Publications by authors named "Susan S Lee"

34 Publications

Episcleral Venous Pressure and the Ocular Hypotensive Effects of Topical and Intracameral Prostaglandin Analogs.

J Glaucoma 2019 09;28(9):846-857

Viterbi Family Department of Ophthalmology, Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, La Jolla, CA.

There is a limit beyond which increasing either the concentration of a prostaglandin analog (PGA) or its dosing frequency fails to produce increases in ocular hypotensive efficacy with topical dosing. Intracameral PGA dosing with a bimatoprost implant, however, does not exhibit the same intraocular pressure (IOP)-lowering plateau at studied concentrations, and the maximum-achievable ocular hypotensive effects are not yet known. This suggests that the bimatoprost intracameral implant may activate another mechanism of action in addition to the mechanism(s) activated by topical application. Episcleral venous pressure (EVP) is a key determinant of IOP, and experimental manipulation of the episcleral vasculature can change both EVP and IOP. The recent observation that topical and intracameral PGA drug delivery routes produce different patterns of conjunctival hyperemia suggested that the differences in the IOP-lowering profiles may be caused by differing effects on the episcleral vasculature. Recent experiments in animals have shown that topical PGAs increase EVP, while the bimatoprost intracameral implant causes a smaller, transient increase in EVP, followed by a sustained decrease. The increase in EVP could be limiting the IOP-lowering efficacy of topical PGAs. In contrast, the decrease in EVP associated with the bimatoprost implant could explain its enhanced IOP-lowering effects. Further research on EVP as a target for IOP lowering is indicated to improve our understanding of this potentially important pathway for treating patients with glaucoma.
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http://dx.doi.org/10.1097/IJG.0000000000001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735525PMC
September 2019

Intraocular Pressure Effects and Mechanism of Action of Topical Versus Sustained-Release Bimatoprost.

Transl Vis Sci Technol 2019 Jan 30;8(1):15. Epub 2019 Jan 30.

Hamilton Glaucoma Center, Shiley Eye Institute and Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.

Purpose: To assess the intraocular pressure (IOP)-lowering effects of bimatoprost sustained-release implant (BimSR) in normotensive monkeys receiving topical bimatoprost.

Methods: Six eyes from six female, normotensive, cynomolgus monkeys were treated with once-daily topical latanoprost 0.005% plus twice-daily fixed-combination dorzolamide 2%/timolol 0.5%. At week 5, topical latanoprost was switched to once-daily topical bimatoprost 0.03% and twice-daily dorzolamide 2%/timolol 0.5% was continued. At week 8, BimSR 20 μg was administered intracamerally to three eyes and topical therapy was continued in all eyes. At week 12, all topical therapy was discontinued and animals were monitored for another 4 weeks. IOP was measured with a TonoVet rebound tonometer in nonsedated animals weekly for 16 weeks.

Results: Average mean (standard deviation) IOP was 19.8 (1.6) mm Hg at baseline, 15.7 (0.9) mm Hg during treatment with topical latanoprost/dorzolamide/timolol from weeks 1 to 5, and 14.2 (0.5) mm Hg during weeks 6 to 8 after topical latanoprost was switched to topical bimatoprost. After BimSR was added, average mean IOP during weeks 9 to 12 was 10.8 (1.3) mm Hg, a decrease of 3.9 mm Hg compared with the topical-only arm. When topical therapy was discontinued, IOP in BimSR-treated eyes remained below that in unmedicated eyes (15.8 [0.9] vs. 20.2 [0.2] mm Hg at weeks 14-16).

Conclusions: Intracameral BimSR has IOP-lowering effects additive to those of topical bimatoprost, suggesting an additional mechanism of action with intracameral drug delivery.

Translational Relevance: Compared with topical bimatoprost, intracameral BimSR may have an additional mechanism of action of IOP lowering.
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http://dx.doi.org/10.1167/tvst.8.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355114PMC
January 2019

Dose-Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular Pressure.

J Ocul Pharmacol Ther 2019 04 30;35(3):138-144. Epub 2019 Jan 30.

Allergan plc, Irvine, California.

Purpose: To compare the dose-response profiles of bimatoprost sustained-release implant (Bimatoprost SR) and topical bimatoprost in lowering intraocular pressure (IOP) in normotensive beagle dogs.

Methods: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. IOP was measured at baseline and up to hour 6 each day. Other studies evaluated the IOP response to a single administration of Bimatoprost SR at dose strengths ranging from 8 to 120 μg. IOP was measured before implant administration and during 3 months of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control.

Results: Mean percentage decrease in IOP from baseline at hour 6 (peak effect) across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, respectively. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 months consistently increased with increasing dose strength and was 38.7% (7.2 mmHg) with Bimatoprost SR 120 μg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6% (5.9 mmHg).

Conclusions: Topical bimatoprost demonstrated a U-shaped dose-response curve; increasing the bimatoprost concentration to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, the dose-response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing maximum IOP lowering not yet determined. At 60- and 120-μg dose strengths, Bimatoprost SR produced greater IOP reductions than were achieved with topical dosing.
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http://dx.doi.org/10.1089/jop.2018.0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479235PMC
April 2019

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

Vet Ophthalmol 2018 Jul 19;21(4):376-381. Epub 2018 Feb 19.

