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The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures 1 . The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system 2 , 3 ; however, their role in the mammalian vasculature remains ill defined 4 , 5 , 6 , 7 , 8 . Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165–induced migration, tube formation and permeability in vitro and VEGF-165–stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.

How individual components of the vascular basement membrane influence endothelial cell behaviour remains unclear. Here we show that laminin α4 (Lama4) regulates tip cell numbers and vascular density by inducing endothelial Dll4/Notch signalling in vivo . Lama4 deficiency leads to reduced Dll4 expression, excessive filopodia and tip cell formation in the mouse retina, phenocopying the effects of Dll4/Notch inhibition. Lama4 ‐mediated Dll4 expression requires a combination of integrins in vitro and integrin β1 in vivo . We conclude that appropriate laminin/integrin‐induced signalling is necessary to induce physiologically functional levels of Dll4 expression and regulate branching frequency during sprouting angiogenesis in vivo . Laminin α4—a component of the vascular basement membrane—is shown to regulate tip cell numbers and vascular density by inducing endothelial Dll4/Notch signalling in vivo , an effect that requires integrin β1.

In Vitro Transcriptional Induction of the Human Apolipoprotein A-II Gene by Glucose Dominique Sauvaget 1 2 , Valérie Chauffeton 2 , Sonia Dugué-Pujol 1 2 , Athina-Despina Kalopissis 1 2 , Isabelle Guillet-Deniau 3 , Fabienne Foufelle 2 4 , Jean Chambaz 1 2 , Armelle Leturque 1 2 , Philippe Cardot 1 2 and Agnès Ribeiro 1 2 1 Institut National de la Santé et de la Recherche Médicale (INSERM) U505, Institut Biomédical des Cordeliers, Paris, France 2 Institut Fédératif de Recherche 58, Institut Biomédical des Cordeliers, Paris, France 3 INSERM U567, Unité Mixte de Recherche 8104 Centre National de la Recherche Scientifique, Institut Cochin, Paris, France 4 INSERM U465, Institut Biomédical des Cordeliers, Paris, France Address correspondence and reprint requests to Agnès Ribeiro, INSERM U505, 15 rue de l’Ecole de Médecine, 75006 Paris, France. E-mail: agnes.ribeiro-pillet-u505{at}bhdc.jussieu.fr Abstract Type 2 diabetic patients present high triglyceride and low HDL levels, significant determinants for the risk of atherosclerosis. Transgenic mice overproducing human apolipoprotein (apo)A-II, one of the two major apos of HDLs, display the same lipid disorders. Here, we investigated the possible regulation of apoA-II gene expression by glucose. In primary rat hepatocytes and in HepG2 cells, the transcription of the human apoA-II gene was upregulated by glucose. This response was mediated by a hormone-responsive element within the enhancer of the apoA-II promoter and was dependent on hepatocyte nuclear factor-4α. Accordingly, in transgenic mice, the human apoA-II gene is stimulated by a high-carbohydrate diet after fasting and at weaning. By contrast, the apoA-II mRNA level is not modified in streptozotocin-induced diabetic rats. In transgenic mice overexpressing the human apoA-II gene, plasma human apoA-II concentration was positively correlated with blood glucose levels. These mice displayed a marked delay in plasma glucose tolerance as compared with control mice. We hypothesize that the following pathogenic pathway might occur in the course of type 2 diabetes: increased apoA-II level causes a rise in plasma triglyceride level and glucose intolerance, resulting in hyperglycemia, which in turn might further increase apoA-II gene transcription. apo, apolipoprotein CAD, coronary artery disease CAT, chloramphenicol acetyl transferase ChoRE, carbohydrate response element DMEM, Dulbecco’s modified Eagle’s medium HNF, hepatocyte nuclear factor HRE, hormone responsive element INSERM, Institut National de la Santé et de la Recherche Médicale MODY1, type 1 maturity-onset diabetes of the young PSK, pBluescript SK RCT, reverse cholesterol transport Footnotes Accepted December 1, 2003. Received June 25, 2003. DIABETES

Nat. Med. 14, 448–453 (2008); published online 16 March 2008; corrected after print 18 April 2008 In the version of this article initially published, the affiliation of Rebecca A. Stockton was incorrect. Her correct affiliation is affiliation 5: the Department of Medicine, University of California, San Diego, 9500 Gilman Dr.

