Publications by authors named "Pascal Roux"

52 Publications

[Recurrent urinary tract infections in men: how to avoid antibiotics].

Rev Prat 2020 Dec;70(10):1053-1057

Service des maladies infectieuses et tropicales, IAME - UMR 1137, université Paris-Diderot et Inserm, site Bichat.Unité Coordination du risque épidémique et biologique, Paris, France.

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December 2020

Childhood asthma outcomes during the COVID-19 pandemic: Findings from the PeARL multinational cohort.

Allergy 2021 Feb 20. Epub 2021 Feb 20.

VN Allergy & Asthma Research Centre, Chennai, India.

Background: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 pandemic on childhood asthma outcomes.

Methods: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4 and 18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control.

Results: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks, and hospitalizations due to asthma, in comparison with the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits, or hospitalizations during the pandemic. However, an increased risk of URTIs emerged.

Conclusion: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.
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http://dx.doi.org/10.1111/all.14787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013557PMC
February 2021

Measurement properties of the one-minute sit-to-stand test in children and adolescents with cystic fibrosis: A multicenter randomized cross-over trial.

PLoS One 2021 12;16(2):e0246781. Epub 2021 Feb 12.

Research and Clinical Experimentation Institute (IREC), Pulmonology, ORL and Dermatology, Louvain Catholic University, Brussels, Brussels Capital Region, Belgium.

Background: Functional exercise capacity assessment is recommended in children with cystic fibrosis (CF). The six-minute walk test (6MWT) is a valid evaluation of exercise capacity but can be technically complex. Inversely, the sit-to-stand test (STST) is a simple method to evaluate exercise capacity, and is validated in healthy children and adults with CF. This study aimed to evaluate STST measurement properties in children and adolescents with CF.

Methods: In this multicenter study, children with CF (6 to 18 years) performed two iterations of both the STST and the 6MWT in a randomized order. Criterion validity was determined by assessing correlations between STST repetitions and 6MWT distance (6MWD). Intra-rater reliability, test-retest repeatability, mean bias and limits of agreement were also assessed. Relationships with other outcomes (i.e. respiratory and quadriceps muscle strength) and cardio-respiratory responses were analysed for both tests.

Results: Thirty-six children with CF were included (mean age 12.0 ±3.5 years and FEV1 95.8 ±25.0%). On average, 39.6 ±10.5 repetitions were performed during the STST and mean 6MWD was 596.0 ±102.6 meters. STST number of repetitions was significantly correlated with 6MWD (r = 0.48; p<0.01). Both tests had very good intra-rater reliability (ICCSTST = 0.91 (95%CI 0.76-0.96) and ICC6MWT = 0.94 (95%CI 0.85-0.97)), and a significant test-retest learning effect. The number of STST repetitions was not correlated with quadriceps or respiratory muscle strength test, and the STST induced fewer cardio-respiratory responses than the 6MWT.

Conclusions: The STST is an easy-to-use functional test with moderate criterion validity when compared to the 6MWT in children with CF, probably because both tests measure different components of functional exercise capacity. The STST is useful when the 6MWT is unfeasible, however further investigations are required to explore the clinical implications of STST results in children with CF.

Clinical Trial Registration: NCT03069625.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880481PMC
February 2021

Oxygen uptake kinetics during treadmill walking in adolescents with clinically stable cystic fibrosis.

Physiother Theory Pract 2021 Jan 4:1-9. Epub 2021 Jan 4.

Institut De Recherche Et d'Expérimentation Clinique (IREC), Pôle De Pneumologie, ORL and Dermatologie, Université Catholique De Louvain , Brussels, Belgium.

: Oxygen uptake (V̇O) kinetics have been shown to be slowed in adolescents with cystic fibrosis (CF) during heavy-intensity cycling and maximal exercise testing. : This study investigated V̇O kinetics in adolescents with CF compared to control adolescents (CON) during a treadmill-walking exercise. : Eight adolescents with CF and mild-to-moderate pulmonary obstruction (5 girls; 13.1 ± 2.5 years; FEV 67.8 ± 21.4%) and 18 CON adolescents (10 girls; 13.8 ± 1.8 years) were recruited. Pulmonary gas exchange and ventilation were measured during a single transition of 10 min of treadmill walking and a 5 min seated recovery period. Participant's walking speed was determined during a one-minute self-paced walking task along a 50-m corridor. A six-parameter, non-linear regression model was used to describe the changes in V̇O function during the treadmill walking and recovery, with monoexponential curve fitting used to describe the mean response time (MRT) at the onset of exercise, and the half-life (TV̇O) at the offset of exercise. V̇O baseline and amplitude, minute ventilation and respiratory equivalents were recorded. : V̇O kinetics were slower in CF group compared to CON group during the treadmill walking with a greater MRT (32 ± 14 s vs 21 ± 16 s; = .04, effect size = 0.75). The TV̇O2 was prolonged during recovery in CF group compared to CON group (86 ± 24 s vs 56 ± 22 s; = .04, effect size = 1.31). The mean VE/V̇CO during exercise was the only parameter significantly greater in CF group compared to CON group (32.9 ± 2.3 vs 29.0 ± 2.4; < .01, effect size = 1.66). : V̇O kinetics were found to be slowed in adolescents with CF during treadmill walking.
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http://dx.doi.org/10.1080/09593985.2020.1868029DOI Listing
January 2021

Pleuropneumonia resulting from varicella and COVID-19 co-infection in a 10-month-old infant.