Allergan plc, Irvine, CA, USA.

Objective: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs.

Methods: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 μg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 μg (n = 8) in one eye; IOP was evaluated through day 66.

Results: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes.

Conclusions: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.
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http://dx.doi.org/10.1111/vop.12522DOI Listing
July 2018

Pediatric Emergency Provider Sexually Transmitted Infection Screening Practices in Adolescents With Oropharyngeal or Anorectal Chief Complaints.

Pediatr Emerg Care 2020 Nov;36(11):e614-e619

From the Department of Pediatrics, Children's Hospital of Philadelphia.

Objectives: Sexually transmitted infections (STIs) may present with oropharyngeal or anorectal symptoms. Little is known about the evaluation of adolescents with these complaints in the pediatric emergency department (PED). This study aimed to determine the frequency of and factors associated with STI consideration and testing in this population.

Methods: Retrospective chart review of patients aged 13 to 18 years who presented to an urban PED with oropharyngeal or anorectal chief complaints between June 2014 and May 2015. Sexually transmitted infection consideration was defined as sexual history documentation, documentation of STI in differential diagnosis, and/or diagnostic testing. Multivariate logistic regression models were used to identify factors associated with consideration.

Results: Of 767 visits for oropharyngeal (89.4%), anorectal (10.4%), or both complaints, 153 (19.9%) had STI consideration. Of the 35 visits (4.6%) that included gonorrhea and/or chlamydia testing, 12 (34.3%) included testing at the anatomic site of complaint. Of those 12 tests, 50.0% were the incorrect test. Patients with older age (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI] = 1.3-1.7), female sex (aOR = 1.6, 95% CI = 1.03-2.5), or anorectal complaints (aOR = 2.4, 95% CI = 1.3-4.3) were more likely to have STI consideration.

Conclusions: In an urban PED, only 20% of visits for adolescents with oropharyngeal or anorectal symptoms included STI consideration. Testing was performed in only 5% of cases and often at an inappropriate anatomic site or with the incorrect test. Interventions to increase awareness of appropriate STI consideration and testing for individuals presenting with possible extragenital complaints may help reduce STIs among adolescents.
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http://dx.doi.org/10.1097/PEC.0000000000001414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077108PMC
November 2020

Pathogen Survey of Pulp and Paper Mill Biosolids Compared with Soils, Composts, and Sewage Biosolids.

J Environ Qual 2017 Sep;46(5):984-993

Regulatory policies to manage land application of organic materials are risk based, with focus on the quality of these residuals. The Ontario Ministry of the Environment and Climate Change (MOECC) determined that limited information was available on pulp and paper biosolids (PPB) with respect to human enteric pathogens. To address this data gap, MOECC conducted an extensive survey (2005-2006) across Ontario to characterize the microbiological quality of PPB. Quantitative testing was performed for fecal indicators (, enterococci, ) and enteric pathogens (, , , and ) using matrix-validated methods. Comparative benchmark materials (soils and soil amendments) were analyzed concurrently for risk comparison. Results showed that detection rates in PPB were low, 5 to 25% for pathogens and <55% for . , and were found at low frequency (6-8% of samples) and at low mean concentrations (2 most probable number g dry wt., 9 oocysts g dry wt., and 7 cells g dry wt., respectively). was more frequently observed (19% of samples), with a mean of 30 cysts g dry wt. Pathogen concentrations in PPB were generally equivalent to or higher than those in soils, composts, and pelletized sewage biosolids but significantly lower than in sewage biosolids. levels exceeded standards (1000 colony-forming units g dry wt.) in one-third of samples, most often in fresh PPB rather than stored and lagoon solids. Microbial quality of PPB across all surveyed mills tended to be variable and sector- and/or site-specific but in many cases would not consistently meet Canadian federal fertilizers standards. These findings were important to inform Ontario's nutrient management regulations, supporting classification of PPB as higher pathogen risk than compost and commercial fertilizers.
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http://dx.doi.org/10.2134/jeq2016.12.0467DOI Listing
September 2017

Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial.

Am J Ophthalmol 2017 Mar 22;175:137-147. Epub 2016 Dec 22.

Allergan plc, Irvine, California.

Purpose: To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR).

Design: Phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial.

Methods: At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 μg, 10 μg, 15 μg, or 20 μg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported.

Results: Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-μg, 10-μg, 15-μg, and 20-μg dose strengths of implant, respectively, vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes).

Conclusions: Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months.
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http://dx.doi.org/10.1016/j.ajo.2016.11.020DOI Listing
March 2017

The effect of topical latanoprost on anterior segment anatomic relationships in normal dogs.

Vet Ophthalmol 2013 Sep 10;16(5):370-6. Epub 2012 Dec 10.

College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.

Objective: Topical latanoprost 0.005% is commonly used in dogs with primary angle closure glaucoma (PACG), and marked miosis has been reported in the literature. To further explore the effect of topical latanoprost on anterior segment anatomy, we performed iridocorneal angle biometrics in normal beagle dogs.

