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Meibomian gland orifices (MGOs) are located along the eyelid margin and secrete meibum into the tear film. The profile of resident innate immune cells (ICs) at this site is not well understood. The distribution and phenotype of resident ICs around MGOs in mice was investigated and herein defined as MGO-associated immune cells (MOICs). The effect of topical 0.1% benzalkonium chloride (BAK) on MOICs was also assessed. Eyelids from healthy CD11ceYFP and Cx3cr1gfp/gfp mice aged three or seven months were compared. ICs were identified as CD11c+, Cx3cr1+, and MHC-II+ using four-colour immunostaining and confocal microscopy. MOIC density was variable but clustered around MGOs. There were more CD11c+ MOICs in three-month-old compared with seven-month-old mice (three-month-old: 893±449 cells/mm2 vs. seven-month-old: 593±493 cells/mm2, p = 0.004). Along the eyelid margin, there was a decreasing gradient of CD11c+ MOIC density in three-month-old mice (nasal: 1003±369 cells/mm2, vs. central: 946±574 cells/mm2, vs. temporal: 731±353 cells/mm2, p = 0.044). Cx3cr1-deficient mice had two-fold fewer MHC-II+ MOICs, suggesting a role for Cx3cr1 receptor signaling in meibomian gland surveillance. CD11c+ MOIC density was lower in BAK-exposed eyes compared to saline-treated controls, suggesting a change in homeostasis. This study provides novel insight into resident ICs located at MGOs, and their contribution to MG homeostasis.

In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4

To evaluate the changes of corneal biomechanics in granular, lattice and macular corneal dystrophy (GCD, LCD and MCD), and to assess the agreement of intraocular pressure (IOP) between Corvis ST tonometer (CST) and Goldmann applanation tonometer (GAT) and the agreement of central corneal thickness (CCT) between CST and ultrasound pachymeter (USP) in patients with corneal dystrophy.Fifty-nine eyes with corneal dystrophy (26 eyes with GCD, 18 eyes with LCD and 15 eyes with MCD) and 48 eyes from healthy subjects were included in this study. All subjects received ocular examination and anterior segment photography under slit-lamp microscope. Corneal biomechanical parameters were obtained using CST. IOP and CCT were obtained using GAT and USP, respectively. Mixed-effects models were fitted for group comparisons and Bland-Altman analyses were applied for assessing the agreement of IOP or CCT between devices.GCD, LCD and MCD showed higher First Applanation Deformation Amplitude (A1DA) and Corvis Biomechanical Index (CBI), and a lower Stiffness Parameter at First Applanation (SPA1), compared to controls. After CCT adjustment, MCD group showed a higher A1DA compared to GCD or LCD. The IOP measured by CST demonstrated an overestimated bias to the one obtained by GAT in all groups. The CCT measured by CST and USP showed good agreement in healthy eyes but not in those with corneal dystrophy.Corneal biomechanical alterations were observed in GCD, LCD and MCD. IOP and CCT measured by CST should be interpreted carefully in eyes with corneal dystrophy.

To evaluate sleep and mood status in patients with dry eye disease (DED) and analyze the association between sleep quality, mood status, and ocular surface characteristics.Consecutive patients with DED (N = 106) and age- and sex-matched healthy controls (N = 50) were enrolled. Tear fluid break up time (TBUT), corneal fluorescein staining, and Schirmer I tests were performed in the order listed here to evaluate dry eye. A visual analog scale was used to assess dry eye symptom severity. All subjects also completed the Pittsburgh Sleep Quality Index (PSQI, scores ≥5.5 indicated poor sleep), Patient Health Questionnaire (scores ≥5 indicated depression), and General Anxiety Disorder Scale (scores ≥5 indicated anxiety).Mean Pittsburgh Sleep Quality Index global score was significantly higher in patients with DED than that in controls (7.8 ± 3.9 vs. 5.4 ± 3.0, respectively; P0.001). Patients with DED demonstrated higher respective depression and anxiety scores compared with controls (P0.001 and 0.013, respectively). In the DED group, patients with poor sleep quality had more severe DED indicated by shorter TBUT and lower Schirmer I findings. A significant correlation was found between sleep quality and mood status in patients with DED. Regression analysis revealed that shorter TBUT and lower Schirmer I test results were associated with poorer sleep quality (adjusted p = 0.011 and 0.037, respectively). More severe symptoms of dry eye were significantly associated with a higher level of anxiety in patients with DED (adjusted p = 0.011).Sleep quality may play an important role in the development of DED by influencing tear secretion and tear film stability and/or by indirectly aggravating anxiety and depression, leading to higher self-reported symptom scores. It is also possible that DED contributes to reduced sleep quality, as well as the development of anxiety and depression.

