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Abstract Objective No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse‐associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. Methods Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score‐matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan–Meier curves were used to show cumulative probabilities of reaching outcomes. Results In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score‐matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab‐ and 10 ocrelizumab‐treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab‐ and 15 ocrelizumab‐treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59–1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57–2.66; p = 0.60) and 6.0 (0.93, 0.32–2.68; p = 0.89). Interpretation Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

Objective. Gait impairment is commonly in people with multiple sclerosis (MS). The 12-item MS walking scale (MSWS-12) assesses patients’ measurement of walking quality. The aim of this study was to cross-culturally adapt and validate the MSWS-12 for the Italian population with MS. Methods. Six MS out-patient clinics across Italy enrolled subjects between June 2013 and December 2013. Construct validity of MSWS-12 was determined by examining correlations with the Italian version of the EDSS, the timed 25-foot walk (T25FW), and the Fatigue Severity Scale (FSS). Results. 321 MS subjects were enrolled. Mean age was 47.55 years and mean disease duration was 13.8 years. Mean EDSS score was 4.46. 185 subjects had a relapsing-remitting course, 92 were secondary progressive, 43 were primary progressive, and 1 had a clinically isolated syndrome. The mean total score of the MSWS-12 was 49.6 (SD: 31) with values ranging between 0 and 100. Correlations between the MSWS-12 with age, disease duration, and disease course were found but not with gender. Values of the MSWS-12/IT were significantly related to EDSS (0.71), to the T25FW (0.65), and to the FSS (0.51). Conclusion. MSWS-12/IT has been adapted and validated, it is a reliable and reproducible scale for Italian patients with MS.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Background and purposeClinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.MethodLogistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.ResultsFrom March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p

The role of emotions in learning has been the focus of much debate in teaching circles, as has the question of discussing controversial issues in the classroom. The aim of this small-scale inquiry was to investigate how two groups of intermediate level students of French as a foreign language expressed emotion in discussing the controversial issue of veganism. Our analysis focuses on the notions of 'emotion lexicon' and 'rich point' in exploring the video recordings of two classes engaged in discussion. We highlight how the students used a range of means to contribute to the discussion; their emotion lexicon appeared to be relatively limited but they made use of interactional and non-verbal means and communicated their feelings through the exchange of personal anecdotes and testimonies. We frame our approach within the tenets of critical pedagogy, and show how discussion of a controversial issue can trigger students' engagement and further reflection. We conclude by emphasising the important role of the teacher, probably best fulfilled as a neutral guide in the discussion.

Background and purposeSome studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS.MethodsData were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity.ResultsIn all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009).ConclusionsEven if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

Being two immune-mediated diseases (IMIDs), the association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is plausible, but data in the literature are conflicting. The aim of our study was to evaluate the possible association between IBD and MS in a cohort of patients with IBD. In a retrospective study, we examined the medical records of 5739 patients with a confirmed diagnosis of IBD followed in our clinic between 1978 and 2022. Among these patients, we identified 14 with MS, with a prevalence of 0.24%. The reported prevalence of MS in the general population in Northern Italy in 2021 was 0.18% (p = 0.24). For each of the patients with MS identified, more than ten patients without MS were analyzed. The 14 MS cases were then compared with 342 controls. From the 14 patients with MS, 12 (85.7%) were female and 2 (14.3%) were male, while in the control group, 158 (46.2%) were female and 184 (53.8%) were male (p = 0.004). As for therapy, significant differences were found in mesalazine (5 (41.7%) cases vs. 317 (92.7%) controls, p < 0.0001) and anti-TNF treatment (0% cases vs. 26.6% controls, p = 0.03, respectively) at the time of MS diagnosis. Moreover, a Kaplan–Meier curve analysis showed that the 20-year survival probability was 98.4% for patients with IBD, while for patients diagnosed with MS and IBD it was 82.1% (p = 0.02). In conclusion, patients with IBD have a similar risk of developing MS compared to the general population, but female sex appears to increase the risk. Indeed, life expectancy at 20 years for patients with IBD and MS is lower than for patients with IBD alone.

