PURPOSE: To demonstrate the histopathologic characteristics of different types of lacrimal drainage system concretions with clinical correlations. METHODS: Thirty lacrimal drainage system concretions submitted to the Cogan Eye Pathology Laboratory at the Massachusetts Eye and Ear Infirmary over a 2-year period were reviewed. Concretions were studied in detail using their histopathologic staining features as revealed with hematoxylin and eosin, Gomori methenamine silver, periodic acid-Schiff, iron stain, and Brown-Hopps tissue gram stain. A separate retrospective chart review was conducted for each patient to identify any clinical correlations. RESULTS: Two major forms of concretions were identified histopathologically: mucopeptide (7) and bacterial (20). Mucopeptide concretions were found exclusively within the lacrimal sac, while bacterial concretions were found chiefly in the canaliculus. A third category of "mixed" concretions with substantial mucopeptide and bacterial characteristics comprised 3 specimens. Bacterial concretions consisted of large matted masses of filamentous, presumed Actinomyces organisms that were easily identified with the Grocott's methenamine silver stain; they were frequently cocolonized at their edges with coccal bacterial forms. Mucopeptide concretions were generally devoid of cellular elements and were composed of broad bland whorls of diffusely eosinophilic, acellular, periodic acid-Schiff-positive material punctuated by lacunae. They were often cocolonized by small numbers of bacterial cocci and occasional fungi. Culture results disclosed low virulence species. All 3 types of concretions predominated in women. Patients with bacterial concretions frequently had dry eye symptoms. CONCLUSIONS: The 2 major types of lacrimal system concretions differ in their primary location and histopathologic composition. Further characterization may lead to an understanding of the mechanisms for their formation. Mucopeptide concretion is more appropriate than terms such as "dacryolith" and "mucolith," and bacterial concretion is a more appropriate term than "canaliculith," because of the absence of significant calcium or stone-like density in these masses.

PURPOSE: We previously reported that calcineurin, a Ca(2+)/calmodulin-dependent serine/threonine phosphatase, is activated and proposed that it participates in retinal ganglion cell (RGC) apoptosis in two rodent ocular hypertension models. In this study, we tested whether calcineurin activation by itself, even in the absence of ocular hypertension, is sufficient to cause RGC degeneration. METHODS: We compared RGC and optic nerve morphology after adeno-associated virus serotype 2 (AAV2)-mediated transduction of RGCs with constitutively active calcineurin (CaNCA) or unactivated, wild-type calcineurin (CaNwt). Retinas and optic nerves were harvested 7-16 weeks after injection of the AAV into mouse vitreous. In flatmounted retinas, the transduced RGCs were identified with immunohistochemistry. The morphology of the RGCs was revealed by immunostaining for neurofilament SMI32 or by using GFP-M transgenic mice. A modified Sholl analysis was applied to analyze the RGC dendritic morphology. Optic nerve damage was assessed with optic nerve grading according to the Morrison standard. RESULTS: CaNwt and CaNCA were highly expressed in the injected eyes. Compared to the CaNwt-expressing RGCs, the CaNCA-expressing RGCs had smaller somas, smaller dendritic field areas, shorter total dendrite lengths, and simpler dendritic branching patterns. At 16 weeks, the CaNCA-expressing eyes had greater optic nerve damage than the CaNwt-expressing eyes. CONCLUSIONS: Calcineurin activation is sufficient to cause RGC dendritic degeneration and optic nerve damage. These data support the hypothesis that calcineurin activation is an important mediator of RGC degeneration, and are consistent with the hypothesis that calcineurin activation may contribute to RGC neurodegeneration in glaucoma.

Heat shock proteins (HSPs) play a critical role in many intracellular processes, including apoptosis and delivery of other proteins to intracellular compartments. Small HSPs have been shown previously to participate in many cellular functions, including IL-8 induction. Human adenovirus infection activates intracellular signaling, involving particularly the c-Src and mitogen-activated protein kinases [Natarajan, K., et al. (2003) J. Immunol. 170, 6234-6243]. HSP27 and MK2 are also phosphorylated, and c-Src, and its downstream targets, p38, ERK1/2, and c-Jun-terminal kinase (JNK), differentially mediate IL-8 and MCP-1 expression. Specifically, activation and translocation of transcription factor NFκB-p65 occurs in a p38-dependent fashion [Rajaiya, J., et al. (2009) Mol. Vision 15, 2879-2889]. Herein, we report a novel role for HSP27 in an association of p38 with NFκB-p65. Immunoprecipitation assays of virus-infected but not mock-infected cells revealed a signaling complex including p38 and NFκB-p65. Transfection with HSP27 short interfering RNA (siRNA) but not scrambled RNA disrupted this association and reduced the level of IL-8 expression. Transfection with HSP27 siRNA also reduced the level of nuclear localization of NFκB-p65 and p38. By use of tagged p38 mutants, we found that amino acids 279-347 of p38 are necessary for the association of p38 with NFκB-p65. These studies strongly suggest that HSP27, p38, and NFκB-p65 form a signalosome in virus-infected cells and influence downstream expression of pro-inflammatory mediators.