The activation of subconjunctival fibroblasts is believed to be responsible for the pathogenesis of pterygium. Vascular endothelial growth factor (VEGF) appears to be the most potent stimulator of formation and progression of pterygium. Pterygium excision is a common procedure, although the recurrence rates remain high. Various postoperative adjuvant therapies are now attempted to lower the recurrence rate, with severe side effects. To offer a greater therapeutic effect and lower side effects, it's necessary to discover a constant nanoparticle drug delivery targeting to subconjunctival fibroblasts in pterygium (PSFs). This study was designed to investigate the expression of low-density lipoprotein receptor (LDLr) stimulated by VEGF in PSFs. We found that after exposure to VEGF, mRNA and protein levels of LDLr were both increased significantly in PSFs, assessed using relative quantitative real-time RT-PCR and Western blot. Moreover, it's demonstrated that the expression of LDLr were positively correlated with the cells proliferation. Uptake of DiI-LDL via live PSFs was increased with time, estimated by confocal microscopy. The protein expression of LDLr in pterygium subconjunctival tissues was significantly higher than in normal subconjunctival tissues. These results suggest that LDLr in the activated PSFs may become a novel target receptor for controlled drug delivery to lower postsurgical recurrence rate.

Additional file 1: Figure S1. Experiment 2: CD45+ dendritic cells (DCs) after 6-hours of topical treatment (i.e., 3 × doses, 2 hours apart) in CD11c-eYFP mice. (A) CD45+ CD11c+ DCs in peripheral cornea after decorin treatment. (B) CD45+ CD11c+ DCs in peripheral cornea after saline treatment. Scale bar (50 μm) applies to all images. Figure S2. Experiment 1: Initial corneal abrasion area at baseline (Time 0h). Figure S3. Experiment 1: Corneal thickness and epithelial cell proliferation after 1-week of topical treatment, dosed 3 times/day. (A) Representative SD-OCT images of the anterior segment from naïve mice. Blue curved line represents the area of central cornea and blue dashed line represents peripheral cornea. Scale bar is 200 μm. (B) A higher magnification image of the boxed area in A. Orange and green double arrows indicate epithelial and stromal thickness respectively. (C) Corneal epithelial and stromal thickness. There were no significant inter-group differences. (D) Representative en face confocal image of Ki67 staining in the central cornea after 1-week treatment of decorin. Scale bar is 50 μm. (E-F) Density of proliferative epithelial cells in the central and peripheral cornea. Summary data are shown as mean ± SD. Each data point represents one cornea. Red symbols represent the contralateral eye of the decorin-treated eye. Legend: DCN, decorin; Gel, fluid gel. Figure S4. Experiment 2: Corneal re-epithelialisation and stromal thickness after 6-hours of topical treatment (i.e., 3 × doses, 2 hours apart). (A) Representative en face OCT image at baseline (0h after abrasion). (B) Representative en face OCT image after 6-hours of treatment. Red dashed lines in panels A and B indicate the margin of the injured epithelium. Scale bar in B is 0.5 mm. (C) Percentage of re-epithelialised corneal area after 6-hours of treatment. (D) Corneal stromal thicknesses after 6-hours of treatment. Red symbols in panels C and D represent the contralateral eye of the decorin-treated eye. Summary data are shown as mean ± SD. Each data point represents one cornea. P-values for each of the inter-group comparisons are provided in Table 2. Legend: DCN, decorin; Gel, fluid gel. Figure S5. Experiment 4: Effect of topical decorin applied before injury (DCN) on corneal immune cells and nerve regeneration. (A-B) Density of DCs in the central and peripheral corneal epithelium after topical application of prophylactic decorin on intact corneas. (C-D) Sum length of the SNTs and SBNP in the central cornea, at 1 week after prophylactic application of decorin. (E-F) Density of DCs in the peripheral epithelium and macrophages in the central stroma, at 1 week after prophylactic application of topical decorin. Summary data are shown as mean ± SD. * indicates a statistically significant difference between saline-treated and decorin-treated eyes. Each data point represents one cornea. Legend: DC, dendritic cell; DCN, decorin; SBNP, sub-basal nerve plexus; SNT, superficial nerve terminal; WT, wild-type. Figure S6 (A) Comparison of initial abrasion area between Experiment 1 and 3. (B) Relationship between the initial abrasion area and the re-epithelialised area at 6h.

