Volume 4, Number 19

Monday, May 10, 2004

In this issue: (click heading to view article)
		Bone Marrow-derived Stem Cells Target Neovascularization in Developing Retinas
		Association Between Chlamydia psittaci and Ocular Adnexal Lymphomas
		Doxycycline"s Role in Ocular Surface Repair
		Corneal Healing After Uncomplicated LASIK and Its Relationship to Refractive Changes
		Human Leukocyte Antigen Subtypes and ACE Gene Polymorphisms: Risk Markers for Severe Diabetic Retinopathy?
		Briefly

Bone Marrow-derived Stem Cells Target Neovascularization in Developing Retinas Adult bone marrow contains a population of hematopoietic stem cells (HSCs) that can give rise to cells capable of targeting sites of neovascularization in the peripheral or retinal vasculature. However, relatively little is known about the mechanism of targeting of these cells to sites of neovascularization. Investigators at California"s Scripps Research Institute analyzed subpopulations of HSCs for the expression of a variety of cell surface adhesion molecules and found that R-cadherin, a calcium-dependent cell-cell adhesion molecule important for normal retinal endothelial cell guidance, was preferentially expressed by functionally targeting HSCs. Preincubation of HSCs with function-blocking anti-R-cadherin antibodies or novel R-cadherin-specific peptide antagonists effectively prevented targeting of bone marrow-derived cells to the developing retinal vasculature in vivo. Whereas control-injected HSCs targeted to all three normal developing retinal vascular layers, blocking R-cadherin-mediated adhesion resulted in mistargeting of the HSCs to the normally avascular outer retina. The results of this study suggest that vascular targeting of bone marrow-derived HSCs is dependent on mechanisms similar to those used by endogenous retinal vascular endothelial cells. Thus, R-cadherin antagonists may be useful in treating neovascular diseases in which circulating HSCs contribute to abnormal angiogenesis.

SOURCE: Dorrell MI, Otani A, Aguilar E, et al. Adult bone marrow-derived stem cells use R-cadherin to target sites of neovascularization in the developing retina. Blood 2004;103(9):3420-7.

Association Between Chlamydia psittaci and Ocular Adnexal Lymphomas Ocular adnexal lymphomas may be antigen-driven disorders; however, the source of the putative antigen or antigens is unknown. A study by the San Raffaele H. Scientific Institute and the IRCCS National Cancer Institute in Italy assessed whether Chlamydiae infection is associated with the development of ocular adnexal lymphomas. Researchers investigated the presence of Chlamydia psittaci, C. trachomatis and C. pneumoniae DNA using polymerase chain reaction (PRC) in 40 ocular adnexal lymphoma samples, 20 nonneoplastic orbital biopsies, 26 reactive lymphadenopathy samples and peripheral blood mononuclear cells (PBMCs) from 21 lymphoma patients and 38 healthy individuals. They treated seven patients with Chlamydia-positive PBMCs with the antibiotic doxycycline and assessed the objective response in four patients with measurable lymphoma lesions. Differences in Chlamydiae DNA detection between the case patients and the control subjects were analyzed using the Fisher exact test. All statistical tests were two-sided. Of the 40 ocular adnexal lymphoma samples, 32 (80 percent) carried C. psittaci DNA, whereas all lymphoma samples were negative for C. trachomatis and C. pneumoniae. In contrast, none of the 20 nonneoplastic orbital biopsies and only three of 26 (12 percent) reactive lymphadenopathy samples (12 percent vs. 80 percent) carried the C. psittaci DNA. Nine of 21 (43 percent) patients with Chlamydia-positive lymphomas carried C. psittaci DNA in their PBMCs, whereas none of the healthy PBMC donors carried C. psittaci DNA in their PBMCs (43 percent versus 0 percent). One month after doxycycline treatment, chlamydial DNA was no longer detectable in the PBMCs of all seven treated patients, and objective response was observed in two of the four evaluable patients. Authors of the study concluded that patients with ocular adnexal lymphoma had a high prevalence of C. psittaci infection in both tumor tissue and PBMCs, and that persistent C. psittaci infection may contribute to the development of these lymphomas. This was also supported by the clinical responses observed in this study with C. psittaci-eradicating antibiotic therapy.

SOURCE: Ferreri AJM, Guidoboni M, Ponzoni M, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Nat Cancer Instit 2004;96(8):586-94.

Doxycycline"s Role in Ocular Surface Repair Doxycycline is a broad-spectrum antibiotic that chelates metal ions and is frequently used as part of the treatment of ocular surface diseases. Its therapeutic value has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and interleukin (IL)-1 synthesis. The aim of this study by the University of Bristol, UK, was to evaluate the role of doxycycline as an inhibitor of corneal MMPs and assess its contribution to ocular surface repair mechanisms. Researchers grew corneal epithelial cell and keratocyte cultures to confluence and incubated with IL-1alpha, LPS, doxycycline or doxycycline and LPS in serum-free medium for four days. The cells were then either harvested and assayed for caspase-3 activity or stained with either AE5 or antivimentin antibodies. Researchers concentrated and assayed media samples for MMP activity by zymography or using a fluorigenic substrate. They used Enzyme-Linked Immunosorbent Assay to quantify IL-1alpha, MMPs -1,-2,-3 and -9, and tissue inhibitor of metalloproteinase (TIMPs)-1 and -2. IL-1alpha and LPS had no effect on MMP/TIMP production by cultured corneal epithelial cells and keratocytes. Corneal MMP-2 inhibition by doxycycline was partially Ca2+dependent but irreversible. At the minimum inhibitory concentration, 100 µm, doxycycline had no apparent effect on MMP and TIMP production, but ultimately caused the death of keratocytes and some of the epithelial cells that detached from their basement membrane. Caspase-3 activity was not detected in dead or dying keratocytes. The mechanism of cell death in cultured corneal epithelial cells was not caspase-3 related apoptosis, since the activity of this enzyme, normally detectable, was lost. The epithelial cells that survived doxycycline treatment did not bind antivimentin antibody, and compared with controls, they reacted less with the AE5 antibody. Investigators presume that they were most likely transient amplifying cells. The authors of the study point out that the therapeutic value of doxycycline may depend upon its effective concentration at the ocular surface and probably relates to its chelating properties.

