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Jean Marc Guilé,1,2,3 Laure Boissel,1,2 Stéphanie Alaux-Cantin,1,2 Sébastien Garny de La Rivière1 1Child and Adolescent Psychiatry Services, Amiens-Picardie University Medical Centre, Amiens, France; 2Psychiatry Residency Program, University of Picardie-Jules Verne, Amiens, France; 3Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract: Using the same Diagnostic and Statistical Manual of Mental Disorders, fifth version (DSM-V) criteria as in adults, borderline personality disorder (BPD) in adolescents is defined as a 1-year pattern of immature personality development with disturbances in at least five of the following domains: efforts to avoid abandonment, unstable interpersonal relationships, identity disturbance, impulsivity, suicidal and self-mutilating behaviors, affective instability, chronic feelings of emptiness, inappropriate intense anger, and stress-related paranoid ideation. BPD can be reliably diagnosed in adolescents as young as 11 years. The available epidemiological studies suggest that the prevalence of BPD in the general population of adolescents is around 3%. The clinical prevalence of BPD ranges from 11% in adolescents consulting at an outpatient clinic to 78% in suicidal adolescents attending an emergency department. The diagnostic procedure is based on a clinical assessment with respect to developmental milestones and the interpersonal context. The key diagnostic criterion is the 1-year duration of symptoms. Standardized, clinician-rated instruments are available for guiding this assessment (eg, the Diagnostic Interview for Borderlines-Revised and the Childhood Interview for DSM-IV-TR BPD). The assessment should include an evaluation of the suicidal risk. Differential diagnosis is a particular challenge, given the high frequency of mixed presentations and comorbidities. With respect to clinical and epidemiological studies, externalizing disorders in childhood constitute a risk factor for developing BPD in early adolescence, whereas adolescent depressive disorders are predictive of BPD in adulthood. The treatment of adolescents with BPD requires commitment from the parents, a cohesive medical team, and a coherent treatment schedule. With regard to evidence-based medicine, psychopharmacological treatment is not recommended and, if ultimately required, should be limited to second-generation antipsychotics. Supportive psychotherapy is the most commonly available first-line treatment. Randomized controlled trials have provided evidence in favor of the use of specific, manualized psychotherapies (dialectic-behavioral therapy, cognitive analytic therapy, and mentalization-based therapy). Keywords: borderline personality, adolescence, prevalence, assessment, treatment