Background Depression is a debilitating and costly disease for our society, especially in the case of treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy in treatment-resistant unipolar and non-psychotic depression. It can be applied according to two therapeutic strategies after an initial rTMS cure: a further rTMS cure can be performed at the first sign of relapse or recurrence, or systematic maintenance rTMS (M-rTMS) can be proposed. TMS adjuvant to treatment as usual (TAU) could improve long-term prognosis. However, no controlled study has yet compared the cost-effectiveness of these two additional rTMS therapeutic strategies versus TAU alone. Methods/design This paper focuses on the design of a health-economic, prospective, randomized, double-blind, multicenter study with three parallel arms carried out in France. This study assesses the cost-effectiveness of the adjunctive and maintenance low frequency rTMS on the right dorsolateral prefrontal cortex versus TAU alone. A total of 318 patients suffering from a current TRD will be enrolled. The primary endpoint is to investigate the incremental cost-effectiveness ratio (ICER) (ratio costs / quality-adjusted life-years [QALY] measured by the Euroqol Five Dimension Questionnaire) over 12 months in a population of patients assigned to one of three arms: systematic M-rTMS for responders (arm A); additional new rTMS cure in case of mood deterioration among responders (arm B); and a placebo arm (arm C) in which responders are allocated in two subgroups: sham systematic M-rTMS and supplementary rTMS course in case of mood deterioration. ICER and QALYs will be compared between arm A or B versus arm C. The secondary endpoints in each three arms will be: ICER at 24 months; the cost-utility ratio analysis at 12 and 24 months; 5-year budget impact analysis; and prognosis factors of rTMS. The following criteria will be compared between arm A or B and arm C: rates of responders; remission and disease-free survival; clinical evolution; tolerance; observance; treatment modifications; hospitalization; suicide attempts; work stoppage; marital / professional statues; and quality of life at 12 and 24 months. Discussion The purpose of our study is to check the cost-effectiveness of rTMS and we will discuss its economic impact over time. In the case of significant decrease in the depression costs and expenditures associated with a good long-term prognosis (sustained response and remission) and tolerance, rTMS could be considered as an efficient treatment within the armamentarium for resistant unipolar depression. Trial registration ClinicalTrials.gov, NCT03701724 . Registered on 10 October 2018. Protocol Amendment Version 2.0 accepted on 29 June 2019.

Major depressive disorder is one of the leading causes of disability worldwide. Although most international guidelines recommend psychological and psychosocial interventions as first-line treatment for mild to moderate depression, access remains limited in France due to the limited availability of trained clinicians, high costs for patients in the context of nonreimbursement, and the fear of stigmatization. Therefore, online blended psychological treatment such as Deprexis could improve access to care for people with depression. It has several advantages, such as easy accessibility and scalability, and it is supported by evidence. This study aims to evaluate the real-life acceptability of Deprexis for people with depression in France outside of a reimbursement pathway. Deprexis Acceptability Study Measure in Real Life (DARE) was designed as a multicenter cross-sectional study in which Deprexis was offered to any patient meeting the inclusion criteria during the fixed inclusion period (June 2022-March 2023). Inclusion criteria were (1) depression, (2) age between 18 and 65 years, (3) sufficient French language skills, and (4) access to the internet with a device to connect to the Deprexis platform. Exclusion criteria were previous or current diagnoses of bipolar disorder, psychotic symptoms, and suicidal thoughts during the current episode. The primary objective was to measure the prospective acceptability of Deprexis, a new digital therapy. Secondary objectives were to examine differences in acceptability according to patient and clinician characteristics and to identify reasons for refusal. All investigators received video-based training on Deprexis before enrollment to ensure that they all had the same level of information and understanding of the program. A total of 245 patients were eligible (n=159, 64.9% were women and n=138, 56.3% were single). The mean age was 40.7 (SD 14.1) years. A total of 78% (n=191) of the patients had moderate to severe depression (according to the Patient Health Questionnaire-9 [PHQ-9]). More than half of the population had another psychiatric comorbidity (excluding bipolar disorder, psychotic disorders, and suicidal ideation). A total of 33.9% (n=83) of patients accepted the idea of using Deprexis; the main reason for refusal was financial at 83.3% (n=135). Multivariate logistic regression identified factors that might favor the acceptability of Deprexis. Among these, being a couple, being treated with an antidepressant, or having a low severity level favored the acceptance of Deprexis. DARE is the first French study aiming at evaluating the prospective acceptability of digital therapy in the treatment of depression. The main reason for the refusal of Deprexis was financial. DARE will allow better identification of factors influencing acceptability in a natural setting. This study highlights the importance of investigating factors that may be associated with the acceptability of digital interventions, such as marital status, medication use, and severity of depression.

