Clinical efficacy of cyclosporin and natamycin for fungal keratitis.

Objectives: To investigate the clinical efficacy of cyclosporin (CYSP) and natamycin (NAT) as a combination therapy in patients with fungal keratitis. Methods: This is a retrospective study. A total of 64 patients (64 eyes) with fungal keratitis treated by Baoding No.1 Central Hospital between December 2018 and May 2022 according to their treatment methods were divided into a monotherapy (MT) group receiving NAT eye drops solely and a combination therapy (CT) group given CYSP eye drops in addition to the exact treatment provided for the MT group. The clinical responses, visual acuity changes, severity of eye symptoms, and adverse reactions were compared between the two groups. Results: At two and four weeks post-treatment, the CT group had an overall response rate (ORR) significantly higher than that of the MT group (P< 0.05, respectively); both groups showed improved visual acuity and eye symptoms compared with the pre-treatment condition, and these improvements were more pronounced in the CT group (P < 0.05, respectively). Compared with the MT group, the CT group experienced a significantly shorter duration of eye symptoms (P < 0.05). The adverse reaction rate(ARR) was 9.38% in the CT group and 6.25% in the MT group, and the difference was not significant (P > 0.05). Conclusion: Using CYSP and NAT as a combination therapy for fungal keratitis can substantially heighten the therapeutic effects, promote visual acuity recovery, and induce rapid remission of eye symptoms without increasing the risk of adverse reactions.

A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis.

OBJECTIVE: Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. METHODS: Experimental fungal keratitis was established in wild-type and gene knockout (TLR4-/- and GSDMD-/-) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. RESULTS: Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. CONCLUSIONS: The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

Natamycin versus natamycin combined with voriconazole in the treatment of fungal keratitis.

Objective: To observe the therapeutic effect of natamycin combined with voriconazole in the treatment of fungal keratitis (FK). Methods: This is a retrospective study. The subjects of this study were 64 patients with FK who were admitted to Baoding No.1 Central Hospital from February 2019 to July 2022. The enrolled patients were divided into control group (n= 32) and study group (n= 32) by the random number table method. The control group was treated with natamycin alone, and the study group was treated with natamycin combined with voriconazole. The total efficacy, time of disappearance of ocular symptoms, visual acuity level, keratitis severity score, corneal ulcer area, tear fungus index and incidence of adverse reactions were compared between the two groups. Results: The total efficacy,of the study group was significantly higher than that of the control group. The disappearance time of corneal ulcer, photophobia, foreign body sensation and hypopyon in the study group was shorter than those in the control group. Keratitis severity score and (1,3)-ß-D-glucan level in the study group were lower than those in the control group. The corneal ulcer area was narrowed in the study group than that of the control group, and the visual acuity level in the former group was higher than that of the latter group. Besides, there was no significant difference in the frequency of adverse reactions between the two groups. Conclusion: Natamycin combined with voriconazole is safe and effective in the treatment of FK.

A comparative study on early vision quality after implantation of refractive segmental and diffractive multifocal intraocular lens.

OBJECTIVES: To compare early subjective and objective vision quality of postoperative patients undergoing phacoemulsification cataract surgery combined with implantation of refractive segmental multifocal intraocular lens (MIOL) SBL-3 and apodized diffractive MIOL SN6AD1. METHODS: As a prospective study, it enrolled 53 patients (53 eyes) to undergo phacoemulsification cataract surgery combined with MIOL implantation. According to differences in MIOL implanted, patients were divided into a SBL-3 group (25 eyes) and a SN6AD1 group (28 eyes). Ophthalmological evaluation included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected intermediate (UIVA) and near (UNVA) visual acuities, distance-corrected intermediate (DCIVA) and near (DCNVA)visual acuities and corrected near(CNVA) visual acuity, contrast sensitivity, modulation transfer function (MTF) and high order aberration (4 mm pupil diameter) at three months postoperatively. Moreover, a questionnaire survey was carried out to assess near spectacle independence, patient satisfaction and symptoms of visual disturbance. RESULTS: At three months after surgery, UIVA and UNVA in the SBL-3 group are statistically significantly superior to those of the SN6AD1 group (P>0.05). There was statistical difference in contrast sensitivity at four spatial frequencies (3, 6, 12, 18cycles/degree) under mesopic conditions and mesopic conditions with glare (P>0.05). The total ocular high order aberration, coma and trefoil were statistically significantly larger in the SBL-3 group than in the SN6AD1 group with 4.0 mm pupil diameters (P>0.05). Statistical differences were found in the MTF at spatial frequencies of 5, 10 and 15 cycles/degree between the groups. There were no significant differences in spectacle independence, patient satisfaction and visual disturbance between the groups (P>0.05). CONCLUSIONS: Both the two multifocal intraocular lens provided an excellent level of quality of vision three months postoperatively. However, the application effect of SBL-3 MIOL is superior to that of SN6AD1 MIOL as far as intermediate vision, near vision and contrast sensitivity are concerned.

