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In the present paper, we investigate how the optical and structural properties, in particular the observed photoluminescence (PL) of photocurable and organic-inorganic TiO 2 -SiO 2 sol-gel films doped with Rhodamine 6G (R6G) are affected by γ-rays. For this, four luminescent films, firstly polymerized with UV photons (365 nm), were submitted to different accumulated doses of 50 kGy, 200 kGy, 500 kGy and 1 MGy while one sample was kept as a reference and unirradiated. The PL, recorded under excitations at 365 nm, 442 nm and 488 nm clearly evidences that a strong signal peaking at 564 nm is still largely present in the γ-irradiated samples. In addition, M-lines and Fourier-transform infrared (FTIR) spectroscopies are used to quantify the radiation induced refractive index variation and the chemical changes, respectively. Results show that a refractive index decrease of 7 × 10 -3 at 633 nm is achieved at a 1 MGy accumulated dose while a photo-induced polymerization occurs, related to the consumption of CH=C, Si-OH and Si-O-CH 3 groups to form Ti-O and Si-O bonds. All these results confirm that the host matrix (TiO 2 -SiO 2 ) and R6G fluorophores successfully withstand the hard γ-ray exposure, opening the way to the use of this material for sensing applications in radiation-rich environments.

Objective: To provide national guidelines for the management of women with severe pre-eclampsia., Design: A consensus committee of 26 experts was formed. A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised., Methods: The last SFAR and CNGOF guidelines on the management of women with severe pre-eclampsia were published in 2009. The literature is now sufficient for an update. The aim of this expert panel guidelines is to evaluate the impact of different aspects of the management of women with severe preeclampsia on maternal and neonatal morbidities separately. The experts studied questions within 7 domains. Each question was formulated according to the PICO (Patients Intervention Comparison Outcome) model and the evidence profiles were produced. An extensive literature review and recommendations were carried out and analysed according to the GRADE® methodology., Results: The SFAR/CNGOF experts panel provided 25 recommendations: 8 have a high level of evidence (GRADE 1+/-), 9 have a moderate level of evidence (GRADE 2+/-), and for 7 recommendations, the GRADE method could not be applied, resulting in expert opinions. No recommendation was provided for 3 questions. After one scoring round, strong agreement was reached between the experts for all the recommendations., Conclusions: There was strong agreement among experts who made 25 recommendations to improve practices for the management of women with severe pre-eclampsia., (Copyright © 2021 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

In many real world situations, the design of social rankings over agents or items from a given raking over groups or coalitions, to which these agents or items belong to, is of big interest. With this aim, we revise the lexicographic excellence solution and introduce two novel solutions which, moreover, take into account the size of the groups. We present some desirable axioms which are interpreted in this context. Next, a comparable axiomatization of these three solutions is established, revealing the main differences among the two new social rankings and the lexicographic excellence solution. Finally, we apply the three social rankings under study to a real scenario. Specifically, the performance of some football players of Paris Saint-Germain during the UEFA Champions League according to these three rules is analyzed., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.)

Objective: Five French oncology institutions had participated in a funded study aiming at implementing an Evidence-Based Practice tool (PAM-13), which allowed nurses to measure the level of activation of the patient to support his or her own empowerment in the cancer care pathway. The purpose of this ancillary study is to (i) describe the caregivers' perceptions of addictions and their management concurrently with cancer treatment, (ii) explore the role that Motivational Interviewing techniques can play., Methods: 15 individual semi-structured interviews of caregivers were performed, using the Theoretical Domains Framework for the interview guide. Qualitative data were analyzed inductively, in a thematic analysis. The COREQ guided the reporting of this qualitative study., Results: Views on addictions influence the way caregivers manage patients suffering from unresolved issues of addiction. Care is mainly focused on the pathology (cancer-centered) and strictly curative. When practiced, Motivational Interviewing is patient-centered, fostering the patient's empowerment on the cancer care pathway., Conclusions: The dissemination of Motivational Interviewing techniques in current practices in oncology, both in terms of doctors and nursing teams, would enable improvement to the management of addictions on the cancer care pathway, by deploying a patient-centered approach. This new paradigm of care would support the empowerment of patients enrolled in the cancer care pathway and promote better communication between caregivers and patients. Hence, a paradigm shift is essential. Motivational Interviewing techniques could provide a caring approach that promotes communication between the patient and the caregiver and also supports the former's empowerment. This research suggests the need to adapt the cancer care pathway in order to integrate the necessary care for patients who concomitantly suffer from unresolved addictive disorders., Trial Registration: NCT03706937., Competing Interests: The authors have declared that no competing interests exist.

Structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, and have reported many contradictory or non-replicated findings. Here, our purpose was to identify through functional magnetic resonance imaging the brain responses of 25 male outpatients with pedophilic disorder to visual stimuli depicting children (VSc) and to compare them with 24 male healthy controls matched on sexual orientation (to female or male adults), age, and handedness. No region was differentially activated across the two groups in response to VSc. However, as shown by a random-effects statistical analysis (cluster-level p FWE -corrected < 0.05), in patients with pedophilia, but not in controls, the presentation of VSc induced a bilateral activation in the lateral occipital and temporal cortices, in particular in the right inferior temporal gyrus, as well as an activation in the declive of the cerebellar vermis. In addition, in patients the level of bilateral activation in the above-mentioned regions was positively correlated with ratings of perceived sexual arousal elicited by VSc. These results implicate these regions as possible candidate areas mediating sexual arousal in patients with pedophilic disorder.

