Safety and Efficacy of Scleral Lenses for Keratoconus.

SIGNIFICANCE: This study affirms the long-term safety and efficacy of scleral contact lens use in patients with keratoconus. PURPOSE: This study aimed to evaluate the safety and efficacy of contemporary scleral contact lenses in the visual rehabilitation of the keratoconic population. METHODS: A retrospective study of keratoconic subjects examined between 2013 and 2018 was conducted. Subjects were included regardless of age, sex, pre-existing morbidity, or scleral lens design. Only eyes fit successfully with scleral contact lenses for ≥1 year were included. Exclusion criteria were prior corneal surgery, dystrophy, degeneration, and trauma. RESULTS: A total of 157 eyes of 86 subjects met the study criteria. The mean Keratoconus Severity Score at initial fitting was 3.6 ± 1.0. Lenses were gas-permeable and nonfenestrated, with a mean overall diameter of 15.8 ± 0.6 mm and 70.1% toric scleral periphery. Physiological adverse events occurred in 9.6% of eyes, including microbial keratitis (0.6%), phlyctenulosis (0.6%), corneal abrasion (1.3%), contact lens-induced acute red eye (1.3%), corneal infiltrative events (1.3%), pingueculitis (1.3%), and hydrops (3.2%). Lens-related adverse events were documented in 55.4% of eyes. Adverse events related to surface issues included poor wetting in 1.9%, handling in 3.8%, reservoir fogging in 7.0%, lens intolerance in 7.6%, deposit in 8.9%, and broken lenses in 26.1% of eyes. The most common management strategies involved refits (54.0% of interventions), patient reeducation (29.5%), medical treatment (5.5%), surgical referral (6.8%), adjustment to wear time (2.5%), surface treatment (1.2%), and lens replacement (0.6%). Best-corrected distance logMAR visual acuity improved significantly from a mean of 0.50 in spectacles to a mean of 0.08 in scleral lenses (P < .0001). During the study period, 14.6% of eyes lost best-corrected scleral lens visual acuity, all from keratoconus progression. CONCLUSIONS: Consistent with other groups, our study demonstrates excellent safety and efficacy of scleral contact lenses in subjects with keratoconus.

Role of MMP-9 in the breakdown of barrier integrity of the corneal endothelium in response to TNF-α.

TNF-α induces loss of barrier integrity of the corneal endothelium through mechanisms involving the activation of p38 MAP kinase. This study has investigated the role of matrix metalloproteinase-9 (MMP-9), known to be activated by mechanisms downstream of p38 MAP kinase, on the breakdown of the barrier integrity. Experiments were performed with primary cultures of bovine corneal endothelium. Changes in the trans-endothelial electrical resistance (TER), a measure of barrier integrity, were measured by electric cell-substrate impedance sensing. The integrity of the apical junctional assembly was imaged by immunolocalization of ZO-1. MMP-9 activity in the conditioned medium of cells treated with TNF-α was visualized by gelatin zymography. Transcriptional activation of MMP-9 was assessed by real-time RT-PCR. Exposure to TNF-α led to significant disruption of ZO-1 and also caused a continuous decline in TER for more than 20 h. These effects were opposed by cycloheximide (protein synthesis inhibitor), GM-6001 (broad spectrum inhibitor of MMPs), minocycline (MMP-2 and MMP-9 inhibitor), and MMP-9 inhibitor I (selective MMP-9 inhibitor). Cycloheximide, GM-6001, and MMP-9 inhibitor I also attenuated the increase in permeability to FITC-dextran (10 kDa). In addition, TNF-α led to an increased MMP-9 activity in the conditioned medium as well as a nearly 20-fold increase in mRNA for MMP-9 but not for MMP-2. The functional activity and increase in mRNA levels of MMP-9 were blocked by SB-203580 (selective p38 MAP kinase inhibitor) and cycloheximide. In conclusion, transcriptional and translational activation of MMP-9, downstream of p38 MAP kinase signaling, is involved in the (TNF-α)-induced loss of corneal endothelial barrier integrity.

Identification of human preformed antibody targets in GTKO pigs.

BACKGROUND: Human preformed antibodies continue to recognize porcine xenografts, despite the advent of α-galactosyltransferase knockout (GTKO) pigs. This study examined the potential reactivity of human preformed IgG and IgM antibodies toward antigens in the GTKO pig liver. METHODS: Human serum was analyzed for the concentration of IgG, IgM, anti-αgal antibody, anti-non-αgal antibody and cytotoxicity toward domestic and GTKO fibroblasts and liver sinusoidal endothelial cells (LSEC). We detected preformed antibodies in human serum directed toward GTKO pig liver cells and tissue samples using advanced proteomic techniques. The targets of preformed antibodies were identified by MALDI TOF TOF mass spectrometry and validated by confocal microscopy, immunoblot, and immunoprecipitation. RESULTS: Human serum used in this study contained 2.06 µg/ml IgG and 0.013 µg/ml IgM directed toward GTKO fibroblasts. Human IgG and IgM bound to GTKO LSEC in a dose-dependent manner and were cytotoxic. We detected 357 protein spots recognized by human IgG and 233 by human IgM. Two hundred and nineteen proteins were common to both human IgG and IgM. Mass spectrometry identified numerous immunoreactive proteins, of which 19 were membrane proteins on liver cells. The most significant to this study were α-enolase, CFTR, and E-cadherin, which were abundant in GTKO pig tissues and expressed on the surface of GTKO LSEC. Human IgG captured α-enolase, CFTR, and E-cadherin by immunoprecipitation validating the proteomic identification. CONCLUSION: These experiments indicate that several membrane antigens in GTKO pigs could be recognized directly by human IgG or IgM. Further studies on the contribution of these antigens to antibody-mediated xenograft rejection are necessary.

MRI-based texture analysis of the primary tumor for pre-treatment prediction of bone metastases in prostate cancer.

PURPOSE: To identify texture features of multiparametric MRI (mp-MRI) for pre-treatment prediction of bone metastases (BM) in patients with prostate cancer (PCa). PATIENTS AND METHODS: One-hundred and seventy-six patients with clinicopathologically confirmed PCa were enrolled，and the data was gathered from January 2008 to January 2018. A total of 976 texture features were extracted from T2-weighted (T2-w) and dynamic contrast-enhanced T1-weighted (DCE T1-w) MRI. Step regression, ridge regression and LASSO regression method model was applied to select features and develop the predicting model for BM. The performance of the radiomics features, PSA level and Gleason Score were explored with the respect to the receiver operating characteristics (ROC) curve. Multivariable logistic regression analysis starting with the following clinical risk factors (PSA level, Gleason Score and age) and imaging biomarkers were applied to develop diagnostic model for BM in PCa. RESULTS: The texture features, which consisted of 15 selected features, were significantly associated with BM (P < 0.01). The combined MRI features derived from T2-w and DCE T1-w showed better prognostic performance (AUC = 0.898) than features derived from single sequence (T2WI AUC = 0.875, DCE T1-w AUC = 0.870) and Gleason Score (AUC = 0.731) for pre-treatment prediction of BM in PCa. MRI -based imaging biomarker combined with clinical risk factors (free PSA, age and Gleason score) yielded the highest AUC(AUC = 0.916). Multivariate regression analysis showed that the imaging biomarker was an independent risk factor for the detection of bone metastases along with f-PSA level (free PSA) and Gleason score. CONCLUSION: Multiparametric MRI-based texture feature was significant predictor for BM in PCa. Clinical risk factors combined with MRI-based texture feature could further improve the prediction performance, which provide an illustrative example of precision medicine and may affect treatment strategies.