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Objectives: To evaluate the prognostic value of cerebral border-zone infarctions (watershed infarctions) on the early postoperative outcomes of patients undergoing carotid endarterectomy (CEA) after acute ischemic stroke (AIS). Methods: Sixty-six (66) patients with symptomatic carotid stenosis (SCS) that underwent ipsilateral CEA after AIS from January 2007 to March 2012 were included in this study. They were divided into two groups according to the topographic patterns of the stroke: group 1, Territorial Cerebral Ischemic Strokes (TCIS) caused by emboli of carotid origin; group 2, cerebral border-zone infarctions (CBZI) related to an SCS associated with hemodynamic impairment. All data was collected in a prospective database and analyzed. Outcome measures included postoperative neurological morbidity and 30-day mortality. Results: Forty-three (43) patients (65.15%) experienced TCIS and were included in group 1, 23 patients (34.85%) had a CBZI and were included in group 2. There were no postoperative deaths. The postoperative neurologic morbidity rate was significantly higher in the CBZI group (22% vs. 2%, p = 0.02). Multivariate analysis demonstrates that CBZI was the only independent predictive factor of neurologic morbidity after CEA for AIS related to an SCS. Furthermore, the risk of postoperative neurologic morbidity remained significantly higher for patients with CBZI after adjustement for age, sex, initial NHISS scores, and associated contralateral carotid occlusion (HR: 0.059, 95% CI 0.004–0.85; p = 0.03). Conclusion: CBZIs, compared to TCIS, were associated with a higher neurological complication rate during the postoperative period after CEA for SCS in cases of AIS. Further studies are required to better define the timing and the best treatment modality for patients with CBZI related to an SCS in order to reduce associated procedural complications. [ABSTRACT FROM AUTHOR]

Objectives: The objective is to report our results with the arm composite autogenous vascular access (ACAVA) using the great saphenous vein (GSV) and the femoral vein (FV) in tertiary vascular access surgery. Design: Retrospective single-centre study. Prospectively collected clinical database. Methods: Between August 2009 and March 2011, 17 patients with no suitable upper extremity vein, repeated prosthetic access failure and/or infection underwent the construction of an ACAVA. Outcome measures included the graft patency and complication rates. Results: The median follow-up was 25 months (5–32). Thirty-day morbidity affected 10 patients (59%): four wound-healing issues, three lower limb swelling, two early thromboses and one upper limb haematoma. No postoperative death occurred. At 3 months, the primary patency rate was 88% ± 8%. At 6 months, the assisted-primary patency rate was 82.4% ± 9.2%. At 12 months, the secondary patency rate was 81.6% ± 9.6%. Twenty-four secondary interventions were performed. Steal syndrome occurred in one patient following a secondary procedure. Swelling of the lower limb remained in two patients at the end of their follow-up. Three ACAVAs developed irreversible occlusion leading to loss of access. Conclusion: With a high rate of postoperative morbidity and re-intervention, the ACAVA is a useful additional technique that should be restricted to difficult cases with limited vascular access options. [ABSTRACT FROM AUTHOR]

Summary: This prospective study compared personalized surgical antibiotic prophylaxis kits (SAPKs) with freely prescribed antibiotics. SAPKs use significantly enhanced national guidelines on surgical antibiotic prophylaxis application (82% vs 41%, P<0.001), and result in limited errors in terms of antibiotic choice (3% vs 28%, P<0.001), timing of administration (12% vs 24%, P=0.003) and prophylaxis duration (1.5% vs 22%, P<0.001), thereby demonstrating their effectiveness. [Copyright &y& Elsevier]