Roles of pattern recognition receptors in response to fungal keratitis.

Fungal keratitis is one of the leading causes of blindness worldwide, which has become an increasingly serious threat to public ocular health, but no effective treatment strategies are available now. Pattern recognition receptors (PRRs) of the innate immune system are the first line of host defense against fungal infections. They could recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and trigger an array of inflammatory responses. Over the last decades, research has resulted in significant progress regarding the roles of PRRs in fungal keratitis. This review will highlight the importance of several pattern recognition receptors (C-type lectin-like receptors, Toll-like receptors, and NOD-like receptors) in regulating the innate immunity under fungal keratitis and describe the crosstalk and collaboration in PRRs contributing to disease pathology. Meanwhile, some potential therapy-based PRRs against corneal fungal infections are discussed.

NLRP3 Inflammasome-Mediated Pyroptosis Pathway Contributes to the Pathogenesis of Candida albicans Keratitis.

Purpose: Fungal keratitis is a sight-threatening corneal infection caused by fungal pathogens, and the pathogenic mechanisms have not been fully elucidated. The aim of this study was to determine whether NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis contributes to Candida albicans (C. albicans) keratitis and explore the underlying mechanism. Methods: An in vivo mouse model of C. albicans keratitis and an in vitro culture model of human corneal epithelial cells (HCECs) challenged with heat-killed C. albicans (HKCA) were established in this study. The degree of corneal infection was evaluated by clinical scoring. Gene expression was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis or immunofluorescence staining was performed to evaluate protein expression. TdT-mediated dUTP nick end labeling (TUNEL) staining was performed to examine the pyroptotic cell death. A lactate dehydrogenase (LDH) release assay was performed to assess cytotoxicity. Results: Compared with the mock-infected group, we observed that the mRNA levels of NLRP3, caspase-1 (CASP1), interleukin (IL)-1ß and gasdermin-D (GSDMD) in C. albicans-infected mice cornea was significantly increased. Our data also demonstrated that the protein expression of NLRP3 and the pyroptosis-related markers apoptosis-associated speck-like protein containing a CARD (ASC), cleaved CASP1, N-GSDMD, cleaved IL-1ß and cleaved IL-18 as well as pyroptotic cell death were dramatically elevated in the mouse model of C. albicans keratitis. More importantly, NLRP3 knockdown markedly alleviated pyroptosis and consequently reduced corneal inflammatory reaction in C. albicans keratitis. In vitro, the presence of activated NLRP3 inflammasome and pyroptotic cell death were validated in HCECs exposed to HKCA. Furthermore, the potassium (K+) channel inhibitor glyburide decreased LDH release and suppressed NLRP3 inflammasome activation and pyroptosis in HCECs exposed to HKCA. Conclusion: In conclusion, the current study revealed for the first time that NLRP3 inflammasome activation and pyroptosis occur in C. albicans-infected mouse corneas and HCECs. Moreover, NLRP3 inflammasome-mediated pyroptosis signaling is involved in the disease severity of C. albicans keratitis. Therefore, This NLRP3 inflammasome-dependent pathway may be an attractive target for the treatment of fungal keratitis.

Clinical and pathological features of bronchiolitis obliterans requiring lung transplantation in paraneoplastic pemphigus associated with Castleman disease.

AT A GLANCE: Bronchiolitis obliterans in paraneoplastic pemphigus associated with Castleman disease possesses the progressive nature even when it is treated with intensive medical therapy. Antibodies were at least in low titers before the Lung transplant and remain negative after the procedure. Explanted lungs showed coexistence of cellular destructive bronchiolitis and constrictive bronchiolitis. BACKGROUND: Bronchiolitis obliterans (BO) in paraneoplastic pemphigus (PNP) associated with Castleman disease (CD) possesses the progressive nature of pulmonary disease even when it is treated with intensive medical therapy. Lung transplantation (LT) offers an acceptable form of treatment. METHODS: We conducted a retrospective study of two cases of BO in PNP associated with CD who underwent LT between March 2017 and March 2020 at the China-Japan Friendship Hospital. We also included one case from the literature. RESULTS: In this patient series, PNP was the primary clinical presentation in all patients, and it was accompanied by respiratory symptoms before/after CD excision. In spite of being treated with various combinations of immunosuppressive and anti-inflammatory agents, the patients had great or total improvement in mucosal erosions, whereas their pulmonary function test (PFT) deteriorated gradually or sharply. The duration times from disease onset to timing of LT were 1, 2 and 5 years. All antibodies were negative or were present at low titers before the LT procedure and remain negative after the procedure. The histopathological features of explanted lungs showed cellular and coexistent destructive bronchiolitis and constrictive bronchiolitis in two cases. Granulation with numerous foamy macrophages, scattered giant cells and cholesterol clefts were especially prominent in case one. CONCLUSION: BO in PNP associated with CD had poor clinical outcomes. LT was preferable choice in end-stage BO when PNP and CD were controlled.