This study assesses the efficacy of Geriatric Assessment (GA)-driven interventions and follow-up on six-month mortality, functional, and nutritional status in older patients with head and neck cancer (HNC). HNC patients aged 65 years or over were included between November 2013 and September 2018 by 15 Ear, Nose, and Throat (ENT) and maxillofacial surgery departments at 13 centers in France. The study was of an open-label, multicenter, randomized, controlled, and parallel-group design, with independent outcome assessments. The patients were randomized 1:1 to benefit from GA-driven interventions and follow-up versus standard of care. The interventions consisted in a pre-therapeutic GA, a standardized geriatric intervention, and follow-up, tailored to the cancer-treatment plan for 24 months. The primary outcome was a composite criterion including six-month mortality, functional impairment (fall in the Activities of Daily Living (ADL) score ≥2), and weight loss ≥10%. Among the patients included (n = 499), 475 were randomized to the experimental (n = 238) or control arm (n = 237). The median age was 75.3 years [70.4–81.9]; 69.5% were men, and the principal tumor site was oral cavity (43.9%). There were no statistically significant differences regarding the primary endpoint (n = 98 events; 41.0% in the experimental arm versus 90 (38.0%); p = 0.53), or for each criterion (i.e., death (31 (13%) versus 27 (11.4%); p = 0.48), weight loss of ≥10% (69 (29%) versus 65 (27.4%); p = 0.73) and fall in ADL score ≥2 (9 (3.8%) versus 13 (5.5%); p = 0.35)). In older patients with HNC, GA-driven interventions and follow-up failed to improve six-month overall survival, functional, and nutritional status.

Background Although clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia, it leads to a poor or partial response in 40 to 70% of patients. Augmentation of clozapine with electroconvulsive therapy (ECT) is a highly effective and relatively safe treatment for these clozapine-resistant patients. However, parameters are not yet well specified, such as the optimal number of sessions, their frequency, and the relevance of maintenance ECT. Our objective is to compare the efficacy and tolerance between two protocols of combined ECT and clozapine treatment in patients with ultra-resistant schizophrenia (URS): a 6-month protocol (short protocol with 20 ECT sessions) and a 12-month protocol (long protocol with 40 ECT sessions). Methods Sixty-four patients with schizophrenia with persistent psychotic symptoms despite clozapine treatment will be enrolled in a prospective multicentric assessor-blinded randomized controlled trial. Patients will be randomly assigned to the short or the long protocol. The main outcome is the response rate assessed by the Positive and Negative Symptoms Scale (PANSS) 3 months after the end of the treatment in patients following the long protocol compared to those following the short protocol. The response was defined as a 30% reduction on the PANSS baseline. Clinical assessments (PANSS, BPRS, HAMD-21, YMRS, CGI, GAF, Modified Overt Aggression Scale (MOAS), and Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS)) and plasma clozapine concentration will be performed at baseline and at 2, 4, 6, 9, 12, and 15 months. Neuropsychological measures (MMSE, RL/RI-16, Doors test, D2 Test of Attention, Copy of the Rey-Osterrieth complex figure) will be performed at baseline and at 6 and 15 months. Discussion The aims of this research are to optimize protocols of combined ECT with clozapine in patients with URS and to offer specific recommendations for these patients’ care. Trial registration ClinicalTrials.gov NCT03542903 . Registered on May 31, 2018. Id RCB: 2017-A02657-46