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2 LD ) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc., Objective: We aimed to assess the safety and biological efficacy of IL-2 LD in patients with SSc., Methods: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6., Results: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4 + T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2 LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period., Conclusion: IL-2 LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2 LD therapeutic efficacy in SSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc., Methods: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors., Results: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence., Conclusions: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: EPHB4 loss of function is associated with type 2 capillary malformation-arteriovenous malformation syndrome, an autosomal dominant vascular disorder. The phenotype partially overlaps with hereditary haemorrhagic telangiectasia (HHT) due to epistaxis, telangiectases and cerebral arteriovenous malformations, but a similar liver involvement has never been described., Methods: Members of the French HHT network reported their cases of EPHB4 mutation identified after an initial suspicion of HHT. Clinical, radiological and genetic characteristics were analysed., Results: Among 21 patients with EPHB4 , 15 had a liver imaging, including 7 with HHT-like abnormalities (2 female patients and 5 male patients, ages 43-69 years). Atypical epistaxis and telangiectases were noted in two cases each. They were significantly older than the eight patients with normal imaging (median: 51 vs 20 years, p<0.0006).The main hepatic artery was dilated in all the cases (diameter: 8-11 mm). Six patients had hepatic telangiectases. All kind of shunts were described (arteriosystemic: five patients, arterioportal: two patients, portosystemic: three patients). The overall liver appearance was considered as typical of HHT in six cases.Six EPHB4 variants were classified as pathogenic and one as likely pathogenic, with no specific hot spot., Conclusion: EPHB4 loss-of-function variants can be associated with HHT-like hepatic abnormalities and should be tested for atypical HHT presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to describe the health status of children and how social deprivation affects their use of healthcare services and mortality. Children living in mainland France were selected from the national health data system (SNDS) on their date of birth or birthday in 2018 (< 18 years) and followed for one year. Information included data on healthcare reimbursements, long-term chronic diseases (LTDs) eligible for 100% reimbursement, geographic deprivation index (FDep) by quintile (Q5 most disadvantaged), and individual complementary universal insurance (CMUc) status, granted to households with an annual income below the French poverty level. The number of children who had at least one annual visit or hospital admission was compared using the ratio of geographic deprivation (rQ5/Q1) and CMUc (rCMUc/Not) after gender and age-standardization. Over 13 million children were included; 17.5% had CMUc, with an increase across quintiles (rQ5/Q1 = 3.5) and 4.0% a LTD (rQ5/Q1 = 1.44). The 10 most frequent LTDs (6 psychiatric) were more common as the deprivation increased. Visits to general practitioners (GPs) were similar (≈84%) for each FDep quintile and the density of GPs similar. The density decreased with increasing deprivation for specialists and visits: paediatricians (rQ5/Q1 = 0.46) and psychiatrists (rQ5/Q1 = 0.26). Dentist visits also decreased (rQ5/Q1 = 0.86) and deprived children were more often hospitalised for dental caries (rQ5/Q1 = 2.17, 2.1% vs 0.7%). Emergency department (ED) visits increased with deprivation (rCMUc/Not = 1.35, 30% vs 22%) but 50% of CMUc children lived in a municipality with an ED vs. 25% without. Approximately 9% of children were admitted for a short stay and 4.5% for a stay > 1 night (rQ5/Q1 = 1.44). Psychiatric hospitalization was more frequent for children with CMUc (rCMUc/Not = 3.5, 0.7% vs 0.2%). Higher mortality was observed for deprived children < 18 years (rQ5/Q1 = 1.59). Our results show a lower use of pediatricians, other specialists, and dentists among deprived children that may be due, in part, to an insufficient supply of care in their area of residence. These results have been used to recommend optimization and specifically adapted individual or area-wide policies on the use of healthcare services, their density, and activities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pergeline et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis-associated Raynaud's phenomenon (SSc-RP) episodes than placebo., Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test., Results: The intent-to-treat analysis included 46 BTA-treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change -1 episode/day [interquartile range (IQR) -1.5, 0 episodes/day] and -1 episode/day [IQR -2.5, 0 episodes/day], respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow-up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003)., Conclusion: Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc-RP., (© 2022 American College of Rheumatology.)

Objective: To observe the real-world utilization patterns, effectiveness and safety profile of follitropin delta in women ≥18 years naïve to ovarian stimulation undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)., Design: Prospective, multinational, multicenter, observational study. All IVF/ICSI treatment protocols were conducted according to routine clinical practice, including undertaking fresh/frozen transfers. Outcomes included use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy rates and adverse drug reactions (ADRs)., Results: The first ovarian stimulation cycle using follitropin delta was initiated in 944 women. Mean baseline demographics were: age, 33.5 ± 4.7 years; bodyweight, 67.1 ± 13.6 kg; anti-Müllerian hormone, 20.3 ± 16.1 pmol/L (2.84 ± 2.25 ng/mL). The dosing algorithm was used to calculate the follitropin delta daily starting dose in 893/944 women (94.5%). The mean difference between the calculated and prescribed daily dose was small (0.2 ± 1.40 µg). The mean daily starting follitropin delta dose was 10.4 ± 2.72 µg and the mean total dose administered was 104 µg. Follitropin delta dose adjustments were reported for 57/944 (6.0%) women. The mean number of retrieved oocytes was 10.1 ± 7.03. Ongoing pregnancy at 10-11 weeks was reported for 255 women (27.0% per initiated cycle and 43.1% per fresh transfer [n=592]). Cumulative ongoing pregnancy rate after fresh and/or frozen transfer was 36.4% (344/944). Four women discontinued follitropin delta due to ADRs. Ovarian hyperstimulation syndrome (OHSS) was the most frequently reported ADR (n=37 [3.9%]); most cases of OHSS were of mild or moderate intensity (n=30 [3.2%])., Conclusions: This large real-world study of follitropin delta utilization patterns confirms its good pregnancy rates while minimizing OHSS risk during first ovarian stimulation cycle., Competing Interests: CB has received honoraria and/or non-financial support from Abbott, Ferring, Gedeon Richter, Merck, MSD, Organon and ObsEva. GG has received honoraria and/or non-financial support from Abbott, Ferring, Gedeon Richter, Guerbet, Merck, MSD, Organon, ObsEva, PregLem, ReprodWissen GmbH, Theramex, Cooper and Vifor. RR: None. PL is an employee of Ferring Pharmaceuticals. YLYS is an employee of Ferring Pharmaceuticals. SR was an employee of Ferring Pharmaceuticals at time of study conduct. JSEL has received an unrestricted research grant from Ferring Pharmaceuticals. He has also received grants and honoraria from AnshLabs, Gedeon-Richter, Ferring Pharmaceuticals, Roche Diagnostics and Titus Healthcare., (Copyright © 2022 Blockeel, Griesinger, Rago, Larsson, Sonderegger, Rivière and Laven.)

