Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics

A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension

Copyright The Author(s) 2016. This article is published with open access at Springerlink.com. Open Access - This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were madePulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.Peer reviewedFinal Published versio

Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study.

BACKGROUND: In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. OBJECTIVE: In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. STUDY DESIGN: This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. RESULTS: A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. CONCLUSION: This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins

Continuation for thin film hydrodynamics and related scalar problems

This chapter illustrates how to apply continuation techniques in the analysis of a particular class of nonlinear kinetic equations that describe the time evolution through transport equations for a single scalar field like a densities or interface profiles of various types. We first systematically introduce these equations as gradient dynamics combining mass-conserving and nonmass-conserving fluxes followed by a discussion of nonvariational amendmends and a brief introduction to their analysis by numerical continuation. The approach is first applied to a number of common examples of variational equations, namely, Allen-Cahn- and Cahn-Hilliard-type equations including certain thin-film equations for partially wetting liquids on homogeneous and heterogeneous substrates as well as Swift-Hohenberg and Phase-Field-Crystal equations. Second we consider nonvariational examples as the Kuramoto-Sivashinsky equation, convective Allen-Cahn and Cahn-Hilliard equations and thin-film equations describing stationary sliding drops and a transversal front instability in a dip-coating. Through the different examples we illustrate how to employ the numerical tools provided by the packages auto07p and pde2path to determine steady, stationary and time-periodic solutions in one and two dimensions and the resulting bifurcation diagrams. The incorporation of boundary conditions and integral side conditions is also discussed as well as problem-specific implementation issues

Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy

<p>Abstract</p> <p>Background</p> <p>For many women finding the right contraceptive method can be challenging and consistent and correct use over a lifetime is difficult. Even remembering to take a birth control pill every day can be a challenge. The primary objective of this study was to evaluate women's experience with a weekly ethinylestradiol/norelgestromin contraceptive patch (EE/NGMN patch), given new technologies recently developed in hormonal contraception to increase women's options in avoiding daily dosing.</p> <p>Methods</p> <p>In 24 Italian sites, 207 women received the EE/NGMN patch for up to 6 cycles. At study end, overall satisfaction and preference, as well as compliance, efficacy and safety, were evaluated.</p> <p>Results</p> <p>175 women (84.5%) completed the study. The overall satisfaction rate was 88%; convenience and once-a-week frequency of the patch were especially appreciated. At baseline, 82 women (39.4%) were using a contraceptive method, mainly oral contraceptives and barrier methods, but only 45.1% were very satisfied/satisfied; after 6 months with the patch, 86.3% of this subset was very satisfied/satisfied. Considering the method used in the 3 months before the study entry, 78.1% strongly preferred/preferred the patch, for convenience (53.9%), ease of use/simplicity (28.9%), fewer (9.2%) and less severe (2.6%) side effects. Compliance was very high: 1034/1110 cycles (93.2%) were completed with perfect compliance and the mean subject's compliance score was 90%. One on-therapy pregnancy occurred. The patch was safe and well tolerated: adverse events frequency was low, with predominantly single reports of each event. Most of them started and subsided during cycle 1.</p> <p>Conclusion</p> <p>This study demonstrated that the EE/NGMN patch is associated with high satisfaction levels and excellent compliance. At study end, the majority of women indicated that they would continue using the patch.</p

The Relationship Between Alcohol Symptoms and Consumption Among Older Drinkers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66310/1/j.1530-0277.1996.tb01104.x.pd

[18F]FDG-6-P as a novel in vivo tool for imaging staphylococcal infections

Background Management of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. Staphylococcal infections can be life-threatening and are frequently complicated by multi-antibiotic resistant strains including methicillin-resistant S. aureus (MRSA). Fluorodeoxyglucose ([18F]FDG) imaging has been used to identify infection sites; however, it is unable to distinguish between sterile inflammation and bacterial load. We have modified [18F]FDG by phosphorylation, producing [18F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes. This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation. Methods [18F]FDG-6-P was synthesised from [18F]FDG. Yield, purity and stability were confirmed by RP-HPLC and iTLC. The specificity of [18F]FDG-6-P for the bacterial universal hexose phosphate transporter (UHPT) was confirmed with S. aureus and mammalian cell assays in vitro. Whole body biodistribution and accumulation of [18F]FDG-6-P at the sites of bioluminescent staphylococcal infection were established in a murine foreign body infection model. Results In vitro validation assays demonstrated that [18F]FDG-6-P was stable and specifically transported into S. aureus but not mammalian cells. [18F]FDG-6-P was elevated at the sites of S. aureus infection in vivo compared to uninfected controls; however, the increase in signal was not significant and unexpectedly, the whole-body biodistribution of [18F]FDG-6-P was similar to that of [18F]FDG. Conclusions Despite conclusive in vitro validation, [18F]FDG-6-P did not behave as predicted in vivo. However at the site of known infection, [18F]FDG-6-P levels were elevated compared with uninfected controls, providing a higher signal-to-noise ratio. The bacterial UHPT can transport hexose phosphates other than glucose, and therefore alternative sugars may show differential biodistribution and provide a means for specific bacterial detection

Exploring the tensions of being and becoming a medical educator

BackgroundPrevious studies have identified tensions medical faculty encounter in their roles but not specifically those with a qualification in medical education. It is likely that those with postgraduate qualifications may face additional tensions (i.e., internal or external conflicts or concerns) from differentiation by others, greater responsibilities and translational work against the status quo. This study explores the complex and multi-faceted tensions of educators with qualifications in medical education at various stages in their career.MethodsThe data described were collected in 2013&ndash;14 as part of a larger, three-phase mixed-methods research study employing a constructivist grounded theory analytic approach to understand identity formation among medical educators. The over-arching theoretical framework for the study was Communities of Practice. Thirty-six educators who had undertaken or were undertaking a postgraduate qualification in medical education took part in semi-structured interviews.ResultsParticipants expressed multiple tensions associated with both becoming and being a healthcare educator. Educational roles had to be juggled with clinical work, challenging their work-life balance. Medical education was regarded as having lower prestige, and therefore pay, than other healthcare career tracks. Medical education is a vast speciality, making it difficult as a generalist to keep up-to-date in all its areas. Interestingly, the graduates with extensive experience in education reported no fears, rather asserting that the qualification gave them job variety.ConclusionThis is the first detailed study exploring the tensions of educators with postgraduate qualifications in medical education. It complements and extends the findings of the previous studies by identifying tensions common as well as specific to active students and graduates. These tensions may lead to detachment, cynicism and a weak sense of identity among healthcare educators. Postgraduate programmes in medical education can help their students identify these tensions in becoming and develop coping strategies. Separate career routes, specific job descriptions and academic workload models for medical educators are recommended to further the professionalisation of medical education