Background & Aims: In the sera of infected patients, hepatitis C virus (HCV) particles display heterogeneous forms with low-buoyant densities (<1.08), underscoring their lipidation via association with apoB-containing lipoproteins, which was proposed to occur during assembly or secretion from infected hepatocytes. However, the mechanisms inducing this association remain poorly-defined and most cell culture grown HCV (HCVcc) particles exhibit higher density (>1.08) and poor/no association with apoB. We aimed to elucidate the mechanisms of lipidation and to produce HCVcc particles resembling those in infected sera., Methods: We produced HCVcc particles of Jc1 or H77 strains from Huh-7.5 hepatoma cells cultured in standard conditions (10%-fetal calf serum) vs. in serum-free or human serum conditions before comparing their density profiles to patient-derived virus. We also characterized wild-type and Jc1/H77 hypervariable region 1 (HVR1)-swapped mutant HCVcc particles produced in serum-free media and incubated with different serum types or with purified lipoproteins., Results: Compared to serum-free or fetal calf serum conditions, production with human serum redistributed most HCVcc infectious particles to low density (<1.08) or very-low density (<1.04) ranges. In addition, short-time incubation with human serum was sufficient to shift HCVcc physical particles to low-density fractions, in time- and dose-dependent manners, which increased their specific infectivity, promoted apoB-association and induced neutralization-resistance. Moreover, compared to Jc1, we detected higher levels of H77 HCVcc infectious particles in very-low-density fractions, which could unambiguously be attributed to strain-specific features of the HVR1 sequence. Finally, all 3 lipoprotein classes, i.e., very-low-density, low-density and high-density lipoproteins, could synergistically induce low-density shift of HCV particles; yet, this required additional non-lipid serum factor(s) that include albumin., Conclusions: The association of HCV particles with lipids may occur in the extracellular milieu. The lipidation level depends on serum composition as well as on HVR1-specific properties. These simple culture conditions allow production of infectious HCV particles resembling those of chronically-infected patients., Lay Summary: Hepatitis C virus (HCV) particles may associate with apoB and acquire neutral lipids after exiting cells, giving them low-buoyant density. The hypervariable region 1 (HVR1) is a majorviral determinant of E2 that controls this process. Besides lipoproteins, specific serum factors including albumin promote extracellular maturation of HCV virions. HCV particle production in vitro, with media of defined serum conditions, enables production of infectious particles resembling those of chronically infected patients., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Early steps of HIV infection are mediated by the binding of the envelope to mucosal receptors as α4β7 and the C-type lectins DC-SIGN and langerin. Previously Env-specific B-cell responses have been reported in highly exposed seronegative individuals (HESN)., Method: Here, we studied gp120-specific antibodies ability to block HIV interaction with α4β7, DC-SIGN and/or langerinin HESN. New cell-based assays were developed to analyze whether antibodies that can alter gp120 binding to α4β7, DC-SIGN and/or langerin are induced in HESN. A mucosal blocking score (MBS) was defined based on the ability of antibodies to interfere with gp120/α4β7, gp120/DC-SIGN, and gp120/langerin binding. A new MBS was evaluated in a cohort of 86 HESN individuals and compared with HIV+ patients or HIV- unexposed healthy individuals., Results: Antibodies reducing gp120 binding to both α4β7 and DC-SIGN were present in HESN serum but also in mucosal secretions, whereas antibodies from HIV+ patients facilitated gp120 binding to DC-SIGN. Any correlation was observed between MBS and the capacity of antibodies to neutralize infection of α4β7 CD4+ T cells with primary isolates., Conclusions: MBS is significantly associated with protection in HESN and might reflect altered HIV spreading to mucosal-associated lymphoid tissues.

Introduction: Some previous studies have suggested a high prevalence of pulmonary embolism (PE) during exacerbations of chronic obstructive pulmonary disease (ECOPD). The SLICE trial aims to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE (vs usual care) in patients hospitalized because of ECOPD., Methods: SLICE is a phase III, prospective, international, multicenter, randomized, open-label, and parallel-group trial. A total of 746 patients hospitalized because of ECOPD will be randomized in a 1:1 fashion to receive either an active strategy for the diagnosis and anticoagulant treatment of PE or usual care (ie, standard care without any diagnostic test for diagnosing PE). The primary outcome is a composite of all-cause death, non-fatal (recurrent) venous thromboembolism (VTE), or readmission for ECOPD within 90 days after enrollment. Secondary outcomes are (a) death from any cause within 90 days after enrollment, (b) non-fatal (recurrent) VTE within 90 days after enrollment, (c) readmission within 90 days after enrollment, and (d) length of hospital stay., Results: Enrollment started in September 2014 and is expected to proceed until 2020. Median age of the first 443 patients was 71 years (interquartile range, 64-78), and 26% were female., Conclusions: This multicenter trial will determine the value of detecting PEs in patients with ECOPD. This has implications for COPD patient morbidity and mortality., Trial Registration Number: NCT02238639., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Importance: Data on neurologic manifestations of fibromuscular dysplasia (FMD) are rare, and current knowledge remains limited., Objectives: To present a comprehensive review of the epidemiologic characteristics, management, and prognosis of the neurologic manifestations associated with cerebrovascular FMD (ie, involving cervical or intracranial arteries) and to guide future research priorities., Evidence Review: References were identified through searches of PubMed from inception to December 2017 using both the medical subject headings and text words. Additional sources were also identified by reviewing reference lists of relevant articles and through searches of the authors' personal files. Selected articles described at least 1 clinical or radiologic feature and/or outcome of cerebrovascular FMD. Isolated case reports could be included if they described interesting or noteworthy manifestations of FMD., Findings: A total of 84 relevant references were identified. Diagnosis of cerebrovascular FMD is based on the appearance of alternating arterial dilatation and constriction ("string of beads") or of focal narrowing, with no sign of atherosclerotic or inflammatory lesions. Although the diagnosis is easily apparent on results of radiographic imaging, making a diagnosis can be challenging in children or individuals with atypical phenotypes, such as purely intracranial FMD and arterial diaphragm. Involvement of multiple arteries is common, and there is increased incidence of cervical artery dissection and intracranial aneurysms. A variant in the PHACTR1 gene has been associated with FMD as well as cervical artery dissection and migraine, although less than 5% of cases of FMD are familial. Headaches, mainly of the migraine type, are observed in up to 70% of patients with FMD. Cerebrovascular FMD is mostly asymptomatic, but the most frequent neurologic manifestations include transient ischemic attack and ischemic stroke, notably in the presence of associated cervical artery dissection. Other conditions associated with FMD include subarachnoid hemorrhage and, rarely, intracranial hemorrhage. Management relies on observational data and expert opinion. Antiplatelet therapy is considered reasonable to prevent thromboembolic complications. Endovascular therapy is typically restricted to cases with symptomatic stenosis despite optimal medical therapy or in those with rupture of an intracranial aneurysm., Conclusions and Relevance: Longitudinal cohort studies of individuals of multiple ethnicities with biosampling are needed to better understand the risk factors, pathophysiological features, and outcomes of FMD. Patient advocacy groups could assist researchers in answering patient-centered questions regarding FMD.

Background: The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear., Methods: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE., Results: From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3)., Conclusions: Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults., Objective: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis., Methods: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172)., Results: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001)., Conclusions: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Viroporins are small transmembrane proteins with ion channel activities modulating properties of intracellular membranes that have diverse proviral functions. Hepatitis C virus (HCV) encodes a viroporin, p7, acting during assembly, envelopment and secretion of viral particles (VP). HCV p7 is released from the viral polyprotein through cleavage at E2-p7 and p7-NS2 junctions by signal peptidase, but also exists as an E2p7 precursor, of poorly defined properties. Here, we found that ectopic p7 expression in HCVcc-infected cells reduced secretion of particle-associated E2 glycoproteins. Using biochemical assays, we show that p7 dose-dependently slows down the ER-to-Golgi traffic, leading to intracellular retention of E2, which suggested that timely E2p7 cleavage and p7 liberation are critical events to control E2 levels. By studying HCV mutants with accelerated E2p7 processing, we demonstrate that E2p7 cleavage controls E2 intracellular expression and secretion levels of nucleocapsid-free subviral particles and infectious virions. In addition, our imaging data reveal that, following p7 liberation, the amino-terminus of p7 is exposed towards the cytosol and coordinates the encounter between NS5A and NS2-based assembly sites loaded with E1E2 glycoproteins, which subsequently leads to nucleocapsid envelopment. We identify punctual mutants at p7 membrane interface that, by abrogating NS2/NS5A interaction, are defective for transmission of infectivity owing to decreased secretion of core and RNA and to increased secretion of non/partially-enveloped particles. Altogether, our results indicate that the retarded E2p7 precursor cleavage is essential to regulate the intracellular and secreted levels of E2 through p7-mediated modulation of the cell secretory pathway and to unmask critical novel assembly functions located at p7 amino-terminus.