Objectives: Acute bronchiolitis is a major public health issue with high number of infants hospitalised worldwide each year. In France, hospitalisations mostly occur between October and March and peak in December. A reduction of emergency visits for bronchiolitis has been observed at onset of the COVID-19 outbreak. We aimed to assess the pandemic effects on the hospitalisations for bronchiolitis during the 2020-2021 winter (COVID-19 period) compared with three previous winters (pre-COVID-19)., Design: Retrospective, observational and cross-sectional study., Setting: Tertiary university paediatric hospital in Paris (France)., Participants: All infants aged under 12 months who were hospitalised for acute bronchiolitis during the autumn/winter seasons (1 October to 31 March) from 2017 to 2021 were included. Clinical and laboratory data were collected using standardised forms., Results: During the COVID-19 period was observed, a 54.3% reduction in hospitalisations for bronchiolitis associated with a delayed peak (February instead of November-December). Clinical characteristics and hospitalisation courses were substantially similar. The differences during the COVID-19 period were: smaller proportion of infants with comorbidities (8% vs 14% p=0.02), lower need for oxygen (45% vs 55%, p=0.01), higher proportions of metapneumovirus, parainfluenzae 3, bocavirus, coronavirus NL63 and OC43 (all p≤0.01) and no influenza. The three infants positive for SARS-CoV-2 were also positive for respiratory syncytial virus, suggesting that SARS-CoV-2 alone does not cause bronchiolitis, despite previous assumptions., Conclusion: The dramatic reduction in infants' hospitalisations for acute bronchiolitis is an opportunity to change our future habits such as advising the population to wear masks and apply additional hygiene measures in case of respiratory tract infections. This may change the worldwide bronchiolitis burden and improve children respiratory outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis, microangiopathy, and autoantibodies. We previously reported that circulating follicular helper T (cTfh) cells are increased in SSc and induce plasmablast differentiation. However, mechanisms leading to cTfh cell expansion and activation in SSc remain to be established. Tfh cells require IL-12 for their expansion and differentiation. 6-Sulfo LacNAc monocytes (slanMo), a subset of monocytes, have a higher capacity to produce IL-12 and to induce CD4+ T cell proliferation in comparison with dendritic cells (DC) or classical monocytes. The aim of this study was to perform a quantitative and functional analysis of monocytes and DC and to correlate them with cTfh cell expansion and clinical manifestations in SSc. Using flow cytometry, we analyzed different monocyte subsets including slanMo and DC from 36 SSc patients and 26 healthy controls (HC). In vitro culture experiments of sorted slanMo were performed for functional analysis and cytokine production. We observed that slanMo, intermediate and non-classical monocytes were increased in SSc in comparison with HC. Furthermore, the increase in slanMo cells was more potent in patients with diffuse SSc. We observed a significant positive correlation between slanMo and cTfh cell levels in SSc patients but not in HC. Other monocyte subsets did not correlate with cTfh cell expansion. In addition, we observed that in vitro, slanMo cells from SSc patients produced less IL-12 than slanMo from HC. SlanMo are increased in SSc and may participate in the activation of cTfh cells in SSc., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Interactions between ecological factors and seed physiological responses during the establishment phase shape the distribution of plants. Yet, our understanding of the functions and evolution of early-life traits has been limited by the scarcity of large-scale datasets. Here, we tested the hypothesis that the germination niche of temperate plants is shaped by their climatic requirements and phylogenetic relatedness, using germination data sourced from a comprehensive seed conservation database of the European flora (ENSCOBASE)., Methods: We performed a phylogenetically informed Bayesian meta-analysis of primary data, considering 18 762 germination tests of 2418 species from laboratory experiments conducted across all European geographical regions. We tested for the interaction between species' climatic requirements and germination responses to experimental conditions including temperature, alternating temperature, light and dormancy-breaking treatments, while accounting for between-study variation related to seed