Pterygium is a degenerative disease that characterized by excessive fibrovascular proliferation. To reduce the recurrence rate, surgery is the main strategy, in combination with adjacent procedures or adjunctive therapy. One of the most common adjunctive agents, mitomycin C (MMC), is known as an alkylating agent that inhibits fibroblast proliferation but is limitedly applied in pterygium due to various complications. A previous study demonstrated that activated pterygium subconjunctival fibroblasts overexpressed low-density lipoprotein (LDL) receptors. In this study, we designed and synthesized MMC-loaded mesoporous silica nanoparticles conjugated with LDL (MMC@MSNs-LDL) to deliver MMC into activated pterygium fibroblasts in a targeted manner. The MMC loading efficiency was approximately 6%. The cell viability test (CCK-8 assay) revealed no cytotoxicity for the empty carrier MSNs at a concentration of ≤1 mg/ml after administration for 48 h in subconjunctival fibroblasts. Primary pterygium and normal human subconjunctival fibroblasts with or without stimulation by vascular endothelial growth factor (VEGF) were treated as follows: 1) 10 μg/ml MMC@MSNs-LDL for 24 h (MMC concentration: 0.6 μg/ml); 2) 0.2 mg/ml MMC for 5 min then cultured for 24 h after MMC removal; and 3) normal culture without any drug treatment. At 24 h, the anti-proliferative effect of MMC@MSNs-LDL in activated pterygium fibroblasts was similar to that of MMC (cell viability: 46.2 ± 5.5% vs 40.5 ± 1.1%, respectively, P = 0.349). Furthermore, the cytotoxicity of MMC@MSNs-LDL to normal fibroblasts with or without VEGF stimulation was significantly lower than that of traditional MMC (cell viability: 75.6 ± 4.4% vs 36.0 ± 1.5%, respectively, P 0.001; 84.7 ± 5.5% vs 35.7 ± 1.3%, P 0.001). The binding of fluorescently labeled MMC@MSNs-LDL in fibroblasts was assessed using confocal fluorescence microscopy. The uptake of targeted nanoparticles in fibroblasts was time dependent and saturated at 6 h. VEGF-activated pterygium fibroblasts showed more uptake of MMC@MSNs-LDL than normal fibroblasts with or without VEGF activation (both P 0.001). Our data strongly suggest that MMC@MSNs-LDL had an effective antiproliferative role in activated pterygium fibroblasts, with reduced toxicity to normal fibroblasts compared to traditional application of MMC. LDL-mediated drug delivery might have great potential in the management of pterygium recurrence.

Recent investigations have uncovered large, consistent deviations from the predictions of Homo economics that individuals are entirely self-regarding. Our study undertook a cross-cultural study of behavior search for the evidences of other-regarding behaviors and its ethnic difference, and accounted for by anatomy of culture. This study recruited 90 subjects of three ethnic groups from market trade-based (ethnic Han), nomadism-based (ethnic Zang) and agriculture-based (ethnic Bouyei) areas in China and conducted public good provision experiment with stranger-treatment design. Under the assumption of self-regarding preferences, the Nash equilibrium is zero contribution by all in public account using backward induction. However, we found contributions did not reduce to zero over all three sessions. Besides, the differences in contributions between ethnicities strongly depended on the degree of ethnic dominance, and Zang harbored the strongest reciprocal preference generally over all group structures. A particular set of measurable factors was identified as proxies for cultural influences on behavioral differences observed in experiments between ethnicities. The results showed all of the cultural factors accounted for the behavioral differences between the ethnic Han and the other two minor ethnicities. However, behavioral difference between minor ethnicities was attributed to group structure only. (1) People may harbor various forms of prosocial emotions in economic affairs, and especially exhibit stronger at the initial phase rather than what canonical model assumes. (2) Behavioral differences between ethnicities are prominent and can be explained by differences in cultural influence.

This report details the natural history of corneal argyrosis over 3 years using in vivo confocal microscopy to document regression of hyperreflective deposits, as well as effects on corneal nerves and endothelial cell morphology.To report the in vivo confocal microscopic features and clinical characteristics of a case of bilateral corneal argyrosis.A 52-year-old man referred to us 3 months following cautery of the palpebral conjunctiva of both eyes with a silver nitrate stick was observed over the course of 3 years, during which slit-lamp photography and in vivo confocal microscopy were performed. At the first visit, slit-lamp examination showed a light blue-green discoloration and a thick, yellow, oval discoloration in the right and left cornea, respectively. One year later, under slit-lamp examination, the right cornea appeared nearly transparent, and the discoloration in the left cornea had remarkably regressed. In vivo confocal microscopy done at that time showed highly reflective deposits in Descemet membrane of the right cornea and throughout Bowman layer, the stroma, and Descemet membrane of the left cornea. Three years later, no accumulation of silver was observed during slit-lamp examination of either eye. In vivo confocal microscopy of the right cornea did not reveal any silver deposits, and the corneal structure appeared normal. In the left cornea, some silver deposits were still evident in Descemet membrane, and alterations of corneal nerve and endothelial cell morphology were also evident.This report reviews the 3-year natural history of a patient with corneal argyrosis. In vivo confocal microscopy demonstrates that over time the corneal argyrosis gradually resolves without any treatment. However, the presence of silver in the cornea may impact the corneal nerves and endothelial cells.