Volume 5, Number 40
Monday, October 10, 2005



In this issue: (click heading to view article)
Evidence Suggesting the Existence of Stem Cells for the Human Corneal Endothelium
UBM for Diagnosing and Managing Anterior Segment Tumors
Normal VF Test Results Following Glaucomatous VF End Points in OHTS
Baseline Topographic Optic Disc Measurements and Development of POAG
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Evidence Suggesting the Existence of Stem Cells for the Human Corneal Endothelium

The reluctance of human corneal endothelial cells (HCECs) to divide has continually intrigued investigators. Related to this, the discovery of an increased endothelial cell population in the periphery of the human cornea has prompted an investigation for evidence of the existence of stem-like cells in the endothelial periphery. Researchers at the University of Alabama and Emory University (Atlanta) conducted a study aimed at showing that stem cells or transient amplifying cells may exist in the periphery of the cornea, which might explain the origin of HCECs and indicate a source for these cells in wound repair.

The researchers obtained human corneas with attached scleral rims from eye banks and assayed them for telomerase activity and bromodeoxyridine (BrdU) incorporation to determine, respectively, the presence of a stem-like cell marker and replicative activity. In the case of telomerase activity, they divided the tissues into central, intermediate and peripheral areas using trephines. They performed BrdU staining on whole corneas plus scleral rims exposed to BrdU antibodies on the endothelial side, whereas BrdU fluorescence was obtained from transverse sections of the these tissues by the same procedure. Some corneas were wounded to determine whether the wounded areas stimulated BrdU (by staining or fluorescence) followed by the synthesis of transforming growth factor beta (TGF-beta). The latter was determined by quantitative ELISA. Rabbit corneas were also assayed for BrdU incorporation to compare their evidence of cell division with that of humans.

After corneas were divided into central, intermediate and peripheral sections, the dissected endothelial tissues exhibited positive telomerase activity in the peripheral and intermediate sections. There was no activity in the central endothelial tissues or the limbus between the trabecular meshwork and Schwalbe's line. BrdU staining with alkaline phosphatase was occasionally observed in the wounded area's human corneal endothelial cells after wounding. When BrdU fluorescence assays were made on corneal transverse sections with fluorescein, fluorescence occurred in an area just at and adjacent to the trabecular meshwork, but was not at the corneal endothelium. After wounding, BrdU fluorescence extended into the corneal endothelium. TGF-beta levels were increased in fluids bathing the endothelium following wounding, but the increases lagged behind the wounding event.

The authors suggest that stem-like cells may be sequestered in a niche at the junctional region where the corneal endothelial cells and the trabecular meshwork come together. These putative stem cells may supply new cells for both the corneal endothelium and the trabeculae. Evidence suggests that cells from this area migrate (perhaps as transient amplifying cells) to the endothelial periphery and, perhaps, to wounded areas of the corneal endothelium when needed. The migration may not be constant and may be age dependent.

SOURCE: Whikehart DR, Parikh CH, Vaughn AV, et al. Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis. 2005;11:816-24.
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UBM for Diagnosing and Managing Anterior Segment Tumors

This study sought to evaluate ultrasound biomicroscopy (UBM) in the management of anterior segment tumors. Investigators conducted a retrospective analysis of medical records of consecutive patients referred to the ocular oncology unit, University of California-San Francisco (UCSF), for suspected anterior segment tumors from 1999 to 2004.

The researchers evaluated 132 eyes from 130 patients, which included 55 uveal melanomas (UM), 21 iris nevi, 30 iris cysts and 26 remaining lesions. Of the melanomas, 45 were also evaluated with conventional A/B-scan. There was 29 percent correspondence between the anatomical structures invaded by melanoma as identified by B-scan vs. disease extent defined by UBM. Ciliary body and peripheral iris involvement by melanomas was significantly more frequently observed by UBM than B-scan. Seven of 30 benign cysts were diagnosed as cystic before UBM evaluation. In three cases, neuroepithelial cysts were associated with intercurrent pathology including iris nevus (two cases) and ciliary body melanoma (one case). Two ciliary body melanomas showed cavitation, including one patient with a pseudocyst. Histopathological correlation was possible in six cases.

The authors believe their results show that UBM is an indispensable tool for managing anterior segment tumors. They maintain that the study demonstrates the superiority of UBM vs. conventional B-scan for the precise localization of uveal melanoma, especially involving the ciliary body and peripheral iris.

SOURCE: Conway RM, Chew T, Golchet P, et al. Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. Br J Ophthalmol. 2005 Aug;89(8):950-5.
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Normal VF Test Results Following Glaucomatous VF End Points in OHTS

The University of California-Davis conducted this study of the Ocular Hypertension Treatment Study (OHTS) results to compare the occurrence of normal visual field (VF) test results following two vs. three consecutive, abnormal and reliable test results in OHTS.

Sixty-four participants (68 eyes) out of a total of 1,636 participants in OHTS developed a VF primary open-angle glaucoma (POAG) end point. Investigators compared the proportion of normal VF test results after a VF POAG end point among eyes whose VF abnormality was confirmed by two (nine eyes) vs. three (59 eyes) consecutive, abnormal and reliable VF test results.

The proportion of VF test results that were normal subsequent to a VF POAG end point in eyes whose abnormality was confirmed by two consecutive, abnormal and reliable test results was significantly higher (73 of 110, or 66 percent) compared with eyes whose abnormality was confirmed by three consecutive, abnormal and reliable test results (46 of 381, or 12 percent). The authors of this study conclude that a VF POAG end point confirmed by three consecutive, abnormal and reliable VF test results appears to have greater specificity and stability than either one or two consecutive, abnormal and reliable VF test results. However, some eyes whose VF POAG end point was confirmed by three consecutive, abnormal, reliable test results nonetheless had one or more normal test results on follow-up.

