death, and extensive chromosomal damage. Strong p53 staining was observed in six cases (50%) and was significantly associated with recent radiotherapy (P = .04). Abnormal cytoplasmic staining for Rb was observed in four cases (33%).
Plaque radiotherapy of uveal melanomas induces DNA damage, inhibits cell division, and promotes cell death. These changes may be due, at least in part, to induction of p53, which activates genes involved in both cell cycle arrest and apoptosis. Plaque radiotherapy can also cause alterations in the expression of Rb, but the significance of this finding will require further study.
American Journal of Ophthalmology 03/2002; 133(2):242-8. · 4.22 Impact Factor