Arch Pediatr 2020 Nov 12;27(8):509-510. Epub 2020 Sep 12.

Department of Infectious Diseases, Le Havre Hospital, 76600 Le Havre, France.

COVID-19 is a new disease leading to respiratory complications in adults. Children appear to have more modest symptoms than adults. Varicella is often described as a benign disease in the pediatric population. However, patients with varicella and COVID-19 co-infection can develop a more serious respiratory infection. We report the case of an infant who had a co-infection with both viruses that led to pleuropneumonia. The main question in the present case concerns the link between COVID-19 and varicella infection, and the possible modulation in immune response due to the two virus infections.
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http://dx.doi.org/10.1016/j.arcped.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836533PMC
November 2020

Clinimetric evaluation of muscle function tests for individuals with cystic fibrosis: A systematic review.

J Cyst Fibros 2020 11 11;19(6):981-995. Epub 2020 Jun 11.

Research and Clinical Experimentation Institute (IREC), Pulmonology, ORL and Dermatology, Louvain Catholic University, Brussels1200, Belgium; Department of Physical Medicine and Rehabilitation, Saint-Luc University Clinics, Brussels1200, Belgium.

Accurate testing of muscle function is essential in individuals with cystic fibrosis (CF). A literature search was conducted in MEDLINE, CENTRAL, CINAHL, PEDro, ScienceDirect and Web of Science according to PRISMA and COSMIN guidelines from inception to September 2019 to investigate the clinimetric properties of muscle tests in individuals with CF. The search identified 37 studies (1310 individuals) and 34 different muscle tests. Maximal inspiratory pressure, inspiratory work capacity and quadriceps strength measured by computerised dynamometry were identified as reliable tests of muscle function. The one-minute sit-to-stand test was found to have high reliability but its validity to measure quadriceps strength is unknown. The clinimetric properties of other routinely used tests have not been reported in people with CF. Very different measurement procedures were identified. Inspiratory muscle and quadriceps testing can be considered as reliable but high-quality studies evaluating tests of other muscles function (e.g. muscle endurance) are lacking.
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http://dx.doi.org/10.1016/j.jcf.2020.05.014DOI Listing
November 2020

Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis.

Sci Rep 2020 03 2;10(1):3850. Epub 2020 Mar 2.

Université Paris Descartes, UTCBS, CNRS, INSERM, F-75006, Paris, France.

Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide, and has no treatment to date. Hepatic stellate cells (HSCs) play a key role in the fibrosis process, because in chronic liver damage, they transdifferentiate from a "quiescent" to an "activated" phenotype responsible for most the collagen deposition in liver tissue. Here, using a diet-induced liver fibrosis murine model (choline-deficient amino acid-defined, high fat diet), we characterized a specific population of HSCs organized as clusters presenting simultaneously hypertrophy of retinoid droplets, quiescent and activated HSC markers. We showed that hypertrophied HSCs co-localized with fibrosis areas in space and time. Importantly, we reported the existence of this phenotype and its association with collagen deposition in three other mouse fibrosis models, including CCl-induced fibrosis model. Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis. These results lead us to conclude that hypertrophied HSCs are closely associated with hepatic fibrosis in a metabolic disease context and may represent a new marker of metabolic liver disease progression.
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http://dx.doi.org/10.1038/s41598-020-60615-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052210PMC
March 2020

Brief Report: Impact of ART Classes on the Increasing Risk of Cerebral Small-Vessel Disease in Middle-Aged, Well-Controlled, cART-Treated, HIV-Infected Individuals.

J Acquir Immune Defic Syndr 2019 08;81(5):547-551

INSERM, Sorbonne Université, Institut Pierre-Louis d'Epidémiologie et de Santé Publique (IPLESP), Paris, France.

Background: Cerebral small-vessel disease (CSVD) is a chronic disease accounting for one-third of strokes and the second etiology of dementia. Despite sustained immunovirological control, CSVD prevalence is doubled in middle-aged persons living with HIV (PLHIVs), even after adjustment for traditional cardiovascular risk factors. We aimed to investigate whether exposure to any antiretroviral drug class could be associated with an increasing risk of CSVD.

Methods: The MicroBREAK-2 case-control study (NCT02210130) enrolled PLHIVs aged 50 years and older, treated with combined antiretroviral therapy for ≥5 years, with plasma HIV load controlled for ≥12 months. Cases were PLHIVs with radiologically defined CSVD, and controls were CSVD-free PLHIVs matched for age (±5 years), sex, and year of HIV diagnosis (±5 years). Multivariable conditional logistic regression analyses focused on cumulative exposure to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and/or exposure to integrase inhibitors (yes or no), adjusted for hypertension, CD4 nadir, current CD4/CD8 ratio, and HIV transmission group.

Results: Between May 2014 and April 2017, 77 cases and 77 controls (85.7% males) were recruited. PLHIVs' median age was 57.6 years, and median HIV diagnosis year was 1992. The increasing risk of CSVD was not associated with exposure to any ART class.