SOURCE: Keltner JL, Johnson CA, Levine RA, et al. Normal visual field test results following glaucomatous visual field end points in the Ocular Hypertension Treatment Study. Arch Ophthalmol 2005; Sep;123(9):1201-6.
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Baseline Topographic Optic Disc Measurements and Development of POAG

The Confocal Scanning Laser Ophthalmoscopy (CSLO) Ancillary Study to the Ocular Hypertension Treatment Study, conducted by University of San Diego’s Hamilton Glaucoma Center and Diagnostic Imaging Laboratory, aimed to determine whether baseline CSLO optic disc topographic measurements are associated with the development of primary open-angle glaucoma (POAG) in individuals with ocular hypertension.

A total of 865 eyes from 438 participants who had good-quality baseline CSLO images were included in this study. Each baseline CSLO parameter was assessed in univariate and multivariate proportional hazards models to determine its association with the development of POAG.

Forty-one eyes from 36 CSLO Ancillary Study participants developed POAG. Several baseline topographic optic disc measurements were significantly associated with the development of POAG in both univariate and multivariate analyses, including larger cup-disc area ratio, mean cup depth, mean height contour, cup volume, reference plane height, smaller rim area, rim area to disc area and rim volume. In addition, classification as "outside normal limits" by the Heidelberg Retina Tomograph classification and the Moorfields Regression Analysis classifications (overall, global, temporal inferior, nasal inferior and superior temporal regions) was significantly associated with the development of POAG. Within the follow-up period of this analysis, the positive predictive value of CSLO indexes ranged from 14 percent (Heidelberg Retina Tomograph classification and Moorfields Regression Analysis overall classification) to 40 percent for Moorfields Regression Analysis temporal superior classification.

The authors of this study believe that longer follow-up is required to evaluate the true predictive accuracy of CSLO measures.

SOURCE: Zangwill LM, Weinreb RN, Beiser JA, et al. Baseline topographic optic disc measurements are associated with the development of primary open-angle glaucoma: the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study. Arch Ophthalmol. 2005 Sep;123(9):1188-97.
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BRIEFLY
  • ALLERGAN ALLIES WITH SIRNA FOR RNAi-BASED AMD THERAPY. Sirna Therapeutics, Inc. and Allergan, Inc. have formed a multi-year alliance to develop Sirna-027, a novel RNAi-based therapeutic currently in Phase I trials for treating age-related macular degeneration (AMD), and to discover and develop other novel RNAi-based therapeutics against selected gene targets in ophthalmic diseases. Under terms of the agreement, Sirna will receive an initial payment of $5 million and will be eligible for development milestones of as much as $245 million, in addition to research funding and royalties on the worldwide sales of products resulting from the alliance. Sirna also will receive contract manufacturing revenues. Allergan will assume all development and future commercialization responsibilities for Sirna-027 and will contribute its proprietary ocular drug delivery technologies for the administration of RNAi-based therapeutics. Sirna will develop optimized lead compounds against Allergan's identified gene targets; Allergan will be responsible for all pre-clinical, clinical and commercialization activities for those compounds. The companies will form a Joint Steering Committee to oversee the alliance and move Sirna compounds through Allergan's discovery and development pipeline.
  • COMBIGAN RECEIVES POSITIVE OPINIONS FROM 21 COUNTRIES IN EUROPEAN UNION. Allergan, Inc. has received positive opinions from all 21 Concerned Member States included in the Combigan Mutual Recognition Procedure (MRP) for the European Union for Combigan, its Alphagan/timolol (brimonidine tartrate/timolol ophthalmic solution) combination product. Combigan is indicated for reduction of intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers. Allergan received notification of the positive opinions from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, which acted as the Reference Member State for the MRP. Marketing authorization and national licenses for Combigan are expected to be issued within the next few months, after each country assesses the local product labeling; this will make Combigan available in all countries of the European Union.
  • LEARNING RETINAL IMPLANT SYSTEM TO BEGIN CLINICAL TRIAL. Intelligent Medical Implants AG (IMI), a neuro-prosthetics device company, has completed development of its first-generation Learning Retinal Implant System, containing a 50-electrode device. The company will begin a clinical study of this device in 2005 at the University of Hamburg (Germany) Medical School; IMI expects to announce preliminary results of study by year’s end. The system is designed to replace the signal-processing functions of a healthy retina and provide input to the retinal nerve cells, which in turn provide input to the optic nerve and the brain. The system is comprised of an implant, which is surgically placed into the eye of a patient; a pair of spectacles containing an integrated mini-camera and transmitter components for wireless signal and energy transmission; and a Pocket Processor, worn at the patient's waist and connected to the spectacles via a cable. The device replaces the information processing function of the formally healthy retina. A high-speed digital signal processor allows the provision of "intelligent information" to the implant (and the nerve cells) by using tuneable software to approximate the information processing normally carried out by the healthy retina. In a previous multi-site European clinical study performed with a single-IMI-electrode protocol, independent researchers reported that 19 of 20 totally blind patients (95 percent) were able to see a small point of light. The initial target market for the system is those who are blind with retinitis pigmentosa; IMI believes that the system will allow these patients to "see" objects by identifying their size, position, movements and shapes. For more information, go to www.intmedimplants.com.


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