X4 Human Immunodeficiency Virus Type 1 gp120 Promotes Human Hepatic Stellate Cell Activation and Collagen I Expression through Interactions with CXCR4

<div><h3>Background & Aims</h3><p>Patients coinfected with HIV-1 and HCV develop more rapid liver fibrosis than patients monoinfected with HCV. HIV RNA levels correlate with fibrosis progression implicating HIV directly in the fibrotic process. While activated hepatic stellate cells (HSCs) express the 2 major HIV chemokine coreceptors, CXCR4 and CCR5, little is known about the pro-fibrogenic effects of the HIV-1 envelope protein, gp120, on HSCs. We therefore examined the <em>in vitro</em> impact of X4 gp120 on HSC activation, collagen I expression, and underlying signaling pathways and examined the <em>in vivo</em> expression of gp120 in HIV/HCV coinfected livers.</p> <h3>Methods</h3><p>Primary human HSCs and LX-2 cells, a human HSC line, were challenged with X4 gp120 and expression of fibrogenic markers assessed by qRT-PCR and Western blot +/− either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Downstream intracellular signaling pathways were evaluated with Western blot and pre-treatment with specific pathway inhibitors. Gp120 immunostaining was performed on HIV/HCV coinfected liver biopsies.</p> <h3>Results</h3><p>X4 gp 120 significantly increased expression of alpha-smooth muscle actin (a-SMA) and collagen I in HSCs which was blocked by pre-incubation with either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Furthermore, X4 gp120 promoted Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and pretreatment with an ERK inhibitor attenuated HSC activation and collagen I expression. Sinusoidal staining for gp120 was evident in HIV/HCV coinfected livers.</p> <h3>Conclusions</h3><p>X4 HIV-1 gp120 is pro-fibrogenic through its interactions with CXCR4 on activated HSCs. The availability of small molecule inhibitors to CXCR4 make this a potential anti-fibrotic target in HIV/HCV coinfected patients.</p> </div

Difficultés de correction d’une épreuve d’analyse critique d’article scientifique : une étude exploratoire

Contexte : L’apprentissage de la lecture critique d’article est évalué dans notre faculté par une épreuve comportant la réalisation d’un résumé d’article. Les résultats obtenus par les étudiants lors des premières éditions de cette épreuve n’étaient apparemment pas corrélés à leur niveau et n’étaient pas reproductibles d’une épreuve à l’autre. Ceci nous a fait suspecter des difficultés de correction de l’épreuve. Méthode : 20 copies ont été tirées au sort et évaluées par 5 correcteurs à l’aide d’une même grille. Nous avons calculé, pour chaque copie, la moyenne des 5 scores obtenues et calculé un pourcentage de variation. Nous avons comparé les 5 correcteurs en calculant pour chacun d’eux la moyenne des 20 scores qu’ils avaient attribués. La concordance entre les différents examinateurs a été étudiée grâce au test de Kendall. Les analyses ont été réitérées avec une deuxième grille de correction plus détaillée. Les pourcentages de variation observés avec chacune des deux grilles ont été comparés par un test du X2. Résultats : Les scores varient de 45 % (extrêmes 17 à 88 %) selon le correcteur avec la première grille, et de 32 % (10 à 60 %) avec la deuxième grille. Les correcteurs sont cependant concordants dans le classement des copies (p < 0,001). Le pourcentage de variation inter-correcteur des scores est significativement réduit avec la deuxième grille (p < 0,01). Conclusion : La réalisation d’un résumé à partir d’un article est une épreuve difficile à corriger. L’utilisation d’une grille de correction, même si elle est détaillée, laisse persister des variations entre correcteurs

Bedside Rapid Flu Test and Zanamivir Prescription in Healthy Working Adults: A Cost-Benefit Analysis

Background: Zanamivir, a neuraminidase inhibitor, reduces the number of days of illness in influenza-positive patients. New bedside rapid flu tests (RFT) should increase the number of influenza-positive patients whom receive zanamivir appropriately. Objective: To estimate the economic effects of implementing RFT and zanamivir among unvaccinated healthy working adults who consult within 2 days of the onset of influenza-like symptoms. Methods: We constructed a decision tree to perform a cost-benefit analysis from a societal perspective. Clinical outcome, i.e. number of influenza days averted, and societal costs were compared for three strategies: 1. RFT and conditional zanamivir prescription; 2. systematic zanamivir prescription; and 3. no zanamivir. A two-way sensitivity analysis was performed including the proportion of influenza-positive patients. Results: During influenza epidemics, systematic zanamivir prescription provided the best health outcome (0.81 influenza days averted) and minimised societal costs (reduced by $US29.80 per person compared with no zanamivir; 1999 values). RFT with conditional zanamivir averted 0.65 influenza days and saved$US14.40 per person. When the proportion of influenza-positive patients was under 39%, the no zanamivir strategy yielded the greatest societal savings; otherwise, systematic zanamivir was the dominant strategy. Medical costs associated with no zanamivir were $US88.70 per patient consulting with influenza-like illness, and increased to$US125.50 with systematic zanamivir and to $US127.60 with RFT and conditional zanamivir. Conclusions: Due to poor sensitivity of current RFT, systematic zanamivir prescription without RFT for unvaccinated healthy working adults should be recommended during influenza epidemics.Antivirals, Cost benefit, Influenza virus infections, Pharmacoeconomics, Zanamivir

Otx2 ChIP-seq Reveals Unique and Redundant Functions in the Mature Mouse Retina.