The current case of conjunctival mucoepidermoid carcinoma offers features that expand the biologic spectrum afforded by this tumor. More focused strategies should be developed for its earlier histopathologic diagnosis and improved management (historical recurrence rate of 85%). A 63-year-old woman with a history of rheumatoid arthritis and idiopathic sclerosing cholangitis developed scleral thinning, anterior chamber cells and flare, and uveal prolapse. Biopsies of the epibulbar lesion were initially misinterpreted as a squamous cell carcinoma but on review harbored CK7-positive cells and contained rare goblet cells brought out with Alcian blue and mucicarmine staining. Intraocular extension exhibited micro-and macrocysts with minimal goblet cells. Focal CK7 immunopositivity in any epibulbar squamous dysplasia or in invasive carcinoma should lead to suspicion of a mucoepidermoid carcinoma. Behaviorally aggressive or rapidly recurrent epithelial squamous tumors with "inflammatory" features or unusual clinical characteristics should be initially stained at multiple levels for the detection of parsimonious mucus secretion. Surgical options include wide excision and partial sclerectomy with cryotherapy for superficial invasion and/or interferon therapy. Results with radiotherapy and cryotherapy for deep scleral invasion have been unpredictable or unacceptable compared with surgery.

Conjunctival cysts unrelated to surgery or trauma are uncommon adnexal lesions in children and may be difficult to recognize. We report the clinical and pathological findings of an apparently spontaneous conjunctival cyst in the upper eyelid of a child whose first ophthalmological examination was at 7 months of age. The cyst was surgically excised at 5 years of age.

BACKGROUND: Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death. METHODOLOGY/PRINCIPAL FINDINGS: Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs. CONCLUSIONS/SIGNIFICANCE: Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation.

Herein, we report that vascular endothelial growth factor A (VEGF-A) engages the PI3K/Akt pathway by a previously unknown mechanism that involves three tyrosine kinases. Upon VEGF-A-dependent activation of VEGF receptor-2 (VEGFR-2), and subsequent TSAd-mediated activation of Src family kinases (SFKs), SFKs engage the receptor tyrosine kinase Axl via its juxtamembrane domain to trigger ligand-independent autophosphorylation at a pair of YXXM motifs that promotes association with PI3K and activation of Akt. Other VEGF-A-mediated signalling pathways are independent of Axl. Interfering with Axl expression or function impairs VEGF-A- but not bFGF-dependent migration of endothelial cells. Similarly, Axl null mice respond poorly to VEGF-A-induced vascular permeability or angiogenesis, whereas other agonists induce a normal response. These results elucidate the mechanism by which VEGF-A activates PI3K/Akt, and identify previously unappreciated potential therapeutic targets of VEGF-A-driven processes.

Bacterial endophthalmitis is a sight threatening infection of the interior structures of the eye. Incidence in the US has increased in recent years, which appears to be related to procedures being performed on an aging population. The advent of outpatient intravitreal therapy for management of age-related macular degeneration raises yet additional risks. Compounding the problem is the continuing progression of antibiotic resistance. Visual prognosis for endophthalmitis depends on the virulence of the causative organism, the severity of intraocular inflammation, and the timeliness of effective therapy. We review the current understanding of the pathogenesis of bacterial endophthalmitis, highlighting opportunities for the development of improved therapeutics and preventive strategies.

Proliferative vitreoretinopathy is a disease process that follows the proliferation of ectopic cell sheets in the vitreous and/or periretinal area, causing periretinal membrane formation and traction, in patients with rhegmatogenous retinal detachments. Currently, vitreous surgery is the standard treatment; however, the results aren't satisfactory given the vision loss that ensues and that redetachment is relatively common. It is becoming clearer that there exists an interplay between various cytokines/growth factors, matrix proteins, and the different cell types that drive the undesirable formation of periretinal membranes. This fundamental understanding is aiding in identifying different adjunct agents that can block the cellular events intrinsic to proliferative vitreoretinopathy. In this review, we describe the current understanding on the pathogenesis and discuss how the fundamental understanding of the biochemical/molecular events is instrumental in developing the novel treatment strategies that are also highlighted.

PURPOSE OF REVIEW: Obtaining precise postoperative target refraction is of utmost importance in today's modern cataract and refractive surgery. Given the growing number of patients undergoing premium intraocular lens (IOL) implantations, patient expectation continues to rise. In order to meet heightened patient expectations, it is crucial to pay utmost attention to patient selection, accurate keratometry and biometry readings, as well as to the application of correct IOL power formula with optimized lens constants. This article reviews recent advances in the field of clinical biometry and IOL power calculations. RECENT FINDINGS: Recently developed low-coherence reflectometry optical biometry is comparable to older ultrasonic biometric and keratometric techniques. In addition, the new IOLMaster software upgrade has improved reproducibility and enhanced signal acquisition. Further, the modern lens power formulas currently determine the effective lens position and the shape of the intraocular lens power prediction curve more accurately. SUMMARY: In order to reach target refraction, precise biometric measurements are imperative. Understanding the strengths and limitations of the currently available biometry devices allows prevention of high variability and inaccuracy, ultimately determining the refractive outcomes.