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Pharmacokinetics of genistein distribution in blood and retinas of diabetic and non-diabetic rats

Hakami, T; Mahmoud, M I; de Juan, E; Cooney, M
Genistein, a natural tyrosine kinase inhibitor, may act as an intraocular antiangiogenic agent. Its therapeutical use, however, is limited by its nonlinear pharmacokinetics. We aimed to determine genistein's kinetics and retinal tissue distributions in normal and diabetic rats. We developed an isocratic, reverse-phase C18 HPLC system to measure genistein concentration in blood and retinas of streptozotocin (65 mg/kg IV)-diabetic and non-diabetic rats receiving two types of genistein-rich diet (150 and 300 mg/kg) for ten days. Genistein's decay exhibited a two-compartmental open model. Half-lives of distribution and elimination were 2.09 and 71.79 min, with no difference between groups. Genistein steady-state concentration in blood for 150 and 300 mg/kg diet did not differ between diabetic (0.259 ± 0.07 and 0.26 ± 0.06 μg/ml) and non-diabetic rats (0.192 ± 0.05 and 0.183 ± 0.09 μg/ml). In retina, genistein concentration was significantly higher in diabetic rats (1.05 ± 0.47 and 0.997 ± 0.47 μg/gm wt. vs. 0.087 ± 0.11 and 0.314 ± 0.18 μg/gm wt., p < 0.05). The study determined that increasing genistein dose did not change its bioavailability, perhaps due to the poor aqueous solubility. The retina's increased genistein could be due to increased permeability of blood-retinal barrier that occurs early in diabetes.
PMID: 34171772
ISSN: 1880-0920
CID: 4924702

Outer Retinal Tubulation Associated With Chronic Retinal Detachment

Dolz-Marco, Rosa; Cooney, Michael J; Engelbert, Michael
PMID: 28984738
ISSN: 1539-2864
CID: 2720102


Vaz-Pereira, Sara; Dansingani, Kunal K; Chen, Kevin C; Cooney, Michael J; Klancnik, James M Jr; Engelbert, Michael
PURPOSE: To describe anatomical relationships of retinal neovascular complexes (NVCs) and the posterior vitreous in proliferative diabetic retinopathy using spectral domain optical coherence tomography. METHODS: Cross-sectional study. Neovascular complexes were imaged using spectral domain optical coherence tomography in 51 eyes of 37 patients. The relationship of NVCs to the posterior vitreous cortex and posterior vitreous spaces, such as the premacular bursa, prevascular vitreous fissures, and perimacular cisterns, was analyzed. RESULTS: In the 77 NVCs evaluated, 61 (79%) had grown along the outer surface of the posterior hyaloid face, and vitreoschisis was present in 37 (48%). The "wolf's jaw" configuration was present in 9% and resulted from NVC arising from the arcades and proliferating along the posterior hyaloid face. By contrast, NVCs that invaded the bursa originated from smaller venous tributaries more distant from the arcades. The premacular bursa and prevascular vitreous fissure/perimacular cistern were invaded infrequently, respectively, in 15% and 38% (P = 0.137). CONCLUSION: Tomographic analysis of diabetic NVCs showed that most NVCs arise and grow along the posterior hyaloid face and that vitreoschisis is more prevalent than what has been found in ultrasound studies. The wolf's jaw configuration does not seem to result from the invasion of the bursa, as previously suggested.
PMID: 27749694
ISSN: 1539-2864
CID: 2279812

Risk Alleles Associated with Neovascularization in a Pachychoroid Phenotype

Dansingani, Kunal K; Perlee, Lorah T; Hamon, Sara; Lee, May; Shah, Vinnie P; Spaide, Richard F; Sorenson, John; Klancnik, James M Jr; Yannuzzi, Lawrence A; Barbazetto, Irene A; Cooney, Michael J; Engelbert, Michael; Chen, Christine; Hewitt, Alex W; Freund, K Bailey
PMID: 27506487
ISSN: 1549-4713
CID: 2255162

Volume-Rendering Optical Coherence Tomography Angiography of Macular Telangiectasia Type 2