Methods: Thirty-five normal female beagle dogs were assessed using anterior segment optical coherence tomography (AS-OCT). One eye of each dog was scanned with the AS-OCT in the superotemporal quadrant. One drop of latanoprost 0.005% was applied topically, and the OCT scan was repeated 30 min later. Images were imported into ImageJ, and pupil diameter, anterior chamber angle, angle opening distance, angle recess area (ARA), anterior chamber hemifield, and anterior chamber depth were measured.

Results: A single drop of latanoprost resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. The anterior segment parameters demonstrated a significant reduction (P-value ≤ 0.001) from baseline following latanoprost with the exception of the ARA (P = 0.07).

Conclusions: Latanoprost significantly decreases pupil diameter and narrows the iridocorneal angle in normal female beagle dogs. Therefore, the utility of latanoprost as a prophylactic treatment for PACG in fellow eyes may be limited. Studies using quantitative iridocorneal angle measurements in goniodysgenic dogs are warranted to understand the changes in iridocorneal angle morphology that occur in PACG in response to topical application of latanoprost.
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http://dx.doi.org/10.1111/vop.12011DOI Listing
September 2013

Iridocorneal angle measurements in mammalian species: normative data by optical coherence tomography.

Vet Ophthalmol 2013 Mar 22;16(2):163-6. Epub 2012 May 22.

Allergan, Inc. Irvine, CA, USA.

Objective  Gonioscopy provides limited quantitative information to compare the iridocorneal anatomy across different species. In addition, the anatomic relationships by histologic examination are altered during processing. As a result, the comparative anatomy of the iridocorneal angle across several mammalian species was evaluated by Optical Coherence Tomography (OCT). Methods  Cats, beagle dogs, minipigs, owl monkeys, cynomolgus monkeys, and rhesus monkeys (n = 6 or 7 per species) were evaluated. Imaging was performed using the OCT. The anterior chamber angle (ACA), angle opening distance (AOD), and the angle recess area (ARA) were evaluated. Results  AC angle: cat (63 ± 6°) > owl monkey (54 ± 4°) > beagle dog (42 ± 4°) > minipig (40 ± 3°) > rhesus monkey (36 ± 1°) > cynomolgus monkey (34 ± 2°). AOD: cat (3.3 ± 0.5 mm) > owl monkey (2.05 ± 0.2 mm) > beagle dog (1.08 ± 0.1 mm) > rhesus monkey (0.92 ± 0.06 mm) > minipig (0.64 ± 0.04 mm) > cynomolgus monkey (0.43 ± 0.03 mm). ARA: cat (3.5 ± 0.1 mm(2) ) > owl monkey (1.41 ± 0.2 mm(2) ) > dog (0.88 ± 0.1 mm(2) ) > rhesus monkey (0.62 ± 0.06 mm(2) ) > minipig (0.21 ± 0.05 mm(2) ) > cynomolgus monkey (0.15 ± 0.01 mm(2) ). Conclusions  This study benchmarks the normative iridocorneal angle measurements across different mammalian species by OCT. These data can be useful to compare iridocorneal angle measurements in disease states as OCT evolves as a common diagnostic tool in veterinary ophthalmic research and practice.
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http://dx.doi.org/10.1111/j.1463-5224.2012.01030.xDOI Listing
March 2013

Topical application of 0.005% latanoprost increases episcleral venous pressure in normal dogs.

Vet Ophthalmol 2012 Mar 30;15 Suppl 1:71-8. Epub 2011 Nov 30.

College of Veterinary Medicine, Colorado State University, 4408 John F Kennedy Parkway, Apt C202, Fort Collins, CO 80525, USA.

Introduction: Episcleral venous pressure (EVP) has an important role in intraocular pressure (IOP) homeostasis and accounts for more than 70% of the IOP in the normal dog. A frequently used species in glaucoma research is the normotensive dog especially when evaluating the efficacy of prostaglandin analogues and prostamides; however, aqueous humor dynamic studies in normal dogs are lacking, and the effect of 0.005% latanoprost on canine EVP is not known. We sought to determine the effects to the EVP of topically applied 0.005% latanoprost in the normotensive beagle dog.

Methods: Female beagle dogs (n = 14) were used and each had a normal ophthalmic examination on study entry. EVP was determined using a standard episcleral venomanometer. Animals were dosed in one eye with 0.005% latanoprost, and the effects on EVP were compared with the averaged baseline EVP's determined in the predosing phase and the fellow nondosed eye. The Mixed Model Repeated Measures method was used to analyze the EVP data.

Results: During the dosing phase of the study with topical 0.005% latanoprost, the mean EVPs of dosed eyes were significantly higher than that of nondosed eyes (P < 0.0001).

Conclusions: The increase in EVP in the dog with exposure to topical 0.005% latanoprost has not been observed in other species that have been studied, such as in the mouse and in humans, where the drug had no significant effect on the EVP. This response may be unique to dogs and suggests that dogs may not fully mimic human aqueous humor dynamics with topical 0.005% latanoprost. Although frequently performed in human studies, EVP should not be regarded to be a constant value in aqueous humor dynamic studies in the normal beagle dog.
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http://dx.doi.org/10.1111/j.1463-5224.2011.00970.xDOI Listing
March 2012

Gender differences in iridocorneal angle morphology: a potential explanation for the female predisposition to primary angle closure glaucoma in dogs.