Conclusion: No deleterious effect of ART class exposure on the risk of CSVD was found for middle-aged treated PLHIVs.
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http://dx.doi.org/10.1097/QAI.0000000000002084DOI Listing
August 2019

Susceptibility vessel sign on MRI predicts better clinical outcome in patients with anterior circulation acute stroke treated with stent retriever as first-line strategy.

J Neurointerv Surg 2019 04 28;11(4):328-333. Epub 2018 Aug 28.

Department of Neuroradiology, Université Paris

Background: Susceptibility vessel sign (SVS) can be a useful MRI biomarker of an occlusion but its relationship with clinical outcomes of acute ischemic stroke (AIS) is yet to be fully elucidated.

Objective: To investigate SVS in relation to the clinical outcomes after mechanical thrombectomy using a stent retriever (SR) as first-line approach in patients with AIS.

Material And Methods: We included patients with a first-line SR approach for anterior AIS from the the trials when both baseline imaging of SVS and 90-day modified Rankin Scale (mRS) scores were available. Patients were assigned to two groups based on the presence of an SVS (independent core laboratory), and the overall distributions of the mRS score at 90 days (shift analysis) and clinical independence (mRS score ≤2) were compared.

Results: 217 patients were included and SVS was diagnosed in 76.0% of cases (n=165, 95% CI 70.4% to 81.7%). After adjustment for potential confounders, SVS+ was significantly associated with 90-day mRS improvement (adjusted common OR=2.75; 95% CI 1.44 to 5.26) and favorable outcome (adjusted common OR=2.76; 95% CI 1.18 to 6.45).

Conclusion: Based on results for patients of the ASTER and THRACE trials receiving first-line SR treatment, SVS was associated with lower disability at 3 months. Large prospective studies using MRI-based thrombus evaluation are warranted.
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http://dx.doi.org/10.1136/neurintsurg-2018-014217DOI Listing
April 2019

MuscleJ: a high-content analysis method to study skeletal muscle with a new Fiji tool.

Skelet Muscle 2018 08 6;8(1):25. Epub 2018 Aug 6.

Experimental Neuropathology Unit, Infection and Epidemiology Department, Institut Pasteur, 25, rue du Docteur Roux, 75015, Paris, France.

Background: Skeletal muscle has the capacity to adapt to environmental changes and regenerate upon injury. To study these processes, most experimental methods use quantification of parameters obtained from images of immunostained skeletal muscle. Muscle cross-sectional area, fiber typing, localization of nuclei within the muscle fiber, the number of vessels, and fiber-associated stem cells are used to assess muscle physiology. Manual quantification of these parameters is time consuming and only poorly reproducible. While current state-of-the-art software tools are unable to analyze all these parameters simultaneously, we have developed MuscleJ, a new bioinformatics tool to do so.

Methods: Running on the popular open source Fiji software platform, MuscleJ simultaneously analyzes parameters from immunofluorescent staining, imaged by different acquisition systems in a completely automated manner.

Results: After segmentation of muscle fibers, up to three other channels can be analyzed simultaneously. Dialog boxes make MuscleJ easy-to-use for biologists. In addition, we have implemented color in situ cartographies of results, allowing the user to directly visualize results on reconstituted muscle sections.

Conclusion: We report here that MuscleJ results were comparable to manual observations made by five experts. MuscleJ markedly enhances statistical analysis by allowing reliable comparison of skeletal muscle physiology-pathology results obtained from different laboratories using different acquisition systems. Providing fast robust multi-parameter analyses of skeletal muscle physiology-pathology, MuscleJ is available as a free tool for the skeletal muscle community.
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http://dx.doi.org/10.1186/s13395-018-0171-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091189PMC
August 2018

Effect of backpack carrying on forced vital capacity in cystic fibrosis: A randomized crossover-controlled trial.

PLoS One 2018 9;13(5):e0196750. Epub 2018 May 9.

Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Brussels, Belgium.

Background: Backpack carrying impacts lung function in healthy children but the effect in children with cystic fibrosis (CF) is unknown.

Methods: Three backpack positions were tested: no backpack (NB), a 12.5% body-weight backpack carried bilaterally (BB) or unilaterally (UB), at rest and during a 10 minute walk. Primary outcome was forced vital capacity (FVC). Secondary outcomes included comparison of cardio-respiratory variables within and between groups.

Results: Nine children with CF (13.3±2.6 years; FEV1 66±22%) and 18 healthy children (13.8±1.8 years; FEV1 107±30%) were included. FVC was reduced with UB compared to NB (68.5±23.3% vs 72.1±24.3%, p = 0.024) in children with CF. FEV1, MIP and MEP decreased more with UB in children with CF than in healthy peers. Increases in VO2, VCO2 and minute ventilation with UB were greater in the CF group during walking.

Conclusions: Unilateral backpack wearing affects FVC in children with CF and requires greater cardio-respiratory adjustments compared to healthy peers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942831PMC
August 2018

Fluorescence imaging host pathogen interactions: fifteen years benefit of hindsight….

Curr Opin Microbiol 2018 06 19;43:193-198. Epub 2018 Mar 19.

Institut Pasteur, Citech, Imagopole-UTechS-PBI Photonic BioImaging, 25-28 rue du Dr Roux, 75015 Paris, France.