Spaide, Richard F; Klancnik, James M Jr; Cooney, Michael J; Yannuzzi, Lawrence A; Balaratnasingam, Chandrakumar; Dansingani, Kunal K; Suzuki, Mihoko
PURPOSE: To evaluate the vascular structure of eyes with macular telangiectasia type 2 (MacTel2) using volume-rendered optical coherence tomography angiography (OCTA). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 14 consecutive patients (20 eyes) with MacTel2 who had a signal strength score >/=55 and could maintain fixation during the scan process. METHODS: The eyes were scanned using optical coherence tomography with split-spectrum amplitude decorrelation techniques to derive flow information. Data were extracted and used to create volume-rendered images of the retinal vasculature that could be rotated about 3 different axes for evaluation. MAIN OUTCOME MEASURES: Descriptive appraisal of the vascular abnormalities associated with MacTel2. RESULTS: Vessels posterior to the outer boundary of the deep retinal plexus were secondary to retinal thinning, vascular invasion, or a combination of both. These vessels had the same shape and distribution as the late staining seen during conventional fluorescein angiography. Lateral contraction in the temporal macula in 5 eyes created an appearance of vessels radiating from a central locus, which was the site of a right angle vein. Loss of macular tissue as part of the disease process led to a central amalgamation of the inner vascular plexus and the deep vascular plexus, which appeared to be in a state of decline. Subretinal neovascularization originated from the retinal circulation but involved not only the subretinal space but also could infiltrate the remaining, thinned, retina. CONCLUSIONS: Volume rendering of OCTA information preserves the 3-dimensional relationships among retinal vascular layers and provides opportunities to visualize retinal vascular abnormalities in unprecedented detail. The retinal vascular leakage and invasion in MacTel2 may arise as a consequence of loss of control with depletion of Muller cells and exposure of the remaining retinal vessels to the more hypoxic environment near the inner segments of the photoreceptors.
PMID: 26315043
ISSN: 1549-4713
CID: 1762662

The Spectrum of Superficial and Deep Capillary Ischemia in Retinal Artery Occlusion

Yu, Suqin; Pang, Claudine E; Gong, Yuanyuan; Freund, K Bailey; Yannuzzi, Lawrence A; Rahimy, Ehsan; Lujan, Brandon J; Tabandeh, Homayoun; Cooney, Michael J; Sarraf, David
PURPOSE: To describe the spectrum of retinal capillary ischemia, including superficial and deep capillary ischemia, as identified with spectral-domain optical coherence tomography (SD-OCT) that occurs in retinal arterial occlusive disease. DESIGN: Retrospective observational case series METHODS: Clinical charts, color fundus photography, red-free fundus photography, fluorescein angiography, near-infrared reflectance and SD-OCT imaging in 40 eyes of 35 patients with retinal arterial occlusive disease were studied in both the acute and chronic phases in multicenter clinical practices. SD-OCT imaging analysis was employed to characterize the presence of superficial and deep capillary ischemia in each eye. RESULTS: Of the 40 eyes, 15 eyes had central retinal artery occlusion (CRAO), 22 eyes had branch retinal artery occlusion (BRAO) and 3 eyes had cilioretinal artery occlusion. During the acute phase, SD-OCT showed the following 3 distinct patterns, related to retinal ischemia occurring at varying levels within the retina: 1. Thickening and hyper-reflectivity of the inner retinal layers, including the nerve fiber and ganglion cell layers due to ischemia of the superficial capillary plexus; 2. A hyper-reflective band at the level of the inner nuclear layer, termed "paracentral acute middle maculopathy" representing ischemia of the intermediate and deep retinal capillary plexuses (deep capillary ischemia); and 3. Diffuse thickening and hyper-reflectivity of both the inner and middle retinal layers, which represented both superficial and deep capillary ischemia. Of all eyes, 31 (78%) had both superficial and deep lesions. The remaining 9 (22%) eyes had isolated deep capillary ischemia producing paracentral acute middle maculopathy with sparing of the superficial capillary plexus and a normal fluorescein angiographic appearance. As the lesions evolved into the chronic phase over the ensuing 3 months, the resultant thinning and atrophy reflected the retinal layers affected during the acute phase. CONCLUSION: SD-OCT imaging reveals the spectrum of capillary ischemia in retinal artery occlusive disease showing variable involvement of the superficial and intermediate/deep capillary plexuses. Isolated deep capillary ischemia manifested as paracentral acute middle maculopathy on SD-OCT and may be seen in some eyes with retinal arterial circulation compromise despite complete absence of perfusion abnormalities on fluorescein angiography.
PMID: 25244976
ISSN: 0002-9394
CID: 1259222

