Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma.

PURPOSE: To investigate the role of interferon (IFN)-gamma in the pathogenesis of conjunctival squamous metaplasia in dry eye. METHODS: Experimental dry eye was created by subjecting C57BL/6 and IFN-gamma-knockout mice to desiccating environmental stress for 5 or 10 days. T-cell antigens and IFN-gamma were detected by immunohistochemistry. Goblet cells were counted in periodic acid Schiff (PAS)-stained sections. Expression of small, proline-rich protein (SPRR)-2 was evaluated by confocal microscopy. Tear IFN-gamma was measured by immunobead assay. RESULTS: Dry eye promoted migration of CD4+ T cells and IFN-gamma+ cells into goblet cell zones of the conjunctiva and increased the concentration of IFN-gamma in tears. This migration was accompanied by progressive goblet cell loss and an increase in SPRR-2 expression in the conjunctival epithelium. A significant inverse correlation was observed between the density of infiltrating CD4+ T cells and goblet cells. Dry eye had no effect on conjunctival goblet cell density in IFN-gamma-knockout mice; however, exogenous administration of IFN-gamma significantly decreased goblet cell density after 5 days. CONCLUSIONS: Conjunctival epithelial response to experimental dryness is related to the degree of CD4+ T-cell infiltration and the level of IFN-gamma production. These findings suggest that IFN-gamma plays a pivotal role in promoting conjunctival squamous metaplasia in dry eye, and they provide insight into the immune pathogenesis of keratoconjunctivitis sicca.

Cystoid macular edema without leakage secondary to nab-Paclitaxel (Abraxane): clinical experience with intravitreal bevacizumab.

PURPOSE: Cystoid macular edema (CME) is a rarely reported side effect of nanoparticle albumin bound (nab)-paclitaxel therapy-an antimitotic agent used for breast cancer. We describe a patient with bilateral CME secondary to Abraxane that was minimally responsive to intravitreal bevacizumab. To our knowledge, this is the first reported case of the use of intravitreal bevacizumab for this condition. A previous report has described the ineffectiveness of concurrent intravenous bevacizumab with Abraxane. This lack of efficacy and knowledge of the mechanism of paclitaxel may provide insights into the mechanisms of CME without angiographic leakage. METHODS: Retrospective, interventional case report of a patient with bilateral CME after starting Abraxane therapy for recurrent breast cancer treated with intravitreal bevacizumab (1.25 mg/0.05 mL) every 4 weeks. Records were reviewed for visual acuity and macular edema as assessed by spectral-domain optical coherence tomography (SD-OCT). RESULTS: A 73-year-old patient with recurrent, metastatic breast cancer presented with bilateral visual loss 3 months after nab-paclitaxel was initiated. Baseline visual acuities (VA) were 20/50 in the right eye (OD) and 20/80 in the left eye (OS). Fundus exam showed marked CME in both eyes (OU). Fluorescein angiography was notable for the marked absence of petalloid late-phase leakage characteristic of vascular, ischemic, and inflammatory causes of CME. SD-OCT showed marked cystoid spaces predominantly involving the outer and inner nuclear layers with central subfield thicknesses (CST) of 398 µm OD and 441 µm OS. Serial intravitreal bevacizumab injections (OD, 2 injections; OS, 3 injections) were administered on a 4-week basis with an improvement and stabilization of VA at 20/50 OD and 20/70 OS. However, CME on SD-OCT persisted with CST of 492 µm OD and 478 µm OS. CONCLUSIONS: The pathogenesis of CME without leakage is poorly understood; however, fluid accumulation in Muller cells due to toxicity has been proposed. The persistence of CME suggests that additional nonvascular endothelial growth factor-mediated mechanisms are involved. Improved understanding of the mechanisms underlying paclitaxel-associated CME is needed, especially in patients with limited systemic options for metastatic carcinoma.

Nocardia veterana endogenous endophthalmitis in a cardiac transplant patient.

BACKGROUND: Endogenous endophthalmitis secondary to Nocardia species is extremely rare but often portends a poor visual prognosis often owing to the advanced nature of disease at presentation and delay in diagnosis. Patients who are systemically immunosuppressed are at greatest risk and early suspicion of the role of this organism in patients with acute panuveitis is paramount. FINDINGS: A 66-year-old cardiac transplant patient on oral prednisone, Myfortic, and tacrolimus developed unilateral panuveitis with a focal white subretinal and retinal lesion. His past medical history was notable for Aspergillus pneumonia and cytomegalovirus retinitis in the contralateral eye 12 months prior. Aqueous humor sampling for eubacterial, eufungal, and viral PCR testing, as well as vitreous cultures for bacteria and fungi were unsuccessful in the identification of a causative organism. Progressive enlargement of the lesion was noted despite intravitreal foscarnet, vancomycin, ceftazidime, and voriconazole. A pars plana vitrectomy and retinal and subretinal biopsy led to the identification of Nocardia veterana, a recently identified Nocardia species. A combination of linezolid, meropenem, azithromycin, ceftriaxone, and intravitreal amikacin resulted in eradication of the infection. CONCLUSION: This is the first reported case of N. veterana endogenous endophthalmitis in an immunosuppressed patient. Pars plana vitrectomy with a subretinal biopsy was required to establish a diagnosis, as other testing including aqueous PCR and vitreous cultures were negative. The poor visual outcome in our patient highlights the importance of early consideration of Nocardia in the differential diagnosis of panuveitis with subretinal disease in the context of immunosuppression.