sources and seed lot physiological status., Key Results: Climate was a strong predictor of germination responses. In warm and seasonally dry climates the seed germination niche includes a cold-cued germination response and an inhibition determined by alternating temperature regimes and cold stratification, while in climates with high temperature seasonality opposite responses can be observed. Germination responses to scarification and light were related to seed mass but not to climate. We also found a significant phylogenetic signal in the response of seeds to experimental conditions, providing evidence that the germination niche is phylogenetically constrained. Nevertheless, phylogenetically distant lineages exhibited common germination responses under similar climates., Conclusion: This is the first quantitative meta-analysis of the germination niche at a continental scale. Our findings showed that the germination niches of European plants exhibit evolutionary convergence mediated by strong pressures at the macroclimatic level. In addition, our methodological approach highlighted how large datasets generated by conservation seed banking can be valuable sources to address questions in plant macroecology and evolution., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Ischemic digital ulcers (DUs) are frequent and severe complications of systemic sclerosis (SSc). Treatment options for SSc-related digital vasculopathy are based on aggressive vasodilation, with the objective to improve blood flow in ischemic areas. Intravenous prostanoids are recommended to treat active DUs. However, the level of evidence for the duration of 5 days is low. Therefore, the aim of this study was to determine whether prolonging the infusion beyond 5 days increases the rate of healing of active DUs in SSc., Methods: This is an observational longitudinal retrospective bicenter study from 2000 to 2017. The objective was to compare the healing rate and time (defined by a healing of at least 50% of DUs) between two durations of iloprost administration: 5 days or less, or more than 5 days., Results: Forty-one patients, with a mean age of 47 ± 15 years at diagnosis and 32 (78%) females have been included. Systemic sclerosis was diffuse in 10 (24%) cases and 13 (32%) had an interstitial lung disease. A total of 243 iloprost infusions for DUs were performed: 140 infusions for 5 days or less, and 103 infusions for more than 5 days (prolonged duration). Patients with active DUs which received >5 days of iloprost had higher modified Rodnan skin scale at the time of iloprost infusion (median 33 vs. 15; p < 0.05), more interstitial lung disease (44 vs. 27%; p < 0.05), more anti-topoisomerase I antibody positivity (59 vs. 44%; p < 0.05), and received more previous cyclophosphamide therapy (48 vs. 19%; p < 0.05). While the number of active DUs before iloprost infusion was not significantly different among those who received ≤5 days and >5 days of iloprost, the time to healing after iloprost infusion significantly decreased in SSc patients who received >5 days iloprost infusion: 48 [7-392] vs. 91 [9-365] days ( p < 0.05). The proportion of SSc patients with healed DUs tended to increase in patients with >5 days iloprost infusion (log rank = 0.06). The number of patients with complete DU healing at day 90 was significantly increased in SSc who received >5 days of iloprost: 53 (51%) vs. 52 (37%) ( p < 0.05). In addition, the time to healing was not significantly associated with the use of calcium channel blockers, endothelin receptor antagonists or a combination of PDE-5 inhibitors., Conclusion: Prolonging duration of iloprost >5 days could improve the healing rate and the time to healing of SSc-related DUs. Prospective randomized studies are needed to confirm these data and define the optimal duration of iloprost therapy., Competing Interests: AM was investigator of CELGENE, ROCHE, CHUGAI founded trials with APHP and Hôpital 15-20 promotion; AM received several fees for congress travels and experts’ use from LFB, SANOFI, SHIRE, and CELGENE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jamart, Levesque, Thietart, Fain, Rivière, Benhamou and Mekinian.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes., Methods: Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells., Results: The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm 3 , p < 0.0001), correlated with age (r =  - 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm 3 , p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002)., Conclusions: Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection., (© 2021. The Author(s).)