The insertion of a DNA copy of its RNA genome into a chromosome of the host cell is mediated by the viral integrase with the help of mostly uncharacterized cellular cofactors. We have recently described that the transcriptional co-activator LEDGF/p75 strongly interacts with HIV-1 integrase. Here we show that interaction of HIV-1 integrase with LEDGF/p75 is important for viral replication. Using multiple approaches including two-hybrid interaction studies, random and directed mutagenesis, we could demonstrate that HIV-1 virus harboring a single mutation that disrupts integrase. LEDGF/p75 interaction, resulted in defective HIV-1 replication. Furthermore, we found that LEDGF/p75 tethers HIV-1 integrase to chromosomes and that this interaction may be important for the integration process and the replication of HIV-1. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nanoparticles made of a PFOB core and a thick PLGA-PEG shell. • Ultrasound-triggered release of Nile red encapsulated into the PLGA-PEG shell. • In the absence of detectable inertial cavitation, release is <5%. • In the presence of detectable inertial cavitation, release ranges from 10% to 100%. • Release over 30% occurs only if both duty cycle and acoustic pressure are high enough. Polymeric nanoparticles are being intensively investigated as drug carriers. Their efficiency could be enhanced if the drug release can be triggered using an external stimulus such as ultrasound. This approach is possible using current commercial apparatus that combine focused ultrasound with MRI to perform ultrasonic surgery. In this approach, nanoparticles made of a perfluoro-octyl bromide core and a thick polymeric (PLGA-PEG) shell may represent suitable drug carriers. Indeed, their perfluorocarbon core are detectable by 19F MRI, while their polymeric shell can encapsulate drugs. However, their applicability in ultrasound-triggered drug delivery remains to be proven. To do so, we used Nile red as a model drug and we measured its release from the polymeric shell by spectrofluorometry. In the absence of ultrasound, only a small amount of Nile red release was measured (<5%). Insonations were performed in a controlled environment using a 1.1 MHz transducer emitting tone bursts for a few minutes, whereas a focused broadband hydrophone was used to detect the occurrence of cavitation. In the absence of detectable inertial cavitation, less than 5% of Nile red was released. In the presence of detectable inertial cavitation, Nile red release was ranging from 10% to 100%, depending of the duty cycle, acoustic pressure, and tank temperature (25 or 37 °C). Highest releases were obtained only for duty cycles of 25% at 37 °C and 50% at 25 °C and for a peak-to-peak acoustic pressure above 12.7 MPa. Electron microscopy and light scattering measurements showed a slight modification in the nanoparticle morphology only at high release contents. The occurrence of strong inertial cavitation is thus a prerequisite to induce drug release for these nanoparticles. Since strong inertial cavitation can lead to many unwanted biological effects, these nanoparticles may not be suitable for a therapeutic application using ultrasound-triggered drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: The prescription drug for hypertension in children remains difficult because of the lack of pharmacological data validated in this age of life. The food and drug administration (FDA) have recently proposed some antihypertensive regimens orally. The authors found useful to reproduce a table by adding all the necessary data for its use in France. Here is a list of French medicines and doses applied to children. Similarly, they made a second table for injectable antihypertensive treatment based on American recommendations – but not yet validated by FDA. [Copyright &y& Elsevier]

Legionella pneumophila, the causative agent of Legionnaire's disease, uses its type IV secretion system to translocate over 300 effector proteins into host cells. These effectors subvert host cell signaling pathways to ensure bacterial proliferation. Despite their importance for pathogenesis, the roles of most of the effectors are yet to be characterized. Key to understanding the function of effectors is the identification of host proteins they bind during infection. We previously developed a novel tandem-affinity purification (TAP) approach using hexahistidine and BirA-specific biotinylation tags for isolating translocated effector complexes from infected cells whose composition were subsequently deciphered by mass spectrometry. Here we further advanced the workflow for the TAP approach and determined the infection-dependent interactomes of the effectors SidM and LidA, which were previously reported to promiscuously bind multiple Rab GTPases in vitro. In this study we defined a stringent subset of Rab GTPases targeted by SidM and LidA during infection, comprising of Rab1A, 1B, 6, and 10; in addition, LidA targets Rab14 and 18. Taken together, this study illustrates the power of this approach to profile the intracellular interactomes of bacterial effectors during infection. [ABSTRACT FROM AUTHOR]

Abstract: The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate TNFα antagonist continuation rates in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). Methods: We retrospectively reviewed the charts of patients treated with etanercept, infliximab, or adalimumab at our teaching hospital. Drug continuation was evaluated using Kaplan–Meier survival curves. The logrank test was used to compare continuation rates. Results: We identified 442 patients who were prescribed 571 TNFα antagonist treatments between August 1999 and June 2005. Among them, 304 had RA, 92 AS, and 46 PsA. In the RA group, continuation rates were high with etanercept (n =157; 87% after 12months and 68% after 24months) and adalimumab (n =43, 83% and 66%) but significantly lower with infliximab (n =104, 68% and 46%; P =0.0001 vs. etanercept and P =0.01 vs. adalimumab). In the AS group, in contrast, infliximab (n =53) showed significantly higher continuation rates (89% and 83%) than did etanercept (n =39; 76% after 12months: P =0.03). Overall continuation rates were higher in AS than in RA (P =0.01). Conclusion: Continuation was better with etanercept than with infliximab in patients with RA, whereas the opposite was noted in patients with AS. [Copyright &y& Elsevier]