Vet Ophthalmol 2012 Mar 17;15 Suppl 1:60-3. Epub 2011 Oct 17.

College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.

Objective: Female dogs have approximately twice the risk of males for developing primary angle closure glaucoma (PACG). The cause of this gender difference is unknown, but one theory proposes that the gender differences in iridocorneal angle morphology are involved in this risk differential.

Procedures: Fifty beagles (25 males, 25 females) were included into this study and had normal baseline ophthalmic examinations. Normal dogs were selected so as to avoid any potentially confounding influence of goniodysgenesis. Standardized 20-MHz high-resolution ultrasound images of the iridocorneal angle were acquired from one eye of each dog with the scan plane perpendicular to the limbus in the superior temporal quadrant. Images were imported into ImageJ, and the angle opening distance (AOD) and angle recess area (ARA) were measured by a masked observer, and the analysis of variance method was used to compare differences.

Results: The mean (±SD) AOD was significantly smaller for female dogs (0.847 ± 0.241 mm) vs. male dogs (1.058 ± 0.322 mm) P-value = 0.012. The mean (± SD) ARA tended to be smaller for female dogs (0.584 ± 0.278 mm) vs. male dogs (0.748 ± 0.385 mm), but this difference was not significant (P-value = 0.092).

Conclusions: Female dogs have a significantly smaller AOD vs. males. This difference may render the female iridocorneal angle more susceptible to closure and may partially explain the 2:1 female/male predisposition to PACG. Further studies using goniodysgenic dogs are warranted.
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http://dx.doi.org/10.1111/j.1463-5224.2011.00956.xDOI Listing
March 2012

Biodegradable implants for sustained drug release in the eye.

Pharm Res 2010 Oct 10;27(10):2043-53. Epub 2010 Jun 10.

Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612, USA.

The safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A critical factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliphatic polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.
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http://dx.doi.org/10.1007/s11095-010-0159-xDOI Listing
October 2010

Vitreous VEGF clearance is increased after vitrectomy.

Invest Ophthalmol Vis Sci 2010 Apr 17;51(4):2135-8. Epub 2009 Dec 17.

Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.

Purpose. Pars plana vitrectomy (PPV) has been reported to reduce macular thickness and improve visual acuity in patients with diabetic macular edema (ME). The hypothesis for the study was that after PPV, clearance is accelerated and VEGF concentrations are reduced. To test this hypothesis, hVEGF(165) injections were performed in rabbit eyes, with and without PPV, and vitreous VEGF levels were measured as a function of time. Methods. The PPV group rabbits had a bilateral 25-gauge PPV, and in the no-PPV group, rabbits had intact vitreous. Intravitreal injections of hVEGF(165) were performed, and the animals were euthanatized at time points up to 7 days. The vitreous was isolated and an enzyme-linked immunosorbent assay was used to measure the VEGF levels. Pharmacokinetic parameters were determined in a noncompartmental analysis approach. Results. Mean vitreous VEGF levels decreased more rapidly in eyes subjected to PPV than in no-PPV eyes. The vitreous VEGF half-life (t([)(1/2)(])) in PPV eyes was 10 times shorter than that in normal eyes. In addition, mean clearance and mean area under the curve (AUC) increased and decreased, respectively, in eyes that underwent PPV. Conclusions. VEGF clearance is increased after PPV. Reducing VEGF concentrations in the vitreous post-PPV may partially explain the improvement in macular thickness in some patients with ME. Unexpectedly, the half-life of VEGF in the vitreous, even in no-PPV eyes, was <3 hours, whereas compounds of similar molecular weight typically have longer vitreous half-lives. The back of the eye may be uniquely adapted with rapid-clearance mechanisms to regulate vitreous VEGF levels. Further study is suggested.
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http://dx.doi.org/10.1167/iovs.09-3582DOI Listing
April 2010

Recent advances in drug delivery systems for treating ocular complications of systemic diseases.

Curr Opin Ophthalmol 2009 Nov;20(6):511-9

Department of Biomedical Engineering, University of Southern California, Los Angeles, USA.

Purpose Of Review: To examine recent advances in the development of pharmacological agents and drug delivery systems for the treatment of ocular conditions associated with systemic diseases including diabetic retinopathy, retinal vein occlusion, uveitis, and HIV-related retinitis.

Recent Findings: Corticosteroids, vascular endothelial-derived growth factor antagonists, and anti-inflammatory agents have been investigated for treating ocular conditions associated with systemic diseases. Systemic pharmacotherapy for specifically treating eye diseases is discouraged as side effects may exacerbate preexisting conditions in patients with a debilitating systemic disease. Local therapy with injections into the vitreous has demonstrated varying degrees of efficacy and safety in treating certain ocular diseases; however, its usefulness in some cases can be limited by a short duration of action and the need for frequent readministration. Efforts have been underway to develop more effective drug delivery systems, such as sustained-release drug implants, to overcome these limitations.

Summary: Pharmacological agents are currently under investigation, and some have been FDA approved, for the treatment of ocular conditions associated with systemic disease. Advances in the development of drug delivery systems for these agents are expected to further improve the efficacy and safety of pharmacotherapy for ocular diseases in the future.
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http://dx.doi.org/10.1097/ICU.0b013e328330ccb9DOI Listing
November 2009

Novel drug delivery systems for retinal diseases. A review.

