Virally delivered, constitutively active NFκB improves survival of injured retinal ganglion cells.

As axon damage and retinal ganglion cell (RGC) loss lead to blindness, therapies that increase RGC survival and axon regrowth have direct clinical relevance. Given that NFκB signaling is critical for neuronal survival and may regulate neurite growth, we investigated the therapeutic potential of NFκB signaling in RGC survival and axon regeneration. Although both NFκB subunits (p65 and p50) are present in RGCs, p65 exists in an inactive (unphosphorylated) state when RGCs are subjected to neurotoxic conditions. In this study, we used a phosphomimetic approach to generate DNA coding for an activated (phosphorylated) p65 (p65mut), then employed an adeno-associated virus serotype 2 (AAV2) to deliver the DNA into RGCs. We tested whether constitutive p65mut expression prevents death and facilitates neurite outgrowth in RGCs subjected to transient retinal ischemia or optic nerve crush (ONC), two models of neurotoxicity. Our data indicate that RGCs treated with AAV2-p65mut displayed a significant increase in survival compared to controls in ONC model (77 ± 7% vs. 25 ± 3%, P-value = 0.0001). We also found protective effect of modified p65 in RGCs of ischemic retinas (55 ± 12% vs. 35 ± 6%), but not to a statistically significant degree (P-value = 0.14). We did not detect a difference in axon regeneration between experimental and control animals after ONC. These findings suggest that increased NFκB signaling in RGCs attenuates retinal damage in animal models of neurodegeneration, but insignificantly impacts axon regeneration.

The TIR-domain-containing adapter inducing interferon-ß-dependent signaling cascade plays a crucial role in ischemia-reperfusion-induced retinal injury, whereas the contribution of the myeloid differentiation primary response 88-dependent signaling cascade is not as pivotal.

Toll-like receptor 4 (Tlr4) plays an important role in ischemia-reperfusion (IR)-induced retinal inflammation and damage. However, the role of two Tlr4-dependent signaling cascades, myeloid differentiation primary response 88 (Myd88) and TIR-domain-containing adapter inducing interferon-ß (Trif), in retinal IR injury is poorly understood. In this study, we investigated the contribution of the Myd88-dependent and Trif-dependent signaling cascades in retinal damage and inflammation triggered by IR, by using Myd88 knockout (Myd88KO) and Trif knockout (TrifKO) mice. Retinal IR injury was induced by unilateral elevation of intraocular pressure for 45 min by direct corneal cannulation. To study IR-induced retinal ganglion cell (RGC) death in vitro, we used an oxygen and glucose deprivation (OGD) model. Our data suggested that Myd88 was present in many retinal layers of sham-operated and ischemic mice, whereas Trif was mainly present in the ganglion cell layer (GCL). The level of Myd88 was increased in the retina after IR. We found that retinas of TrifKO mice had a significantly reduced neurotoxic pro-inflammatory response and significantly increased survival of the GCL neurons after IR. Although Myd88KO mice had relatively low levels of inflammation in ischemic retinas, their levels of IR-induced retinal damage were notably higher than those of TrifKO mice. We also found that Trif-deficient RGCs were more resistant to death induced by OGD than were RGCs isolated from Myd88KO mice. These data suggested that, as compared with the Myd88-dependent signaling cascade, Trif signaling contributes significantly to retinal damage after IR.

Common inflammatory and infectious conditions of the eyelid.

Patients with infection or inflammation of the eyelid will often first present to their primary care physicians with symptoms such as redness, swelling, tearing, itchiness, or a foreign body sensation. There are a variety of conditions that affect the eyelid which can cause such symptoms, and the exam and history can help a provider differentiate some of the more common conditions. This article will provide a comprehensive review of the background, diagnosis and management of dry eye disease, chalazion, hordeolum (stye), and preseptal cellulitis.

Corneal perforation with uveal prolapse: An initial presentation of orbital metastatic breast cancer.