SOURCE: Smith VA, Cook SD. Doxycycline--a role in ocular surface repair. Br J Ophthalmol 2004;88(5):619-25.

Corneal Healing After Uncomplicated LASIK and Its Relationship to Refractive Changes A weak but significant negative correlation between the thickness of the keratocyte activation zone and spheroequivalent refraction occurs after LASIK, according to a six-month prospective confocal study by the Louisiana State University Eye Center. The different refractive properties of activated keratocytes may be responsible for the myopic shift after LASIK. Investigators examined 20 eyes of 10 patients who underwent LASIK for myopia clinically and by real-time confocal microscopy for six months. They measured epithelial and posterior stromal thicknesses and the thickness of the keratocyte activation zone, and they compared refractive changes with these values. They also studied keratocyte morphology, flap thickness and sub-basal nerve fiber bundle morphology after LASIK. Results showed no significant change over time in epithelial thickness after LASIK treatment; however, the posterior stromal thickness was significantly higher one month after surgery. Researchers detected a slight but statistically significant negative correlation between the thickness of the keratocyte activation zone and the spheroequivalent refraction after LASIK. The sub-basal nerve fiber bundle’s morphology returned to its preoperative appearance six months after LASIK, but in the flap stroma and the nerve fiber bundle, morphology remained abnormal at six months after LASIK surgery. Authors of the study note that further investigation is necessary to clarify their hypothesis.

SOURCE: Avunduk AM, Senft CJ, Emerah S, et al. Corneal healing after uncomplicated LASIK and its relationship to refractive changes: a six-month prospective confocal study. Invest Ophthalmol Vis Sci 2004;45:1334-9.

Human Leukocyte Antigen Subtypes and ACE Gene Polymorphisms: Risk Markers for Severe Diabetic Retinopathy? Malmo, Sweden"s University Hospital Department of Ophthalmology tested the hypothesis that human leukocyte antigens (HLA)-DRB1, -DQA1, and -DQB1 subgroups or angiotensin-converting enzyme (ACE) gene polymorphisms are associated with severe retinopathy in younger Type I diabetic patients. Researchers compared 24 Type I diabetic patients who had received panretinal photocoagulation for severe nonproliferative or proliferative diabetic retinopathy with 24 Type I diabetic patients (participating in a photographic screening program with regular fundus examinations) with no or minimal retinopathy, matched for age at onset and duration of diabetes. The HLA-DRB1-DQA1-B1 haplotype 04-03-0302 represented 46 percent in the severe and 44 percent in the no/minimal retinopathy group, respectively. The most common genotype, 03-0501-0201/04-03-0302, occurred in 33 percent of those with severe retinopathy and 42 percent with no/minimal retinopathy, respectively. No statistical differences occurred between patients with severe and no/minimal retinopathy, regardless of whether DRB1, DQA1, or DQB1 alleles, haplotypes, or genotypes were analyzed. The ACE gene polymorphism was almost identical between patients with severe and no/minimal retinopathy, and serum ACE levels did not differ. The authors of the study concluded that in a small group with carefully characterized diabetic retinopathy phenotypes, there was no indication that HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms were associated with severe retinopathy in younger Type I diabetic patients.

SOURCE: Agardh E, Gaur LK, Lernmark A, Agardh CD. HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms do not seem to be risk markers for severe retinopathy in younger Type 1 diabetic patients. J Diabetes Comp 2004;18(1):32-6.

 

BRIEFLY ALLERGAN A PARTNER IN NEI-SPONSORED MACULAR EDEMA CLINICAL TRIALS. Allergan, Inc. was recently selected as a partner to supply its ophthalmic formulation of triamcinolone for two National Eye Institute (NEI)-sponsored clinical trials on macular edema. The multi-center, randomized trials will investigate the efficacy and safety of the new intravitreal triamcinolone formulation for macular edema associated with diabetic retinopathy, which will be studied through the Diabetic Retinopathy Clinical Research Network (DRCR.net) and retinal vein occlusion, which will be studied through the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study. Under the agreement, Allergan will be responsible for all costs associated with drug development, manufacturing, pharmacokinetic studies and regulatory aspects of the trials. In addition, the company will pay a total of $1.8 million to DRCR.net and SCORE coordinating centers for the conduct of the trials. VIGAMOX APPROVED FOR ADDITIONAL SUSCEPTIBLE PATHOGENS. Alcon, Inc. has received FDA approval to add a supplemental list of susceptible pathogens to the in vitro labeling of Vigamox ophthalmic solution (moxifloxacin hydrochloride 0.5%), a fourth-generation fluoroquinolone eye drop. An additional 22 pathogens will be added to the in vitro efficacy section of the product"s package insert, including atypical mycobacteria (M. avium and M. marinum and Propionibacterium acnes), Listeria monocytogenes and several Streptococcus species.

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