Of all echocardiographic variables investigated, tricuspid annular E/E' ratio is identified as the best index for noninvasive determination of RAP.

PURPOSE. The degenerative corneal disease keratoconus is a leading indicator for corneal transplant with an unknown etiology. We recently identified the activation of the integrated stress response (ISR) in ex vivo human corneas and in vitro cell culture. Utilizing small molecules to modulate the ISR we sought to investigate the effects of stimulating the ISR in healthy cells to recapitulate aspects of the in vitro keratoconic phenotype and whether relieving the ISR signaling would recover the disease phenotype. METHODS. Corneal fibroblasts were extracted from patients undergoing corneal transplant or unaffected cadaverous donor limbal rings. Cells were exposed to the DNA damage-inducible protein (GADD34) inhibitor SAL003 to stimulate the ISR, or Trans-ISRIB to relieve ISR signaling pathway. Collagen production was assessed through hydroxyproline production, Sirius Red incorporation, or quantitative (q)PCR. Western blotting, hydroxyproline, and qPCR were used to assess components of the ISR pathway and collagen production. RESULTS. ISR stimulation through SAL003 resulted in significant decrease of hydroxyproline and COL1A1 transcription and eventual apoptosis in normal fibroblasts. Patient (KC) fibroblast production of hydroxyproline was increased in response to ISRIB, while matrix metalloproteinase (MMP)9 production was lowered. The prospective biomarker of keratoconus prolactin-inducible factor was also upregulated in KC fibroblast cultures in response to ISRIB. Inflammatory markers TNFa and IL-1b were unaffected. CONCLUSIONS. Activation of the ISR is sufficient to recapitulate many key aspects of the KC phenotype in unaffected cells in vitro. Inhibition of the ISR also relieves many of the hallmarks of KC in affected cells. Therefore, targeting of the ISR through small molecules is a potential therapeutic path for small molecule treatment of keratoconus.

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is properly cited.Purpose. is study aims to correlate the clinical signs of keratoconus (KC) which include superficial apical scarring, Fleischer rings, and Vogt striae with best spectacle-corrected visual acuity (BSCVA) and corneal tomography findings. Patients and methods. A retrospective observational study. 72 consecutive KC patients seen by the senior author over the course of one year were included in this case series. Eyes with pellucid marginal degeneration, postrefractive ectasia, history of a corneal graft, prior corneal collagen cross-linking, intracorneal ring segments or hydrops were excluded from analysis. Subsequently, the final analysis included only treatment-naïve KC eyes with varying degrees of disease severity. Results. BSCVA with manifest refraction was 0.5 logMAR higher in eyes with apical scarring (p < 0.001). Eyes with apical scarring had worse vision than eyes with Fleischer rings alone (0.43 logMAR higher in the former, p < 0.009). Eyes with apical scarring had higher keratometry readings (K2 = 64.56 ± 12.89 D versus 49.07 ± 6.61 D, p < 0.001); this was also true for eyes with Fleischer rings compared with ring-free eyes (K2 = 56.23 ± 11.52 D versus 48.91 ± 7.79 D, p < 0.001) and eyes with Vogt striae (K2 = 56.19 ± 10.27 D versus 50.68 ± 9.21 D, p � 0.01). Atopic disease was a risk factor for scarring: odds ratio (OR) = 2.87 (p � 0.03). e OR of observing Fleischer rings in KC eyes was 12% per year (p � 0.001). Additionally, each mm of corneal apex displacement from the pupillary center led to a 0.76 logMAR increase in visual acuity (p � 0.001). Conclusion. e presence of apical scarring and Fleischer rings on biomicroscopy can aid the clinician in making the distinction between severe or long-standing disease (respectively). Apical scarring is a sign of advanced disease and is associated with worse BSCVA and tomography findings. Fleischer rings are markers of intermediate disease and their presence correlates with disease duration.