Ophthalmic Res 2009 26;41(3):124-35. Epub 2009 Mar 26.

Department of Biomedical Engineering, University of Southern California, Los Angeles, Calif, USA.

Introduction: Retinal diseases, such as macular edema from diabetic retinopathy and neovascular age-related macular degeneration, are important causes of visual impairment. Pharmacologic intervention has been employed, since laser can have limited success with improving vision. Topical eye drops and systemic therapy deliver low drug levels to the retina and the potential for systemic drug absorption and the accompanying side effects are high. As a result, transscleral and intravitreal drug delivery systems have had increasing importance in treating retinal diseases to deliver therapeutic drug concentrations and to limit the systemic drug exposure. Herein, we will review the novel drug delivery approaches for treating diabetic macular edema and neovascular age-related macular degeneration.

Material And Methods: A Medline search was performed to identify articles that described novel drug delivery systems for treating diabetic macular edema and neovascular age-related macular degeneration. Our review was limited to intravitreal drug delivery systems that have recently completed phase II/III clinical trials and/or have been approved by the US Food and Drug Administration.

Results: Journal articles were identified from the literature search and reviewed.

Conclusions: Local administration of drugs using primarily intravitreal delivery systems is important in treating retinal diseases. Novel drug delivery approaches for treating diabetic macular edema currently are focused on sustained-release corticosteroids. For neovascular age-related macular degeneration, frequent intravitreal injections of anti-vascular endothelial growth factor compounds are the standard of care. Unmet needs in this population are therapies that reduce the treatment burden and improve visual acuity in a greater proportion of patients.
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http://dx.doi.org/10.1159/000209665DOI Listing
May 2009

Developmental changes in the neural basis of interpreting communicative intent.

Soc Cogn Affect Neurosci 2006 Sep;1(2):107-21

Department of Psychology, University of California, Los Angeles, CA 90095, USA.

Understanding the intended meaning of a remark beyond what is explicitly stated is an integral part of successful social interactions. Here, we examined the neural circuitry underlying the interpretation of communicative intent in children and adults using irony comprehension as a test case. Participants viewed cartoon drawings while listening to short scenarios ending with a potentially ironic remark and were asked to decide whether the speaker was being sincere or ironic. In both children and adults, instructions to attend to the cues provided by the speaker's facial expression or tone of voice modulated the activity in visual and language cortices, respectively. Overall, children engaged the medial prefrontal cortex and left inferior frontal gyrus more strongly than adults, whereas adults recruited the fusiform gyrus, extrastriate areas and the amygdala more strongly than children. Greater involvement of prefrontal regions in children may subserve the integration of multiple cues to reconcile the discrepancy between the literal and intended meaning of an ironic remark. This developmental shift from a reliance on frontal regions to posterior occipitotemporal regions may reflect the automatization of basic reasoning about mental states. This study is the first to examine developmental changes in the neural circuitry underlying natural language pragmatics.
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http://dx.doi.org/10.1093/scan/nsl018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2555444PMC
September 2006

Reading affect in the face and voice: neural correlates of interpreting communicative intent in children and adolescents with autism spectrum disorders.

Arch Gen Psychiatry 2007 Jun;64(6):698-708

Department of Psychiatry, University of California, Los Angeles, USA.

Context: Understanding a speaker's communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion.

Objectives: To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity.

Design, Setting, And Participants: Eighteen boys with ASD (aged 7-17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles.

Main Outcome Measures: Blood oxygenation level-dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded.

Results: Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group x condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region.

Conclusions: Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.
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http://dx.doi.org/10.1001/archpsyc.64.6.698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713233PMC
June 2007

A pharmacokinetic and safety evaluation of an episcleral cyclosporine implant for potential use in high-risk keratoplasty rejection.

Invest Ophthalmol Vis Sci 2007 May;48(5):2023-9

National Eye Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.

Purpose: To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection.

Methods: CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year.

Results: A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year.

Conclusions: Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.
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http://dx.doi.org/10.1167/iovs.06-0985DOI Listing
May 2007

New corticosteroid-eluting porous polyethylene implant for the management of lower eyelid retraction: a pilot study.

Ophthalmic Plast Reconstr Surg 2006 Nov-Dec;22(6):424-9

The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Purpose: Lower eyelid retraction after trauma presents a challenging management problem. We postulated that a porous polyethylene (pPE) eyelid spacer coated with a polyvinyl alcohol (PVA) and triamcinolone acetonide (TA) matrix could deliver corticosteroid locally over extended periods and modulate inflammation and scar formation. We designed a pPE corticosteroid-eluting implant and evaluated its characteristics in vitro and in vivo.

Methods: The release characteristics of pPE implants coated with a PVA/TA matrix of low, intermediate, and high doses of TA were studied in vitro. The implants were then placed in the posterior lamella of lower eyelids of Dutch Belted rabbits for 12 weeks. Clinical events were recorded and eyelids were examined for gross and histologic features, including capsular thickness and degree of vascularity, fibrovascular ingrowth, and inflammatory response.