Full details on the design, development, and successful implementation of suitable synthetic strategies directed toward the total synthesis of iso -archazolids and archazologs are reported. Both a biomimetic and a multistep total synthesis of iso -archazolid B, the most potent and least abundant archazolid, are described. The bioinspired conversion from archazolid B was realized by a high-yielding 1,8-Diazabicyclo[5.4.0]undec-7-ene catalyzed one-step double-bond shift. A highly stereoselective total synthesis was accomplished in 25 steps, involving a sequence of highly stereoselective aldol reactions, an efficient aldol condensation to forge two elaborate fragments, and a challenging ring-closing metathesis macrocyclization with an unusual Stewart-Grubbs catalyst. These strategies proved to be generally useful and could be successfully implemented for the preparation of three novel iso -archazolids as well as five novel archazologs, lacking the thiazole side chain. A wide variety of further archazolids and archazologs may now be targeted for exploration of the promising anticancer potential of these polyketide macrolides.

While behavioral problems are the main reasons for adolescents to be referred to an emergency room for mental health problems, their clinical management remain usually heterogenous, poorly standardized, and associated with a low level of patient and family satisfaction. So far, most attention has been paid to the treatment of agitation, and few insights have been provided on the treatment plan of behavioral problems once the crisis is over and a psychiatric or medical condition ruled out. This perspective article represents an attempt to incorporate multiple theoretical approaches to provide a comprehensive and operational model for the management of adolescents with behavioral problems in an emergency department. Short hypothetical case vignettes illustrate the importance of considering several levels of analysis to understand the adolescent's problematic behavior which can be seen as a symptom of a medical/psychiatric condition (medical model), as a maladaptive strategy in a context of vulnerability (developmental model), and finally as a mode of communication in a context of ill-adapted relational patterns (systemic model). As behavioral problems in adolescence are a complex issue, frequently involving the intervention of professionals from various disciplines, being aware of such different levels of understanding could help to preclude any role confusion and to provide better targeted interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guedj-Bourdiau, Guilé, Garny de la Rivière, Pace, Cohen and Benarous.)

Background: Borderline personality disorder (BPD) and history of prior suicide attempt (SA) have been shown to be high predictors for subsequent suicide. However, no previous study has examined how both factors interact to modify clinical and suicide severity among adolescents., Methods: This study presents a comprehensive assessment of 302 adolescents (265 girls, mean age = 14.7 years) hospitalized after a SA. To test clinical interactions between BPD and history of prior SA, the sample was divided into single attempters without BPD (non-BPD-SA, N = 80), single attempters with BPD (BPD-SA, N = 127) and multiple attempters with BPD (BPD-MA, N = 95)., Results: Univariate analyses revealed a severity gradient among the 3 groups with an additive effect of BPD on the clinical and suicide severity already conferred by a history of SA. This gradient encompassed categorical (anxiety and conduct disorders and non-suicidal-self-injury [NSSI]) and dimensional comorbidities (substance use and depression severity) and suicide characteristics (age at first SA). According to regression analyses, the BPD-MA group that was associated with the most severe clinical presentation also showed specific features: the first SA at a younger age and a higher prevalence of non-suicidal self-injury (NSSI) and anxiety disorders. The BPD-MA group was not associated with higher impulsivity or frequency of negative life events., Conclusions: Based on these findings and to improve youth suicide prevention, future studies should systematically consider BPD and the efficacy of reinforcing early interventions for anxiety disorders and NSSI.

Objectives: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype., Methods: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors., Results: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP., Conclusion: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter's titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12., Methods: MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV., Results: At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV., Conclusions: We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment ( p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment ( p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.

Cancer among patients with systemic sclerosis (SSc) would appear to be more prevalent than in the general population. Pathophysiological hypotheses are multiple, involving intertwined factors such as immune system antitumoral response, oxygen species dysregulation, and immunosuppressive treatments. We aimed to identify SSc patients with cancer monitored at our center, describing their clinical and immunological characteristics, such as cancer-specific outcomes. We focused in particular on the temporal relationships between cancer onset and SSc diagnosis. A retrospective study was conducted on SSc patients from Montpellier University Hospital from 2003 to 2018. Clinical characteristics and outcomes of each SSc patient with cancer were recorded. Fifty-five patients with SSc and at least one cancer was included (median age 56 years (47-66)), with a median follow-up time of 11 years (4-15). Sixty-four metachronous malignancies were identified (12 patients had two cancers). Among them, early-onset cancer occurrences (±5 years from SSc diagnosis) included 23 cancers (39% breast cancers, 13% lung cancers, and 13% gastro-intestinal tract cancers). Twenty-two cancers occurred 10 years (±5 years) after SSc diagnosis (14% breast cancers, 23% gastrointestinal (GI) tract cancers, and 18% lung cancers). Patients without any of the two autoantibodies (anti-centromere (ACA) and anti-topoisomerase (ATA-scl70) antibodies) were more prevalent in the early-onset cancer subgroup (14 vs. 6, p = 0.02). This study brought to light two peaks of cancer occurrence in SSc patients. Early-onset cancers were associated with SSc with a specific immunological signature. Late-onset cancers might be the consequence of a subtle interplay between repeated target organ inflammation, immunosuppressant use, mesenchymal cell dysfunction and subsequent genetic alterations.