We consider in review current state-of-the-art fluorescence microscopy for investigating the host-pathogen interface. Our perspective is honed from years with literally thousands of microbiologists using the variety of imaging technologies available within our dedicated BSL2/BSL3 optical imaging research service facilities at the Institut Pasteur Paris founded from scratch in 2001. During fifteen years learning from the success and failures of introducing different fluorescence imaging technologies, methods, and technical development strategies we provide here a synopsis review of our experience to date and a synthesis of how we see the future in perspective for fluorescence imaging at the host-pathogen interface.
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http://dx.doi.org/10.1016/j.mib.2018.03.001DOI Listing
June 2018

Magnetic resonance post-contrast vascular hyperintensities at 3 T: a new highly sensitive sign of vascular occlusion in acute ischaemic stroke.

Eur Radiol 2018 Jul 9;28(7):2903-2913. Epub 2018 Feb 9.

Department of Radiology, Adolphe de Rothschild Foundation, 29 rue Manin, 75019, Paris, France.

Background: Magnetic resonance imaging (MRI) is the diagnostic cornerstone for precisely identifying acute ischaemic strokes and locating vascular occlusions, especially since mechanical thrombectomy has become a reference treatment. We observed that a post-contrast three-dimensional turbo-spin-echo T1-weighted sequence showed striking post-contrast vascular hyperintensities (PCVH) in ischaemic territories. We aimed to evaluate the prevalence and the meaning of this finding.

Methods: This retrospective single centre study included 130 consecutive patients admitted for acute ischaemic stroke with a 3-T MRI performed in the first 12 h of symptom onset from September 2014 through September 2016. Two neuroradiologists blinded to clinical data analysed the first MRI assessments. The association between PCVH and clinical, radiological and follow-up findings was assessed, as well as inter- and intra-observer agreements.

Results: Of 130 patients, 105 (81%) had PCVH in the ischaemic territory. PCVH were associated with the presence of thrombus on susceptibility weighted imaging (p < 0.0001) and vascular occlusions on MR angiography (p < 0.0001). All patients with a visible thrombus had PCVH closely surrounding the clot. PCVH were associated with higher initial (p < 0.01) and follow-up (p < 0.01) National Institutes of Health Stroke Scale score, and higher mRS score (p < 0.05). Thrombectomy was the reference treatment for all patients with arterial occlusions. Inter- and intra-observer agreements for the detection of PCVH were excellent (κ = 0.95 and κ = 0.91, respectively).

Conclusions: PCVH during acute strokes are a striking sensitive and reproducible tool for diagnosing and locating vascular occlusions. It may help triage patients who can benefit from thrombectomy.

Key Points: • Post-contrast vascular hyperintensities (PCVH) are a sensitive MR finding in acute stroke • PCVH are strongly associated with the presence and location of arterial occlusions • Inter- and intra-observer agreements for the detection of PCVH are excellent • PCVH are visible even in the case of significant motion artefacts • PCVH may help triage patients who can benefit from mechanical thrombectomy.
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http://dx.doi.org/10.1007/s00330-018-5312-7DOI Listing
July 2018

Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy-Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals.

Clin Infect Dis 2018 05;66(11):1762-1769

Sorbonne Universités, Institut national de la santé et de la recherche médicale (INSERM), UPMC Université Paris 06, Institut Pierre-Louis d'Epidémiologie et de Santé Publique (UMRS 1136).

Background: Silent cerebral small-vessel disease (CSVD) is defined as white matter hyperintensities, silent brain infarction, or microbleeds. CSVD is responsible for future vascular events, cognitive impairment, frailty, and shorter survival. CSVD prevalence among middle-aged people living with well-controlled human immunodeficiency virus (HIV) infection (PLHIV) is unknown.

Methods: The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP51 Microvascular Brain Retina and Kidney Study (MicroBREAK; NCT02082574) is a cross-sectional study with prospective enrollment of treated PLHIV, ≥50 years old with viral load controlled for ≥12 months, and frequency age- and sex-matched HIV-uninfected controls (HUCs). It was designed to estimate CSVD prevalence on 3T magnetic resonance imaging (3D fluid-attenuated inversion recovery, transversal T2-weighted gradient-echo imaging and diffusion-weighted imaging), as diagnosed by 2 blinded neuroradiologists. A logistic regression model was used to assess the impact of HIV on CSVD after adjustment for traditional risk factors.

Results: Between June 2013 and May 2016, 456 PLHIV and 154 HUCs were recruited. Median age was 56 and 58 years, respectively (P = .001), among whom 84.9% and 77.3%, respectively (P = .030), were men. CSVD was detected in 51.5% of PLHIV and 36.4% of HUCs with an adjusted odds ratio (aOR) of 2.3. The HIV impact differed according to age, with aOR values of 5.3, 3.7, and 1.0 for age groups <54, 54-60, and >60 years, respectively (P = .022). Older age, hypertension, and lower CD4 cell count nadir were independently associated with a higher risk of CSVD among PLHIV.

Conclusions: HIV is an independent risk factor for CSVD. Despite sustained immunovirological control, the CSVD prevalence was twice as high among middle-aged PLHIV than HUCs.

Clinical Trials Registration: NCT02082574.
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http://dx.doi.org/10.1093/cid/cix1075DOI Listing
May 2018

Augmented 3D venous navigation for neuroendovascular procedures.

