Microvesicles and exosomes released by amnion epithelial cells under oxidative stress cause inflammatory changes in uterine cells†.

Extracellular vesicles play a crucial role in feto-maternal communication and provide an important paracrine signaling mechanism in pregnancy. We hypothesized that fetal cells-derived exosomes and microvesicles (MVs) under oxidative stress (OS) carry unique cargo and traffic through feto-maternal interface, which cause inflammation in uterine cells associated with parturition. Exosomes and MVs, from primary amnion epithelial cell (AEC) culture media under normal or OS-induced conditions, were isolated by optimized differential centrifugation method followed by characterization for size (nanoparticle tracking analyzer), shape (transmission electron microscopy), and protein markers (western blot and immunofluorescence). Cargo and canonical pathways were identified by mass spectroscopy and ingenuity pathway analysis. Myometrial, decidual, and cervical cells were treated with 1 × 107 control/OS-derived exosomes/MVs. Pro-inflammatory cytokines were measured using a Luminex assay. Statistical significance was determined by paired T-test (P < 0.05). AEC produced cup-shaped exosomes of 90-150 nm and circular MVs of 160-400 nm. CD9, heat shock protein 70, and Nanog were detected in exosomes, whereas OCT-4, human leukocyte antigen G, and calnexin were found in MVs. MVs, but not exosomes, were stained for phosphatidylserine. The protein profiles for control versus OS-derived exosomes and MVs were significantly different. Several inflammatory pathways related to OS were upregulated that were distinct between exosomes and MVs. Both OS-derived exosomes and MVs significantly increased pro-inflammatory cytokines (granulocyte-macrophage colony-stimulating factor, interleukin 6 (IL-6), and IL-8) in maternal cells compared with control (P < 0.05). Our findings suggest that fetal-derived exosomes and MVs under OS exhibited distinct characteristics and a synergistic inflammatory role in uterine cells associated with the initiation of parturition.

Trends and Outcomes of Elective Thoracic Aortic Repair and Acute Thoracic Aortic Syndromes in the United States.

BACKGROUND: There is a paucity of data on the contemporary outcomes and trends of elective thoracic aortic aneurysm repair and aneurysm-associated acute aortic syndrome. METHODS: We queried the National Inpatient Sample (NIS) database years 2012-2016 to identify hospitalizations for elective thoracic aortic aneurysm repair and aneurysm-associated acute aortic syndrome. The main study outcome was in-hospital mortality. RESULTS: The analysis yielded 24,295 hospitalizations for elective thoracic aortic aneurysm repair and 8875 hospitalizations for aneurysm-associated acute aortic syndrome. The number of hospitalizations for elective aortic repair significantly increased from 4375 in 2012 to 5450 in 2016 (Ptrend = .01). The number of hospitalizations for acute aortic syndrome numerically increased from 1545 in 2012 to 2340 in 2016 (Ptrend = .10). Overall in-hospital mortality for elective aortic repair was 2.4% with no change over time. In-hospital mortality for acute aortic rupture was 39.4% and for acute aortic dissection was 6.2% with no change over time. Hospitalizations for elective aortic repair had lower incidence of complications compared with those for aneurysm-associated acute aortic syndrome, including cardiogenic shock, cardiac arrest, acute stroke, and shorter length of stay. Factors associated with higher mortality among admissions undergoing elective aortic repair included older age, heart failure, valvular disease, and chronic kidney disease. Older age, coagulopathy, and fluid/ electrolytes disorders were associated with increased mortality among those with acute aortic syndrome. CONCLUSION: Contemporary elective thoracic aortic aneurysm repair is associated with lower in-hospital mortality and morbidity when compared with a clinical presentation for an aneurysm-associated acute aortic syndrome. This should be taken into account when deciding the timing of elective aortic aneurysm repair and balancing the risks and benefits.

Comparative Outcomes of Transapical Versus Transfemoral Access for Transcatheter Aortic Valve Replacement in Diabetics.

