Rhino-orbito-cerebral mucormycosis(ROCM) is an invasive fungal infection that usually occurs in immunocompromised patients and sometimes presents as orbital apex syndrome(OAS) initially. It is rapidly fatal without an early diagnosis and treatment. We report the cases of invasive ROCM presenting with OAS initially in order to raise the attention of clinicians. We retrospectively investigated eleven cases of invasive ROCM presenting initially with OAS admitted between January 2006 and December 2013. We analyzed clinical features, results of laboratory and radiological examinations, nasal endoscopy, aggressive surgical excision and debridement, and medical management outcomes of each case. A total of eleven cases of invasive ROCM with OAS as an initial sign were presented. Mucormycosis was accompanied by type II diabetes mellitus in nine cases, renal transplant in one case, and injury caused by traffic accident in one case. Anterior rhinoscopy revealed palatine or nasal necrotic lesions in all patients, and transethmoidal optic nerve decompression was carried out in three patients at the same time. CT scan revealed rhino-orbital-cerebral involvement in every patient. All patients were given intravenous amphotericin B. Nine patients underwent surgical debridement of necrotic tissue. Three patients survived. ROCM is a severe, emergent and fatal infection requiring multidisciplinary management. It may often present with OAS initially. For ophthalmologist, mucormycosis must be considered in immunocompromised patients presenting with OAS initially, and anterior rhinoscopy is imperative before hormonotherapy, even in the cases absent of ketoacidosis induced by diabetes mellitus.

To evaluate the visual quality of patients with different angle κ sizes after a trifocal diffractive intraocular lens (IOL) implantation. The Affiliated Hospital of Qingdao University, Qingdao, China. Prospective case series. Patients who had phacoemulsification with the implantation of the trifocal IOL AT LISA tri 839MP were enrolled in the study. The patients were divided into 3 groups based on the size of the preoperative angle κ. Monocular far, intermediate, and near uncorrected visual acuities were measured during a 3-month follow-up. Other outcome measurements taken were the modulation transfer function (MTF) cutoff, the Strehl ratio, and objective scatter index. All the patients completed a subjective questionnaire survey. The study comprised 89 patients (89 eyes). The 3 groups showed statistically significant differences in the incidence of glare and halo after their surgery. There were no significant differences in the following variables: uncorrected far, intermediate, and near visual acuities, MTF cutoff, Strehl ratio, and spectacle independence. There was a significant difference in the MTF cutoff and Strehl ratio between the patients with the largest and the smallest angle κ. The patients' postoperative far, intermediate, and near vision was not affected by their angle κ. However, when angle κ was greater than 0.4 mm, the incidence of glare and halo increased and when it was greater than 0.5 mm, patients' visual quality decreased. In clinical work, for patients with a larger angle κ, the choice to implant a trifocal IOL should be carefully evaluated.

Purpose: To investigate the antifungal and anti-inflammatory effects of baicalein on Aspergillus fumigatus (A. fumigatus) keratitis and the underlying mechanisms. Methods: The noncytotoxic antifungal concentration of baicalein was determined using CCK8, cell scratch assay, minimum inhibitory concentration, biofilm formation, scanning electron microscopy, propidium iodide uptake test and adherence assay in vitro and Draize test in vivo. In fungal keratitis (FK) mouse models, clinical score and plate count were used to evaluate FK severity, and myeloperoxidase assay and immunofluorescence staining were performed to examine neutrophil infiltration and activity. Real-time PCR, ELISA, and Western blot were performed to explore the anti-inflammatory activity of baicalein and the underlying mechanisms in vivo and in vitro. Results: Baicalein at 0.25 mM (noncytotoxic) significantly inhibited A. fumigatus growth, biofilm formation, and adhesion in vitro. In A. fumigatus keratitis mice, baicalein mitigated FK severity, reduced fungal load, and inhibited neutrophil infiltration and activity. Baicalein not only suppressed mRNA and protein levels of proinflammatory factors IL-1β, IL-6, and TNF-α, but also inhibited the expression of thymic stromal lymphopoietin (TSLP) and TSLP receptor (TSLPR) in vivo and in vitro. In HCECs, mRNA and protein levels of IL-1β, IL-6, and TNF-α were significantly lower in the TSLP siRNA–treated group, while higher in the rTSLP-treated group than in the corresponding control. Baicalein treatment significantly inhibited rTSLP induced the expression of IL-1β, IL-6, and TNF-α. Conclusions: Baicalein plays a protective role in mouse A. fumigatus keratitis by inhibiting fungal growth, biofilm formation, and adhesion, and suppressing inflammatory response via downregulation of the TSLP/TSLPR pathway.

Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐related factor‐2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling in this process. Eyes of C57BL/6 (B6) mice were treated with 2 mm DI after infection with Aspergillus fumigatus. Human corneal epithelial cells (HCECs) were pretreated with 0.25 mm DI and then incubated with A. fumigatus. Clinical scoring, slit‐lamp photography, myeloperoxidase determination, flow cytometry and immunostaining were used to assess the disease response and treatment efficacy. PCR, Western blot and ELISA were used to assess the expression of interleukin‐1β (IL‐1β), chemokine (C–X–C motif) ligand 1, IL‐6, IL‐8, Nrf2 and HO‐1. In addition, quantification of viable fungi, absorbance assays and fluorimetry were used to measure DI fungistatic activity. We observed that DI‐treated eyes showed decreased clinical scores, fungal loads, polymorphonuclear neutrophil (PMN) infiltration and cytokine expression, compared with phosphate‐buffered saline‐treated infected eyes. DI treatment decreased the cytokine levels in infected corneas and in HCECs stimulated with A. fumigatus. Moreover, DI treatment increased Nrf2 and HO‐1 expression in corneas and nuclear Nrf2 accumulation in HCECs. DI‐induced cytokine downregulation was inhibited by pretreatment with an Nrf2 or HO‐1 inhibitor. Finally, DI treatment reduced the A. fumigatus absorbance and fungal mass. These data indicate that DI protects against fungal keratitis by limiting inflammation via the Nrf2/HO‐1 signaling pathway and that DI inhibits the growth of A. fumigatus.

Purpose: The purpose of this study was to investigate the therapeutic effect of perillaldehyde (PAE) on Aspergillus fumigatus (A. fumigatus) keratitis. Methods: Human corneal epithelial cells (HCECs) were pretreated with PAE and stimulated with A. fumigatus mycelium. C57BL/6 mice were infected with A. fumigatus and treated with or without PAE 1 day after infection. Clinical scores, PCR, ELISA, and Western blotting were used to detect the expression of pro-inflammatory mediators, dendritic cell-associated c-type lectin-1 (Dectin-1), nuclear factor (erythroid-derived 2) like 2 (Nrf2), and heme oxygenase (HO-1). Nrf2 expression in HCECs pretreated with PAE was observed by immunofluorescence. NIMP-R14 protein expression and localization in mouse corneas were observed by immunofluorescence staining after treatment with PAE. Corneal colony counting, time-kill tests, and mycelial transformation inhibition tests were used to evaluate the antifungal effect of PAE. Results: C57BL/6 mice treated with PAE at 1 day after infection had a lower clinical score and decreased IL-1β, TNF-α, IL-6, Dectin-1, and MPO levels. PAE treatment significantly reduced neutrophil recruitments to the corneal stroma. Compared with the DMSO-treated group, PAE treatment significantly decreased mRNA and protein levels of pro-inflammatory cytokines and Dectin-1 in HCECs. PAE pretreatment before A. fumigatus stimulation obviously elevated the mRNA and protein levels of components of the Nrf2/HO-1 axis. HCECs pretreated with PAE before infection showed a weakened ability to inhibit inflammation in the presence of brusatol (BT; an Nrf2 inhibitor) or ZnPP (an HO-1 inhibitor). PAE treatment significantly reduced the fungal load of C57BL/6 mouse corneas and inhibited fungal growth in vitro. Conclusions: These data proved that PAE may ameliorate A. fumigatus keratitis by activating the Nrf2/HO-1 signaling pathway and inhibiting the Dectin-1 mediated inflammatory response and neutrophil recruitment. Furthermore, PAE exerts direct fungicidal activity on A. fumigatus.

Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on Aspergillus fumigatus (A. fumigatus), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.