Association between MIF gene variation and Meniere's disease

Several pieces of evidence support the involvement of immune system in Menière's disease (MD). Macrophage migration inhibitory factor (MIF) plays a key role in immune‐mediated reactions. Several studies have shown an association between MIF gene polymorphisms and susceptibility to various inflammatory and autoimmune disorders. The aim of this study was to explore the association between MIF‐173 G/C polymorphism and MD in an Iranian population. In this case–control association study, MD cases (N = 72) were recruited and were comprised of definitive MD (N = 58) and probable MD (N = 14) subjects. Normal healthy subjects (N = 100) were also included. Genotyping for MIF‐173 G/C polymorphism was carried out using PCR‐RFLP technique. There was a significant increase in genotype GG in patients with MD compared with the control group. (GG vs. GC + CC, P = 0.02, OR = 2.08, 95% CI: 1.02–4.3). This was more significant when definitive MD was stratified and compared with the controls (GG vs. GC + CC, P = 0.009, OR = 2.6, 95% CI = 1.19–6.18). This study's result indicates the potential role of MIF in MD of which further evaluation is required. Also, the more significant association between MIF gene polymorphism and definitive MD designates the involvement of specific pathogenic mechanisms which may be considered as a marker for diagnosis.     

High‐sensitive Troponin T measurements early after heart transplantation predict short‐ and long‐term survival

Following heart transplantation, cardiac biomarkers remain elevated for several weeks eventually as a result of membrane leakage of the donor organ. We now test the predictive power of blood levels of troponin T (TNT) measured by the new hsTNT assay (Roche Diagnostics, Roche Diagnostics, Mannheim, Germany) early after heart transplantation. TNT was determined in 141 cardiac allograft recipients and 40 controls. Our findings demonstrate that patients who died within the first year after transplantation had significantly higher median hsTNT serum levels 6 weeks after transplantation (156 ng/l ± 203 vs. 29 ng/l ± 21, P = 0.0002). Using ROC analysis, a serum hsTNT concentration of 33.55 ng/l 6 weeks after transplantation was found to be the best cutoff to predict death at 1 year (HR 0.16, 95%CI:0.05–0.46, P = 0.001) with a sensitivity of 90.91% and a specificity of 70.97%. In addition, survival at 5 years (HR 0.15, 95% CI 0.06–0.35, P < 0.0001) was significantly better among patients below that cutoff value. In multivariate analysis, hsTNT serum level 6 weeks after transplantation emerged as an independent predictor for first‐year mortality (hsTNT–HR 0.90, 95% CI: 0.81–1.00, P = 0.03). Cardiac troponin T concentrations early after transplantation as measured with a highly sensitive assay represent a strong and independent risk predictor of death after heart transplantation.     

Measuring the Impact of Gastrointestinal Variables on the Systemic Outcome of Two Suspensions of Posaconazole by a PBPK Model

For the last two decades, the application of physiologically based pharmacokinetic (PBPK) models has grown exponentially in the field of oral absorption and in a regulatory context. Although these models are widely used, their predictive power should be validated and optimized in order to rely on these models and to know exactly what is going on “under the hood”. In this study, an automated sensitivity analysis (ASA) was performed for 11 gastrointestinal (GI) variables that are integrated into the PBPK software program Simcyp®. The model of interest was a previously validated workspace that was able to predict the intraluminal and systemic behavior of two different suspensions of posaconazole in the Simcyp® Simulator. The sensitivity of the following GI parameters was evaluated in this model: gastric and duodenal pH, gastric and duodenal bicarbonate concentrations (reflecting buffer capacity), duodenal bile salts concentration, gastric emptying, the interdigestive migrating motor complex (IMMC), small intestinal transit time (SITT), gastric and jejunal volumes, and permeability. The most sensitive parameters were gastric/duodenal pH and gastric emptying, for both suspensions. The outcome of the sensitivity analyses highlights the important GI variables that must be integrated into an in vivo predictive dissolution test to help and create a rational and scientific framework/design for product development of novel and generic drug products.     

Special issues regarding redo mitral valve procedures in the developing countries

Redo mitral valve replacement remains the standard treatment for recurrent mitral valve disease. Most patients referred for a redo surgery in the western world are older and present with multiple comorbidities. With the successful broad implementation of anti-infective treatment, rheumatic mitral valve disease has become highly uncommon. Nonetheless, rheumatic heart disease is still thriving in developing countries causing the most severe mitral valve conditions. The guidelines are there to help us in our decision-making process, but the actual decision has to be made based on each patients' individual criteria.     

Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture,Studied in Weight-Bearing and Non–Weight-Bearing Human Bone

We investigated mechanisms resulting in low bone mineral density (BMD) and susceptibility to fracture by comparing noncoding RNAs (ncRNAs) in biopsies of non–weight-bearing (NWB) iliac (n = 84) and weight bearing (WB) femoral (n = 18) postmenopausal bone across BMDs varying from normal (T-score > −1.0) to osteoporotic (T-score ≤ −2.5). Global bone ncRNA concentrations were determined by PCR and microchip analyses. Association with BMD or fracture, adjusted by age and body mass index, were calculated using linear and logistic regression and least absolute shrinkage and selection operator (Lasso) analysis. At 10% false discovery rate (FDR), 75 iliac bone ncRNAs and 94 femoral bone ncRNAs were associated with total hip BMD. Eight of the ncRNAs were common for the two sites, but five of them (miR-484, miR-328-3p, miR-27a-5p, miR-28-3p, and miR-409-3p) correlated positively to BMD in femoral bone, but negatively in iliac bone. Of predicted pathways recognized in bone metabolism, ECM-receptor interaction and proteoglycans in cancer emerged at both sites, whereas fatty acid metabolism and focal adhesion were only identified in iliac bone. Lasso analysis and cross-validations identified sets of nine bone ncRNAs correlating strongly with adjusted total hip BMD in both femoral and iliac bone. Twenty-eight iliac ncRNAs were associated with risk of fracture (FDR < 0.1). The small nucleolar RNAs, RNU44 and RNU48, have a function in stabilization of ribosomal RNAs (rRNAs), and their association with fracture and BMD suggest that aberrant processing of rRNAs may be involved in development of osteoporosis. Cis-eQTL (expressed quantitative trait loci) analysis of the iliac bone biopsies identified two loci associated with microRNAs (miRNAs), one previously identified in a heel-BMD genomewide association study (GWAS). In this comprehensive investigation of the skeletal genetic background in postmenopausal women, we identified functional bone ncRNAs associated to fracture and BMD, representing distinct subsets in WB and NWB skeletal sites. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Prevalence of primary aldosteronism in hypertensive kidney transplant recipients: A cross-sectional study

Due to high prevalence of primary aldosteronism (PA) in the general hypertensive population, and its association with worse cardiovascular and renal outcomes, the 2016 Endocrine Society Guidelines explicitly recognize PA as a major public health issue requiring urgent attention. Its prevalence in hypertensive kidney transplant recipients (KTRs) is unknown. In this cross-sectional study, we screened KTRs with hypertension who were on ≥4 antihypertensive medications, on 3 antihypertensive medications with BP ≥ 140/90, and on potassium supplements, or were hypokalemic. 172 of 280 eligible patients successfully completed the testing. A positive screen for PA defined by an aldosterone-to-renin ratio of ≥20 and a plasma aldosterone concentration of >15 ng/dL yielded a prevalence of 15.7%. Potassium supplement requirement (52% vs 27%, P = .01) and hypokalemia (25.9% vs 4.8%, P < .01) were more common in patients who screened positive compared with those who screened negative. 67% of patients who screened positive were on potassium supplements and/or were hypokalemic. Our study is the first to systematically explore the prevalence of PA among the hypertensive KTR population, which has inherently high cardiovascular risk. Further studies are needed to determine the cardiovascular and renal risk attributable to PA, and define optimal therapy for KTRs with PA.     

Comparison of Hemodynamics in the Ascending Aorta Between Pulsatile and Continuous Flow Left Ventricular Assist Devices Using Computational Fluid Dynamics Based on Computed Tomography Images

This study aims to investigate differences in hemodynamic conditions in the thoracic aorta for pulsatile and continuous‐flow left ventricular assist devices (LVADs) using computational fluid dynamics (CFD). Patient‐specific models were reconstructed from three patients with continuous‐flow LVAD (HeartMate II, Thoratec Corporation) and three patients with biventricular assist devices (Excor, Berlin Heart) where only the aortic part was included in the simulations. CFD simulations were performed with constant inflow for the continuous‐flow LVADs and time‐varying inflow for the pulsatile devices. Differences in flow patterns, wall shear stress (WSS), and dynamic pressure in the ascending aorta were compared for both cases. Retrograde flow patterns were observed in all cases proximal to the location of the outflow cannula anastomosis site. On average, dynamic pressures derived from the retrograde flow velocities were higher in the continuous‐flow group with large variations dependent on the angle of the cannula anastomosis relative to the ascending aorta (continuous group: 0.14 ± 0.2 mm Hg, pulsatile group: 0.013 ± 0.008 mm Hg). Elevated WSS contralaterally to the anastomosis site was observed in three of the six models with higher values for the continuous cases. Lower WSS and reduced pressure in the ascending aorta, both favorable hemodynamic conditions, were found in pulsatile versus continuous‐flow LVADs by means of CFD. These findings indicate, along with clinical observations reported by others, the superior performance of pulsatile LVADs.