Résumé: Le but de cette étude rétrospective est de définir le maintien thérapeutique des anti-TNF, dans la polyarthrite rhumatoïde (PR), la spondylarthrite ankylosante (SA) et le rhumatisme psoriasique (RP). Méthode: Nous avons inclus les patients traités par anti-TNF (étanercept, infliximab, adalimumab). Les courbes de survie ont été construites selon la méthode de Kaplan-Meier et la comparaison effectuée par le test du logrank. Résultats: Quatre cent quarante-deux dossiers de patients ont été analysés (08/1999–06/2005), dont 304 PR, 92 SA et 46 RP ayant bénéficié de 571 prescriptions d''anti-TNF. Les PR (n =304), traitées par étanercept (n =157) ont un maintien thérapeutique de 87% à 12 mois, 68% à 24 mois; traitées par infliximab (n =104), le maintien est de 68% à 12 mois, 46% à 24 mois; traitées par adalimumab (n =43), le maintien est de 83% à 12 mois, 66% à 24 mois. Il existe un maintien thérapeutique supérieur de l''étanercept et de l''adalimumab/l''infliximab (p =0,0001, p =0,01) dans la PR. Les SA (n =92), traitées par infliximab (n =53) ont un maintien thérapeutique de 89% à 12 mois, 83% à 24 mois qui est supérieur aux SA traitées par étanercept (n =39) avec un maintien thérapeutique de 76% à 12 mois (p =0,03). Le maintien des anti-TNF est supérieur dans la SA/PR (p =0,01). Conclusion: Il existe un maintien supérieur de l''étanercept par rapport à l''infliximab dans la PR, de l''infliximab par rapport à l''étanercept dans la SA. [Copyright &y& Elsevier]

Introduction et objectifs: Les MFI sont des pathologies infectieuses sévères des patients immunodéprimés. Les traitements antifongiques (AF) systémiques recommandés font partie depuis 2005 des médicaments tarifiés en sus de l’activité. Depuis 2005, pour chaque suspicion de MFI une documentation systématique est demandée en cellule antifongiques (RCP hebdomadaire pluridisciplinaire : infectiologue, hématologue, mycologue, pharmacien) et les traitements AF en cours sont discutés. Matériels et méthodes: En 2008, 179 avis ont été communiqués en temps réel aux prescripteurs concernant 109 patients traités par AF. Ces avis ont été donnés au cours de 31 RCP au vu des données diagnostiques, microbiologiques et d’imagerie accessibles dans le dossier patient informatisé. Résultats: 7 diagnostics d’aspergillose invasive (AI) probable ont été posés, 1 d’AI possible (tous en hématologie, 1 en hématologie pédiatrique). 4 patients sont décédés, et pour un l’AI peut avoir constitué un facteur favorisant du décès. L’incidence des AI est de 4,7 % parmi les patients présentant une leucémie aigüe et greffés de CSH ; ce qui semble faible par rapport à la littérature. 90 % des avis diagnostiques et thérapeutiques ont été suivis. 95 % des traitements tarifiés en sus sont conformes aux AMM. La recherche systématique d’une documentation explique une diminution des poursuites de traitements empiriques, avec pour conséquence une réduction de 17 % des AF facturables en sus et 12 % des autres AF systémiques en 2008. Conclusion: En optimisant la démarche diagnostique et thérapeutique, avec aujourd’hui 100 % des patients bénéficiant de la recherche des critères microbiologiques et tomodensitométriques, notre action a permis de réduire le nombre de poursuites de traitements empiriques. La bonne observance des avis souligne l’adhésion des prescripteurs à notre démarche. Les consommations en AF en doses définies journalières permettront de préciser mieux encore l’évolution des pratiques. [Copyright &y& Elsevier]

Situation: Les aspergilloses invasives (AI) sont des pathologies infectieuses sévères des patients immunodéprimés. Les traitements antifongiques (AF) recommandés font partie depuis 2005 des traitements coûteux tarifiés en sus de l’activité. Afin de s’assurer de leur Bon Usage, un référentiel institutionnel a été élaboré basé sur la conférence de consensus nationale de 2004 complété par des recommandations sur l’utilisation des outils disponibles localement. Parallèlement, une cellule antifongique (CAF), pluridisciplinaire (hématologue, infectiologue, mycologue, pharmacien) a été créée et fait une revue hebdomadaire de toutes les prescriptions spécifiques d’AF ; les avis sont adressés systématiquement aux prescripteurs. Objectif: Le but de ce travail est d’évaluer le nombre de diagnostics certains d’AI et la conformité des traitements au référentiel. Méthode: Sur une période de 18 mois (janvier 2006 à juin 2007), 48 patients (83 % en hématologie, 10 % en réanimation et 7 % en infectiologie) ont été traités pour suspicion d’AI. Vingt-sept pour cent des patients était allogreffé. Les critères biologiques (données mycologiques et antigénémies) et d’imagerie ont été recherchés respectivement pour 84 % et 67 % des patients. Nous avons diagnostiqué 5 cas certains d’AI parmi les 48 patients. Le voriconazole a été prescrit en première intention dans 87 % des cas, conformément au référentiel. Sept bithérapies AF, non recommandées au niveau national, ont été instaurées, 2 avec avis favorable de la CAF. Conclusion: Le faible taux de diagnostic certain est conforme à la littérature, mais sera optimisé par la future utilisation d’une PCR Aspergillus en temps réel. Une formation spécifique pour renforcer l’expertise en imagerie thoracique est en cours. Enfin, l’adhésion au référentiel en termes de traitement est satisfaisante et souligne l’implication des prescripteurs à notre démarche. [Copyright &y& Elsevier]