[Suicide attempts with a violent method: Experience of a transdisciplinary psychiatric ward combining psychiatric and somatic care]. / Prise en charge des tentatives de suicide graves : expérience d'un service transdisciplinaire de psychiatrie.

INTRODUCTION: Suicide is the second leading cause of death in young adults. Suicide attempts by violent methods predict later completed suicide and premature mortality. Suicide prevention is a major public health issue in this specific population. The French Student Health Foundation (FSEF) developed a psychiatric ward that includes psychiatric and somatic approaches. This transdisciplinary unit provides mixed psychiatric and rehabilitation treatments for those persons who have attempted suicide and have severe somatic injuries. METHODS: We conducted a retrospective study including all subjects admitted into the transdisciplinary unit from 1st January 2011 to 31 December 2017, after a suicide attempt by jumping from a height, in front of a moving object, or by crashing of a motor vehicle. Data was obtained from the medical and administrative records of the clinic. RESULTS: In total, 215 persons were admitted into the transdisciplinary unit after a suicide attempt by a violent mean. Among them, 91.6% had jumped from a height, 7.4% had jumped in front of a train or a metro and 0.9% had crashed a motor vehicle. They were on average 25.5years old and 50.2% were men. 45.1% had a diagnosis of schizophrenic disorders and 34.4% of mood disorders. A total of 35.6% presented at least one previous suicide attempt, and among them 40.3% had previously attempted suicide with a violent mean. Substance abuse, mostly alcohol and/or cannabis, featured in 40.8% of subject history. The subjects hospitalised in the transdisciplinary unit had multiple, severe injuries: 78.1% had spine fractures, 69.8% had lower limb fractures, 47.9% had pelvic fractures and 43.3% had upper limb fractures. Moreover, 25.5% of them had sacral root damages. The length of stay averaged 184days and varied in a large range (less than a month to more than two years). The Activities of Daily Living scores were higher than 3 (out of a maximum score of 4) reflecting an important need of assistance. These scores decreased significantly during the hospitalisation for dressing, feeding, continence and locomotion but remained high for comportment and communication. At discharge, the physical sequelae were still important: 61% of people hospitalised had pain that required step 2 or 3 analgesics, 44% had analgesics for neuropathic pain, 80% had lower limb impairments, most often with walking limitation, and 26% had continence disorders. The psychotropic treatments at discharge were related to the psychiatric disorders observed and included 42% antidepressants, 63% neuroleptics and 16% mood stabilizers. CONCLUSION: This study highlights the severity of the somatic and psychiatric disorders affecting people who are admitted into this transdisciplinary unit. These subjects who have attempted suicide require particular care with multidisciplinary management in order to promote their rehabilitation, reintegration and prevent a suicide reattempt.

Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: Results of the MESAMI 1 pilot trial.

BACKGROUND: The MESAMI 1 trial was a bicentric pilot study designed to test the feasibility and safety of intramyocardially injected autologous bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of ischemic cardiomyopathy. METHODS AND RESULTS: The study included 10 patients with chronic myocardial ischemia, left ventricular (LV) ejection fractions (EFs) of ≤35%, and reversible perfusion defects who were on stable optimal medical therapy and were not candidates for revascularization. MSCs (mean: 61.5×10(6) cells per patient) were injected into 10-16 viable sites at the border of the LV scar via a NOGA-guided catheter. Both primary endpoints, feasibility (successful harvest, expansion, and injection of autologous MSCs) and safety (absence of severe adverse events [SAEs]) were met in all 10 patients at the 1-month follow-up time point, and none of the SAEs reported during the full 2-year follow-up period were attributable to the study intervention. The results of secondary efficacy endpoint analyses identified significant improvements from baseline to Month 12 in LVEF (29.4±2.0% versus 35.7±2.5%; p=0.003), LV end-systolic volume (167.8±18.8mL versus 156.1±28.6mL; p=0.04), 6-min walk test and NYHA functional class. CONCLUSIONS: Our results suggest that autologous MSCs can be safely administered to the hearts of patients with severe, chronic, reversible myocardial ischemia and impaired cardiac function and may be associated with improvements in cardiac performance, LV remodeling, and patient functional status. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficacy of this treatment approach in a larger patient population. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01076920.

Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT.

Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.

[Cell therapy for acute myocardial infarction]. / Thérapie cellulaire en phase aiguë d'infarctus du myocarde.

Despite important progress in cardiology, acute myocardial infarction (AMI) is the major cause of congestive heart failure and subsequent mortality. The rationale for cell therapy to be administered after AMI is derived from the assumption that given the insufficient regeneration in the injured heart tissue, stem cells from the bone marrow may be able to replace or repair damaged vascular and cardiac tissue. Results of the first phase I clinical trials using bone marrow stem/progenitor cell therapy for AMI were published in 2002 to 2004. Although not designed to test the efficacy of the intervention, the initial trials indicated a promising improvement in a number of clinical outcomes and cardiac function and suggested the intervention was safe. Recently, randomized controlled trials of cardiac cell therapy for AMI were published, with mixed results. A meta-analysis including 13 trials with a total of 811 participants showed an improved left ventricular ejection fraction by 2.99%. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy on clinical outcomes.

Gene- and cell-based therapeutics for type I diabetes mellitus.

Type 1 diabetes mellitus, an autoimmune disorder is an attractive candidate for gene and cell-based therapy. From the use of gene-engineered immune cells to induce hyporesponsiveness to autoantigens to islet and beta cell surrogate transplants expressing immunoregulatory genes to provide a local pocket of immune privilege, these strategies have demonstrated proof of concept to the point where translational studies can be initiated. Nonetheless, along with the proof of concept, a number of important issues have been raised by the choice of vector and expression system as well as the point of intervention; prophylactic or therapeutic. An assessment of the current state of the science and potential leads to the conclusion that some strategies are ready for safety trials while others require varying degrees of technical and conceptual refinement.