Results: In vitro, implants coated with the intermediate and high doses of TA released the drug at a steady rate for at least 78 days. In rabbits, the PVA and PVA/TA coating prevented fibrovascular ingrowth, except where breaks in the PVA/TA coat were present. Implants with PVA/TA coating demonstrated less inflammation and capsule vascularity. An inverse correlation between TA dose and capsule thickness was noted.

Conclusions: We describe a novel drug-release pPE eyelid implant. The corticosteroid-eluting implant demonstrated antiangiogenic and anti-inflammatory properties, which could prove beneficial in the treatment of lower eyelid retraction.
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http://dx.doi.org/10.1097/01.iop.0000245487.61479.56DOI Listing
January 2007

Outcomes of meniscal repair: minimum of 2-year follow-up.

Bull Hosp Jt Dis 2006 ;63(3-4):100-4

NYU-Hospital for Joint Diseases Department of Orthopaedic Surgery, New York, New York, USA.

Purpose: The purpose of this study was to determine the success rate of meniscal repair achieved in our sports medicine practice, particularly with interest in characterizing the outcomes observed with the newer all-inside repair devices.

Type Of Study: Retrospective chart review with telephone follow-up.

Methods: 157 patients that had undergone a meniscal repair procedure between 1996 and 2001 were identified. Twenty-four of these patients were lost to follow-up. Thus, the study group consisted of 133 patients providing a follow-up rate of 85%. All patients included had a minimum of two years of follow up. Failure was defined as the need for meniscectomy in the area of the meniscus that was initially repaired. The time interval from injury to surgery was divided into less than six weeks (acute) and greater than six weeks (chronic). The etiology of the meniscal tear was broken down into three categories; sports related trauma, non-sports trauma, and atraumatic. The repair techniques used in these patients included outside-in sutures, inside-out sutures, darts, arrows, meniscal screws, T-fix, FasT-fix, and the RapidLoc.

Results: The failure rate was 36%. No association was found between failure and the length of preoperative symptoms, rim width, etiology, concomitant meniscectomy, chondroplasty or anterior cruciate ligament (ACL) reconstruction. There was a higher rate of failure of tears in the medial versus lateral meniscus (20.3% vs. 44.8%). No statistical comparisons could be made between devices due to small sample sizes.

Conclusions: The all-inside meniscal repair devices have simplified the meniscal repair procedure. This may have lead to a broadening of the indications for repair

Clinical Relevance: The newer generation meniscal repair devices, while simplifying the procedure, do not appear to lead to an increased clinical success rate.
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November 2006

A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis.

Invest Ophthalmol Vis Sci 2006 Jun;47(6):2596-605

Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.

Purpose: To determine the feasibility, safety, and effectiveness of an episcleral or deep scleral lamellar sustained release cyclosporine (CsA) device in a naturally occurring animal model of uveitis.

Methods: A two-compartment perfusion chamber was used to assess in vitro human and equine scleral permeability of fluorescein, dexamethasone-fluorescein, or CsA. A biodegradable, matrix-reservoir CsA implant was designed, and release rates of CsA were determined in vitro. Tissue CsA levels were measured in eyes with the implant. Horses with equine recurrent uveitis (ERU) received episcleral or deep scleral lamellar CsA implants and were monitored for up to 3 years.

Results: Dexamethasone-fluorescein and CsA penetrated the in vitro equine sclera poorly; however, low but detectable levels of CsA were detected intraocularly in vivo. The implant placed episclerally failed to control inflammatory episodes in ERU. CsA implants placed in the deep sclera adjacent to the suprachoroidal space resulted in high levels of CsA in most ocular tissues. In clinical equine patients with ERU, frequency of uveitic flare-ups was significantly decreased after implantation of a deep scleral lamellar CsA implant.

Conclusions: Diffusion of CsA across the sclera from the episcleral space was not a feasible method of drug delivery to the equine eye. However, placing a deep scleral lamellar CsA implant adjacent to the suprachoroidal space was effective in achieving therapeutic ocular drug concentrations and controlling uveitis in horses with ERU.
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http://dx.doi.org/10.1167/iovs.05-1540DOI Listing
June 2006

Neural basis of irony comprehension in children with autism: the role of prosody and context.

Brain 2006 Apr 15;129(Pt 4):932-43. Epub 2006 Feb 15.

Department of Psychology, University of California, Los Angeles, CA, USA.

While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.
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http://dx.doi.org/10.1093/brain/awl032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713234PMC
April 2006

A functional magnetic resonance imaging study of discourse coherence in typically developing children.

Neuroreport 2005 Oct;16(15):1661-5

Ahmanson-Lovelace Brain Mapping Center, University of California at Los Angeles, 90095, USA.

Using functional magnetic resonance imaging and a previously validated activation paradigm, we investigated the neural networks involved in detecting discourse coherence in a sample of typically developing children. Study participants listened to short question-answer dialogues and determined whether the answers made sense. Consistent with prior adult findings, when this decision involved an implicit appraisal of the conversation logic, frontotemporal activity was strongly left lateralized. In contrast, when this determination involved detecting a change in the conversation topic, activity in frontotemporal regions was bilateral, with a right hemisphere bias. Despite behavioral performance differences, children and adults showed remarkably similar activation profiles when making sense of conversation, indicating that the neural architecture subserving this fundamental communicative function is established relatively early during normal development.
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http://dx.doi.org/10.1097/01.wnr.0000183332.28865.11DOI Listing
October 2005

A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide.