Main Objective: To prospectively assess the cost-consequence of a standardized diagnostic strategy as to compared to an open one for the etiological diagnosis of uveitis., Design: This was a prospective, non-inferiority, multicentre, randomized controlled trial., Methods: We included all consecutive patients with uveitis who had visited at least one of the Departments of Ophthalmology. In the standardized group, patients had a minimal work-up regardless of the type of uveitis (including evaluation of the CBC, ESR, C-reactive protein, tuberculin skin test, syphilis serology and chest X-ray). Depending on ophthalmological findings, further investigations could be performed. In the open strategy, ophthalmologists were free to order any kind of investigation. The main outcome was the mean cost per patient of each strategy., Results: 903 uveitis patients were included from January, 2010 to May, 2013. The mean cost per patient of the standardized strategy was 182.97 euros [CI 95% (173.14; 192.80)], and the mean cost per patient of the open strategy was 251.75 euros [CI 95% (229.24; 274.25)]. Therefore, the mean cost per patient of the standardized strategy was significantly lower than the mean cost per patient of the open strategy (p<0.001). There were significantly fewer visits (p<0.001), fewer radiological procedures (p<0.004) and fewer laboratory investigations (p<0.001) in the standardized group., Conclusion: A standardized strategy is a cost-saving approach for the etiological diagnosis of uveitis., Competing Interests: The authors have declared that no competing interests exist.

Background: Gastrointestinal therapeutic drugs (GTDs) are extensively prescribed. The aim of this study was to investigate the characteristics of GTD use in a large population: the French general health scheme beneficiaries (87% of the 66 million inhabitants) in 2016., Methods: The national health data system was used to identify individual characteristics, diseases and GTD classes reimbursed, together with the costs, using anatomical therapeutic chemical class., Results: Among the 57.5 million individuals included, 45% received at least one reimbursement among the 130 million prescriptions reimbursed (90% prescribed by a general practitioner): proton-pump inhibitors (PPI; A02BC: 24%), drugs for functional gastrointestinal disorders (A03: 20%), drugs for constipation (A06: 10%), antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07: 10%), antiemetics and antinauseants (A04: 7%), other drugs for acid-related disorders (A02X: 6%), other drugs for peptic ulcer and gastro-oesophageal reflux disease (A02BX: 4.5%), antacids (A02A: 1.5%). The overall cost of reimbursed GTDs was €707 million and the mean cost per user was €28. Marked variations were observed according to age, sex, and disease. The rates of at least one reimbursement among infants were A07: 28%, A03: 17%, A02BX: 9%, A02X: 7%, A02BC: 6% and A06: 5%. Women more frequently received a reimbursement than men for each GTD class. Reimbursement rates also varied according to health status (end-stage renal disease A02BC: 66%, pregnancy A03: 53%, A04: 11%), treatments (people with at least six reimbursements for nonsteroidal anti-inflammatory drugs in 2016 A02BC: 62%). Chronic GTD use (>10 reimbursements/year) was observed in 19% of people with at least one A02BC reimbursement, A02BX: 11%, A03: 7%, A04: 2%, A06: 17% and A07: 3%., Conclusions: This study demonstrates extensive and chronic use of GTD in France, raising the question of their relevance according to current guidelines. They must be disseminated to general practitioners, who are the main prescribers of these drugs., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Irritable bowel syndrome (IBS) can be responsible for alteration in quality of life and economic burden. The aim of this study was to evaluate healthcare use related to this disorder in France., Methods: The French health data system was used to select adults covered by the general health scheme (87% of population) through their first IBS hospitalization in 2015. We studied the healthcare refunded during the previous 5 years, 1 year before and after hospitalization., Results: Among 43.7 million adults who used refunded healthcare in 2015, 29,509 patients were identified (0.07, 33% males, 67% females, mean age 52 years, 30% admitted through emergency room). During their hospitalization, 33% had upper endoscopy and 64% colonoscopy. Over the five previous years, 3% had at least one hospitalization with an IBS diagnosis, 58% had abdominal ultrasonography, 27% CT scan, 21% upper endoscopy, 13% colonoscopy and 83% a gastroenterologist visit. The year before, these rates were respectively: 0, 36, 16, 6, 4 and 78%. Some of those rates decreased the year after the hospitalization with respectively: 1, 27, 13, 5, 4 and 19%. The year before, 65% had at least one CRP dosage (13% three or more), 58% a TSH dosage (7%) and 8% a test for coeliac diseases (1%) and the year after: 44% (8%), 43% (5%) and 3% (0.3%). At least one refund of a drug used to treat IBS was found for 85% of patients 5 years before, 65% one year before and 51% one year after., Conclusion: This first study using French health data system for healthcare consumption assessment in IBS points out the repetition of outpatient visits, examinations and in particular radiological examinations, without a strong decrease after hospitalization for IBS and gastroenterologist visit.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.