Abstract Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS.

BackgroundThe debate on how to manage women affected by multiple sclerosis (MS) during reproductive age is still open, as is the issue of fertility in such patients. Main issue regard the identification of the optimal window for pregnancy and how to deal with medical therapy before and during conception. The aim of this Delphi consensus was to collect the opinions of a multidisciplinary group, involving reproductive medicine specialists and neurologists with experience in the management of multiple sclerosis women with reproductive desire.MethodsFour experts plus scientific coordinators developed a questionnaire distributed online to 10 neurologists and later discussed the responses and amended a list of statements. The statements were then distributed via an online survey to 23 neurologists (comprising the first 10), who voted on their level of agreement/disagreement with each statement. Consensus was achieved if agreement or disagreement with a statement exceeded 66%.ResultsTwenty-one statements reached consensus after two rounds of voting, leading to the following main recommendations: (1) Fertility evaluation should be suggested to wMS, in case of the need to shorten time to pregnancy and before treatment switch in women on DMTs contraindicated in pregnancy, particularly in case of highly active disease and age > 35 years. (2) ART should not be discouraged in wMS, but the use of DMTs until pregnancy confirmation should be suggested; ART may be considered in order to reduce time to pregnancy in MS women with a reduced ovarian reserve and/or age > 35 years, but in case of an expected poor ART prognosis and the need for more than one ART cycle, a switch to a high-efficacy DMD before ART should be offered. (3) Oocyte cryopreservation may be considered in women with reduced ovarian reserve, with unpredictable time to complete diagnostic workup and achieve disease control; a risk/cost–benefit analysis must be performed in women >35 years, considering the diminished ovarian reserve.ConclusionThis consensus will help MS neurologists to support family planning in wMS, respecting MS therapeutic needs while also taking into account the safety and impact of advancing age on fertility.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