Exp Eye Res 2006 Mar 15;82(3):479-87. Epub 2005 Sep 15.

National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Transscleral delivery of triamcinolone acetonide into the vitreous using sub-Tenon's injections may be a safer alternative to reduce the sight-threatening complications of direct intravitreal injections. However, sub-Tenon's injections have demonstrated low and poorly sustained vitreous drug levels in animal studies. To improve our understanding of the clearance mechanisms of corticosteroids, we evaluated vitreous drug levels following sub-Tenon's injection of triamcinolone acetonide in rabbits with selective elimination of conjunctival lymphatic/blood vessels and the choroid. Pigmented rabbits were given a sub-Tenon's injection of a preservative-free triamcinolone acetonide formulation of either a 10- or 20-mg dose in the superotemporal quadrant. The effect eliminating both conjunctival and choroidal clearance was evaluated by injecting the drug, followed by immediate euthanasia, effectively terminating both lymph and blood flow in the conjunctiva and choroid. To inhibit only the clearance from conjunctival lymphatics/blood vessels of a sub-Tenon's injection of triamcinolone acetonide, a group of rabbits had a 'conjunctival window' created by incising an 7 mmx7 mmx7 mm square through the conjunctiva to bare sclera in the superotemporal quadrant. To eliminate only the clearance of drug from the choroidal circulation, cryotherapy was performed in another group of rabbits creating a chorioretinal scar in the superotemporal quadrant. Following the sub-Tenon's drug injection, the eyes were enucleated in all groups after 3 hr and vitreous drug levels were measured with HPLC. In normal animals, a 10-mg sub-Tenon's injection showed no detectable vitreous drug levels; however, a 20-mg injection showed positive vitreous drug levels. This suggested that collectively, the transscleral clearance mechanisms inhibiting delivery into the vitreous may be saturated with a drug depot that has a higher release rate. A 10-mg sub-Tenon's drug depot was able to deliver drug into the vitreous when both the conjunctival and choroidal drug clearance was eliminated by euthanizing the animal immediately following the drug injection. In rabbits that had only a 'conjunctival window', selectively eliminating conjunctival drug clearance, vitreous drug levels were detected. However, in rabbits that had only cryotherapy, selectively eliminating choroidal drug clearance, vitreous drug levels were not detected suggesting that the conjunctival lymphatics/blood vessels may be an important barrier to the transscleral delivery of triamcinolone acetonide. Variability in the vitreous drug levels between rabbits in each group precluded statistical testing. In summary, the rabbit appeared to demonstrate saturable ocular barriers to transscleral delivery of triamcinolone acetonide into the vitreous following a sub-Tenon's injection. The results suggested that the conjunctival lymphatics/blood vessels may be an important barrier to the delivery of triamcinolone acetonide to the vitreous in this rabbit model. The barrier location and clearance abilities of the ocular tissues are important to consider when developing a successful transscleral drug delivery system. Animal models, retaining the dynamics of blood and lymph flow, may improve the basic understanding of the ocular barriers involved with transscleral drug transport and warrants further investigation.
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http://dx.doi.org/10.1016/j.exer.2005.08.007DOI Listing
March 2006

Metaphorical vs. literal word meanings: fMRI evidence against a selective role of the right hemisphere.

Neuroimage 2006 Jan 13;29(2):536-44. Epub 2005 Sep 13.

Department of Psychiatry and Biobehavioral Sciences, Ahmanson-Lovelace Brain Mapping Center, UCLA, 660 Charles Young Drive South, Los Angeles, CA 90095, USA.

The neural networks associated with processing metaphorical word meanings were investigated in normal adults using fMRI. Subjects listened to sets of three adjectives and decided whether the last two had a similar meaning. One condition required accessing the literal meaning of the middle word (e.g., hot-cold-chilly), whereas the other condition required accessing its nonliteral, or metaphorical, meaning (e.g., hot-cold-unfriendly). Direct comparison of the nonliteral vs. literal condition showed reliable activity only in left prefrontal and temporo-parietal regions. These results argue against a selective role of the right hemisphere (RH) in accessing metaphorical word meanings. In line with a growing literature, these findings suggest that prior reports of greater RH involvement for metaphorical language might reflect the increased complexity of figurative language rather than an RH specialization for understanding metaphors.
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http://dx.doi.org/10.1016/j.neuroimage.2005.08.003DOI Listing
January 2006

Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease.

Invest Ophthalmol Vis Sci 2005 Feb;46(2):655-62

National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1863, USA.

Purpose: To develop a local drug delivery system that provides therapeutic cyclosporine levels to treat lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Methods: Episcleral cyclosporine implants were manufactured with a silicone-based matrix design, and in vitro release rates were determined. Preclinical evaluation included toxicology (clinical examination, serial electroretinography, and histopathology) in normal rabbits and dogs, pharmacokinetics in normal rabbits, and pharmacodynamics in a canine model of aqueous tear deficiency and keratoconjunctivitis sicca.