J Neurointerv Surg 2018 Jul 11;10(7):649-652. Epub 2017 Oct 11.

Department of Interventional Neuroradiology, Fondation Rothschild Hospital, Paris, France.

Background: Endovascular venous access is increasingly used for the treatment of many cerebrovascular diseases. The quality of venous roadmapping through arterial injection can be problematic because of contrast media dilution, slow flow velocity, and unilateral opacification of the venous system.

Objective: To describe our experience with the VesselNavigator (Philips Healthcare, Best, The Netherlands) in performing live 3D roadmapping for intracranial venous procedures.

Material And Methods: Live 3D roadmapping is an image-processing technique that allows dynamic roadmapping of vessels with immediate adaptation to the C-arm movements without the need for contrast injection. For this purpose, 3D MR venography is overlaid on live fluoroscopy images after semiautomatic coregistration. The technique was applied to cases of idiopathic venous stenosis and arteriovenous fistula.

Results: The process of coregistration was performed by the principal operator in <5 min, just before the treatment. The accuracy was controlled peroperatively and was judged satisfactory. Three illustrative cases demonstrate the use of this software for venous navigation and pressure measurement (case 1), venous stenting (case 2), and transvenous embolization of a carotid-cavernous fistula (case 3).

Conclusion: Our preliminary experience suggests that it is a feasible and safe technique for intracranial venous navigation and procedures. The potential lowering of overall radiation dose and contrast media use needs to be verified with further studies.
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http://dx.doi.org/10.1136/neurintsurg-2017-013365DOI Listing
July 2018

Co-Infection of Mosquitoes with Chikungunya and Dengue Viruses Reveals Modulation of the Replication of Both Viruses in Midguts and Salivary Glands of Aedes aegypti Mosquitoes.

Int J Mol Sci 2017 Aug 4;18(8). Epub 2017 Aug 4.

Unité Environnement et Risques Infectieux, Institut Pasteur, 75015 Paris, France.

Arthropod-borne virus (arbovirus) infections cause several emerging and resurgent infectious diseases in humans and animals. Chikungunya-affected areas often overlap with dengue-endemic areas. Concurrent dengue virus (DENV) and chikungunya virus (CHIKV) infections have been detected in travelers returning from regions of endemicity. CHIKV and DENV co-infected have also been collected in the vicinity of co-infected human cases, emphasizing the need to study co-infections in mosquitoes. We thus aimed to study the pathogen-pathogen interaction involved in these co-infections in DENV/CHIKV co-infected mosquitoes. In mono-infections, we detected CHIKV antigens as early as 4 days post-virus exposure in both the midgut (MG) and salivary gland (SG), whereas we detected DENV serotype 2 (DENV-2) antigens from day 5 post-virus exposure in MG and day 10 post-virus exposure in SG. Identical infection rates were observed for singly and co-infected mosquitoes, and facilitation of the replication of both viruses at various times post-viral exposure. We observed a higher replication for DENV-2 in SG of co-infected mosquitoes. We showed that mixed CHIKV and DENV infection facilitated viral replication in . The outcome of these mixed infections must be further studied to increase our understanding of pathogen-pathogen interactions in host cells.
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http://dx.doi.org/10.3390/ijms18081708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578098PMC
August 2017

Phenotypic clustering: a novel method for microglial morphology analysis.

J Neuroinflammation 2016 06 17;13(1):153. Epub 2016 Jun 17.

Imagopole - CITech, Institut Pasteur, Paris, France.

Background: Microglial cells are tissue-resident macrophages of the central nervous system. They are extremely dynamic, sensitive to their microenvironment and present a characteristic complex and heterogeneous morphology and distribution within the brain tissue. Many experimental clues highlight a strong link between their morphology and their function in response to aggression. However, due to their complex "dendritic-like" aspect that constitutes the major pool of murine microglial cells and their dense network, precise and powerful morphological studies are not easy to realize and complicate correlation with molecular or clinical parameters.

Methods: Using the knock-in mouse model CX3CR1(GFP/+), we developed a 3D automated confocal tissue imaging system coupled with morphological modelling of many thousands of microglial cells revealing precise and quantitative assessment of major cell features: cell density, cell body area, cytoplasm area and number of primary, secondary and tertiary processes. We determined two morphological criteria that are the complexity index (CI) and the covered environment area (CEA) allowing an innovative approach lying in (i) an accurate and objective study of morphological changes in healthy or pathological condition, (ii) an in situ mapping of the microglial distribution in different neuroanatomical regions and (iii) a study of the clustering of numerous cells, allowing us to discriminate different sub-populations.

Results: Our results on more than 20,000 cells by condition confirm at baseline a regional heterogeneity of the microglial distribution and phenotype that persists after induction of neuroinflammation by systemic injection of lipopolysaccharide (LPS). Using clustering analysis, we highlight that, at resting state, microglial cells are distributed in four microglial sub-populations defined by their CI and CEA with a regional pattern and a specific behaviour after challenge.

Conclusions: Our results counteract the classical view of a homogenous regional resting state of the microglial cells within the brain. Microglial cells are distributed in different defined sub-populations that present specific behaviour after pathological challenge, allowing postulating for a cellular and functional specialization. Moreover, this new experimental approach will provide a support not only to neuropathological diagnosis but also to study microglial function in various disease models while reducing the number of animals needed to approach the international ethical statements.
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http://dx.doi.org/10.1186/s12974-016-0614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912769PMC
June 2016

Physical Sequestration of Bacillus anthracis in the Pulmonary Capillaries in Terminal Infection.

