Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C

Objective: Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. Design: Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. Results: Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. Conclusions: Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens

Treatment of nocturnal leg cramps by primary care patients over the age of 60

Background. Approximately one out of two individuals over the age of 60 suffers from nocturnal leg cramps. These often have an important impact on the person's quality of life. Different drug and non-drug treatments are proposed to treat these cramps, but none to date have been shown to be both safe and effective. The objective of this study was to describe the drug and non-drug treatments used by primary care patients suffering from cramps. Methods. We used data collected as part of two cross-sectional surveys of patients aged 60 years and older attending general practices in the French region of Alsace. We asked the participants suffering from cramps if they were currently using a treatment for their cramps. We distinguished potentially harmful from unharmful treatments. Results. Overall, 632 patients suffering from cramps were included in our study. Only 133 patients (19.5%) were taking a treatment for cramps. 82 patients used one or several of 17 different drug treatments. 58 patients used one or several of 13 different types of non-drug treatments. Potentially harmful treatments, mostly Quinine made up 16,7% (n = 25) of all treatments used for cramps. Conclusions. This study sheds light on the great diversity of therapeutic practices for cramps in outpatient care. Many of the treatments reported by patients have not previously been described in the medical literature. We recommend GPs to as

Surface charge influences protein corona, cell uptake and biological effects of carbon dots

International audienceCarbon dots are emerging nanoparticles (NPs) with tremendous applications, especially in the biomedical field. Herein is reported the first quantitative proteomic analysis of the protein corona formed on CDs with different surface charge properties. Four CDs were synthesized from citric acid and various amine group-containing passivation reagents, resulting in cationic NPs with increasing zeta (ζ)-potential and density of positive charges. After CD contact with serum, we show that protein corona identity is influenced by CD surface charge properties, which in turn impacts CD uptake and viability loss in macrophages. In particular, CDs with high ζ-potential (>+30 mV) and charge density (>2 μmol mg−1) are the most highly internalized, and their cell uptake is strongly correlated with a corona enriched in vitronectin, fibulin, fetuin, adiponectin and alpha-glycoprotein. On the contrary, CDs with a lower ζ-potential (+11 mV) and charge density (0.01 μmol mg−1) are poorly internalized, while having a corona with a very different protein signature characterized by a high abundance of apolipoproteins (APOA1, APOB and APOC), albumin and hemoglobin. These data illustrate how corona characterization may contribute to a better understanding of CD cellular fate and biological effects, and provide useful information for the development of CDs for biomedical application

Left Ventricular Function Evaluation on a 3T MR Scanner with Parallel RF Transmission Technique: Prospective Comparison of Cine Sequences Acquired before and after Gadolinium Injection

<div><p>Objectives</p><p>To compare cine MR b-TFE sequences acquired before and after gadolinium injection, on a 3T scanner with a parallel RF transmission technique in order to potentially improve scanning time efficiency when evaluating LV function.</p><p>Methods</p><p>25 consecutive patients scheduled for a cardiac MRI were prospectively included and had their b-TFE cine sequences acquired before and right after gadobutrol injection. Images were assessed qualitatively (overall image quality, LV edge sharpness, artifacts and LV wall motion) and quantitatively with measurement of LVEF, LV mass, and telediastolic volume and contrast-to-noise ratio (CNR) between the myocardium and the cardiac chamber. Statistical analysis was conducted using a Bayesian paradigm.</p><p>Results</p><p>No difference was found before or after injection for the LVEF, LV mass and telediastolic volume evaluations. Overall image quality and CNR were significantly lower after injection (estimated coefficient cine after > cine before gadolinium: -1.75 CI = [-3.78;-0.0305], prob(coef>0) = 0% and -0.23 CI = [-0.49;0.04], prob(coef>0) = 4%) respectively), but this decrease did not affect the visual assessment of LV wall motion (cine after > cine before gadolinium: -1.46 CI = [-4.72;1.13], prob(coef>0) = 15%).</p><p>Conclusions</p><p>In 3T cardiac MRI acquired with parallel RF transmission technique, qualitative and quantitative assessment of LV function can reliably be performed with cine sequences acquired after gadolinium injection, despite a significant decrease in the CNR and the overall image quality.</p></div

A step toward essential tremor gene discovery: identification of extreme phenotype and screening of HTRA2 and ANO3

International audienceBACKGROUND: Essential tremor (ET) is characterized by a frequent family history. No monogenic form of ET has been identified. We aimed at exploring ET patients to identify distinct subgroups and facilitate the identification of ET genes. We tested for the presence of HTRA2 p.G399S, and ANO3 p. W490C, p. R484 W and p. S685G mutations.METHODS: Between June 2011 and November 2013, all consecutive patients suspected with ET were prospectively included in a prospective, monocentric study. Family history, age at onset (AAO), features of tremor, benefit of alcohol and drugs, electrophysiological recording findings were collected. Sanger sequencing was performed for HTRA2 and ANO3 mutations screening.RESULTS: Sixty eight patients were investigated. Fourteen diagnosed with psychogenic (5) or dystonic tremor (9) were excluded. Regarding the 54 ET patients, mean AAO was 48 years (6-77), and mean disease duration 15 years (1-55). Bimodal distribution of AAO was consistent with phenotypic subgroups. In patients with AAO before 30 years, marked benefit of alcohol (p < 0.01) and ET family history (p < 0.01) were more frequent and the disease progression less severe (p < 0.0001). Neither HTRA2 nor ANO3 mutation were identified in our patients.CONCLUSIONS: Our data support that distinct ET phenotypic subgroups may be encountered. We recommend to study separately extreme phenotypes of ET, particularly autosomal dominant families with early AAO (<30 years) and marked benefit of alcohol, to facilitate the identification of ET genes. Electromyographic recording remains a support to distinguish ET from differential diagnosis. HTRA2 and ANO3 mutations are not common causes of ET

Results of the inferential bayesian analysis for the qualitative evaluation.

<p>Results of the inferential bayesian analysis for the qualitative evaluation.</p

The interplay between lysosome, protein corona and biological effects of cationic carbon dots: Role of surface charge titratability

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Results of the descriptive analysis for qualitative evaluation.

<p>Results of the descriptive analysis for qualitative evaluation.</p

Placement of the ROIs in the left ventricular short axis before and after gadolinium injection.

<p>Placement of the ROIs in the left ventricular short axis before and after gadolinium injection.</p

Acquisition parameters of the b-TFE cine sequences in the LV short axis plane.

<p>Acquisition parameters of the b-TFE cine sequences in the LV short axis plane.</p