International audienceDuring mouse retinal development and into adulthood, the transcription factor Otx2 is expressed in pigment epithelium, photoreceptors and bipolar cells. In the mature retina, Otx2 ablation causes photoreceptor degeneration through a non-cell-autonomous mechanism involving Otx2 function in the supporting RPE. Surprisingly, photoreceptor survival does not require Otx2 expression in the neural retina, where the related Crx homeobox gene, a major regulator of photoreceptor development, is also expressed. To get a deeper view of mouse Otx2 activities in the neural retina, we performed chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on Otx2. Using two independent ChIP-seq assays, we identified consistent sets of Otx2-bound cis-regulatory elements. Comparison with our previous RPE-specific Otx2 ChIP-seq data shows that Otx2 occupies different functional domains of the genome in RPE cells and in neural retina cells and regulates mostly different sets of genes. To assess the potential redundancy of Otx2 and Crx, we compared our data with Crx ChIP-seq data. While Crx genome occupancy markedly differs from Otx2 genome occupancy in the RPE, it largely overlaps that of Otx2 in the neural retina. Thus, in accordance with its essential role in the RPE and its non-essential role in the neural retina, Otx2 regulates different gene sets in the RPE and the neural retina, and shares an important part of its repertoire with Crx in the neural retina. Overall, this study provides a better understanding of gene-regulatory networks controlling photoreceptor homeostasis and disease

Comment fait-on avec la BPCO ?

La question de l’expérience quotidienne de la bronchopneumopathie chronique obstructive (BPCO) se pose avec une force particulière tant elle frappe par son invisibilité, pour la société et pour l’individu, malgré sa prévalence. Notre analyse, fondée sur les récits d’expérience de 69 personnes atteintes, vise à montrer comment et pourquoi cette pathologie, pourtant à forte prévalence et invalidante, reste socialement invisible. Les sujets ne décrivent pas systématiquement une rupture dans leur parcours biographique qui entraînerait des modifications identitaires. L’expérience de la BPCO est à la fois celle d’une continuité des trajectoires individuelles et de désordres périodiquement introduits par les symptômes mais pas toujours associés à une « maladie » étiquetée comme telle. Elle se résume à des processus d’ajustement et de normalisation, ainsi qu’à des stratégies d’invisibilisation de la pathologie. Ces trois tendances donnent de nouvelles indications sur les processus de (re)définition de soi du sujet malade.The issue of coping daily with COPD (chronic obstructive pulmonary disease) is particularly important: despite its prevalence, not only is this an invisible disease for society but also for patients themselves. Studying the illness behavior of patients with COPD is thus capital, thought of as a phenomenological approach to the response to symptoms. Our analysis is based on narrative materials from 69 interviews with COPD patients. The grounded analysis based on patients’ narratives and their cross-checking provides new elements to explain how and why this disease remains invisible and very little known by the general population despite its high public health impact. Patients do not systematically deal with disruption affecting their identities and biographies. The experience of COPD is one of both continuity and disorder due to an illness which is not always called a “disease”. The experience of COPD boils down to behavioral adjustments and normalization processes in order to live with symptoms, as well as concrete strategies for making the disease invisible. These tendencies contribute to keeping the disease in the dark and allow to review approaches on the self-image of the sick

Bordetella pertussis Adenylate Cyclase-Hemolysin Induces Interleukin-6 Secretion by Human Tracheal Epithelial Cells

After interaction with tracheal epithelial cells, Bordetella pertussis induces the secretion of interleukin-6. This secretion is dependent on the expression of adenylate cyclase-hemolysin by the bacterium but not on the expression of other characterized bacterial toxins or adhesins. This finding confirms the important role of adenylate cyclase-hemolysin in the pathogenicity of the bacterium

Standardized protocol improves asthma management in emergency department.

International audienceThis study assessed, 30 months after its initiation, the impact of a standardized asthma management program designed to facilitate the implementation of asthma management guidelines in a tertiary teaching hospital adult emergency department. The program was initiated in a stepwise manner: first, a retrospective baseline audit; followed by generation of local guidelines; validation of these guidelines by all staff involved; distribution of the guidelines; a second practice audit; use of these results to further improve the program; feedback to the staff; twice-yearly information meetings; and a new audit 2 years later. The main results were a significant improvement in history taking (p < 0.001), increased use of serial airflow measurements (p < 0.001), increased steroid use (p < 0.001), and better documentation of follow-up arrangements (p < 0.01). Several tests of questionable value were no longer prescribed routinely. The improvements persisted after 2.5 years. In contrast, there was no improvement in the proportion of medical files that contained records of discharge prescriptions for outpatients. Implementation of locally agreed guidelines resulted in a marked improvement in several aspects of asthma management in an emergency department; the program must be pursued to maintain and further improve quality of care