Retinal Vascular Layers Imaged by Fluorescein Angiography and Optical Coherence Tomography Angiography

Spaide, Richard F; Klancnik, James M Jr; Cooney, Michael J
Importance: The retinal vasculature is involved in many ocular diseases that cause visual loss. Although fluorescein angiography is the criterion standard for evaluating the retina vasculature, it has risks of adverse effects and known defects in imaging all the layers of the retinal vasculature. Optical coherence tomography (OCT) angiography can image vessels based on flow characteristics and may provide improved information. Objective: To investigate the ability of OCT angiography to image the vascular layers within the retina compared with conventional fluorescein angiography. Design, Setting, and Participants: In this study, performed from March 14, 2014, through June 24, 2014, a total of 5 consecutive, overlapping B-scan OCT angiography images composed of 216 A-scans were obtained at 216 discrete positions within a region of interest, typically a 2 x 2-mm area of the retina. The flow imaging was based on split-spectrum amplitude decorrelation angiography (SSADA), which can dissect layers of vessels in the retina. These distinct layers were compared with the fluorescein angiograms in 12 healthy eyes from patients at a private practice retina clinic to evaluate the ability to visualize the radial peripapillary capillary network. The proportion of the inner vs outer retinal vascular layers was estimated by 3 masked readers and compared with conventional fluorescein angiograms of the same eyes. Main Outcomes and Measures: Outcome measures were visualization of the radial peripapillary capillary network in the fluorescein and SSADA scans and the proportion of the inner retinal vascular plexus vs the outer retinal capillary plexus as seen in SSADA scans that would match the fluorescein angiogram. Results: In none of the 12 eyes could the radial peripapillary capillary network be visualized completely around the nerve head by fluorescein angiography, whereas the network was readily visualized in the SSADA scans. The fluorescein angiograms were matched, with a mean proportion of the inner vascular plexus being 95.3% (95% CI, 92.2%-97.8%) vs 4.7% (95% CI, 2.6%-5.7%) for the outer capillary plexus from the SSADA scans. Conclusions and Relevance: Fluorescein angiography does not image the radial peripapillary or the deep capillary networks well. However, OCT angiography can image all layers of the retinal vasculature without dye injection. Therefore, OCT angiography, and the findings generated, have the potential to affect clinical evaluation of the retina in healthy patients and patients with disease.
PMID: 25317632
ISSN: 2168-6165
CID: 1310162

Retinal Vascular Layers in Macular Telangiectasia Type 2 Imaged by Optical Coherence Tomographic Angiography

Spaide, Richard F; Klancnik, James M Jr; Cooney, Michael J
Importance: Macular telangiectasia type 2 (MacTel 2) is a rare disease in which abnormalities of the retinal vasculature play a key role. The vascular abnormalities are typically evaluated using fluorescein angiography, a modality with known defects in imaging the deeper layers of the retinal vasculature. Angiography based on optical coherence tomography can image vessels based on flow characteristics without dye injection and may provide improved information concerning the pathophysiology of MacTel 2. Objective: To investigate MacTel 2 using optical coherence tomographic angiography. Design, Setting, and Participants: Fourteen eyes of 7 patients with MacTel 2 were analyzed in a community-based retina practice. The flow imaging was based on split-spectrum amplitude decorrelation angiography, which can dissect layers of vessels in the retina. The inner retinal vascular plexus, the outer plexus, and deeper vascular invasion into the outer and subretinal spaces were optically dissected in en face images based on flow. Main Outcomes and Measures: Visualization and qualitative evaluation of the vascular layers of the retina as they may be affected by MacTel 2, both in terms of depth and topographic characteristics. Results: A consistent set of retinal vascular changes were seen in the eyes with MacTel 2. There was some loss of capillary density in the inner retinal vascular plexus but many more prominent alterations in the deep retinal vascular plexus. In milder forms of the disease, the deep plexus showed dilation and telangiectasis and, in more advanced cases, thinning and loss. The remaining vessels were elongated and widely spaced capillary segments. Invasion by new vessels into the outer and subretinal spaces occurred subjacent to the regions showing greatest flow imaging abnormalities in the inner and deep retinal vascular layers. Conclusions and Relevance: As evidenced by the patients in this study, important retinal vascular changes in MacTel 2 occur in the deep capillary plexus of the retina, a layer poorly visualized by fluorescein angiography and, to a lesser extent, in the inner vascular plexus. The proliferation of vessels in the outer and subretinal spaces may be in part compensatory for poor retinal perfusion by established vascular layers in the retina.
PMID: 25317692
ISSN: 2168-6165
CID: 1310172

MULTIFOCAL CHOROIDITIS WITHOUT PANUVEITIS: Clinical Characteristics and Progression

Fung, Adrian T; Pal, Samriti; Yannuzzi, Nicolas A; Christos, Paul; Cooney, Michael; Slakter, Jason S; Klancnik, James M Jr; Freund, K Bailey; Cunningham, Emmett T Jr; Yannuzzi, Lawrence A
PURPOSE:: To describe the clinical characteristics and progression of patients with multifocal choroiditis lesions who had minimal or no evidence of anterior uveitis and/or vitritis. METHODS:: Retrospective, observational, single-center consecutive case series. Clinical histories, examination, and multimodal imaging findings were analyzed. RESULTS:: Sixty-five eyes of 41 patients were identified. The mean age at diagnosis was 38.4 years (median, 35 years; range, 15-81 years), and 70.7% of the patients were women. Involvement was bilateral in 21 patients (51.2%) at presentation. The 60-month bilateral event-free survival was 75.0% (95% confidence interval, 49.8-91.2%). The mean visual acuity was 20/46 (median, 20/25; range, 20/20 to count fingers at 2 feet) at presentation and 20/42 (median, 20/25; range, 20/20-5/400) at the last recorded visit. The 60-month "20/50 or worse" event-free survival was 100%. Between the first presentation and final follow-up (a mean duration of 92.6 months; range, 0-343 months), 46.7% of the eyes developed new or larger chorioretinal spots and 32.6% developed new or recurrent choroidal neovascularization. The 60-month choroidal neovascularization event-free survival was 68.1% (95% confidence interval, 39.2-85.4%). CONCLUSION:: Patients with multifocal choroiditis lesions, but with minimal or no anterior uveitis or vitritis, tended to be young women. Approximately half of the patients presented with bilateral involvement, which is less than has been reported in most case series of multifocal choroiditis with panuveitis. One quarter of all unilaterally affected patients will develop bilateral involvement by 60 months.
PMID: 23670288
ISSN: 0275-004x
CID: 543192

Sustained Increased Intraocular Pressure Related to Intravitreal Antivascular Endothelial Growth Factor Therapy for Neovascular Age-related Macular Degeneration

Tseng JJ; Vance SK; Della Torre KE; Mendonca LS; Cooney MJ; Klancnik JM; Sorenson JA; Freund KB
PURPOSE: To describe a series of previously normotensive eyes experiencing sustained elevated intraocular pressure (IOP) associated with long-term intravitreal antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Clinical data were reviewed for 25 eyes of 23 patients with neovascular AMD who had increased IOP while receiving interval doses of intravitreal ranibizumab and/or bevacizumab. All eyes had tolerated multiple anti-VEGF injections in the past without IOP elevations. RESULTS: After a mean of 20.0 anti-VEGF injections (range, 8-40 injections), the mean IOP was 29.8 mm Hg (range, 22-58 mm Hg), compared with a baseline of 16.9 mm Hg (range, 14-21 mm Hg). The mean highest IOP while receiving intravitreal anti-VEGF therapy was 35.8 mm Hg (range, 23-58 mm Hg). Overall, 23 of 25 cases required IOP management. In the remaining 2 cases, anti-VEGF dosing was switched from regular interval dosing to an optical coherence tomography-guided variable regimen, with subsequent improvement in IOP without antiglaucoma treatment. CONCLUSIONS: Serial injections of anti-VEGF agents may lead to persistent IOP elevations that require glaucoma therapy. The clinician should recognize this phenomenon, as it can occur even if the patient has tolerated multiple prior injections without IOP elevation. Further exploration of the relationship between anti-VEGF therapy and IOP is needed
PMID: 21423038
ISSN: 1536-481x
CID: 141294