This article describes two experiments on the teaching of the lexicon of affects in FFL (French as a Foreign Language) class with Mongolian students of A2 and B1 accordinge to the Common European Framework of Reference for Languages (CECRL, 2001) in Mongolia. Recent works in semantics, as in other disciplines, underlines the specificities of the lexicon of affects and feelings (cf. Grossmann & Tutin, 2005). The frequency of use of this lexicon makes it important in the field of foreign language didactics. We will be reflecting the teaching of this lexicon to learners of French as a foreign language and to suggest ways to overcome the particular difficulties that such a teaching method raises. The underlying hypothesis of this work is twofold: (1) the teaching of this lexicon should enable learners to better write fictional texts in which the characters feel emotions (2) To express the variety, the subtlety and the intensity of the emotions felt, it is necessary to have a imaged vocabulary and expressions based on collocations, idioms or metaphorical constructions wich allow to set up an atmosphere related to the taught emotion (see Boch & Cavalla, 2005 ; Berdal-Masuy, 2015 ; Cavalla, 2015). Of course, it should be noted that we are not discussing of an exhaustive teaching of all these expressions. The educational objectives of the sequences are (1) the acquisition of expressions of emotions; (2) the distinction of different mood elements from expressions of emotions (« fantôme » [ghost], « avoir la chair de poule » [having goose bumps], for example); (3) improving the setting in text of emotions. The purpose of these courses is therefore to improve the learners’ use of the vocabulary of emotions - affects for the description of the emotions of the characters, during written tasks. Having this in mind, we introduced a set of vocabulary explaining fear and sadness from audio and audiovisual media, to put learners in the mood of those affects. These documents made it possible for the learners to be first aware of this emotion, as well as a reminder of their previous knowledge of the lexicon related to it. This approach is innovative as soon as the teacher takes into account the psychological aspect of the introduction of this type of lexicon into a language class. This is to encourage the learners to produce a speech by appealing to the atmosphere previously created and the feelings of their own culture. The expressions of feelings discussed in this work are of three types: (1) The lexicon of affects: « inquiétude, angoisse » [anxiety, distress] (2) The collocations: « être submergée de joie » [to be overwhelmed with joy] (Tutin et al., 2006) (3) The idioms: « il a la gorge nouée » [he felt a lump in his throat](Cavalla et al., 2005) The analysis proposed by Grossmann et al. (2006) of these three categories of expressions through literary corpus serves as a support in the present work for the creation of scenarios for the teaching of this lexicon. These experiments have creative introduction of an atmosphere around the evoked emotions: fear and sadness, we will show how students articulate learned lexicon and description of an atmosphere to detect the taught emotion. In addition, the texts produced reveal a certain creativity from the learners’ side, but also significant cultural aspects for the expression of emotions. We will attempt here to explain these phenomena in terms of the results of text analysis both quantitative aspects (statistics of use of words) and qualitative aspects (linguistic analysis of texts). A quantitative analysis of the learners’ productions at the end of the pedagogical sequences validates their achievements (see Boch & Cavalla, 2005). This analysis is summarized by the diagrams of Figures 1 and 2 and by Table 1, which synthesizes them. A qualitative analysis makes it possible to observe ease and difficulties in writing texts that effectively express the emotions studied by comparing them. This comparison allows us to address the cultural aspects inherent to this specific the lexicon of affects by comparing in particular the universal physiological manifestations and the cultural influences relating to each of the chosen emotions. We observe several metaphors that are likely to be direct translations from Mongolian into French (for example “he shouted to the world again” to express the sadness), but which are quite inappropriate to express the emotion sought in French. The use of such tropes reveals the desire for creativity that lack of linguistic knowledge cannot be accepted in French. As Iordanskaja’s (1986) work for Russian clearly shows, the metaphorical expressions describing the symptoms of emotions can vary widely from one culture to another, especially when expressions refer to social manifestations rather than to physiological manifestations. However, this variation mainly informs the cultural differences that can exist between two languages (see Wierzbicka, 1993, for a comparison between Russian and English). Considering the above, and despite cultural differences in emotional evaluation (Scherer & Brosch, 2009), the physiological manifestations of these emotions are universal (Scherer, 1986). It could therefore be easier for a learner to grasp the meaning of a metaphorical expression denoting the physical symptom of an emotion that he has already been able to experience himself and/or for which he could have seen a talking image (cold sweat, shaking like a leaf), rather than remembering an abstract sign (to feel blue) almost never use expressions involving the body. In a result, during micro-productions exercises performed during the two sequences, students spontaneously proposed free expressions intended to express the taught emotion, expressions translated directly from Mongol: they were imaged expressions that did not work in French, but whose motivation was clear. From this point of view, the lexicon of sadness, with few references to physical manifestations of emotion, could be more complex to integrate and therefore be at the root of some of the difficulties encountered by learners to use it in a proper context. In conclusion of this work, we will emphasize the importance of the setting in text to develop the expression of affects in the writing: the terms must be used in contexts that are appropriate to be interpreted correctly. Therefore, if the mastery of a minimum number of vocabulary is required, it does not seem necessary to control a large number, but rather to learnthe lexical associations of the affects studied and where and how to use it: find “the right place at the right time” - and this is especially true in writing. On the other hand, similarities and cultural differences can be an interesting subject to study in order to set up a lexicon of affects -feelings that allows learners to grasp the subtle variations of meaning. For that, the emotional frameworks proposed by Cavalla (2015), can be a powerful tool to present the atmosphere related to the lexicon of the taught emotion. Once some semantic concepts are well assimilated by the learners, it will be possible to focus on the text in order to better make them work the coherence of their writings. An effective teaching method of the lexicon of affects-feelings will have to suggest a specific educational program for each type of affect. The method will have to be able to insist more or less on the different aspects of the vocabulary: it will be important to produce sequences adapted to each affect, considering the cultural aspect of this specific lexicon, the ambiances which are culturally related, the frequency of use of this or that expression by a native speaker, the possible descriptions of physical manifestations and the more or less universal character of the concepts used, depending on the languages ​​and cultures of the learners.

The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.

The release of the prototypic DAMP High Mobility Group Box 1 (HMGB1) into extracellular environment and its binding to the Receptor for Advanced Glycation End Products (RAGE) has been described to trigger sterile inflammation and regulate healing outcome. However, their role on host response to Ti-based biomaterials and in the subsequent osseointegration remains unexplored. In this study, HMGB1 and RAGE inhibition in the Ti-mediated osseointegration were investigated in C57Bl/6 mice. C57Bl/6 mice received a Ti-device implantation (Ti-screw in the edentulous alveolar crest and a Ti-disc in the subcutaneous tissue) and were evaluated by microscopic (microCT [bone] and histology [bone and subcutaneous]) and molecular methods (ELISA, PCR array) during 3, 7, 14, and 21 days. Mice were divided into 4 groups: Control (no treatment); GZA (IP injection of Glycyrrhizic Acid for HMGB1 inhibition, 4 mg/Kg/day); RAP (IP injection of RAGE Antagonistic Peptide, 4 mg/Kg/day), and vehicle controls (1.5% DMSO solution for GZA and 0.9% saline solution for RAP); treatments were given at all experimental time points, starting 1 day before surgeries. HMGB1 was detected in the Ti-implantation sites, adsorbed to the screws/discs. In Control and vehicle groups, osseointegration was characterized by a slight inflammatory response at early time points, followed by a gradual bone apposition and matrix maturation at late time points. The inhibition of HMGB1 or RAGE impaired the osseointegration, affecting the dynamics of mineralized and organic bone matrix, and resulting in a foreign body reaction, with persistence of macrophages, necrotic bone, and foreign body giant cells until later time points. While Control samples were characterized by a balance between M1 and M2-type response in bone and subcutaneous sites of implantation, and also MSC markers, the inhibition of HMGB1 or RAGE caused a higher expression M1 markers and pro-inflammatory cytokines, as well chemokines and receptors for macrophage migration until later time points. In conclusion, HMGB1 and RAGE have a marked role in the osseointegration, evidenced by their influence on host inflammatory immune response, which includes macrophages migration and M1/M2 response, MSC markers expression, which collectively modulate bone matrix deposition and osseointegration outcome.

Background. Takotsubo syndrome (TTS) is characterized by acute transient, stress-induced, left ventricular systolic dysfunction, generally presenting with apical ballooning. It can mimic an acute coronary syndrome, but with a milder increase in cardiac enzymes and without culprit coronary artery disease on angiography. Data on long-term follow-up and survival in patients with TTS, compared with patients with ST-elevation myocardial infarction (STEMI), are scarce. Purpose. To assess all-cause mortality rate and survival in a consecutive series of female patients with TTS compared with age- and sex-matched STEMI patients on long-term follow-up. Methods and Results. We collected data of 65 TTS female patients (TTS group) with a mean age of 73.42 ± 11.35 years from 2001 to 2013. Collection of follow-up information was concluded for all patients in 2016. To compare the mortality and survival of TTS patients with those of the STEMI population, we used data from our STEMI Registry, a prospective registry of 7446 STEMI patients admitted from 2001 to 2013 to our cath-lab for primary percutaneous coronary intervention (p-PCI). From the registry, we selected 104 STEMI patients (STEMI group) comparable to our TTS group in terms of age (mean age of 72.33 ± 11.92 years) and sex. On follow-up examination after a median of 1000 days, the TTS group had a lower all-cause mortality rate than the STEMI group (7.69% versus 23.08%). This difference was statistically different between the two groups (log-rank test, p value = 0.03). Conclusions. In our study, TTS and STEMI patients displayed a statistically significant difference in long-term survival. Specifically, the TTS group had a lower mortality rate than the STEMI group. This seems to suggest that TTS and STEMI are two different clinical entities with two different clinical outcomes.