Background: Following publication of guidelines on routine preoperative tests, the French Society of Anaesthesiology and Intensive Care (SFAR), in association with French national public health insurance, conducted a survey to evaluate adherence to guidelines and the economic consequences., Methods: Using the French Hospital Discharge Database and National Health Insurance Information system, tests performed during the 30 days before surgery were analysed for two situations: (1) standard laboratory coagulation tests and ABO blood typing in children able to walk and scheduled for tonsillectomy/adenoidectomy; and (2) ABO blood typing in adults before laparoscopic cholecystectomy, thyroidectomy, lumbar discectomy or breast surgery. Guidelines do not recommend any preoperative tests in these settings., Results: Between 2013 and 2015, a coagulation test was performed in 49% of the 241 017 children who underwent tonsillectomy and 39% of the 133 790 children who underwent adenoidectomy. A similar pattern was observed for ABO blood typing although re-operation rates for bleeding on the first postoperative day were very low (0.12-0.31% for tonsillectomy and 0.01-0.02% for adenoidectomy). Between 2012 and 2015, ABO blood typing was performed in 32-45% of the 1 114 082 patients who underwent one of the four selected procedures. The transfusion rate was very low (0.02-0.31%). The mean cost for the four procedures over the 4 yr period was €5 310 000 (sd €325 000)., Conclusions: Standard laboratory coagulation tests and ABO blood typing are still routinely prescribed before surgery and anaesthesia despite current guidelines. This over-prescription represents a high and unnecessary cost, and should therefore be addressed., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent in situ hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases., (Copyright© 2017 Ferrata Storti Foundation.)

Purpose: Azacitidine inhibits DNA methyltransferases, including DNMT1, and is currently the standard of care for patients with higher-risk myelodysplastic syndrome (HRMDS) or low blast count acute myeloid leukemia (AML). Experimental Design: The expression of 754 miRNAs was compared in azacitidine-resistant and azacitidine-sensitive myelodysplastic syndrome cells. We investigated the role of differentially expressed miRNAs on DNMT1 expression and azacitidine resistance in vitro We next evaluated anti-DNMT1 miRNA expression in pretreatment bone marrow samples derived from 75 patients treated with azacitidine for HRMDS or AML. Results: Seven miRNAs, including 5 that in silico targeted the DNMT1 3' UTR, were repressed in azacitidine-resistant cells in which DNMT1 protein levels were significantly higher. Ectopic anti-DNMT1 miRNA expression decreased DNMT1 expression and increased azacitidine sensitivity, whereas specific inhibition of endogenous anti-DNMT1 miRNAs increased DNMT1 expression and triggered azacitidine resistance. In patients treated with azacitidine, decreased expression of anti-DNMT1 miRNAs was associated with poor outcome. miR-126* had the strongest prognostic impact. Patients with miR-126* low myelodysplastic syndrome had significantly lower response rates ( P = 0.04) and higher relapse rates ( P = 0.03), as well as shorter progression-free (PFS; P = 0.004) and overall survival (OS; P = 0.004). Multivariate analysis showed that age, miR-126* expression, and revised International Prognostic Scoring System risk independently predicted PFS and OS. In 15 patient samples collected over time, decreased miRNA expression levels were associated with secondary resistance. Conclusions: A decreased expression of anti-DNMT1 miRNAs might account for azacitidine resistance in HRMDS and AML, and measuring miRNA expression before and during treatment might help predict primary or secondary azacitidine resistance. Clin Cancer Res; 23(12); 3025-34. ©2016 AACR ., (©2016 American Association for Cancer Research.)

: Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step toward reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody-dependent cell-mediated cytotoxicity activities have been described in highly exposed seronegative individuals. Conversely, some IgGs may facilitate the crossing of HIV free-particles through epithelial barriers by transcytosis. Hence knowledge of the mechanisms underlying anti-HIV antibody production in the genital tract and their exact role in sexual transmission may help to develop appropriate preventive strategies based on passive immunization or mucosal vaccination approaches. Our review focuses on the characteristics of the humoral immune responses against HIV in the male genital tract and related prevention strategies.

Lavender essential oils (EOs) of higher quality are produced by a few Lavandula angustifolia cultivars and mainly used in the perfume industry. Undesirable compounds such as camphor and borneol are also synthesized by lavender leading to a depreciated EO. Here, we report the cloning of bornyl diphosphate synthase of lavender (LaBPPS), an enzyme that catalyzes the production of bornyl diphosphate (BPP) and then by-products such as borneol or camphor, from an EST library. Compared to the BPPS of Salvia officinalis, the functional characterization of LaBPPS showed several differences in amino acid sequence, and the distribution of catalyzed products. Molecular modeling of the enzyme's active site suggests that the carbocation intermediates are more stable in LaBPPS than in SoBPPS leading probably to a lower efficiency of LaBPPS to convert GPP into BPP. Quantitative RT-PCR performed from leaves and flowers at different development stages of L. angustifolia samples show a clear correlation between transcript level of LaBPPS and accumulation of borneol/camphor, suggesting that LaBPPS is mainly responsible of in vivo biosynthesis of borneol/camphor in fine lavender. A phylogenetic analysis of terpene synthases (TPS) pointed out the basal position of LaBPPS in the TPSb clade, suggesting that LaBPPS could be an ancestor of others lavender TPSb. Finally, borneol could be one of the first monoterpenes to be synthesized in the Lavandula subgenus. Knowledge gained from these experiments will facilitate future studies to improve the lavender oils through metabolic engineering or plant breeding. Accession numbers: LaBPPS: KM015221., (Copyright © 2017. Published by Elsevier Ltd.)

