Pirfenidone in idiopathic pulmonary fibrosis:expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.Correction in: Advances in Therapy, Volume 31, Issue 5, pp 575-576 , doi: 10.1007/s12325-014-0118-8</p

Identification and multi-environment validation of resistance to rust (Uromyces viciae-fabae) in Vicia faba

A germplasm collection of 484 accessions of Vicia faba was screened for resistance to rust (Uromyces viciae-fabae) under field conditions. Accessions varied in the levels of rust infection, although no complete resistance was identified. Stability of resistance of the 39 most-resistant accessions was tested in a multi-location experiment in Austria, Egypt, Tunisia, United Kingdom and Spain over three additional field seasons. Genotype×environment interaction accounted for 43% of the sum of squares of the multi-environment evaluation, revealing instability of the phenotypic expression across environments. This might hamper the efficiency of selection suggesting the need for selection in different environments. Three possible mega-environments were discerned in the studied area, Mediterranean (Spain, Tunisia and Egypt), Oceanic (UK) and Continental (Austria). Córdoba (Spain) and Kafr El-Sheik (Egypt) showed as ideal environments for rust resistance screenings within Mediterranean environment. Several accessions (300, 303, 311, 313, 720, 1196 and 1271) were grouped as moderately to highly resistant in the three defined mega-environments. These accessions showed clear differences both in terms of reduced disease severity and high stability, which make them good candidates for international faba bean breeding programmes. Concerning each mega-environment, accessions 300 and 311 were the most resistant and stable ones across the Mediterranean one, followed by accessions 720, 1022, 1272, 1320 and BPL261. On the contrary other accessions (313, 452, 481 and 1196) were the most resistant in Oceanic and Continental environments. However, 452 and 481 were susceptible in the Mediterranean mega-environment. This contrasting performance across the environments was also supported by contradictory performance of the checks BPL261 and Baraca in Oceanic and Continental environments, suggesting differential virulence in rust populations, which deserves further attention.Published versio

Immediate thoracotomy for penetrating injuries: Ten years' experience at a Dutch level I trauma center

Background: An emergency department thoracotomy (EDT) or an emergency thoracotomy (ET) in the operating theater are both beneficial in selected patients following thoracic penetrating injuries. Since outcome-descriptive European studies are lacking, the aim of this retrospective study was to evaluate ten years of experience at a Dutch level I trauma center. Method: Data on patients who underwent an immediate thoracotomy after sustaining a penetrating thoracic injury between October 2000 and January 2011 were collected from the trauma registry and hospital files. Descriptive and univariate analyses were performed. Results: Among 56 patients, 12 underwent an EDT and 44 an ET. Forty-six patients sustained one or multiple stab wounds, versus ten with one or multiple gunshot wounds. Patients who had undergone an EDT had a lower GCS (p < 0. 001), lower pre-hospital RTS and hospital triage RTS (p < 0. 001 and p = 0. 009, respectively), and a lower SBP (p = 0. 038). A witnessed loss of signs of life generally occurred in EDT patients and was accompanied by 100 % mortality. Survival following EDT was 25 %, which was significantly lower than in the ET group (75 %; p = 0. 002). Survivors had lower ISS (p = 0. 011), lower rates of pre-hospital (p = 0. 031) and hospital (p = 0. 003) hemodynamic instability, and a lower prevalence of concomitant abdominal injury (p = 0. 002). Conclusion: The overall survival rate in our study was 64 %. The outcome of immediate thoracotomy performed in this level I trauma center was similar to those obtained in high-incidence regions like the US and South Africa. This suggests that trauma units where immediate thoracotomies are not part of the daily routine can achieve similar results, if properly trained

Adipocyte extracellular matrix composition, dynamics and role in obesity

The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

MiTF links Erk1/2 kinase and p21CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells

As a survival factor for melanocytes lineage cells, MiTF plays multiple roles in development and melanomagenesis. What role MiTF plays in the DNA damage response is currently unknown. In this report we observed that MiTF was phosphorylated at serine 73 after UVC radiation, which was followed by proteasome-mediated degradation. Unlike after c-Kit stimulation, inhibiting p90RSK-1 did not abolish the band shift of MiTF protein, nor did it abolish the UVC-mediated MiTF degradation, suggesting that phosphorylation on serine 73 by Erk1/2 is a key event after UVC. Furthermore, the MiTF-S73A mutant (Serine 73 changed to Alanine via site-directed mutagenesis) was unable to degrade and was continuously expressed after UVC exposure. Compared to A375 melanoma cells expressing wild-type MiTF (MiTF-WT), cells expressing MiTF-S73A mutant showed less p21WAF1/CIP1 accumulation and a delayed p21WAF1/CIP1 recovery after UVC. Consequently, cells expressing MiTF-WT showed a temporary G1 arrest after UVC, but cells expressing MiTF-S73A mutant or lack of MiTF expression did not. Finally, cell lines with high levels of MiTF expression showed higher resistance to UVC-induced cell death than those with low-level MiTF. These data suggest that MiTF mediates a survival signal linking Erk1/2 activation and p21WAF1/CIP1 regulation via phosphorylation on serine 73, which facilitates cell cycle arrest. In addition, our data also showed that exposure to different wavelengths of UV light elicited different signal pathways involving MiTF

Alterations in the Aedes aegypti Transcriptome during Infection with West Nile, Dengue and Yellow Fever Viruses

West Nile (WNV), dengue (DENV) and yellow fever (YFV) viruses are (re)emerging, mosquito-borne flaviviruses that cause human disease and mortality worldwide. Alterations in mosquito gene expression common and unique to individual flaviviral infections are poorly understood. Here, we present a microarray analysis of the Aedes aegypti transcriptome over time during infection with DENV, WNV or YFV. We identified 203 mosquito genes that were ≥5-fold differentially up-regulated (DUR) and 202 genes that were ≥10-fold differentially down-regulated (DDR) during infection with one of the three flaviviruses. Comparative analysis revealed that the expression profile of 20 DUR genes and 15 DDR genes was quite similar between the three flaviviruses on D1 of infection, indicating a potentially conserved transcriptomic signature of flaviviral infection. Bioinformatics analysis revealed changes in expression of genes from diverse cellular processes, including ion binding, transport, metabolic processes and peptidase activity. We also demonstrate that virally-regulated gene expression is tissue-specific. The overexpression of several virally down-regulated genes decreased WNV infection in mosquito cells and Aedes aegypti mosquitoes. Among these, a pupal cuticle protein was shown to bind WNV envelope protein, leading to inhibition of infection in vitro and the prevention of lethal WNV encephalitis in mice. This work provides an extensive list of targets for controlling flaviviral infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses