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Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

Background The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-α-1,3-galactose (α-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-α-Gal IgE before treatment. Methods This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts. Results Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a ≥ 0.525 kU A /L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%). Conclusion Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-α-Gal IgE screening before treatment.

The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-[alpha]-1,3-galactose ([alpha]-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-[alpha]-Gal IgE before treatment. This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts. Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a [greater than or equal to] 0.525 kU.sub.A/L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%). Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-[alpha]-Gal IgE screening before treatment.

ObjectiveHepatic steatosis accompanying obesity is a major health concern, since it may initiate non-alcoholic fatty liver disease (NAFLD) and associated complications like cirrhosis or cancer. Intestinal gluconeogenesis (IGN) is a recently described function that contributes to the metabolic benefits of specific macronutrients as protein or soluble fibre, via the initiation of a gut-brain nervous signal triggering brain-dependent regulations of peripheral metabolism. Here, we investigate the effects of IGN on liver metabolism, independently of its induction by the aforementioned macronutrients.DesignTo study the specific effects of IGN on hepatic metabolism, we used two transgenic mouse lines: one is knocked down for and the other overexpresses glucose-6-phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine.ResultsWe report that mice with a genetic overexpression of IGN are notably protected from the development of hepatic steatosis and the initiation of NAFLD on a hypercaloric diet. The protection relates to a diminution of de novo lipogenesis and lipid import, associated with benefits at the level of inflammation and fibrosis and linked to autonomous nervous system. Conversely, mice with genetic suppression of IGN spontaneously exhibit increased hepatic triglyceride storage associated with activated lipogenesis pathway, in the context of standard starch-enriched diet. The latter is corrected by portal glucose infusion mimicking IGN.ConclusionWe conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.

Riverbank erosion is an essential morphodynamic process for the improvement of river health and the ecohydrogeomorphological functioning of alluvial rivers. Lateral channel dynamics and sediment supply caused by bank erosion largely create and maintain heterogeneous in-channel habitats for fauna and aquatic or riparian plant species. However, humans very early started to stabilize riverbanks in order to favour navigation or to prevent valuable land and infrastructures close to the channel from eroding. During the 20th century, bank protection works such as riprap considerably increased and blocked lateral channel erosion, causing a loss of local sediment supply, which in turn resulted in a decrease in local bedload transport and channel incision. The aim of the article is to evaluate to what extent riprap removal may be an efficient restoration measure in terms of the reactivation of bank erosion and the replenishment of the local bedload in gravel-bed floodplain rivers with a sufficient amount of freedom space. An experimental in situ restoration approach was chosen. First, riprap was removed at two geomorphologically contrasting sites on the Allier River, France. Second, bank retreat was monitored, and the volumes eroded were quantified using photogrammetric and LiDAR surveys. Third, in the case of post-restoration bank erosion, grain size and morphological channel evolution analyses were carried out. Our results suggested that the removal of riprap is an effective measure for certain but not all channelized floodplain reaches. The geomorphological and sedimentary contexts are two criteria that should be considered when selecting sites for restoration. Thus, this study helps river managers to better target the criteria to be taken into account for the selection of sites with high potential for the restoration of lateral channel dynamics.

The purpose of this study is to gather the opinion of experts from the sports/association context on the theme of physical activity for chronically ill patients in the out-of-hospital context. To conduct this study, we used the DELPHI methodology (Dalkey & Helmer, 1963). This method is used to reach a convergence of opinions on a subject with experts from the related field. This methodology consists in a succession of survey submitted to our population of sport experts (n = 62). Every survey is preceded by a feedback about the previous results: in that way experts can answer the following survey taking into account the opinion from the majority of respondents. Surveys have been sent to the expert electronically using SurveyMonkey®. This study contains three consecutive surveys (rounds). Each survey has been validated by the Content Validity Index (CVI) methodology to assess the relevance and the clarity of statements (Rubio et al., 2003). Each steps of the DELPHI process have been segmented in six sections: participants, stakeholders, communication/transition, type of activity, financial aspects and motivation. After the three rounds of the DELPHI a consensus has been reached for every section of the survey (more than 60% of approval on the topic). 81% of the experts agreed that assessments were needed for participants before taking part in sport activities. 63% of the experts agreed that stakeholders needed at least a bachelor’s degree in sport sciences to supervise activities. 75% agreed that the groups must be rather small (4-5 persons). 78% agreed that participants have to pay, at least partly, for their participation. 81% agreed that social interactions are the main motivational factor of out-of-hospital sport activity among those participants. Despite several limitations, this study led to encouraging results concerning the development of physical activities for chronically ill patient in out of hospital context. We believe that these results will enable sports associations to have a basis for developing “sport-health” activities, tailored to the local context. In the other hand, we also believe that our research will raise awareness of the role of local specialists in physical activity promotion among this type of population.

The introduction of a commitments procedure in EU antitrust policy (Article 9 of Council Regulation 1/2003) has entitled the the European Commission to extensively settle cases of alleged anticompetitive conduct. In this paper, we use a formal model of law enforcement to identify the optimal procedure to remedy cases in a context of partial legal uncertainty (Katsoulacos and Ulph in Eur J Law Econ 41(2):255–282, 2016). We discuss in particular the merits of a policy of selective commitments where firms either take strong commitments or are investigated under the standard infringement procedure.

Background The community pharmacist is a key player in medication reviews of older outpatients. However, it is not always clear which individuals require a medication review. The objective of the present study was to identify high-priority older patients for intervention by a community pharmacist. Methods As part of their final-year placement in a community pharmacy, pharmacy students conducted 10 interviews each with older adults (aged 65 or over) taking at least five medications daily. The student interviewer also offered to examine the patient’s home medicine cabinet. An interview guide was developed by an expert group to assess the difficulties in managing and taking medications encountered by older patients. Results The 141 students interviewed a total of 1370 patients (mean age: 81.5; mean number of medications taken daily: 9.3). Of the 1370 interviews, 743 (54.2%) were performed in the patient’s home, and thus also included an examination of the home medicine cabinet. Adverse events were reported by 566 (42.0%) patients. A total of 378 patients (27.6%) reported difficulties in preparing, administering and/or swallowing medications. The inspections of medicine cabinets identified a variety of shortcomings: poorly located cabinets (in 15.0% of inspections), medication storage problems (21.7%), expired medications (40.7%), potentially inappropriate medications (15.0%), several different generic versions of the same drug (19.9%), and redundant medications (20.4%). Conclusions In a community pharmacy setting, high-priority older patients for intervention by a community pharmacist can be identified by asking simple questions about difficulties in managing, administering, taking or storing medications.

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3 signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.