Psychiatric, psychological and addiction management in obesity surgery: Early identification for better support.

Although bariatric surgery results in a significant weight reduction and an improvement in the quality of life in most people who undergo surgery, there are inter-individual differences in terms of postoperative results. Psychological, psychiatric and addictive disorders contribute substantially to these difficulties. Between 20% and 50% of bariatric surgery candidates have a current psychiatric/addictive disorder and approximately 30-75% have a history of a psychiatric/addictive disorder within their lifetime. Surgery is accompanied in the short-term by an improvement in depressive symptoms and binge eating, but these symptoms tend to increase again beyond the 3rd postoperative year. Over the long-term, only the improvement in depression remains durable, whilepostoperative anxiety and disordered eating symptoms do not differ significantly from the preoperative levels. There is a two to four fold increased risk of post-surgical suicide and suicide attempts (from the 1st postoperative year onward), as well as an increased risk of alcohol-abuse (beyond two years after surgery). Psychological support must therefore continue long-term. Several psychotherapeutic and pharmacological treatments have demonstrated their effectiveness in improving the postoperative prognosis of patients with psychological/psychiatric disorders. The early integration of psychological/psychiatric/addiction evaluation and support into multidisciplinary management makes it easier to identify these difficulties and to optimize the postoperative prognosis, both in terms of weight and quality of life. Prior to surgery, patients should be systematically evaluated by a psychologist or psychiatrist in order to identify and to manage disorders that could negatively impact the postoperative prognosis. After surgery, this assessment and support can be carried out in a programmed and systematic way for those patients who were identified preoperatively as the most vulnerable, but support can also be offered during follow-up in the event of specific symptoms (i.e., loss of control over food intake, failure in terms of weight or quality of life, suicidal ideation, loss of control over alcohol use, significant depression or anxiety symptoms).

Long-term evaluation of the impact of delivery modalities on anal continence in women with Crohn's disease.

CONTEXT: Crohn's disease (CD) and sphincter injury during childbirth are two risk factors for anal incontinence (AI). The long-term risk of developing AI in women with CD after childbirth has never been studied. GOAL: The main objective of the study is to assess the risk of developing severe AI after childbirth in women with CD. METHODS: A retrospective study was performed in women with CD who gave birth in a French "Level 3" maternity hospital between 2000 and 2015. The primary endpoint was severe AI as defined by a Wexner score≥9 or a St. Mark's score≥9, at least five years after childbirth. The association between delivery route and occurrence of severe AI was assessed by univariate and multivariate analyses. RESULTS: Forty-six women were included, 32 of whom were delivered vaginally and 14 by Caesarean section. Thirty-one percent of the women had severe AI according to the Wexner score, and 41% according to the St. Mark's score. Two factors were associated with severe AI: vaginal delivery and the occurrence of an obstetric perineal injury: (crude OR=8.89, 95% (CI: 1.03-76.57) and crude OR=4.16, 95% (CI: 1.06-16.27) respectively for AI defined by the Wexner score, and crude OR=6.8, 95% (CI: 1.30-35.41) and crude OR=4.3, 95% (CI: 1.23-15.2) for AI defined by the St. Mark's score). After adjusting for confounding factors, only vaginal delivery was associated with severe AI (adjusted OR=22.86, 95% CI: 1.52-931.28 for a Wexner score≥9 and adjusted OR=16. 11 (95% CI: 1.43-533.26) for a St Mark score≥9). CONCLUSION: Vaginal birth was associated with the development of severe long-term AI in women with CD.

New in vivo model to analyse the expression of angiogenic genes in the borders of a cleft lip.

Defects in the fusion of facial buds can result from an anomaly in tissue development or apoptosis, or both. Our working hypothesis was that anomalies in the development of tissues could be caused by a genetic angiogenic defect. Our main objective was to design a reproducible experimental model to study the expression of angiogenic genes in the borders of cleft lips with or without cleft palate. We therefore prospectively studied seven non-syndromic patients, three with a cleft lip (2 right, 1 left), and four with a cleft lip and palate (1 bilateral, 2 right, 1 left), with no CGH (comparative genomic hybridisation) array, who had primary operations to repair their clefts. We also used four controls (cultured fibroblasts from healthy skin samples). The mean (range) age at operation was 44 (13-77) days. We studied the lateral and medial borders histologically and did qPCR (quantitative real-time polymerase chain reaction) analysis for gene expression with 22 genes of interest (and two housekeeping genes) involved in cleft lip and angiogenesis. The qPCR analysis found significant (p<0.05) overexpression of eight genes in the medial border and seven in the lateral border, and underexpression of nine genes in the medial, and ten in the lateral border. The difference in expression between the two borders was not significant. This preliminary study has enabled us to develop a new method to analyse the expression of angiogenic genes in the borders of cleft lips.