Hexachlorobenzene (HCB) is a dioxin-like environmental pollutant, widely distributed in the environment. New research links exposure to high levels of persistent organic environmental toxicants to cardiovascular disease, however little is known about the effect of HCB on vascular function and on blood pressure. The purpose of the present study was to evaluate biochemical and cardiovascular changes resulting from subchronic HCB exposure. Adult female Sprague-Dawley rats were treated with vehicle or HCB (5 or 500 mg/kg b.w) for 45 days. Systolic blood pressure (BP), recorded by tail cuff plethysmography, was significantly increased at 35, 40 and 45 days of 500 mg/kg HCB-treatment. HCB (500 mg/kg) increased arterial thickness, while both 5 and 500 mg/kg HCB decreased proliferating cell nuclear antigen (PCNA) protein levels and cellular nuclei in abdominal aortas indicating a hypertrophic process. Also, aortas from both groups of HCB-treated rats presented higher sensitivity to noradrenalin (NA) and a significant decrease in maximum contractile response. Arteries from 500 mg/kg HCB-treated rats showed a significant increase in the levels of transforming growth factor-β1 (TGF-β1) mRNA and angiotensin II type1 receptor (AT 1 ), and a significant decrease in estrogen receptor alpha (ERα), endothelial nitric oxidide synthase (eNOS) protein expression and deiodinase II (DII) mRNA levels. In conclusion, we have demonstrated for the first time that subchronic HCB administration significantly increases BP and alters associated cardiovascular parameters in rats. In addition, HCB alters the expression of key vascular tissue molecules involved in BP regulation, such as TGF-β1, AT1, ERα, eNOS and DII., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France., Methods: Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network., Results: Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients., Conclusion: Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.

Background: Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT)., Methods and Results: We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH., Conclusion: This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.

Objectives: Properties of mesenchymal stromal/stem cells (MSCs) from systemic sclerosis (SSc) patients have been reported to be altered. MSC-based therapy may therefore rely on the use of allogeneic MSCs from healthy subjects. Here, we investigated whether heterologous MSCs could exhibit altered properties following exposure to oxidative environment of SSc sera., Methods: Human bone marrow-derived MSCs were cultured in the presence of various sera: control human serum AB (SAB), SAB with HOCl-induced AOPPs at 400 or 1,000 µmol/L (SAB 400 or SAB 1000 , respectively), or H 2 O 2 -induced AOPPs or SSc patient serum (PS). Proliferation, apoptosis, and senescence rates of MSCs were evaluated after 3, 6, and 10 days in culture. Reactive oxygen species and nitric oxide production were quantified at 24 h. Trilineage potential of differentiation was tested after 21 days in specific culture conditions and immunosuppressive function measured in a T lymphocyte proliferative assay., Results: In the presence of oxidative environment of PS, MSCs retained their proliferative potential and survived for at least the first 3 days of exposure, while the number of senescent MSCs increased at day 6 and apoptosis rate at day 10. Exposure to PS enhanced the antioxidant capacity of MSCs, notably the expression of SOD2 antioxidant gene. By contrast, the osteoblastic/adipogenic potential of MSCs was increased, whereas their immunosuppressive function was slightly reduced., Discussion: Although some functional properties of MSCs were affected upon culture with PS, evidence from preclinical studies and the present one suggested that MSCs can adapt to the oxidative environment and exert their therapeutic effect.

