Human adenovirus infection of the ocular surface is associated with severe keratoconjunctivitis and the formation of subepithelial corneal infiltrates, which may persist and impair vision for months to years following infection. Long term pathology persists well beyond the resolution of viral replication, indicating that the prolonged immune response is not virus-mediated. However, it is not clear how these responses are sustained or even initiated following infection. This review discusses recent work from our laboratory and others which demonstrates different entry pathways specific to both adenovirus and cell type. These findings suggest that adenoviruses may stimulate specific pattern recognition receptors in an entry/trafficking-dependent manner, leading to distinct immune responses dependent on the virus/cell type combination. Additional work is needed to understand the specific connections between adenoviral entry and the stimulation of innate immune responses by the various cell types present on the ocular surface.

PURPOSE. Ocular infection by human adenovirus species D type 37 (HAdV-D37) causes epidemic keratoconjunctivitis, a severe, hyperacute condition. The corneal component of epidemic keratoconjunctivitis begins upon infection of corneal epithelium, and the mechanism of viral entry dictates subsequent proinflammatory gene expression. Therefore, it is important to understand the specific pathways of adenoviral entry in these cells. METHODS. Transmission electron microscopy of primary and tert-immortalized human corneal epithelial cells infected with HAdV-D37 was performed to identify the means of viral entry. Confocal microscopy was used to determine intracellular trafficking. The results of targeted small interfering RNA and specific chemical inhibitors were analyzed by quantitative PCR, and Western blot. RESULTS. By transmission electron microscopy, HAdV-D37 was seen to enter by both clathrin-coated pits and macropinocytosis; however, entry was both pH and dynamin 2 independent. Small interfering RNA against clathrin, AP2A1, and lysosome-associated membrane protein 1, but not early endosome antigen 1, decreased early viral gene expression. Ethyl-isopropyl amiloride, which blocks micropinocytosis, did not affect HAdV-D37 entry, but IPA, an inhibitor of p21-activated kinase, and important to actin polymerization, decreased viral entry in a dose-dependent manner. CONCLUSIONS. HAdV-D37 enters human corneal epithelial cells by a noncanonical clathrinmediated pathway involving lysosome-associated membrane protein 1 and PAK1, independent of pH, dynamin, and early endosome antigen 1. We showed earlier that HAdV-D37 enters human keratocytes through caveolae. Therefore, epidemic keratoconjunctivitis-associated viruses enter different corneal cell types via disparate pathways, which could account for a relative paucity of proinflammatory gene expression upon infection of corneal epithelial cells compared with keratocytes, as seen in prior studies.

Background: As the incidence of youth pitching injuries and surgical procedures attributed to overuse has drastically increased, there are quality concerns about popular internet resources regarding arm care for youth pitchers. Purpose/Hypothesis: To assess the medical advisability of online arm care recommendations for youth pitchers. It was hypothesized that websites contain misleading arm-care information that is discordant with medical advice. Study Design: Cross-sectional study. Methods: We reviewed the first 100 websites populated after a Google search for youth pitching recommendations. Websites were categorized by type (athletic organization, commercial, or educational) and content quality (medically advisable, discordant, or neutral), the latter with respect to the Pitch Smart guidelines used by Major League Baseball. Chi-square tests of independence and z tests of independent proportions were used to compare column proportions among categories of website content quality for each type of website source. Given the small sample sizes in some instances, the Fisher-Freeman-Halton exact test was performed to assess the relationship between website source type and quality of information. Results Of the 99 qualifying websites, 76 were categorized as medically advisable, 16 as discordant, and 7 as neutral. In addition, 92% of educational websites and 94.7% of athletic organization websites featured exclusively advisable content, whereas only 54.8% of commercial websites were advisable. Of the 16 discordant websites, 15 were commercial sites. Educational websites were significantly more advisable and neutral in content when compared with discordant information, while commercial websites were significantly predictive of discordant content. Among the first 50 websites populated according to Google, 42 (84%) were advisable, 6 (12%) discordant, and 2 (4%) neutral. The remaining websites (n = 49) featured 34 (69.4%) that were advisable, 10 (20.4%) discordant, and 5 (10.2%) neutral. Conclusion: Study findings indicated that websites of an educational nature are predictive of medically advisable content, while commercial websites (eg, blogs) are associated with discordant information. The abundance and availability of inaccurate internet information should be appreciated by medical professionals and parents/coaches of youth baseball players.