Alterations in Mitochondrial Function in Pulmonary Vascular Diseases.

Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status.

Erk1/2 is not required for endothelial barrier establishment despite its requirement for cAMP-dependent Rac1 activation in heart endothelium.

The contribution of Erk1/2 to endothelial barrier regulation is convoluted and differs depending on the vascular bed. We explored the effects of Erk1/2 inhibition on endothelial barrier maintenance and its relationship with cAMP-dependent barrier strengthening. Thus, myocardial endothelial cells (MyEnd) were isolated and protein expression, localization and activity of structural and signaling molecules involved in maintenance of endothelial function were investigated by Western blot, immunostainings and G-LISA, respectively.

Health-Related Quality of Life Across the Spectrum of Pulmonary Hypertension.

Background: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH).

Research Question: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?

Study Design And Methods: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study.

Cortactin is in a complex with VE-cadherin and is required for endothelial adherens junction stability through Rap1/Rac1 activation.

Vascular permeability is mediated by Cortactin (Cttn) and regulated by several molecules including cyclic-adenosine-monophosphate, small Rho family GTPases and the actin cytoskeleton. However, it is unclear whether Cttn directly interacts with any of the junctional components or if Cttn intervenes with signaling pathways affecting the intercellular contacts and the cytoskeleton. To address these questions, we employed immortalized microvascular myocardial endothelial cells derived from wild-type and Cttn-knock-out mice.

Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension.

Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear.

Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival.

cAMP: A master regulator of cadherin-mediated binding in endothelium, epithelium and myocardium.

Regulation of cadherin-mediated cell adhesion is crucial not only for maintaining tissue integrity and barrier function in the endothelium and epithelium but also for electromechanical coupling within the myocardium. Therefore, loss of cadherin-mediated adhesion causes various disorders, including vascular inflammation and desmosome-related diseases such as the autoimmune blistering skin dermatosis pemphigus and arrhythmogenic cardiomyopathy. Mechanisms regulating cadherin-mediated binding contribute to the pathogenesis of diseases and may also be used as therapeutic targets.

Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.

Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris.

Cytoskeletal anchorage of different Dsg3 pools revealed by combination of hybrid STED/SMFS-AFM.

Desmoglein 3 (Dsg3) is a desmosomal cadherin mediating cell adhesion within desmosomes and is the antigen of the autoimmune blistering skin disease pemphigus vulgaris. Therefore, understanding of the complex desmosome turnover process is of high biomedical relevance. Recently, super resolution microscopy was used to characterize desmosome composition and turnover.

Association of Shear Stress with Subsequent Lumen Remodeling in Hemodialysis Arteriovenous Fistulas.

Background: Blood flow-induced wall shear stress is a strong local regulator of vascular remodeling, but its effects on arteriovenous fistula (AVF) remodeling are unclear.

Methods: In this prospective cohort study, we used computational fluid dynamics simulations and statistical mixed-effects modeling to investigate the associations between wall shear stress and AVF remodeling in 120 participants undergoing AVF creation surgery. Postoperative magnetic resonance imaging data at 1 day, 6 weeks, and 6 months were used to derive current wall shear stress by computational fluid dynamic simulations and to quantify subsequent changes in AVF lumen cross-sectional area at 1-mm intervals along the proximal artery and AVF vein.

Lack of adducin impairs the stability of endothelial adherens and tight junctions and may be required for cAMP-Rac1-mediated endothelial barrier stabilization.

Adducin (Add) is an actin binding protein participating in the stabilization of actin/spectrin networks, epithelial junctional turnover and cardiovascular disorders such as hypertension. Recently, we demonstrated that Add is required for adherens junctions (AJ) integrity. Here we hypothesized that Add regulates tight junctions (TJ) as well and may play a role in cAMP-mediated barrier enhancement.

Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane.

The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients' IgG.

Damage of the ocular surface from indoor suntanning-Insights from in vivo confocal microscopy.

Purpose: To evaluate the ocular surface at the microstructural level of adults who habitually undertake indoor-suntanning utilising in vivo confocal microscopy.

Methods: Participants were prospectively recruited and enrolled into either а study group (n = 75) with a history UV indoor tanning, or a control group (n = 75) with no prior history of artificial tanning. The study group participated in voluntary tanning sessions performed with standard equipment and maintained their usual routine for eye protection.

Surgical lymph node assessment influences adjuvant therapy in clinically apparent stage I endometrioid endometrial carcinoma, meeting Mayo criteria for lymphadenectomy.

Objective: To evaluate the impact of surgical lymph node assessment for clinically apparent, stage I endometrioid endometrial adenocarcinoma meeting Mayo criteria for lymphadenectomy.