J Infect Dis 2016 07 14;214(2):281-7. Epub 2016 Mar 14.

Institut Pasteur, Histopathologie Humaine et Modèles Animaux Pathogénie des Toxi-Infections Bactériennes.

The lung is the terminal target of Bacillus anthracis before death, whatever the route of infection (cutaneous, inhalational, or digestive). During a cutaneous infection in absence of toxins, we observed encapsulated bacteria colonizing the alveolar capillary network, bacteria and hemorrhages in alveolar and bronchiolar spaces, and hypoxic foci in the lung (endothelial cells) and brain (neurons and neuropil). Circulating encapsulated bacteria were as chains of approximately 13 µm in length. Bacteria of such size were immediately trapped within the lung capillary network, but bacteria of shorter length were not. Controlling lung-targeted pathology would be beneficial for anthrax treatment.
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http://dx.doi.org/10.1093/infdis/jiw098DOI Listing
July 2016

Metallic Profile of Whole Blood and Plasma in a Series of 99 Healthy Children.

J Anal Toxicol 2015 Nov-Dec;39(9):707-13. Epub 2015 Aug 10.

Laboratoire de Toxicologie, ABTE ToxEMAC EA 4651, Faculté de Médecine et de Pharmacie, 22 boulevard Gambetta, 76183 Rouen Cedex 1, France.

In recent years, special emphasis has been put on heavy metals. Children are very sensitive to accumulation of metals. Furthermore, as regards elements, the reference values in children are scarce in the literature as it is difficult to obtain the large quantity of blood necessary to analyze many metals by the conventional atomic absorption spectrometry technique. An inductively coupled plasma mass spectrometry (ICP-MS) procedure that uses a reduced sample of 0.3 mL whole blood or plasma is adapted to multielemental determinations. We applied a previously validated technique for adults that simultaneously quantifies 25 elements by ICP-MS in whole blood and 23 in plasma in a series of 99 healthy children ranging from under 5 years to <18 years, without exposure to metal or drug-containing metals. The aims of the study were to compare metallic concentrations according to the age among children and metallic concentration differences between children and adults. The blood and plasma pediatric metallic profile is a practical useful tool for many purposes in clinical toxicology, forensic toxicology and any cases of metal environmental exposure.
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http://dx.doi.org/10.1093/jat/bkv088DOI Listing
August 2016

Spontaneous regression of neuro-ophthalmological sarcoidosis.

Clin Neurol Neurosurg 2015 Mar 19;130:6-7. Epub 2014 Dec 19.

Department of Neurology, Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.clineuro.2014.11.025DOI Listing
March 2015

Microtubule-associated proteins 1 (MAP1) promote human immunodeficiency virus type I (HIV-1) intracytoplasmic routing to the nucleus.

J Biol Chem 2015 Feb 11;290(8):4631-4646. Epub 2014 Dec 11.

From INSERM U941, Institut Universitaire d'Hématologie de l'Hôpital Saint-Louis, 75010 Paris, France,. Electronic address:

After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE. Depletion of MAP1A/MAP1S in indicator cell lines and primary human macrophages led to a profound reduction in HIV-1 infectivity as a result of impaired retrograde trafficking, demonstrated by a characteristic accumulation of capsids away from the nuclear membrane, and an overall defect in nuclear import. MAP1A/MAP1S did not impact microtubule network integrity or cell morphology but contributed to microtubule stabilization, which was shown previously to facilitate infection. In addition, we found that MAP1 proteins interact with HIV-1 cores both in vitro and in infected cells and that interaction involves MAP1 light chain LC2. Depletion of MAP1 proteins reduced the association of HIV-1 capsids with both dynamic and stable microtubules, suggesting that MAP1 proteins help tether incoming viral capsids to the microtubular network, thus promoting cytoplasmic trafficking. This work shows for the first time that following entry into target cells, HIV-1 interacts with the cytoskeleton via its p24 capsid protein. Moreover, our results support a role for MAP1 proteins in promoting efficient retrograde trafficking of HIV-1 by stimulating the formation of stable microtubules and mediating the association of HIV-1 cores with microtubules.
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http://dx.doi.org/10.1074/jbc.M114.613133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335204PMC
February 2015

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2014 Sep 29;85(9):1038-40. Epub 2014 May 29.

Department of Neurology, Fondation Ophtalmologique A. de Rothschild, Paris, France.

Objective: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.

Methods: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.

Results: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.

Conclusions: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.
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http://dx.doi.org/10.1136/jnnp-2014-307591DOI Listing
September 2014

Virulent Shigella flexneri affects secretion, expression, and glycosylation of gel-forming mucins in mucus-producing cells.

Infect Immun 2013 Oct 22;81(10):3632-43. Epub 2013 Jul 22.

Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France.

