Minas T. Coroneo

Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases.

Pterygium is a common ocular surface disease apparently only observed in humans. Chronic UV exposure is a widely accepted aetiological factor in the pathogenesis of this disease and this concept is supported by epidemiological data, ray tracing models and histopathological changes that share common features with UV damaged skin. The mechanism(s) of pterygium formation is incompletely understood. Recent data have provided evidence implicating a genetic component, anti-apoptotic mechanisms, cytokines, growth factors, extracellular matrix remodelling (through the actions of matrix metalloproteinases), immunological mechanisms and viral infections in the pathogenesis of this disease. In this review, the current knowledge on pterygium pathogenesis is summarised, highlighting recent developments. In addition, we provide novel data further demonstrating the complexity of this intriguing disease.

A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction.

Background. A healthy cornea is reliant on a distinct population of stem cells (SC) that replace damaged or aging epithelium throughout life. Depletion of the SC pool or damage to the niche can result in a blinding and painful condition known as limbal-SC deficiency (LSCD). Although current treatment strategies for reconstituting the ocular surface for patients suffering LSCD are promising, they are complicated by transferring autologous or allogeneic progenitors in the presence of animal, human, and synthetic products. We report on the safe and efficacy of a unique autologous SC transfer technique that utilizes an Food and Drug Administration-approved contact lens (CL) as the SC substrate and carrier for patients with LSCD. Methods. Three patients with LSCD due to aniridia (n=1) and posttreatment for recurrent ocular surface melanoma (n=2) were included. Limbal (n=2) or conjunctival biopsies (n=1) were harvested and progenitors expanded ex vivo on therapeutic CLs in the presence of autologous serum. Cell-laden CLs were transferred to the patients corneal surface and clinical outcome measures were recorded (follow-up range, 8–13 months). Results. A stable transparent corneal epithelium was restored in each patient. There was no recurrence of conjunctivalization or corneal vascularization, and a significant improvement in symptom score occurred in all patients. Best-corrected visual acuity was increased in all eyes after the procedure. Conclusion. Ex vivo expansion of ocular surface epithelium in the presence of autologous serum and transplantation with the aid of a soft CLs is a promising new technique capable of achieving ocular surface rehabilitation.

The Pathogenesis of Pterygium: Current Concepts and Their Therapeutic Implications

Pterygium is a disease of the ocular surface that is associated with chronic UV exposure and is characterized by proliferation, inflammatory infiltrates, fibrosis, angiogenesis and extracellular matrix breakdown. Although pterygium is not fully understood, significant progress has been made toward understanding the mechanisms involved in its pathogenesis. In this review, we provide an update on the signaling pathways activated by UV light that result in induction of mediators responsible for the growth of pterygium. We also review the recent genetic studies on hereditary factors and provide a brief overview of the role of epithelial mesenchymal transition, bone marrow progenitor cells, and neuronal signals that may also contribute to the pathogenesis of pterygium. Therapeutic options for pterygium are discussed based on the mechanisms that perpetuate its growth.

Primary phacoemulsification for uncontrolled angle-closure glaucoma

PURPOSE To report the results of primary phacoemulsification to treat uncontrolled angle-closure glaucoma. SETTING Private practice and teaching hospital department. METHODS This retrospective interventional case series assessed 3 patients having phacoemulsification and posterior chamber intraocular lens implantation for uncontrolled intraocular pressure (IOP) after acute primary angle-closure glaucoma. RESULTS Intraocular pressure control was achieved in all patients postoperatively. CONCLUSIONS Primary phacoemulsification with the option of future trabeculectomy should be considered in selected patients with persistent appositional angle closure and uncontrolled IOP after angle-closure glaucoma.

The Role of Ultraviolet Irradiation and Heparin-Binding Epidermal Growth Factor-Like Growth Factor in the Pathogenesis of Pterygium