Results: The cyclosporine implants showed sustained release of drug over time with in vitro assays. Histopathology showed normal ocular tissues in both dogs and rabbits 6 months after implantation. The cyclosporine implant produced lacrimal gland drug levels 1 to 2 log units higher than those reported with a variety of topical cyclosporine formulations and oral administration. The cyclosporine implant was effective in a canine model of keratoconjunctivitis sicca, with all animals able to discontinue topical cyclosporine and maintain normal Schirmer scores over a 6-month follow-up.

Conclusions: This preclinical evaluation showed that the episcleral cyclosporine implant was safe, delivered potentially therapeutic cyclosporine levels to the lacrimal gland, and showed efficacy in a clinically relevant model of keratoconjunctivitis sicca. The episcleral cyclosporine implant shows promise in reducing the morbidity associated with lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. In addition, continuous release of cyclosporine in the subconjunctival space with the episcleral implant was an effective means of delivering drug to the ocular surface and may have potential in treating other ocular inflammatory diseases.
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http://dx.doi.org/10.1167/iovs.04-1076DOI Listing
February 2005

Conjunctival involvement with T-cell prolymphocytic leukemia: report of a case and review of the literature.

Surv Ophthalmol 2004 Sep-Oct;49(5):525-36

National Eye Institute, NIH, Bethesda, Maryland 20892-1863, USA.

T-cell prolymphocytic leukemia is a rare and highly aggressive hematological neoplasm. A patient with T-cell prolymphocytic leukemia presented with bilateral perilimbal conjunctival infiltrates. Conjunctival biopsy showed aggregates of large atypical lymphocytes in the substantia propria with a concentration of atypical cells in the perivascular areas. Immunophenotyping of the malignant cells identified an abnormal clonal T-cell population consistent with T-cell prolymphocytic leukemia. A literature review of all reports of conjunctival involvement with leukemia was performed. The three cases of ocular prolymphocytic leukemia, including the one case of ocular T-cell prolymphocytic leukemia, are discussed in detail as well as 14 reported clinical cases of biopsy-proven conjunctival leukemia. The majority of cases occurred in the setting of acute leukemia, and conjunctival involvement was frequently a presenting sign of the disease or signified disease relapse. Conjunctival involvement with leukemia was consistent with good visual acuity; however, it portended a poor prognosis.
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http://dx.doi.org/10.1016/j.survophthal.2004.06.005DOI Listing
November 2004

Selective loss of imprinting in the placenta following preimplantation development in culture.

Development 2004 Aug 7;131(15):3727-35. Epub 2004 Jul 7.

Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Preimplantation development is a period of dynamic epigenetic change that begins with remodeling of egg and sperm genomes, and ends with implantation. During this time, parental-specific imprinting marks are maintained to direct appropriate imprinted gene expression. We previously demonstrated that H19 imprinting could be lost during preimplantation development under certain culture conditions. To define the lability of genomic imprints during this dynamic period and to determine whether loss of imprinting continues at later stages of development, imprinted gene expression and methylation were examined after in vitro preimplantation culture. Following culture in Whitten's medium, the normally silent paternal H19 allele was aberrantly expressed and undermethylated. However, only a subset of individual cultured blastocysts (approximately 65%) exhibited biallelic expression, while others maintained imprinted H19 expression. Loss of H19 imprinting persisted in mid-gestation conceptuses. Placental tissues displayed activation of the normally silent allele for H19, Ascl2, Snrpn, Peg3 and Xist while in the embryo proper imprinted expression for the most part was preserved. Loss of imprinted expression was associated with a decrease in methylation at the H19 and Snrpn imprinting control regions. These results indicate that tissues of trophectoderm origin are unable to restore genomic imprints and suggest that mechanisms that safeguard imprinting might be more robust in the embryo than in the placenta.
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http://dx.doi.org/10.1242/dev.01241DOI Listing
August 2004

Post-surgical scleritis associated with the ganciclovir implant.

Ophthalmic Surg Lasers Imaging 2004 May-Jun;35(3):254-5

National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1863, USA.

Although the ganciclovir implant is an effective and well-tolerated treatment for cytomegalovirus retinitis in patients with human immunodeficiency virus infection, complications that may occur include retinal detachment, implant extrusion, and endophthalmitis. A 22-year-old woman with human immunodeficiency virus infection presented with a painful left eye with scleritis overlying previous ganciclovir implant sclerotomy sites. The inflammation progressed 360 degrees around the pars plana with progressive thinning at the implant sites. Post-surgical necrotizing scleritis is another complication that can occur in patients with ganciclovir implants.
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July 2004

Fibrovascular changes misdiagnosed as cytomegalovirus retinitis reactivation in a patient with immune recovery.

Clin Infect Dis 2004 Jan 5;38(1):139-41. Epub 2003 Dec 5.

National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1863, USA.

A patient with human immunodeficiency virus infection and cytomegalovirus (CMV) retinitis developed immune recovery uveitis as a result of receipt of highly active antiretroviral therapy. Fibrovascular changes occurred in the CMV retinitis scar, were misdiagnosed as CMV retinitis reactivation, and were treated with anti-CMV medication. Fibrovascular membranes can be misdiagnosed as reactivated CMV retinitis, and a proper diagnosis is essential to avoid unnecessary therapy with potentially toxic antiviral medications.
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http://dx.doi.org/10.1086/380127DOI Listing
January 2004