Mucin glycoproteins are secreted in large amounts by the intestinal epithelium and constitute an efficient component of innate immune defenses to promote homeostasis and protect against enteric pathogens. In this study, our objective was to investigate how the bacterial enteropathogen Shigella flexneri, which causes bacillary dysentery, copes with the mucin defense barrier. We report that upon in vitro infection of mucin-producing polarized human intestinal epithelial cells, virulent S. flexneri manipulates the secretion of gel-forming mucins. This phenomenon, which is triggered only by virulent strains, results in accumulation of mucins at the cell apical surface, leading to the appearance of a gel-like structure that favors access of bacteria to the cell surface and the subsequent invasion process. We identify MUC5AC, a gel-forming mucin, as a component of this structure. Formation of this gel does not depend on modifications of electrolyte concentrations, induction of trefoil factor expression, endoplasmic reticulum stress, or response to unfolded proteins. In addition, transcriptional and biochemical analyses of infected cells reveal modulations of mucin gene expression and modifications of mucin glycosylation patterns, both of which are induced by virulent bacteria in a type III secretion system-dependent manner. Thus, S. flexneri has developed a dedicated strategy to alter the mucus barrier by targeting key elements of the gel-forming capacity of mucins: gene transcription, protein glycosylation, and secretion.
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http://dx.doi.org/10.1128/IAI.00551-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811771PMC
October 2013

Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes.

J Cell Sci 2013 Aug 18;126(Pt 16):3678-85. Epub 2013 Jun 18.

Institut Pasteur, Unité de traffic membranaire et pathogenèse, 28 rue du Docteur Roux 75724 Paris, Cedex 15, France.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by CAG expansion in the huntingtin gene, which adds a homopolymeric tract of polyglutamine (polyQ) to the encoded protein leading to the formation of toxic aggregates. Despite rapidly accumulating evidences supporting a role for intercellular transmission of protein aggregates, little is known about whether and how huntingtin (Htt) misfolding progresses through the brain. It has been recently reported that synthetic polyQ peptides and recombinant fragments of mutant Htt are readily internalized in cell cultures and able to seed polymerization of a reporter wild-type Htt. However, there is no direct evidence of aggregate transfer between cells and the mechanism has not been explored. By expressing recombinant fragments of mutant Htt in neuronal cells and in primary neurons, we found that aggregated fragments formed within one cell spontaneously transfer to neighbors in cell culture. We demonstrate that the intercellular spreading of the aggregates requires cell-cell contact and does not occur upon aggregate secretion. Interestingly, we found that the expression of mutant, but not wild-type Htt fragments, increases the number of tunneling nanotubes, which in turn provide an efficient mechanism of transfer.
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http://dx.doi.org/10.1242/jcs.126086DOI Listing
August 2013

Shigella impairs T lymphocyte dynamics in vivo.

Proc Natl Acad Sci U S A 2013 Mar 15;110(12):4458-63. Epub 2013 Feb 15.

Molecular Microbial Pathogenesis Unit, Department Cell Biology and Infection, Institut National de Santé et de Recherche Médicale U786, 75724 Paris Cedex 15, France.

The Gram-negative enteroinvasive bacterium Shigella flexneri is responsible for the endemic form of bacillary dysentery, an acute rectocolitis in humans. S. flexneri uses a type III secretion system to inject effector proteins into host cells, thus diverting cellular functions to its own benefit. Protective immunity to reinfection requires several rounds of infection to be elicited and is short-lasting, suggesting that S. flexneri interferes with the priming of specific immunity. Considering the key role played by T-lymphocyte trafficking in priming of adaptive immunity, we investigated the impact of S. flexneri on T-cell dynamics in vivo. By using two-photon microscopy to visualize bacterium-T-cell cross-talks in the lymph nodes, where the adaptive immunity is initiated, we provide evidence that S. flexneri, via its type III secretion system, impairs the migration pattern of CD4(+) T cells independently of cognate recognition of bacterial antigens. We show that bacterial invasion of CD4(+) T lymphocytes occurs in vivo, and results in cell migration arrest. In the absence of invasion, CD4(+) T-cell migration parameters are also dramatically altered. Signals resulting from S. flexneri interactions with subcapsular sinus macrophages and dendritic cells, and recruitment of polymorphonuclear cells are likely to contribute to this phenomenon. These findings indicate that S. flexneri targets T lymphocytes in vivo and highlight the role of type III effector secretion in modulating host adaptive immune responses.
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http://dx.doi.org/10.1073/pnas.1300981110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606969PMC
March 2013

Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration.

PLoS One 2012 25;7(9):e46037. Epub 2012 Sep 25.

Molecular Virology and Vaccinology Unit, CNRS URA 3015, Department of Virology, Institut Pasteur, Paris, France.

The nuclear pore complex (NPC) mediates nucleo-cytoplasmic transport of macromolecules and is an obligatory point of passage and functional bottleneck in the replication of some viruses. The Human Immunodeficiency Virus (HIV) has evolved the required mechanisms for active nuclear import of its genome through the NPC. However the mechanisms by which the NPC allows or even assists HIV translocation are still unknown. We investigated the involvement of four key nucleoporins in HIV-1 docking, translocation, and integration: Nup358/RanBP2, Nup214/CAN, Nup98 and Nup153. Although all induce defects in infectivity when depleted, only Nup153 actually showed any evidence of participating in HIV-1 translocation through the nuclear pore. We show that Nup358/RanBP2 mediates docking of HIV-1 cores on NPC cytoplasmic filaments by interacting with the cores and that the C-terminus of Nup358/RanBP2 comprising a cyclophilin-homology domain contributes to binding. We also show that Nup214/CAN and Nup98 play no role in HIV-1 nuclear import per se: Nup214/CAN plays an indirect role in infectivity read-outs through its effect on mRNA export, while the reduction of expression of Nup98 shows a slight reduction in proviral integration. Our work shows the involvement of nucleoporins in diverse and functionally separable steps of HIV infection and nuclear import.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457934PMC
April 2013

A quantitative method for measuring phototoxicity of a live cell imaging microscope.