In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S high patients were found to be younger than TET2 low patients without a difference in the rate of complete remission. However, TET2E2S high patients exhibited a significantly lower CIR (p<10 -4 ). TET2E2S and FLT3-ITD, but not age or NPM1 mutation status were independent prognostic factors for DFS and event-free survival (EFS), while TET2E2S was the sole prognostic factor that we identified for overall survival (OS). In both the intermediate-1 and favorable ELN genetic categories, TET2E2S remained significantly associated with prolonged survival. There was no correlation between TET2E2S status and outcomes in 34 additional AML patients who were unfit for IC. Therefore our results suggest that assessments of TET2 exon 2 splicing status might improve risk stratification in CN-AML patients treated with IC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Over the last several years, converging lines of evidence have indicated that miR-206 plays a pivotal role in promoting muscle differentiation and regeneration, thereby potentially impacting positively on the progression of neuromuscular disorders, including Duchenne muscular dystrophy (DMD). Despite several studies showing the regulatory function of miR-206 on target mRNAs in skeletal muscle cells, the effects of overexpression of miR-206 in dystrophic muscles remain to be established. Here, we found that miR-206 overexpression in mdx mouse muscles simultaneously targets multiple mRNAs and proteins implicated in satellite cell differentiation, muscle regeneration, and at the neuromuscular junction. Overexpression of miR-206 also increased the levels of several muscle-specific mRNAs/proteins, while enhancing utrophin A expression at the sarcolemma. Finally, we also observed that the increased expression of miR-206 in dystrophin-deficient mouse muscle decreased the production of proinflammatory cytokines and infiltration of macrophages. Taken together, our results show that miR-206 acts as a pleiotropic regulator that targets multiple key mRNAs and proteins expected to provide beneficial adaptations in dystrophic muscle, thus highlighting its therapeutic potential for DMD., (Copyright © 2017 the American Physiological Society.)

Objectives: The aim of this study was to assess the effectiveness of inferior vena cava (IVC) filter use among patients who develop recurrent symptomatic venous thromboembolism (VTE) on anticoagulant therapy., Background: There is a lack of efficacy evidence of IVC filter therapy in patients with VTE recurrence on anticoagulant therapy., Methods: In this cohort study of patients with acute VTE identified from the RIETE (Registro Informatizado de la Enfermedad Tromboembólica) registry, the associations between IVC filter placement for VTE recurrence in the first 3 months of anticoagulant therapy and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, second recurrent VTE, and major bleeding rates through 30 days after diagnosis of recurrence were assessed., Results: Among 17 patients treated with filters and 49 matched patients treated without filters for VTE recurrence that presented as deep vein thrombosis, propensity score-matched groups showed no significant differences in death for filter insertion compared with no insertion (17.7% vs. 12.2%; p = 0.56). Among 48 patients treated with filters and 91 matched patients treated without filters for VTE recurrence that presented as PE, propensity score-matched groups showed a significant decrease in all-cause death for filter insertion compared with no insertion (2.1% vs. 25.3%; p = 0.02). The PE-related mortality rate was not significantly lower for filter insertion than no insertion (2.1% vs. 17.6%; p = 0.08), though the point estimates markedly differed., Conclusions: Among patients with VTE recurrence during the first 3 months of anticoagulant therapy, IVC filter insertion was not associated with a survival benefit in patients who recurred with deep vein thrombosis, although it was associated with a lower risk for all-cause death in patients who recurred with PE., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Correlation between GALT homing markers on lymphocytes and the low blood CD4 T-cell reconstitution in immunological nonresponders (INRs) has been studied., Design: Thirty-one INRs, 19 immunological responders (IRs), and 12 noninfected controls were enrolled in this study. INRs were defined by an undetectable plasma viral load RNA less than 40 copies per milliliter and CD4 T-cell count <500 cells per cubic milliliter in at least 3 years., Methods: A complete peripheral and mucosal lymphocyte immunophenotyping was performed on these patients with a focus on the CCR9, CCR6, and α4β7 gut-homing markers., Results: A highly significant upregulation of α4β7 on INRs peripheral lymphocytes compared with that of IRs has been observed. This upregulation impacts different lymphocyte subsets namely CD4, CD8, and B lymphocytes. The frequency of β7 Th17 and Treg cells are increased compared with IRs and healthy controls. The frequency of β7 CD8 T cells in the blood is negatively correlated with integrated proviral DNA in rectal lymphoid cells in contrast to β7 CD4 T cells associated with HIV integration., Conclusions: Alteration of lymphocyte homing abilities would have deleterious effects on GALT reconstitution and could participate to HIV reservoir constitution. These results emphasize the great interest to consider α4β7-targeted therapy in INR patients to block homing of lymphocytes and/or to directly impair gp120-α4β7 interactions.

Background: A persistent immune activation is observed in gut during HIV-1 infection, which is not completely reversed by a combined antiretroviral therapy (cART). The impact of the time of cART initiation may highly influence the size of the viral reservoir and the ratio of CD4(+)/CD8(+) T cells in the gut. In this study, we analyzed the characteristics of HIV rectal reservoir of long-term treated patients, regarding their blood CD4(+) T cells count at the time of cART initiation., Results: Twenty-four consenting men were enrolled: 9 exhibiting a CD4(+) T cells count >350/mm(3) ("high-level CD4 group") and 15 < 350/mm(3) ("low-level CD4 group") in blood, at the start of cART. An immunophenotypical analysis of T and B cells subpopulations was performed in blood and rectal biopsies. HIV cell-associated DNA loads and qualitative intra-cellular RNA were determined in both compartments. The ratio of CD4(+)/CD8(+) T cells was significantly decreased in the blood but not in the rectum of the "low-level CD4 group" of patients. The alteration in β7(+) CD4(+) T cells homing was higher in this group and was correlated to a low ratio of CD4(+)/CD8(+) T cells in blood. An initiation of cART in men exhibiting a low-level CD4 count was also associated with an alteration of B cells maturation. HIV blood and gut DNA reservoirs were significantly lower in the "high-level CD4 group" of men. A high HIV DNA level was associated to a detectable intracellular HIV RNA in rectum., Conclusions: An early initiation of cART could significantly preserve gut immunity and limit the viral reservoir constitution.

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in predicting patient outcomes is unknown. Here, we screened serum samples from 50 patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1 deletion mutants covering the extracellular domains. We identified reactive epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1 by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14), and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1 antigens were not statistically different between subgroups. Patients with anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission (P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01) during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR epitope were independent risk factors of poor renal prognosis in multivariable Cox regression analysis. Epitope spreading during follow-up associated with disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back to a CysR profile associated with favorable outcome (n=1). We conclude that analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring disease severity and stratifying patients by renal prognosis., (Copyright © 2016 by the American Society of Nephrology.)

This paper describes a fast and one-step technique to grow single gold filaments at the apex of commercial conductive AFM tips. It is implemented with an atomic force microscope in air with a high relative humidity at room temperature and is based on a bias-assisted electro-reduction of gold ions directly at the tip apex. The technique requires only ad hoc substrates made of a mesoporous silica layer loaded with gold salt deposited on a conductive electrode. It leads to the growth, at the tip apex, of filaments whose length can be monitored and controlled during the growth between tens and hundreds of nanometers and whose radius of curvature can be as low as 3 nm. Made of polycrystalline gold nanostructures, the filaments are chemically and mechanically stable and conductive.

In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro, 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents.

