ABSTRACT
Pulmonary hypertension (PH) is a multifactorial, progressive disease with poor outcomes. Group 2 PH is defined by pulmonary vascular disease with elevated pulmonary capillary wedge pressure including both left-sided obstructive lesions and diastolic heart failure (HF). Sildenafil was historically discouraged in this population as pulmonary vasodilation can lead to pulmonary edema. However, evidence suggests that sildenafil can help to treat the precapillary component of PH. This is a single center, retrospective pilot study of pediatric PH patients with left-sided HF who were treated with sildenafil for ≥ 4 weeks. HF patients without mechanical support (HF group) and HF patients with a left ventricular assist device (HF-VAD) were analyzed. The exploratory analysis described the safety and side effects of the drug. Echocardiographic parameters were compared before and after sildenafil treatment in a paired analysis. The changes in medical therapy during treatment, mechanical support, and mortality was reported; 19/22 patients tolerated sildenafil. Pulmonary edema in two patients resolved upon discontinuation of sildenafil. In the HF group, both the right atrial volume and right ventricular diastolic area decreased, and the tricuspid regurgitation (TR) S/D ratio decreased after therapy (p = 0.02). Across both the groups, four patients weaned off milrinone and seven weaned off inhaled nitric oxide. Of the thirteen HF patients, four received a transplant, and all of the nine HF-VAD patients received a transplant. Sildenafil can be safely used in carefully selected patients with HF and mixed pre/postcapillary PH with judicious titration and inpatient surveillance, with patients showing improvements in echocardiographic parameters.
ABSTRACT
PURPOSE: To understand the mechanism of corneal keratin expression and clearance in corneal epithelium with Limbal Stem Cell Deficiency (LSCD). The hypothesis is that LSCD-induced proteasome dysfunction is a contributing factor to keratin aggregation, causing corneal keratin aggresome (CKAGG) formation. METHOD: LSCD was surgically induced in rabbit corneas. LSCD corneal epithelial cells (D-CEC) were collected to investigate keratin K4 and K13 expression and CKAGG formation. Oral mucosal epithelial cells (OMECS) were isolated and cultured to study K4 and K13 expression. Cultured cells were treated with proteasome inhibitor to induce CKAGG formation. RESULTS: K4 and K13 were strongly expressed in D-CEC, with additional higher molecular weight bands of K4 and K13, suggesting CKAGG formation. Double staining of K4/K13 and ubiquitin showed co-localization of these keratins with ubiquitin in D-CEC. Proteasome inhibition also showed K4/K13 modification and accumulation in cultured OMECS, similar to D-CEC. Proteasome activation was then performed in cultured OMEC. There was no accumulation of keratins, and levels of unmodified keratins were found significantly reduced. CONCLUSION: Results showed an abnormal expression of K4 and K13 after LSCD-induced proteasome dysfunction, which coalesce to form CKAGG in Corneal Epithelial Cells (CEC). We propose that CKAGG formation may be one of the causative factors of morphological alterations in the injured corneal epithelium, and that CKAGG could potentially be cleared by enhancing proteasome activity.