Bone healing depends of a transient inflammatory response, involving selective migration of leukocytes under the control of chemokine system. CCR2 has been regarded as an essential receptor for macrophage recruitment to inflammation and healing sites, but its role in the intramembranous bone healing on craniofacial region remains unknown. Therefore, we investigated the role of CCR2 on F4/80+ cells migration and its consequences to the intramembranous healing outcome. C57BL/6 wild-type (WT) and CCR2KO mice were subjected to upper right incisor extraction, followed by micro-computed tomography, histological, immunological, and molecular analysis along experimental periods. CCR2 was associated with F4/80+ cells influx to the intramembranous bone healing in WT mice, and CCR2+ cells presented a kinetics similar to F4/80+ and CCR5+ cells. By contrast, F4/80+ and CCR5+ cells were significantly reduced in CCR2KO mice. The absence of CCR2 did not cause major microscopic changes in healing parameters, while molecular analysis demonstrated differential genes expression of several molecules between CCR2KO and WT mice. The mRNA expression of TGFB1, RUNX2, and mesenchymal stem cells markers (CXCL12, CD106, OCT4, NANOG, and CD146) was decreased in CCR2KO mice, while IL6, CXCR1, RANKL, and ECM markers (MMP1, 2, 9, and Col1a2) were significantly increased in different periods. Finally, immunofluorescence and FACS revealed that F4/80+ cells are positive for both CCR2 and CCR5, suggesting that CCR5 may account for the remaining migration of the F4/80+ cells in CCR2KO mice. In summary, these results indicate that CCR2+ cells play a primary role in F4/80+ cells migration along healing in intramembranous bones, but its deficiency does not critically impact healing outcome.

Abstract Despite the successful clinical application of titanium (Ti) as a biomaterial, the exact cellular and molecular mechanisms responsible for Ti osseointegration remains unclear, especially because of the limited methodological tools available in this field. Objective: In this study, we present a microscopic and molecular characterization of an oral implant osseointegration model using C57Bl/6 mice. Material and Methods: Forty-eight male wild-type mice received a Ti implant on the edentulous alveolar crest and the peri-implant sites were evaluated through microscopic (μCT, histological and birefringence) and molecular (RealTimePCRarray) analysis in different points in time after surgery (3, 7, 14 and 21 days). Results: The early stages of osseointegration were marked by an increased expression of growth factors and MSC markers. Subsequently, a provisional granulation tissue was formed, with high expression of VEGFb and earlier osteogenic markers (BMPs, ALP and Runx2). The immune/inflammatory phase was evidenced by an increased density of inflammatory cells, and high expression of cytokines (TNF, IL6, IL1) chemokines (CXCL3, CCL2, CCL5 and CXC3CL1) and chemokine receptors (CCR2 and CCR5). Also, iNOS expression remained low, while ARG1 was upregulated, indicating predominance of a M2-type response. At later points in time, the bone matrix density and volume were increased, in agreement with a high expression of Col1a1 and Col21a2. The remodelling process was marked by peaks of MMPs, RANKL and OPG expression at 14 days, and an increased density of osteoclasts. At 21 days, intimate Ti/bone contact was observed, with expression of final osteoblast differentiation markers (PHEX, SOST), as well as red spectrum collagen fibers. Conclusions: This study demonstrated a unique molecular view of oral osseointegration kinetics in C57Bl/6 mice, evidencing potential elements responsible for orchestrating cell migration, proliferation, ECM deposition and maturation, angiogenesis, bone formation and remodeling at the bone-implant interface in parallel with a novel microscopic analysis.