This chapter reviews the different options available for the use of ultrasound in the enhancement of fracture healing or in the reactivation of a failed healing process: LIPUS, shock waves and ultrasound-mediated delivery of bioactive molecules, such as growth factors or plasmids. The main emphasis is on LIPUS, or Low Intensity Pulsed Ultrasound, the most widespread and studied technique. LIPUS has pronounced bioeffects on tissue regeneration, while employing intensities within a diagnostic range. The biological response to LIPUS is complex as the response of numerous cell types to this stimulus involves several pathways. Known to-date mechanotransduction pathways involved in cell responses include MAPK and other kinases signaling pathways, gap-junctional intercellular communication, up-regulation and clustering of integrins, involvement of the COX-2/PGE2 and iNOS/NO pathways, and activation of the ATI mechanoreceptor. Mechanisms at the origin of LIPUS biological effects remain intriguing, and analysis is hampered by the diversity of experimental systems used in-vitro. Data point to clear evidence that bioeffects can be modulated by direct and indirect mechanical effects, like acoustic radiation force, acoustic streaming, propagation of surface waves, heat, fluid-flow induced circulation and redistribution of nutrients, oxygen and signaling molecules. One of the future engineering challenge is therefore the design of dedicated experimental set-ups allowing control of these different mechanical phenomena, and to relate them to biological responses. Then, the derivation of an 'acoustic dose' and the cross-calibration of the different experimental systems will be possible. Despite this imperfect knowledge of LIPUS biophysics, the clinical evidence, although most often of low quality, speaks in favor of the clinical use of LIPUS, when the economics of nonunion and the absence of toxicity of this ultrasound technology are taken into account.

Objective: To evaluate the mutational patterns on the pol gene of the main HIV-1 strain archived in cell genome of 10 chronically infected men according to their clinical and therapeutic history. The genotyping resistance profiles were compared between the first blood plasma available at the time of HIV diagnosis and rectal biopsies and PBMC sampled 1-5 years after the initiation of combined antiretroviral therapy (cART)., Methods: HIV-1 RNA and cell-associated HIV-1 DNA were quantified by Abbott Real-Time HIV-1 and Generic HIV® DNA cell (Biocentric) assays. The mutations in protease and reverse transcriptase genes were assessed by the Trugene® assay (Siemens). The C2V3 region was amplified to determine the viral tropism., Results: In 9 patients, slight or no differences were observed between the 3 resistance profiles. Those mostly detected were related to the resistance to nucleos(t)ide (D67N, L210W, T215A, T69D) and nonnucleoside (K103N, V106I, V179I) inhibitors. In 1 rilpivirine-treated patient, the M230I mutation was detected in PBMC. No change of viral tropism was observed between samples., Conclusion: These data suggest that resistance mutations harbored by the main HIV strain in plasma at the time of diagnosis are durably archived in DNA cells whatever the delay between infection and initiation of therapy in patients well controlled by cART., (© 2017 S. Karger AG, Basel.)

To quantify the drug-drug interactions between dabigatran etexilate (DE) and proton pump inhibitors (PPI) and in particular the role of P-gp activity modulation. In the first part of the study, efflux ratios of DE were evaluated using the caco-2 cell line in the presence of pantoprazole, omeprazole, rabeprazole, lansoprazole and ciclosporin A (positive control). The two PPI that reduced the efflux ratio of dabigatran to the greatest and least extent, respectively, were used during the second part of the study, comprising a single-centre, randomised, open-label study with an incomplete Latin square design. Nine healthy volunteers received DE (150 mg) alone, DE (150 mg) with the first PPI and DE (150 mg) with the second PPI in randomised sequence. Dabigatran plasma concentration and thrombin time were measured in blood samples withdrawn at 11 time points after each treatment. Models were built using a nonlinear mixed-effect modelling approach. Omeprazole and rabeprazole were the two PPI that reduced the efflux ratio of DE least and most, respectively. The PK model was based on an inverse Gaussian absorption process with one compartment. The relationship between dabigatran concentration and thrombin time was considered linear. Some PK profiles had dramatically low concentration values due to poor absorption. These profiles were clustered using a between subject model mixture with interoccasion variability. The concomitant administration of PPI did not significantly change dabigatran pharmacokinetics. DE is subject to high absorption variability, precluding evaluation of the effect of PPI on its pharmacokinetics., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Background: Immunological mechanisms are suspected in sensory neuropathy (SN) occurring with systemic autoimmune diseases and in some idiopathic cases, but so far there are no antibodies (Abs) identifying these neuropathies., Methods: In the search for such specific antibodies, serum samples were collected from 106 patients with SN of these 72 fulfilled the diagnosis criteria of sensory neuronopathy (SNN) and 211 control subjects including patients with sensorimotor neuropathies, other neurological diseases (ONDs), systemic autoimmune diseases and healthy blood donors., Results: In the first step, a protein array with 8000 human proteins allowed identification of the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) as a target of Abs in 7/16 SNN and 0/30 controls. In the second step, an ELISA method was used to test the 317 patients and controls for anti-FGFR3 Abs. Abs were detected in 16/106 patients with SN and 1/211 controls (p<0.001). Among the 106 patients with SN, anti-FGFR3 Abs were found in 11/38 patients with autoimmune context, 5/46 with idiopathic neuropathy and 0/22 with neuropathy of other aetiology (p=0.006). The only control patient with anti-FGFR3 Abs had lupus and no recorded neuropathy. Sensitivity, specificity, and positive and negative predictive values of anti-FGFR3 Abs for a diagnosis of idiopathic or dysimmune SN were 19%, 99.6%, 94.1% and 77.3%, respectively. A cell-based assay confirmed serum reactivity against the intracellular domain of FGFR3. The neuropathy in patients with anti-FGF3 Abs was non-length dependent in 87% of patients and fulfilled the criteria of probable SNN in 82%. Trigeminal nerve involvement and pain were frequent features., Conclusions: A anti-FGFR3 Abs identify a subgroup of patients with SN in whom an underlying autoimmune disorder affecting sensory neurons in the dorsal root and trigeminal nerve ganglia is suspected., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

About 70% of patients with idiopathic membranous nephropathy (iMN) have autoantibodies to the phospholipase A2 receptor PLA2R1. We screened sera from iMN patients for their cross-reactivity to human (h), rabbit (rb) and mouse (m) PLA2R1 by western blot (WB) and antigen-specific ELISAs. All iMN patients recognized hPLA2R1 and rbPLA2R1 by WB, and a rbPLA2R1 ELISA was as sensitive as the standardized hPLA2R1 ELISA to monitor anti-PLA2R1 in patients with active disease or in drug-induced remission. In contrast, only 51% of patients were reactive to mPLA2R1 by WB, and a maximum of 78% were weakly to highly positive in the mPLA2R1 ELISA, suggesting that iMN patients exhibit different subsets of anti-PLA2R1 autoantibodies against epitopes that are shared or not among PLA2R1 orthologs. In a cohort of 41 patients with a mean follow-up of 42 months from anti-PLA2R1 assay, the detection of anti-mPLA2R1 autoantibodies was an independent predictor of clinical outcome in multivariate analysis (p = 0.009), and a ROC curve analysis identified a threshold of 605 RU/mL above which 100% of patients (12 patients) had a poor renal outcome (p < 0.001). A similar threshold could not be defined in hPLA2R1 and rbPLA2R1 ELISAs. We conclude that rbPLA2R1 is an alternative antigen to hPLA2R1 to measure anti-PLA2R1 in active disease while mPLA2R1 is a unique antigen that can detect a subset of anti-PLA2R1 autoantibodies present at high levels (>605 RU/mL) only in iMN patients at risk of poor prognosis, and is thus useful to predict iMN outcome., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Importance: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear., Objective: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence., Design, Setting, and Participants: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers., Interventions: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement., Main Outcomes and Measures: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications., Results: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients., Conclusions and Relevance: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation., Trial Registration: clinicaltrials.gov Identifier: NCT00457158.