French intensive training course in laparoscopic surgery (HUGOFirst) on live porcine models: Validation of a performance assessment scale and residents' satisfaction in a prospective study.

INTRODUCTION: Simulation as a method for practical teaching of surgical residents requires objective evaluation in order to measure the student's acquisition of knowledge and skills. The objectives of this article are to publish our evaluation and validation grids and also the measure of student satisfaction. METHOD: A teaching platform based on practical exercises with a porcine model was created in 2009 at seven French University Hospitals. Three times a year, 31 Diplôme d'Études Spécialisées Complémentaires (DESC) surgical residents underwent timed assessment of the performance of five surgical tasks: trocar insertion (trocars) testing the convergence of instruments (convergence), intra-corporeal knot tying (knots), running of the small intestine to find a lesion (exploration), and performance of a running suture closure of the peritoneum (closure). Two experts evaluated performances prospectively on grid score sheets specifically designed and validated for these exercises. We measured time, scores on a rating scale, and the interest and satisfaction of the residents. RESULTS: Data for 31 residents between May 2011 and March 2012 were analyzed. Rating scales were statistically validated and correlated (Kappa correlation coefficient K>0.69) for each task. The performance times of the most experienced residents decreased significantly for all tasks except for small bowel exploration (P=0.2). After four sessions, times were significantly improved with better quality (fewer errors and higher average scores [>88%]), regardless of the residents' experience. Of the participants, 92% were satisfied, 86% thought that the sessions improved their technical skills and 74% thought it had a favorable impact on their clinical practice. CONCLUSION: This study shows that the performance of surgical techniques can be improved through simulation, that HUFEG grids are valid, and that this teaching program is popular with surgical residents.

Characterization and comparison of bone marrow and peripheral blood mononuclear cells used for cellular therapy in critical leg ischaemia: towards a new cellular product.

BACKGROUND AND OBJECTIVES: Autologous transplantation of either bone marrow (BM) or peripheral blood (PB) mononuclear cells (MNC) induces therapeutic angiogenesis in patients with peripheral arterial occlusive disease. Yet, the precise nature of the cellular product obtained from BM or PB and used in these therapeutic strategies remains unclear. MATERIALS AND METHODS: We have analysed the characteristics of BM-MNC and PB-MNC collected without mobilization and implanted in patients with critical limb ischaemia in a clinical trial of cellular therapy including 16 individuals treated by BM-MNC and eight by PB-MNC. These MNCs were characterized by cell counts, viability assessment and enumeration of leucocyte subsets, CD34 stem and endothelial progenitor cells (EPCs) (CD34+/CD133+/VEGF-R2+) by flow cytometry. Mean fluorescence intensity ratios were determined for CD34, CD133 and VEGF-R2 markers. All analyses were simultaneously performed in two laboratories. RESULTS: Accuracy and reliability between both laboratories were achieved. BM-MNCs and PB-MNCs were quantitatively and qualitatively heterogeneous and quite different from each other. Stem cells and EPCs were significantly more present in BM- compared to PB-cell products, but with similar mean fluorescence intensity ratios. A weakly positive correlation was observed between CD34+ cell counts and EPCs levels, confirming the specificity of cell identification. CONCLUSION: A great variability was observed in cell product characteristics according to their origin and also between individuals. These data stress the necessity of optimal characterization of cell products especially in multicentric clinical trials.

Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice.

A correlation between high plasma serotonin levels and total pulmonary resistance was reported in more than 80% of pulmonary hypertensive patients. When submitted to chronic hypoxia (10% O(2) for more than 3 weeks), wild-type mice develop lung vascular remodeling and pulmonary hypertension. We previously reported that, in contrast, the development of these hypoxia-dependent alterations is totally abolished in mice with permanent (genetic) or transient (pharmacologic) inactivation of the serotonin 5-hydroxytryptamine (5-HT)(2B) receptor. In the present study, we asked whether 5-HT(2B) receptors could be involved in the control of plasma serotonin levels. Further investigating the chronic hypoxic mouse model of pulmonary hypertension, we first show that in wild-type mice, plasma serotonin levels and 5-HT(2B) receptors expression were significantly increased after chronic exposure to hypoxia. This increase appeared before significant changes in remodeling factors could be detected and persisted when the pathology was established. Conversely, in mice with either genetically or pharmacologically inactive 5-HT(2B) receptors, plasma serotonin levels were not modified by chronic hypoxia. We then confirmed that 5-HT(2B) receptors can control plasma serotonin levels by providing in vivo evidence that an acute agonist stimulation of 5-HT(2B) receptor triggers a transient increase in plasma serotonin that is serotonin transporter dependent and blocked by 5-HT(2B) receptor-selective antagonist or genetic ablation. Our data support the notion that a 5-HT(2B) receptor-dependent regulation of serotonin uptake is implicated in the control of plasma serotonin levels.

Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension.

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.

Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation.

The murine F9-derived 1C11 clone exhibits a stable epithelial morphology, expresses nestin, an early neuroectodermal marker, and expresses genes involved in neuroectodermal cell fate. Upon appropriate induction, 100% of 1C11 precursor cells develop neurite extensions and acquire neuronal markers (N-CAM, synaptophysin, gammagamma-enolase, and neurofilament) as well as the general functions of either serotonergic (1C11*(/5HT)) (5HT, 5-hydroxytryptamine) or noradrenergic (1C11**(/NE)) (NE, norepinephrine) neurons. The two programs are shown to be mutually exclusive. 1C11 thus behaves as a neuroepithelial cell line with a dual bioaminergic fate. 1C11*(/5HT) cells implement a functional 5-HT transporter and thereby a complete serotonergic phenotype within 4 days, whereas 5-HT(1B/D), 5-HT(2B), and 5-HT(2A) receptors are sequentially induced. The accurate time schedule of catecholaminergic differentiation was defined. Catecholamine synthesis, storage, and catabolism are acquired within 4 days; the noradrenergic phenotype is complete at day 12 and includes a functional norepinephrine transporter and an alpha(1D)-adrenoreceptor (day 8). The time-dependent onset of neurotransmitter-associated functions proper to either program is similar to in vivo observations. Along each pathway, the selective induction of serotonergic or adrenergic receptors is shown to be an essential part of the differentiation program, since they promote an autoregulation of the corresponding phenotype.

5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways.

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the G(q) protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.

Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line. Involvement of arachidonic acid metabolism.

The study of signaling cascades and of functional interactions between 5-hydroxytryptamine (5-HT) receptor pathways with heterogenous brain cell populations remains an arduous task. We took advantage of a serotonergic cell line to elucidate cross-talks between 5-HT receptors and to demonstrate the involvement of two 5-HT2 receptor subtypes in the regulation of 5-HT1B/1D function. The inducible 1C11 cell line has the unique property of acquiring within 4 days a complete serotonergic phenotype (1C11* cells), including three 5-HT receptors. 5-HT1B/1D and 5-HT2B receptors are expressed since day 2 of the serotonergic differentiation while 5-HT2A receptors are induced at day 4. We first established that 5-HT2B receptors are coupled with the phospholipase A2 (PLA2)-mediated release of arachidonic acid (AA) and that the activation of 5-HT2B receptors in 1C11*d2 cells inhibits the 5-HT1B/1D receptor function via a cyclooxygenase-dependent AA metabolite. At day 4, this 5-HT2B-mediated inhibition of the 5-HT1B/1D function can be blocked upon concomitant 5-HT2A activation although a 5-HT2A/PLA2 positive coupling was evidenced. This suggests the existence in 1C11*d4 cells of pathway(s) for 5-HT2A receptors, distinct from PLC and PLA2. Finally, this study reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in regulating the function of 5-HT1B/1D, a receptor involved in neuropsychiatric disorders and migraine pathogenesis.

Mouse 5-HT2B receptor-mediated serotonin trophic functions.

5-HT2B receptors, in addition to phospholipase C stimulation, are able to trigger activation of the proto-oncogene product p21ras. During mouse embryogenesis, a peak of 5-HT2B receptor expression is detected at the neurulation stage; we localized the 5-HT2B expression in neural crest cells, heart myocardium, and somites. The requirement for functional 5-HT2B receptors shortly after gastrulation, is supported by culture of embryos exposed to 5-HT2B-high affinity antagonist such as ritanserin, which induces morphological defects in the cephalic region, heart and neural tube. Functional 5-HT2B receptors are also expressed during the serotonergic differentiation of the mouse F9 teratocarcinoma-derived clonal cell line 1C11. Upon 2 days of induction by cAMP, 5-HT2B receptors become functional, and on day 4, the appearance of 5-HT2A receptors coincides with the onset of active serotonin transporter by these cells. Active serotonin uptake is modulated by serotonin suggesting autoreceptor functions for 5-HT2B receptors.