Retinal metastasis simulating cytomegalovirus retinitis.

A 62-year-old man with lung cancer presented with a 2-week history of decreased vision and clinical features of cytomegalovirus retinitis. The patient was empirically treated for viral retinitis, but microbiological testing of the vitreous fluid was negative. Based on the suspicion for retinal metastasis, the patient underwent pars plana vitrectomy with retinal biopsy. Surgical techniques included the use of a chandelier illumination to enable bimanual manipulation of the retinal tissue, creation a focal retinal detachment with a 41-gauge subretinal cannula, diathermy demarcation of the biopsy site, localized retinectomy with vertical scissors, endolaser, and long-acting gas tamponade. Histopathologic examination revealed sheets of tumor cells with pleomorphic nuclei and positive staining for cytokeratins consistent with metastatic adenocarcinoma. The patient subsequently underwent external beam radiation and was alive 10 months after presentation. This surgical technique may be valuable in select patients with retinal metastasis for diagnostic, therapeutic, and counseling purposes.

Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy.

PURPOSE: Oxygen-induced retinopathy in the mouse is the standard experimental model of retinopathy of prematurity. Assessment of the pathology involves in vitro analysis of retinal vaso-obliteration and retinal neovascularization. The authors studied the clinical features of oxygen-induced retinopathy in vivo using topical endoscopy fundus imaging (TEFI), in comparison to standard investigations, and evaluated a system for grading these features. METHODS: Postnatal day (P)7 mice were exposed to 75% oxygen for five days to induce retinopathy or maintained in room air as controls. Retinal vascular competence was graded against standard photographs by three masked graders. Retinal photographs were obtained at predetermined ages using TEFI. Postmortem, retinal vaso-obliteration was measured in whole mounts with labeled vasculature, and retinal neovascularization was quantified in hematoxylin- and eosin-stained ocular cross sections. RESULTS: Fundus photography by TEFI was possible from P15, when retinal vascular incompetence, including dilatation and tortuosity, was significant in mice with oxygen-induced retinopathy in comparison to controls. Vascular incompetence peaked in severity at P17 and persisted through P25. Comparison with in vitro analyses indicated that vascular changes were most severe after retinal avascularity had begun to decrease in area, and coincident with the maximum of retinal neovascularization. A weighted Fleiss-Cohen kappa indicated good intra- and interobserver agreement for a 5-point grading system. CONCLUSIONS: Topical endoscopy fundus imaging demonstrates retinal vascular incompetence in mice with oxygen-induced retinopathy. The technique complements standard postmortem analysis for following the course of the model. TRANSLATIONAL RELEVANCE: Topical endoscopy fundus imaging has application in the evaluation of novel biologic drugs for retinopathy of prematurity.

Repressors of androgen and progesterone receptor action.

Androgen and progesterone receptors (AR and PR) are two determining factors in gonadal differentiation that are highly expressed in developing and mature gonads. Loss of AR results in XY sex reversal and mutations causing reduced AR activity lead to varying degrees of defects in masculinization. Female PR knockout mice are infertile due to ovarian defects. While much has been discovered about positive regulation of these receptors by coactivators little is known about repression of the transcriptional activity of AR and PR in the presence of agonists. In this study we assessed the effect of SMRT and DAX-1 on AR and PR activity in the presence of both agonists and partial antagonists. We show that SMRT and DAX-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. We demonstrate that endogenous agonist-bound PR and DAX-1 in T47D breast cancer cells and endogenous AR and DAX-1 in LNCaP prostate cancer cells can be coimmunoprecipitated suggesting that the interaction is physiological. Surprisingly, although DAX-1 represses partial antagonist activity of AR, it was ineffective in repressing partial antagonist induced activity of PR. In contrast to most reported repressors, the expression of DAX-1 is restricted. We found that although DAX-1 is expressed in normal human prostate, its expression is strongly reduced in benign prostatic hyperplasia suggesting that DAX-1 plays a role in limiting AR activity in prostate.