Emerging infectious diseases can induce rapid changes in population dynamics and threaten population persistence. In socially structured populations, the transfers of individuals between social units, for example, from breeding groups to non-breeding groups, shape population dynamics. We suggest that diseases may affect these crucial transfers. We aimed to determine how disturbance by an emerging disease affects demographic rates of gorillas, especially transfer rates within populations and immigration rates into populations. We compared social dynamics and key demographic parameters in a gorilla population affected by Ebola using a long-term observation data set including pre-, during and post-outbreak periods. We also studied a population of undetermined epidemiological status in order to assess whether this population was affected by the disease. We developed a multistate model that can handle transition between social units while optimizing the number of states. During the Ebola outbreak, social dynamics displayed increased transfers from a breeding to a non-breeding status for both males and females. Six years after the outbreak, demographic and most of social dynamics parameters had returned to their initial rates, suggesting a certain resilience in the response to disruption. The formation of breeding groups increased just after Ebola, indicating that environmental conditions were still attractive. However, population recovery was likely delayed because compensatory immigration was probably impeded by the potential impact of Ebola in the surrounding areas. The population of undetermined epidemiological status behaved similarly to the other population before Ebola. Our results highlight the need to integrate social dynamics in host-population demographic models to better understand the role of social structure in the sensitivity and the response to disease disturbances., (© 2014 The Authors. Journal of Animal Ecology © 2014 British Ecological Society.)

Introduction: Thrombosis and inflammation are intimately linked. Inflammatory component of venous thromboembolism (VTE) may allow the use of FDG positron emission tomography / computed tomography (FDG PET/CT) in the detection of thrombotic process. Published studies remain limited and contradictory. We aimed at evaluating the performance of FDG PET/CT in the detection of VTE in a population of patients enrolled in a prospective study evaluating FDG PET/CT for cancer screening in etiological assessment of idiopathic VTE., Materials and Methods: The first consecutive 100 patients who underwent FDG PET/CT were included. Visual and quantitative analyses of vascular axes was performed and compared with lower limb veins compression ultrasonography, lung scintigraphy and/or computed tomography pulmonary angiography., Results: Out of the 100 patients, 63 presented lobar pulmonary embolism for a total of 217 embolic sites and 62 had a deep vein thrombosis for a total of 143 thrombotic sites. Regarding pulmonary embolism, sensitivity and specificity of FDG PET/CT were 3% (95%CI: 1-6%) and 99% (95%CI: 98-100%). SUV max ratio between pulmonary embolism location and non-pathological contralateral vessel was 1.04±0.18 (p=0.7). Regarding deep vein thrombosis, sensitivity and specificity were 31% (95%CI: 24-39%) and 88% (95%CI: 81-92%). The metabolic activity was significantly higher than in contralateral vessels (p<0.001), with a SUV max ratio of 1.25±0.53, but without any significant SUVmax threshold applicable in routine practice for deep vein thrombosis diagnosis., Conclusions: FDG PET/CT is not accurate enough for the diagnosis of VTE., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Disease phenotype reorganizations are the consequences of signaling pathway perturbations and protein abundance modulations. Characterizing the protein signature of a biological event allows the identification of new candidate biomarkers, new targets for treatments and selective patient therapy. The combination of discovery LC-MS/MS analyses and targeted mass spectrometry using selected reaction monitoring (SRM) mode has emerged as a powerful technology for biomarker identification and quantification owing to faster development time and multiplexing capability. The epithelial-mesenchymal transition (EMT) is a process that controls local invasion and metastasis generation by stimulating changes in adhesion and migration of cells but also in metabolic pathways. In this study, the non-transformed human breast epithelial cell line MCF10A, treated by TGFβ or overexpressing mutant K-Ras(v12), two EMT inducers frequently involved in cancer progression, was used to characterize protein abundance changes during an EMT event. The LC-MS/MS analysis and label-free quantification revealed that TGFβ and K-Ras(v12) induce a similar pattern of protein regulation and that besides the expected cytoskeletal changes, a strong increase in the anabolism and energy production machinery was observed., Biological Significance: To our knowledge, this is the first proteomic analysis combining a label-free quantification with an SRM validation of proteins regulated by TGFβ and K-Rasv12. This study reveals new insights in the characterization of the changes occurring during an epithelial-mesenchymal transition (EMT) event. Notably, a strong increase in the anabolism and energy production machinery was observed upon both EMT inducers., (Copyright © 2014. Published by Elsevier B.V.)

Reliable transmission of acoustic information about individual identity is of critical importance for pair bond maintenance in numerous monogamous songbirds. However, information transfer can be impaired by environmental constraints such as external noise or propagation-induced degradation. Birds have been shown to use several adaptive strategies to deal with difficult signal transmission contexts. Specifically, a number of studies have suggested that vocal plasticity at the emitter's level allows birds to counteract the deleterious effects of sound degradation. Although the communication process involves both the emitter and the receiver, perceptual plasticity at the receiver's level has received little attention. Here, we explored the reliability of individual recognition by female zebra finches (Taeniopygia guttata), testing whether perceptual training can improve discrimination of degraded individual vocal signatures. We found that female zebra finches are proficient in discriminating between calls of individual males at long distances, and even more so when they can train themselves with increasingly degraded signals over time. In this latter context, females succeed in discriminating between males as far as 250 m. This result emphasizes that adaptation to adverse communication conditions may involve not only the emitter's vocal plasticity but also the receptor's decoding process through on-going learning., (© 2014. Published by The Company of Biologists Ltd.)