Ultraviolet (UV) light is one of the major factors implicated in the pathogenesis of pterygium. The mechanism by which UV light induces this disease remains elusive. The aim of this study was to evaluate the effects of UVB irradiation on the expression of growth factors in cultured pterygium epithelial cells and to demonstrate their distribution within pterygium. We cultured pterygial epithelial cells from pterygium explants and these cells were exposed to 20 mJ/cm(2) of UVB. Total RNA was extracted at 0, 6, and 12 hours after irradiation. (32)P-labeled cDNA was synthesized and analyzed using microarray technology to determine the differential expression of 268 growth factor and cytokine related genes. Semiquantitative reverse transcriptase-polymerase chain reaction was used to corroborate this data. Conditioned media derived from cells exposed to UVB irradiation was analyzed for protein expression by enzyme-linked immunosorbent assay. Immunohistochemistry was used to evaluate the distribution of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pterygium tissue. Analysis of the hybridization signals revealed that the genes encoding HB-EGF, fibroblast growth factor 3, and cytotoxic trail ligand receptor were consistently elevated at 6 and 12 hours after UVB treatment. HB-EGF mRNA was elevated 6.8-fold at 6 hours after irradiation and was augmented in culture supernatants after the same treatment. Furthermore, HB-EGF reactivity was identified in the epithelium and vasculature of pterygium by immunohistochemistry. HB-EGF was present in normal limbal epithelium, although it was not induced in cultured limbal epithelial cells by UV irradiation. HB-EGF is a potent mitogen, localized in pterygium tissue, and significantly induced by UVB in pterygium-derived epithelial cells. We postulate that this growth factor is a major driving force in the development of pterygia and a means by which UV irradiation causes the pathogenesis of pterygium.

A systematic review of the diagnostic accuracy of ocular signs in pediatric abusive head trauma

TOPIC To review systematically the diagnostic accuracy of various ocular signs for pediatric abusive head trauma (AHT). CLINICAL RELEVANCE Intraocular hemorrhages (IOH), perimacular retinal folds, traumatic retinoschisis and optic nerve sheath hemorrhages have been reported as cardinal signs of AHT. The evidence base supporting the accuracy of this interpretation, however, has not been systematically reviewed. METHODS A systematic keyword search of MEDLINE, EMBASE, and Evidence-Based Medicine Reviews was conducted for original studies reporting ocular findings in AHT. Articles were graded using a checklist for systematic reviews of diagnostic accuracy. RESULTS The initial search yielded 971 articles, of which 55 relevant studies were graded, and 20 studies met inclusion criteria and were included in the review. The overall sensitivity of IOH for AHT was 75% and their specificity was 94%. Intraretinal hemorrhage at the posterior pole was the most common finding, although extensive, bilateral, and multilayered IOH were the most specific for AHT. Optic nerve sheath hemorrhages had a sensitivity and specificity for AHT of 72% and 71%, respectively. Traumatic retinoschisis and perimacular retinal folds were reported in 8% and 14% of AHT, respectively, but were not reported in other conditions. CONCLUSIONS Prospective, consecutive studies confirm that IOH in infants-particularly bilateral, extensive, and multilayered-are highly specific for AHT. Optic nerve sheath hemorrhages are significantly more common in AHT than in other conditions, in autopsy studies. Traumatic retinoschisis and perimacular folds are present in a minority of AHT, but rarely seen in other conditions.

Australasian orbital and adnexal Wegener’s granulomatosis

OBJECTIVE To report a retrospective case series of 29 Australian and New Zealand patients with orbital and adnexal Wegeners granulomatosis (WG). DESIGN Retrospective case series. PARTICIPANTS Twenty-nine cases of orbital and adnexal WG were identified. METHODS A number of oculoplastic surgeons and other clinicians in Australia and New Zealand was asked about their experience with orbital and adnexal WG. Clinical data regarding these cases were conveyed by means of a questionnaire. Cases of ophthalmic WG without features of orbital or adnexal disease were excluded. MAIN OUTCOME MEASURES Data obtained from the questionnaire includes age, gender, limited or generalized disease, antineutrophil cytoplasmic antibody (ANCA) status, symptoms and signs: nasolacrimal obstruction, sinusitis, fistula/orbital bone erosion, orbital mass/proptosis, extraocular muscle/diplopia, visual acuity reduction caused by optic nerve compression, orbital pain, lid edema/erythema, biopsy status, and treatment status. RESULTS Twenty-nine patients with orbital and adnexal WG were identified and described. Symptoms included awareness of an orbital mass, epiphora, orbital pain and diplopia. Signs included an orbital mass or proptosis (69%), nasolacrimal duct obstruction (52%), limited ocular rotations (52%), lid erythema and edema (31%), bony destruction (21%), and reduced visual acuity (17%). Two patients had a persistent nasolacrimocanthal fistula. Cytoplasmic pattern antineutrophil cytoplasmic antibodies (c-ANCA) were present in 52% of patients, and in 9 of 10 patients with generalized disease. However, c-ANCA was positive in only 32% (6 of 19) of patients with limited WG. Perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) was positive in 10% of cases. CONCLUSIONS To diagnose and treat ophthalmic WG effectively, the clinician must be aware of its protean orbital and adnexal manifestations. WG may occur with or without systemic involvement, and c-ANCA was negative in approximately half our cases. Our cases also demonstrated two orbital fistulae, an observation previously believed to be rare.