Methods: Patients with endometrioid endometrial adenocarcinoma meeting Mayo criteria for lymphadenectomy who underwent hysterectomy and lymphadenectomy were identified. Algorithms for adjuvant therapy with and without lymphadenectomy were developed utilizing NCCN guidelines, PORTEC 1, and PORTEC 2.

Reliability of a Risk-Factor Questionnaire for Osteoporosis: A Primary Care Survey Study with Dual Energy X-ray Absorptiometry Ground Truth.

(1) Purpose: Predisposing factors to osteoporosis (OP) as well as dual-source x-ray densitometry (DXA) steer therapeutic decisions by determining the FRAX index. This study examines the reliability of a standard risk factor questionnaire in OP-screening. (2) Methods: = 553 eligible questionnaires encompassed 24 OP-predisposing factors.

Epac1 Is Crucial for Maintenance of Endothelial Barrier Function through A Mechanism Partly Independent of Rac1.

Epac1 (exchange protein activated by cAMP) stabilizes the endothelial barrier, but detailed studies are limited by the side effects of pharmacological Epac1 modulators and transient transfections. Here, we compare the key properties of barriers between endothelial cells derived from wild-type (WT) and Epac1-knockout (KO) mice myocardium. We found that KO cell layers, unlike WT layers, had low and cAMP-insensitive trans-endothelial resistance (TER).

Metabolomic analysis in ophthalmology.

Modern science takes into account phenotype complexity and establishes approaches to track changes on every possible level. Many "omics" studies have been developed over the last decade. Metabolomic analysis enables dynamic measurement of the metabolic response of a living system to a variety of stimuli or genetic modifications.

Risk of urinary tract infection following vaginal delivery: a comparison between intermittent and indwelling bladder catheterization.

Objectives: The primary objective of the study was to determine the risk of postpartum urinary tract infection (UTI) in women exposed to intermittent versus indwelling catheterization in labor. The secondary objective was to identify risk factors for development of postpartum UTI.

Methods: A case-control study was conducted between 1 January 2013 and 31 December 2016.

Characterizing the efficacy and trends of adjuvant therapy versus observation in women with early stage (uterine confined) leiomyosarcoma: a National Cancer Database study.

Objective: The utility of adjuvant therapy for women with uterine confined leiomyosarcoma remains uncertain. We sought to identify trends, analyze efficacy, and assess survival impact of adjuvant therapy in this patients.

Methods: We performed an observational cohort study of 1030 women with early stage leiomyosarcoma from the 2008-2014 National Cancer Database.

Endometrial cancer in young women: prognostic factors and treatment outcomes in women aged ≤40 years.

Objective: Endometrial cancer in pre-menopausal patients aged ≤40 years is rare and poses both diagnostic and management challenges. The goal of this study was to investigate the clinical and pathologic factors associated with endometrial cancer in this group and their impact on survival.

Methods: Patients with endometrial cancer treated between January 2004 and August 2016 were retrospectively reviewed.

Evaluation of non-completion of intraperitoneal chemotherapy in patients with advanced epithelial ovarian cancer.

Objective: To identify factors associated with non-completion of intraperitoneal with intravenous chemotherapy [IP/IV] in women with epithelial ovarian cancer (EOC).

Methods: This was an Institutional Review Board approved, retrospective cohort study in women with stage III EOC following optimal cytoreductive surgery (CRS) (<1 cm) followed by IP/IV chemotherapy from 2000-2016. Demographic, surgical, and oncologic variables were collected.

Antenatal ultrasound compared to MRI evaluation of fetal myelomeningocele: a prenatal and postnatal evaluation.

Background Spina bifida affects 0.5-1 in 1000 pregnancies in the United States and is often diagnosed in the mid-second trimester. The objective of the study was to directly compare ultrasounds (US) and magnetic resonance imaging (MRI) obtained in the antenatal period in the diagnosis and localization of fetal myelomeningocele (MMC) and compare these with the postnatal outcomes of these infants Methods A retrospective analysis of patients referred to the Fetal Care Center at the Cleveland Clinic from 2005 to 2017.

Fetal myelomeningocele diagnosed in the antenatal period: Maternal-fetal characteristics and their relationship with pregnancy decision-making.

Background: Spina bifida is the most common fetal anomaly of the central nervous system, which affects approximately 1:1000 live births in the United States. Myelomeningocele (MMC) is the most common presentation of spina bifida, representing half of these cases. Given the deformation to the spinal cord and the nerve roots, this defect may result in significant morbidity to infants and major life-long disabilities.