Knee orthotic devices are commonly prescribed by physicians and medical practitioners for preventive or therapeutic purposes with the aim of supporting, aligning or immobilising the joint. However, the evaluation of these devices relies on few biomechanical studies or therapeutic trials and the level of their mechanical actions remain unclear. The objectives of this work are to develop and validate an experimental testing machine regarding its realism as compared to a standardised human limb by using a finite element approach, and then to use this machine to characterise the efficiency of different categories of orthoses under different pathological kinematics and investigate the influence of various design characteristics. It was found that the measured mechanical actions should be corrected to compensate for the rigid design of the test machine. Experimental results showed that the tested orthoses highly differed in their ability to restrain motions and that the stiffening effects of these devices may be able to compensate for deficient internal structures only under low load. Although results remain to be confronted to clinical evidence, this approach paves the way to a standardised procedure for evaluating knee orthoses and developing new designs., (© IMechE 2014.)

Background: Quality of life (QoL) is recognized internationally as an efficient tool for evaluating health interventions. To our knowledge, QoL has not been specifically assessed in children after neonatal arterial ischemic stroke (AIS)., Aim: To study the QoL of early school-aged children who suffered from neonatal AIS, and QoL correlation to functional outcome., Method: We conducted a multicenter prospective cohort study as part of a larger study in full-term newborns with symptomatic AIS. Participating families were sent anonymous QoL questionnaires (QUALIN). Functional outcome was measured using the Wee-FIM scale. Healthy controls in the same age range were recruited in public schools. Their primary caregivers filled in the QUALIN questionnaires anonymously. We used Student's t-test and a rank test to compare patients and controls' QoL and functional outcomes., Results: 84 children with neonatal AIS were included. The control group was composed of 74 children, of which ten were later excluded due to chronic conditions. Mean ages and QUALIN median scores did not differ between patients and controls. Median Wee-FIM scores were lower in hemiplegic children than in non-hemiplegic ones (p < 0.001). QoL scores did not seem correlated to functional outcome., Interpretation: Those results could support the presence of a "disability paradox" in young children following neonatal AIS., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

The systematic microbiological evaluation of endophthalmitis allows the confirmation of the infectious nature of the disease and the possible adaptation of treatment at the individual level and, at the collective level, the epidemiological characterization of the bacterial spectrum of endophthalmitis. Long reserved for research, the use of molecular biology techniques to complement conventional culture techniques has become important for the diagnosis of endophthalmitis in recent years. These new diagnostic techniques are particularly useful for the microbiological study of bacteria that are difficult or impossible to grow because of their intrinsic properties, their presence in only a small inoculum, their sequestration on prosthetic materials, or their inactivation by prior antibiotic treatment. These techniques are based on the polymerase chain reaction (PCR), which allows the amplification and detection of extracted bacterial deoxyribonucleic acid (DNA) that is initially present in minute quantities in an ocular sample. In practice, these conventional or real-time PCRs allow either the a priori detection of bacterial DNA (universal PCR) or the identification of a specific DNA fragment of a bacterial genus or species (specific PCR). New techniques of PCR will allow more rapid bacterial identification and also characterization of genotypic properties, such as genes of virulence or antibiotic resistance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate the survival effects of inferior vena cava filters in patients with venous thromboembolism (VTE) who had a significant bleeding risk., Background: The effectiveness of inferior vena cava filter use among patients with acute symptomatic VTE and known significant bleeding risk remains unclear., Methods: In this prospective cohort study of patients with acute VTE identified from the RIETE (Computerized Registry of Patients With Venous Thromboembolism), we assessed the association between inferior vena cava filter insertion for known significant bleeding risk and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, and VTE rates through 30 days after the initiation of VTE treatment. Propensity score matching was used to adjust for the likelihood of receiving a filter., Results: Of the 40,142 eligible patients who had acute symptomatic VTE, 371 underwent filter placement because of known significant bleeding risk. A total of 344 patients treated with a filter were matched with 344 patients treated without a filter. Propensity score-matched pairs showed a nonsignificant trend toward lower risk of all-cause death for filter insertion compared with no insertion (6.6% vs. 10.2%; p = 0.12). The risk-adjusted PE-related mortality rate was lower for filter insertion than no insertion (1.7% vs. 4.9%; p = 0.03). Risk-adjusted recurrent VTE rates were higher for filter insertion than for no insertion (6.1% vs. 0.6%; p < 0.001)., Conclusions: In patients presenting with VTE and with a significant bleeding risk, inferior vena cava filter insertion compared with anticoagulant therapy was associated with a lower risk of PE-related death and a higher risk of recurrent VTE. However, study design limitations do not imply a causal relationship between filter insertion and outcome., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Rosa chinensis 'Pallida' (Rosa L.) is one of the most important ancient rose cultivars originating from China. It contributed the 'tea scent' trait to modern roses. However, little information is available on the gene regulatory networks involved in scent biosynthesis and metabolism in Rosa. In this study, the transcriptome of R. chinensis 'Pallida' petals at different developmental stages, from flower buds to senescent flowers, was investigated using Illumina sequencing technology. De novo assembly generated 89,614 clusters with an average length of 428bp. Based on sequence similarity search with known proteins, 62.9% of total clusters were annotated. Out of these annotated transcripts, 25,705 and 37,159 sequences were assigned to gene ontology and clusters of orthologous groups, respectively. The dataset provides information on transcripts putatively associated with known scent metabolic pathways. Digital gene expression (DGE) was obtained using RNA samples from flower bud, open flower and senescent flower stages. Comparative DGE and quantitative real time PCR permitted the identification of five transcripts encoding proteins putatively associated with scent biosynthesis in roses. The study provides a foundation for scent-related gene discovery in roses., (Copyright © 2014. Published by Elsevier B.V.)

Aims: The well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure., Methods and Results: All randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67-0.86]) than in those with heart failure (RR = 0.90 [0.78-1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0-1 (RR 0.67 CI 0.57-0.79) than in those with a score ≥2 (RR 0.85 CI 0.74-0.98). Comparison of MB in patients with (RR 0.97 CI 0.79-1.18) and without (RR 0.76 CI 0.65-0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction., Conclusions: NOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.