INTRODUCTION: The outcomes of transfemoral (TF) compared with transapical (TA) access for transcatheter aortic valve replacement (TAVR) in diabetics are unknown. METHODS: We queried the NIS database (2011-2014) to identify diabetics who underwent TAVR. We performed a propensity matching analysis comparing TF-TAVR versus TA-TAVR. RESULTS: The analysis included 14.555 diabetics who underwent TAVR. After matching, in-hospital mortality was not different between TF-TAVR and TA-TAVR. (3.5 vs. 4.4%, p = 0.11). TF-TAVR was associated with lower rates of cardiogenic shock (2.7 vs. 4.7%, p = 0.02), use of mechanical circulatory support (2.0 vs. 2.9%, p = 0.03), acute renal failure (17.8 vs. 26.5%, p < 0.001), major bleeding (35.8 vs. 40.7%, p < 0.001) and respiratory complications (1.1 vs. 4.4%, p < 0.001) compared with TA-TAVR. However, TF-TAVR was associated with a higher rate of vascular complications (2.9 vs. 0.9%, p < 0.001), cardiac tamponade (0.5 vs. 0.0%, p < 0.001), complete heart block (10.8 vs. 7.7%, p < 0.001) and pacemaker insertion (11.8 vs. 8.3%, p < 0.001). There was no difference between both groups in acute stroke (1.8 vs. 2.2%, p = 0.39), hemodialysis (2.0 vs. 2.2%, p = 0.71), and ventricular arrhythmias (4.9 vs. 4.2%, p = 0.19). Notably, TF-TAVR was associated with higher mortality, acute stroke, AKI, hemodialysis, PCI, and respiratory complications in complicated diabetics compared with non-complicated diabetics. CONCLUSIONS: This observational analysis showed no difference in-hospital mortality between TF-TAVR and TA-TAVR among diabetic patients. Studies exploring the optimal access for TAVR among diabetics are recommended.

Design and evaluation of novel inhalable sildenafil citrate spray-dried microparticles for pulmonary arterial hypertension.

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the "Extreme Vertices Mixture" design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 µm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68-8 5%, and average mass median aerodynamic diameter of 4.6-4.8 µm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood Cmax, AUC, extended half-life, and mean residence time in comparison to orally administered sildenafil citrate of the same dose. In conclusion, the formulated drug-loaded spray dried hydrogel microparticles showed promising in-vitro and in-vivo results for the pulmonary delivery of sildenafil citrate. The spray dried hydrogel microparticles formulation can be considered as a potential alternative of oral sildenafil citrate for treatment of PAH.

Racial Variation in the Complexity of Coronary Artery Disease in Patients with Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Racial variations in presentation of patients with ST-segment elevation myocardial infarction (STEMI) have been suggested. METHODS: This was a retrospective analysis of a tertiary center from 2012 to 2016. We included patients presenting with acute STEMI who received primary percutaneous coronary intervention (PCI). The main outcome was racial variation in the complexity of coronary artery disease assessed by SYNTAX score. We also reported predictors of higher SYNTAX scores in the study population. RESULTS: Our final analysis included 260 patients: 201 Whites (77.3%), 24 African Americans-AA (9.2%), 19 Hispanics (7.3%) and 15 were of other ethnicities (5.8%). The mean SYNTAX score was 13.8 ±â€¯7.7. There was no significant difference between Whites, AA, Hispanics and other races in the SYNTAX score (13.8 ±â€¯7.7, 13.4 ±â€¯7.9, 14.5 ±â€¯9 and 13.5 ±â€¯6.6, p = 0.965). Logistic regression analysis identified chronic kidney disease as the only significant predictor of higher SYNTAX score (Coefficient = 3.5, 95%CI:0.41-6.60, p = 0.026), while no significant association was identified between different races and higher SYNTAX score. CONCLUSION: The current study did not identify racial variations in the complexity of coronary artery disease for STEMI patients. Further studies are needed at a larger scale to identify racial variations in STEMI patients.

Meta-Analysis of Trials on Prophylactic Use of Levosimendan in Patients Undergoing Cardiac Surgery.