[The influence of preoperative corneal spherical aberration on relatively personalized implantation of aspheric intraocular lens].

OBJECTIVE: To analysis the feasibility of selectively targeting zero total postoperative spherical aberration by selecting the best fit aspheric intraocular lens (IOL) based on preoperative corneal spherical aberration of patients. METHODS: It was a prospective case series study. The corneal spherical aberration (Z40) with 6 mm aperture of 57 eyes (46 patients) was measured with a iTrace Visual Function Analyzer 1 day before surgery, the target postoperative total spherical aberration was set at zero. Thus, for corneal spherical aberration<+0.100 microm, the Sofport Advanced Optic (AO)IOL(10 eyes) was selected; for corneal spherical aberration>+0.100 microm but if <+0.235 microm, the AcrySof IQ IOL (20 eyes) was selected; and for corneal spherical aberration>+0.235 microm, Tecnis ZA9003 IOL (27 eyes)was selected. Aspherical IOL was implanted after phacoemulsification through a clear-cornea, 3.2 mm incision without suture. Uncorrected visual acuity, best corrected visual acuity (BCVA), spherical aberration of the whole eye and internal optics (IOL) at 6 mm pupil diameter were examined at 3 months postoperatively. ANOVA and t-test were used to analyze the data at 3 months postoperatively. RESULTS: Total postoperative ocular spherical aberration at 6 mm pupil diameter for the entire population measured (0.015+/-0.056) microm [AO: (0.081+/-0.013) microm; IQ: (0.006+/-0.038) microm; Tecnis: (0.007+/-0.070) microm]. For the entire population, there was no significantly different between the predicted value and actual value of ocular spherical aberration at 6 mm pupil diameter: t=1.983, P=0.052 (AO:t=1.957, P=0.082; IQ: t=0.030, P=0.976; Tecnis: t=2.031, P=0.053). For the entire population, the predictive error measured (0.014+/-0.044) microm [AO: (0.006+/-0.012) microm; IQ: (-0.000+/-0.037) microm; Tecnis: (0.027+/-0.052) microm; F=2.626, P=0.082]. The postoperative visual activity was not significantly different among the three groups (P>0.05). CONCLUSION: Customized selection of aspheric IOL based on preoperative corneal spherical aberration of patients is feasible and produces satisfactory target postoperative total spherical aberration.

[The influences on modulation transfer function as a function of age and pupil in adult emmetropic eyes].

OBJECTIVE: To explore the influences on modulation transfer function (MTF) as a function of age and pupil in adult emmetropic eyes. METHODS: It was a prospective clinical study. All the 102 emmetropic eyes were divided into three groups according age: group A, 40 eyes (age 20 - 30 years); group B, 30 eyes (age 31 - 40 years); group C, 30 eyes (age 41 - 50 years). The total MTF and subtracted lower order aberration MTF curve were measured in all emmetropic eyes in 3.0 mm, 4.0 mm and 5.0 mm pupil sizes with a iTrace Visual Function Analyzer at six spatial frequencies (5, 10, 15, 20, 25, 30 cpd). The association between age and the two MTFs was analyzed, the two MTFs were compared among different age groups and different pupils using univariate analysis. RESULTS: In 3.0 mm, 4.0 mm and 5.0 mm pupil sizes and at all six spatial frequencies, there was a negative correlation between age and the two MTFs, there were significant differences among the three groups (F = 18.773, P < 0.05). At all six spatial frequencies, the two MTFs decreased with the increasing pupil. CONCLUSIONS: The total MTF and subtracted lower order aberration MTF in adult emmetropic eyes decreased with aging and increasing pupil, so when using the two MTFs to evaluate the visual quality of human eyes, we must use different criteria according to the different age and pupil size.