Objective: The nature and impact of food and other external triggers in recurrences of Behçet's disease (BD)-related oral ulcers (OUs) remain unknown. This survey investigated dietary and nondietary triggers of BD-related OU recurrences., Methods: Patients with BD who were followed in 7 French hospital departments completed a self-administered patient questionnaire. General and specific dietary triggering factors were sought in open questions. The questionnaire also included closed questions, notably to evaluate the effect of 6 general triggering situations and 24 selected foods. The results were expressed as number (percentage) of positive responses., Results: Among the 101 questionnaires distributed, 81 were usable. Among the 81 patients, 96% fulfilled the International Criteria for Behçet's Disease classification criteria, and 53% qualified their OU recurrences during the previous 12 months as very discomforting or discomforting. For the 6 general situations suggested, 50 patients (62%) declared ≥1 as a "sure" trigger of OU recurrences. In both open and closed questions, the most frequent triggers were fatigue/stress (37-47% of patients) and food (32-35%). Among the 24 suggested foods, nuts (48%), pineapple (42%), peanuts (32%), Emmental cheese (30%), almonds (23%), lemons (22%), and other cheeses (21%) were the most frequently reported. The corresponding open question gave consistent findings but with lower frequencies., Conclusion: Most patients can identify triggers of recurring BD-related OUs, with fatigue/stress and food representing the most frequent triggers. The management of OU must consider such external factors. The histamine-rich or -liberating properties of the commonly cited OU-triggering foods suggest a hyperreactivity mechanism., (© 2016, American College of Rheumatology.)

Background: Environmental exposures, for instance to chemicals, are known to impact plant and animal phenotypes on the long term, sometimes across several generations. Such transgenerational phenotypes were shown to be promoted by epigenetic alterations such as DNA methylation, an epigenetic mark involved in the regulation of gene expression. However, it is yet unknown whether transgenerational epigenetic inheritance of altered phenotypes exists in birds. The purpose of this study was to develop an avian model to investigate whether changes to the embryonic environment had a transgenerational effect that could alter the phenotypes of third-generation offspring. Given its impact on the mammalian epigenome and the reproductive system in birds, genistein was used as an environment stressor., Results: We compared several third-generation phenotypes of two quail "epilines", which were obtained from genistein-injected eggs (Epi+) or from untreated eggs (Epi-) from the same founders. A "mirrored" crossing strategy was used to minimize between-line genetic variability by maintaining similar ancestor contributions across generations in each line. Three generations after genistein treatment, a significant difference in the sexual maturity of the females, which, after three generations, could not be attributed to direct maternal effects, was observed between the lines, with Epi+ females starting to lay eggs later. Adult body weight was significantly affected by genistein treatment applied in a previous generation, and a significant interaction between line and sex was observed for body weight at 3 weeks. Behavioral traits, such as evaluating the birds' reaction to social isolation, were also significantly affected by genistein treatment. Yet, global methylation analyses revealed no significant difference between the epilines., Conclusions: These findings demonstrate that embryonic environment affects the phenotype of offspring three generations later in quail. While one cannot rule out the existence of some initial genetic variability between the lines, the mirrored animal design should have minimized its effects, and thus, the observed differences in animals of the third generation may be attributed, at least partly, to transgenerational epigenetic phenomena.

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

Type 2 Diabetes (T2D), a major public health issue reaching worldwide epidemic, has been correlated with lower olfactory abilities in humans. As olfaction represents a major component of feeding behavior, its alteration may have drastic consequences on feeding behaviors that may in turn aggravates T2D. In order to decipher the impact of T2D on the olfactory epithelium, we fed mice with a high fructose diet (HFruD) inducing early diabetic state in 4 to 8 weeks. After only 4 weeks of this diet, mice exhibited a dramatic decrease in olfactory behavioral capacities. Consistently, this decline in olfactory behavior was correlated to decreased electrophysiological responses of olfactory neurons recorded as a population and individually. Our results demonstrate that, in rodents, olfaction is modified by HFruD-induced diabetes. Functional, anatomical and behavioral changes occurred in the olfactory system at a very early stage of the disease.