Methods Enzymol 2012 ;506:291-309

Institut Pasteur, Imagopole, Plateforme d'imagerie dynamique, Paris, France.

Fluorescence-based imaging regimes require exposure of living samples under study to high intensities of focused incident illumination. An often underestimated, overlooked, or simply ignored fact in the design of any experimental imaging protocol is that exposure of the specimen to these excitation light sources must itself always be considered a potential source of phototoxicity. This can be problematic, not just in terms of cell viability, but much more worrisome in its more subtle manifestation where phototoxicity causes anomalous behaviors that risk to be interpreted as significant, whereas they are mere artifacts. This is especially true in the case of microbial pathogenesis, where host-pathogen interactions can prove especially fragile to light exposure in a manner that can obscure the very processes we are trying to observe. For these reasons, it is important to be able to bring the parameter of phototoxicity into the equation that brings us to choose one fluorescent imaging modality, or setup, over another. Further, we need to be able to assess the risk that phototoxicity may occur during any specific imaging experiment. To achieve this, we describe here a methodological approach that allows meaningful measurement, and therefore relative comparison of phototoxicity, in most any variety of different imaging microscopes. In short, we propose a quantitative approach that uses microorganisms themselves to reveal the range over which any given fluorescent imaging microscope will yield valid results, providing a metrology of phototoxic damage, distinct from photobleaching, where a clear threshold for phototoxicity is identified. Our method is widely applicable and we show that it can be adapted to other paradigms, including mammalian cell models.
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http://dx.doi.org/10.1016/B978-0-12-391856-7.00039-1DOI Listing
August 2012

Newly visualized fibrillar collagen scaffolds dictate Entamoeba histolytica invasion route in the human colon.

Cell Microbiol 2012 May 15;14(5):609-21. Epub 2012 Feb 15.

Institut Pasteur, Unité Biologie Cellulaire du Parasitisme, Paris, France. INSERM U786, Paris, France.

The extracellular matrix (ECM) and its role in the outcome of infectious diseases have been poorly investigated. In this study, we determined the impact of the collagen fibres architecture on the invasive process of the enteric parasite Entamoeba histolytica. The behaviour of E. histolytica wild-type and silenced for the cysteine protease A5 (CP-A5) were compared on a three-dimensional collagen matrix and within human colon fragments for fibrillar collagen cleavage and migration. The interstitial collagen fibres within the connective tissue of the human colon, visualized by multiphoton and second harmonic generation signals imaging, presented a dense scaffold at the subepithelial level and a loose meshwork within the chorion. To penetrate the tissue, E. histolytica migrated on the dense scaffold that remained intact, reached the crypt of Lieberkhün, migrated along and then disorganized the loose scaffold to escape into the mucosa. Interestingly, in vitro, CP-A5 was not required for collagenase activity and migration through the matrix but was necessary within the tissue environment for collagen meshwork remodelling and subsequent invasion. The data point out that further step of invasion relay with ECM destruction that requires human components induced or activated in the presence of CP-A5.
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http://dx.doi.org/10.1111/j.1462-5822.2012.01752.xDOI Listing
May 2012

Contribution of the glycolytic flux and hypoxia adaptation to efficient biofilm formation by Candida albicans.

Mol Microbiol 2011 May 6;80(4):995-1013. Epub 2011 Apr 6.

Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, F-75015 Paris, France.

The fungal pathogen Candida albicans forms therapeutically challenging biofilms on biomedical implants. Using a transcript profiling approach genes whose expression is favoured upon biofilm growth compared with planktonic growth have been previously identified. Knock-out mutants for 38 of these genes were constructed, six of which showed a specific defect in biofilm formation. Among these genes, TYE7 that encodes a transcriptional activator of glycolytic genes in planktonic and biofilm growth conditions was identified as being required for the cohesiveness of biofilms. Biofilms formed by the tye7Δ knock-out mutant showed a hyperfilamentous morphology, and growth of this mutant on solid medium under hypoxia was also associated with the production of hyphae. Similar to TYE7 inactivation, inhibition of glycolysis or ATP synthesis using oxalate or an uncoupler, respectively, triggered morphogenesis when a wild-type strain was grown under hypoxia. These treatments also induced the formation of weakly cohesive, hyper-filamentous biofilms by a wild-type strain. Our data indicate that a hypoxic environment is generated within C. albicans biofilms and that continued biofilm development requires a Tye7p-dependent upregulation of glycolytic genes necessary to adapt to hypoxia and prevent uncontrolled hyphal formation. Thus, adaptation to hypoxia is an integral component of biofilm formation in C. albicans.
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http://dx.doi.org/10.1111/j.1365-2958.2011.07626.xDOI Listing
May 2011