BACKGROUND: The role of prophylactic levosimendan in patients undergoing cardiac surgery is controversial. METHODS: We performed a computerized search of Medline, Embase, and Cochrane databases through September 2017 for randomized trials evaluating the prophylactic use of levosimendan in patients undergoing cardiac surgery (ie, patients without low cardiac output syndrome). The main study outcome was mortality at 30 days. RESULTS: The final analysis included 16 randomized trials with total of 2,273 patients. There was no statistically significant difference in mortality at 30 days between levosimendan and control groups (relative risk 0.68, 95% confidence interval [CI]: 0.45 to 1.03). Subgroup analysis showed no statistically significant difference in mortality at 30 days for patients with reduced left ventricular ejection fraction compared with patients having preserved left ventricular ejection fraction (p for interaction = 0.12). Further analysis suggested that levosimendan might be associated with improved mortality at 30 days when compared with active-control but not when compared with placebo (p for interaction = 0.01). The levosimendan group had a significant reduction in acute kidney injury (relative risk 0.59, 95% CI: 0.38 to 0.92), intensive care unit stay (standardized mean difference = -0.21, 95% CI: -0.29 to -0.13), and ventilation time (standardized mean difference = -0.43, 95% CI: -0.61 to -0.25), whereas it had higher rates of atrial fibrillation (relative risk 1.11, 95% CI: 1.00 to 1.24). No statistically significant differences were observed between groups in mortality beyond 30 days, postoperative dialysis, or myocardial infarction. CONCLUSIONS: Prophylactic use of levosimendan does not appear to reduce the mortality at 30 days or beyond 30 days in patients undergoing cardiac surgery. This lack of benefit was noted irrespective of the LVEF.

Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets.

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties.

Impact of Left Atrial Appendage Exclusion on Cardiovascular Outcomes in Patients With Atrial Fibrillation Undergoing Coronary Artery Bypass Grafting (From the National Inpatient Sample Database).

Left atrial appendage (LAA) exclusion is performed by some surgeons in patients with atrial fibrillation (AF) who undergo coronary artery bypass grafting (CABG). However, the available evidence regarding the efficacy and safety of this procedure remains mixed. We queried the Nationwide Inpatient Survey Database for the 10-year period from 2004 to 2013. Using International Classification of Diseases, Ninth Edition, Clinical Modification diagnosis codes, we identified patients who had a diagnosis of AF and underwent a primary procedure of CABG with or without LAA exclusion. We then performed a 1:5 matching based on the CHA2DS2VASc score between patients who got LAA exclusion and those who did not (control group). The primary outcome was the incidence of in-hospital cerebrovascular events, whereas the secondary outcomes included in-hospital bleeding events, pericardial effusion, cardiac tamponade, postoperative shock, and mortality. Our analysis included a total of 15,114 patients. Patients who underwent LAA exclusion had significantly less incidence of cerebrovascular events (2.0% vs 3.1%, p = 0.002). However, LAA exclusion group had higher incidences of bleeding events (36.4% vs 21.3%, p <0.001), pericardial effusion (2.7% vs 1.2%, p <0.001), cardiac tamponade (0.6% vs 0.2%, p <0.001), and postoperative shock (1.2% vs 0.4%, p <0.001). LAA exclusion was associated with higher in-hospital mortality (1.6% vs 0.3%, p <0.001). Multivariate regression analysis showed that LAA exclusion was significantly associated with lower cerebrovascular accident events and higher in-hospital mortality. In conclusion, LAA exclusion in patients with AF undergoing CABG might be associated with a lower incidence of in-hospital cerebrovascular events. This benefit is offset by a higher incidence of higher bleeding events, pericardial effusion, cardiac tamponade, postoperative shock, and in-hospital mortality.

Design and In Vitro/In Vivo Evaluation of Ultra-Thin Mucoadhesive Buccal Film Containing Fluticasone Propionate.

Fluticasone propionate is a synthetic corticosteroid drug distinguished by its potent anti-inflammatory action with low systemic side effects in comparison to other corticosteroids making it a potential drug for local buccal delivery. The aim of the present study was to design mucoadhesive buccal film containing fluticasone that is aesthetically acceptable and could maintain local drug release for a sustained period to manage the sign and symptoms of severe erosive mouth lesions. Solvent casting technique was used in film preparation. Different polymeric blends were used either alone or in combination with mucoadhesive polymers, sodium carboxymethyl cellulose (SCMC), or Carbopol 971P at different concentrations. The physicochemical properties, in vitro mucoadhesion time as well as the drug release properties for all prepared formulations were determined. Selected formulations with adequate properties were further examined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) and subjected to in vivo evaluation. Films containing hydroxypropyl methylcellulose (HPMC)/ethyl cellulose (EC) showed acceptable physicochemical properties, homogenous drug distribution, convenient mucoadhesion time, moderate swelling as well as sustained drug release up to 12 h. The biological performance of these formulations was assessed on healthy human volunteers and compared with a prepared mouthwash which showed enhanced pharmacokinetic parameters for the selected films in comparison to the mouthwash. The results revealed that the optimized formulation containing HPMC/EC and 10% SCMC could successfully achieve sustained drug release for 10 h which is considered promising for local treatment of severe mouth lesions.