Acute haptic-induced pigmentary glaucoma with an AcrySof intraocular lens

A 49-year-old man had uneventful endocapsular phacoemulsification with in-the-bag implantation of an AcrySof SA60AT single-piece intraocular lens (IOL) (Alcon) in the right eye. Twenty-seven days postoperatively, he presented with ocular pain, intraocular pressure of 48 mm Hg, 360 degrees of hyperpigmentation of the trabecular meshwork, and iris pigment epithelial atrophy in the region of the upper temporal haptic, which had dislocated into the sulcus. The patient made an excellent recovery following IOL removal and exchange. Scanning electron microscopy of the explanted IOL demonstrated that the haptic had a rough lateral surface and anterolateral edge. We do not think this IOL should be implanted in the sulcus placement of the heptics. In this article, we report the case of a patient with an AcrySof SA60ATIOL (Alcon) who developed acute pigmentary glaucoma when the inferior haptic slipped out of the bag and came into contact with the pigmented iris and ciliary body.

Pressure related apoptosis in neuronal cell lines

Pressure is a crucial component of the cellular environment, and can lead to pathology if it varies beyond its normal range. The increased intra‐ocular pressures in acute glaucoma are associated with the loss of neurons by apoptosis. Little is known regarding the interaction between pressure and apoptosis at the level of the cell. The model developed in this study examines the effects of elevated ambient hydrostatic pressure directly upon cultured neuronal lines. Conditions were selected to be within physiological limits: 100 mmHg over and above atmospheric pressure for a period of 2 hr, as seen clinically in acute glaucoma. This system can be used to investigate pressure relatively independently of other variables. Neuronal cell line cultures (B35 and PC12) were subjected to pressure conditions in specially designed pressure chambers. Controls were treated identically, except for the application of pressure, and positive controls were treated with a known apoptotic stimulus. Apoptosis was detected by cell morphology changes and by 2 specific apoptotic markers: TUNEL (Terminal transferase dUTP Nick‐End Labeling) and Annexin V. These fluorescent markers were detected and quantified by automated Laser Scanning Cytometry. All techniques showed that increased pressure was associated with a greater level of apoptosis compared to equivalent controls. Our results suggest that pressure alone may act as a stimulus for apoptosis in neuronal cell cultures. This raises the possibility of a more direct relationship at the cellular level between pressure and neuronal loss. J. Neurosci. Res. 60:495–503, 2000

High-dose (2000-μg) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis1

Abstract Objective The authors prospectively studied visual outcome, relapse, complications, and survival of patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus (CMV) treated with high-dose intravitreous ganciclovir (2 mg/0.1 ml) injections. The outcomes were compared with those of patients treated with standard doses of intravenous ganciclovir in the same institution. The histopathologic and electrophysiologic effects of high-dose intravitreous ganciclovir injections in rabbits also were studied. Design A nonrandomized case series. Participants A total of 42 patients (74 eyes) were treated with intravitreous injections and 18 patients (27 eyes) were treated with intravenous ganciclovir. Five eyes of three New Zealand white rabbits were injected with ganciclovir, and the sixth eye was a control specimen. Intervention Patients treated with intravitreous injections received twice-weekly doses of 2 mg/0.1 ml ganciclovir for 3 weeks, then weekly injections. Patients treated with intravenous ganciclovir received standard doses. Patients were monitored with regular examinations. Rabbit eyes were given intravitreous injections of 1 mg/0.1 ml of ganciclovir weekly for 4 weeks. Main outcome measures Assessments of vision, retinal inflammation, and survival were made. Electroretinograms were performed on the rabbit eyes, and they were processed for light and electron microscopy. Results In the intravitreous group, visual acuity (VA) was stable in 64 of 74 eyes, 5 improved, and 5 deteriorated. Sixty-three (85%) of 74 eyes had final VA of 20/20 to 20/40. Relapse occurred in five eyes (7%; median time, 42 weeks). There were three cases of endophthalmitis. Median survival after diagnosis of CMV retinitis was 36 weeks. In the intravenous group, VA was stable in 18 eyes, 0 improved, and 9 deteriorated. Sixteen (59%) of 27 eyes had final VA of 20/20 to 20/40. Relapse occurred in 15 eyes (56%) at a median time of 21 weeks. Median survival was 21 weeks. The rabbit studies showed no evidence of toxicity. Conclusion High-dose intravitreous ganciclovir effectively suppressed CMV retinitis, preserved vision, and prevented relapse without deterioration in survival.