Background: South Asians are at high risk for chronic kidney disease. However, unlike those in the United States and United Kingdom, laboratories in South Asian countries do not routinely report estimated glomerular filtration rate (eGFR) when serum creatinine is measured. The objectives of the study were to: (1) evaluate the performance of existing GFR estimating equations in South Asians, and (2) modify the existing equations or develop a new equation for use in this population., Study Design: Cross-sectional population-based study., Setting & Participants: 581 participants 40 years or older were enrolled from 10 randomly selected communities and renal clinics in Karachi., Predictors: eGFR, age, sex, serum creatinine level., Outcomes: Bias (the median difference between measured GFR [mGFR] and eGFR), precision (the IQR of the difference), accuracy (P30; percentage of participants with eGFR within 30% of mGFR), and the root mean squared error reported as cross-validated estimates along with bootstrapped 95% CIs based on 1,000 replications., Results: The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation performed better than the MDRD (Modification of Diet in Renal Disease) Study equation in terms of greater accuracy at P30 (76.1% [95% CI, 72.7%-79.5%] vs 68.0% [95% CI, 64.3%-71.7%]; P < 0.001) and improved precision (IQR, 22.6 [95% CI, 19.9-25.3] vs 28.6 [95% CI, 25.8-31.5] mL/min/1.73 m(2); P < 0.001). However, both equations overestimated mGFR. Applying modification factors for slope and intercept to the CKD-EPI equation to create a CKD-EPI Pakistan equation (such that eGFRCKD-EPI(PK) = 0.686 × eGFRCKD-EPI(1.059)) in order to eliminate bias improved accuracy (P30, 81.6% [95% CI, 78.4%-84.8%]; P < 0.001) comparably to new estimating equations developed using creatinine level and additional variables., Limitations: Lack of external validation data set and few participants with low GFR., Conclusions: The CKD-EPI creatinine equation is more accurate and precise than the MDRD Study equation in estimating GFR in a South Asian population in Karachi. The CKD-EPI Pakistan equation further improves the performance of the CKD-EPI equation in South Asians and could be used for eGFR reporting., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Drug-drug interactions may contribute to the variability of the response of clopidogrel. Several hypotheses have been proposed concerning the potential modification of clopidogrel pharmacokinetics and pharmacodynamics by fluoxetine. This open-label crossover study assessed the effect of fluoxetine on the pharmacological activity of clopidogrel in healthy volunteers. Eight healthy male volunteers received a single 600-mg loading dose of clopidogrel followed by 20 mg of fluoxetine on 4 days and then 20 mg of fluoxetine plus 600 mg of clopidogrel on the fifth day. Eleven blood samples were withdrawn after clopidogrel administration to determine plasma concentrations of clopidogrel active metabolite (CAM) and platelet function. Platelet aggregation was measured by light transmittance aggregometry (LTA) and platelet reactivity index by flow cytometric vasodilator-stimulated phosphoprotein (VASP) analysis. The areas under the curve and maximum plasma concentrations of CAM were, respectively, 20.6 and 25.3% lower after co-administration of fluoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values in the presence of 5 μM and 10 μM adenosine diphosphate, measured by LTA, were, respectively, 13.9 and 22.4% lower after fluoxetine co-administration. The platelet reactivity index measured by the flow cytometric VASP method was 36.8% lower when clopidogrel was administered in conjunction with fluoxetine., (© 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Société Française de Pharmacologie et de Thérapeutique.)

Social interactions with adults are often critical for the development of mating behaviours. However, the potential role of other primary social partners such as juvenile counterparts is rarely considered. Most interestingly, it is not known whether interactions with juvenile females improve males' courtship and whether, similar to the winner and loser effects in a fighting context--outcome of these interactions shapes males' behaviour in future encounters. We investigated the combined effects of male quality and juvenile social experience on pairing success at adulthood in zebra finches (Taeniopygia guttata). We manipulated brood size to alter male quality and then placed males in either same- or mixed-sex juvenile dyads until adulthood. We found that males from reduced broods obtained more copulations and males from mixed-sex dyads had more complete courtships. Furthermore, independent of their quality, males that failed to pair with juvenile females, but not juvenile males, had a lower pairing success at adulthood. Our study shows that negative social experience with peers during adolescence may be a potent determinant of pairing success that can override the effects of early environmental conditions on male attractiveness and thereby supports the occurrence of an analogous process to the loser effect in a mating context.

The aim of this study was to show the feasibility and the performances of nanoparticle biosensing. A glucose conductometric biosensor was developed using two types of nanoparticles (gold and magnetic), glucose oxidase (GOD) being adsorbed on PAH (poly(allylamine hydrochloride)) modified nanoparticles, deposited on a planar interdigitated electrode (IDEs). The best sensitivities for glucose detection were obtained with magnetic nanoparticles (70 μM/mM and 3 μM of detection limit) compared to 45 μM/mM and 9 μM with gold nanoparticles and 30 μM/mM and 50 μM with GOD directly cross-linked on IDEs. When stored in phosphate buffer (20 mM, pH 7.3) at 4 °C, the biosensor showed good stability for more than 12 days., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Playback experiments have been a useful tool for studying the function of sounds and the relevance of different sound characteristics in signal recognition in many different species of vertebrates. However, successful playback experiments in sound-producing fish remain rare, and few studies have investigated the role of particular sound features in the encoding of information. In this study, we set-up an apparatus in order to test the relevance of acoustic signals in males of the cichlid Metriaclima zebra. We found that territorial males responded more to playbacks by increasing their territorial activity and approaching the loudspeaker during and after playbacks. If sounds are used to indicate the presence of a competitor, we modified two sound characteristics, that is, the pulse period and the number of pulses, in order to investigate whether the observed behavioural response was modulated by the temporal structure of sounds recorded during aggressive interactions. Modified sounds yielded little or no effect on the behavioural response they elicited in territorial males, suggesting a high tolerance for variations in pulse period and number of pulses. The biological function of sounds in M. zebra and the lack of responsiveness to our temporal modifications are discussed.

Biodiversity is the diversity of life at all scales, from genes to ecosystems. Predicting its patterns of variation across the globe is a fundamental issue in ecology and evolution. Diversity within species, that is, genetic diversity, is of prime importance for understanding past and present evolutionary patterns, and highlighting areas where conservation might be a priority. Using published data on the genetic diversity of species whose populations occur in the Mediterranean basin, we calculated a coefficient of correlation between within-population genetic diversity indices and longitude. Using a meta-analysis framework, we estimated the role of biological, ecological, biogeographic, and marker type factors on the strength and magnitude of this correlation in six phylla. Overall, genetic diversity increases from west to east in the Mediterranean basin. This correlation is significant for both animals and plants, but is not uniformly expressed for all groups. It is stronger in the southern than in the northern Mediterranean, in true Mediterranean plants than in plants found at higher elevations, in trees than in other plants, and in bi-parentally and paternally than in maternally inherited DNA makers. Overall, this correlation between genetic diversity and longitude, and its patterns across biological and ecological traits, suggests the role of two non-mutually exclusive major processes that shaped the genetic diversity in the Mediterranean during and after the cold periods of the Pleistocene: east-west recolonization during the Holocene and population size contraction under local Last Glacial Maximum climate in resident western and low elevation Mediterranean populations.

Sounds produced by male cichlids Metriaclima zebra during aggressive interactions were recorded to conduct a detailed analysis and to search for potential individual acoustic signatures. Fish from two different size groups (small and large individuals) were analysed. The two groups were significantly different for all acoustic variables considered; six of seven features demonstrated a significant interindividual variability and most of them were correlated with the size of the emitter. A cross-validated and permuted discriminant function analysis (pDFA) separated the two groups and correctly classified around 50% of the sounds to the correct individuals. Acoustic features that best distinguished among males were the instantaneous frequency of sounds and the modulation of pulse amplitude. These results suggest that acoustic signals could bear information about individual identity. The long-term stability of this signature is likely to be weak since the signature of a growing individual may change over time., (© 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.)