PURPOSE: Metastasis to the orbit is a rare and typically late manifestation of a systemic malignancy. Breast cancer is the most common orbital metastatic malignancy and as the prevalence of breast cancer rises, the incidence of orbital metastasis is expected to increase concomitantly. The purpose of this report is to illustrate a unique case of orbital metastatic breast cancer with grave ophthalmic sequelae and to review the salient findings and features of orbital metastatic disease. OBSERVATIONS: Herein, we describe the case of a 61-year-old woman with no known history of malignancy who presented with a large compressive orbital mass that resulted in corneal perforation with uveal prolapse after initial treatment for orbital cellulitis followed by orbital pseudotumor. Anterior orbitotomy with biopsy of the mass ultimately revealed a diagnosis of metastatic breast carcinoma. CONCLUSION: As the incidence of breast cancer increases, ophthalmologists will play an increasingly important role in detecting both undiagnosed and recurrent breast cancer.

Physical activity training in US medical schools: Preparing future physicians to engage in primary prevention.

BACKGROUND: Medical professionals serve as influential sources of information and guidance for their patients. Medical school may be an opportune time to provide future physicians with training in physical activity (PA) so that it can be more effectively addressed in clinical practice. METHODS: To assess the inclusion and amount of PA training in US medical school curricula, we attempted to conduct structured interviews with the program directors of the 171 accredited US medical education programs in the spring of 2013. RESULTS: Seventy-four schools (allopathic, n = 64; osteopathic, n = 10) completed the structured interviews. Fifty-eight programs (78.4%) reported having PA training included as a part of their curriculum. Thirty-five (61.4%) and 25 (43.9%) programs included instruction on national aerobic and strength training guidelines, respectively. Thirty-one programs (56.4%) felt that they offered a sufficient level of PA-related training for their students to successfully counsel their patients in the future. Over the 4 years of medical school, an average of 8.1 (± 9.8) h of mandatory PA training was offered. CONCLUSION: Though many medical schools report providing some level of PA content, the time dedicated for this training is still low in comparison to other topics, such as nutrition education, which are featured more prominently. New and innovative ideas are needed for the integration of more, higher quality PA training for our next generation of medical practitioners.

Molecular Characterization of Notch1 Positive Progenitor Cells in the Developing Retina.

The oscillatory expression of Notch signaling in neural progenitors suggests that both repressors and activators of neural fate specification are expressed in the same progenitors. Since Notch1 regulates photoreceptor differentiation and contributes (together with Notch3) to ganglion cell fate specification, we hypothesized that genes encoding photoreceptor and ganglion cell fate activators would be highly expressed in Notch1 receptor-bearing (Notch1+) progenitors, directing these cells to differentiate into photoreceptors or into ganglion cells when Notch1 activity is diminished. To identify these genes, we used microarray analysis to study expression profiles of whole retinas and isolated from them Notch1+ cells at embryonic day 14 (E14) and postnatal day 0 (P0). To isolate Notch1+ cells, we utilized immunomagnetic cell separation. We also used Notch3 knockout (Notch3KO) animals to evaluate the contribution of Notch3 signaling in ganglion cell differentiation. Hierarchical clustering of 6,301 differentially expressed genes showed that Notch1+ cells grouped near the same developmental stage retina cluster. At E14, we found higher expression of repressors (Notch1, Hes5) and activators (Dll3, Atoh7, Otx2) of neuronal differentiation in Notch1+ cells compared to whole retinal cell populations. At P0, Notch1, Hes5, and Dll1 expression was significantly higher in Notch1+ cells than in whole retinas. Otx2 expression was more than thirty times higher than Atoh7 expression in Notch1+ cells at P0. We also observed that retinas of wild type animals had only 14% (P < 0.05) more ganglion cells compared to Notch3KO mice. Since this number is relatively small and Notch1 has been shown to contribute to ganglion cell fate specification, we suggested that Notch1 signaling may play a more significant role in RGC development than the Notch3 signaling cascade. Finally, our findings suggest that Notch1+ progenitors--since they heavily express both pro-ganglion cell (Atoh7) and pro-photoreceptor cell (Otx2) activators--can differentiate into either ganglion cells or photoreceptors.