[How to manage very elderly patients in the emergency room? Evaluation of 150 very elderly patients at the Rouen university hospital center]. / Quelle prise en charge des personnes très âgées aux urgences? Evaluation de 150 patients très âgés au CHU de Rouen.

OBJECTIVES: There are few data in the literature concerning care provided to very elderly subjects referred to emergency care units. The emergency room setting would not be particularly adapted to management of this rising population. The purpose of our work was to assess the frequency of referral to emergency care units, the characteristics of the elderly population, and patient management. PATIENTS AND METHODS: One hundred fifty consecutive patients aged over 90 years addressed to the emergency unit of the Charles Nicolle hospital in Rouen France were studied. These patients were cared for by the medical and surgical teams. We recorded, type of referral, hour and reason for admission, degree of handicap and residence, gravity at admission using the clinical classification for emergency care patients (CCMU), complementary tests performed in the emergency unit, duration of stay in the unit and subsequent referral. The characteristics of these "very" elderly patients aged over 90 years were compared with those of "elderly" patients aged 75-90 years. RESULTS: Over a period of 33 days, the unit cared for 4888 patients, including 150 very elderly patients aged over 90 years (mean age 92.6 years). Daily, 4.4 patients were referred by a primary care physician (76.), mainly between 8 a.m. and 8 p.m. (81.3%). Forty-two percent of the patients had a surgical problem. Two-thirds were unable to walk, one-third had cognitive disorders, and one-third had urinary incontinence. However, half of these very elderly patients lived in a private home. According to the CCMU classification, 14.6% of the patients had a life-threatening disorder. Complementary tests were ordered for most patients (85%). Mean duration of stay in the emergency unit was 3.6 +/- 2.6 days. One quarter of the patients returned to their former residence, with a higher percentage among the surgery patients (37%) than among the medical patients (14.6%). There was no significant difference between the "very elderly" and "elderly" patients in terms of type of referral, duration of stay in the unit and subsequent referral. CONCLUSION: "Very elderly" patients are frequently addressed to emergency care units by their primary care physician. They have severe conditions with major handicaps that largely explain their hospitalization. Our results point out possible improvements for care in the emergency unit.

Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats.

Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstriction and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. To test whether lung overexpression of the angiogenic factor vascular endothelial growth factor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding the human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad. VEGF) or control vector containing no gene in the expression cassette (Ad.Null) was administered intratracheally to rats. With Ad. VEGF (10(8) plaque-forming units [pfu]), VEGF protein was present in bronchoalveolar lavage fluid as early as 2 d and until 17 d after gene transfer, but was not detected in serum. Only small patchy areas of mononuclear cells without cell damage, edema, or hemorrhage were observed on lung histology with no significant change in lung permeability. In rats pretreated with Ad.VEGF (10(8) pfu) 2 d before a 2-wk exposure to hypoxia (10% O(2)), lower values versus Ad. Null-pretreated controls were found for pulmonary artery pressure (25 +/- 1 versus 30 +/- 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-septum weight (0.37 +/- 0.01 versus 0.47 +/- 0. 02, P < 0.001), normalized wall thickness of 50- to 200-microm vessels (P < 0.001), and muscularization of distal vessels (P < 0. 001). Pretreatment with Ad.VEGF (10(8) pfu) increased endothelial nitric oxide synthase activity in lung tissue and partially restored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodilation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-L-arginine methylester. We conclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent function.

Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase.

In the liver, glucose induces the expression of a number of genes involved in glucose and lipid metabolism, e.g., those encoding L-type pyruvate kinase and fatty acid synthase. Recent evidence has indicated a role for the AMP-activated protein kinase (AMPK) in the inhibition of glucose-activated gene expression in hepatocytes. It remains unclear, however, whether AMPK is involved in the glucose induction of these genes. In order to study further the role of AMPK in regulating gene expression, we have generated two mutant forms of AMPK. One of these (alpha1(312)) acts as a constitutively active kinase, while the other (alpha1DN) acts as a dominant negative inhibitor of endogenous AMPK. We have used adenovirus-mediated gene transfer to express these mutants in primary rat hepatocytes in culture in order to determine their effect on AMPK activity and the transcription of glucose-activated genes. Expression of alpha1(312) increased AMPK activity in hepatocytes and blocked completely the induction of a number of glucose-activated genes in response to 25 mM glucose. This effect is similar to that observed following activation of AMPK by 5-amino-imidazolecarboxamide riboside. Expression of alpha1DN markedly inhibited both basal and stimulated activity of endogenous AMPK but had no effect on the transcription of glucose-activated genes. Our results suggest that AMPK is involved in the inhibition of glucose-activated gene expression but not in the induction pathway. This study demonstrates that the two mutants we have described will provide valuable tools for studying the wider physiological role of AMPK.

Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells.

AIMS/HYPOTHESIS: Vulnerability of pancreatic islets to oxygen free radicals and nitric oxide contributes to islet transplantation obstacles. This susceptibility can be linked to the low expression levels of antioxidant enzymes in islets. Our aim was to investigate the effect of overexpressing Cu/Zn superoxide dismutase in human islets through a simple procedure on the cytotoxic effects of two nitric oxide donors: 3-morpholinosydnonimine (SIN-1) and S-Nitroso-N-acetyl-D,L-penicillamine (SNAP). METHODS: Cultured human islets and INS-1 rat-derived insulin-secreting cells were transfected by an E1-deleted adenovirus carrying Cu/Zn SOD cDNA under the control of a cytomegalovirus (CMV) promoter (AdSOD). The viability of the cells was tested by the WST-1 assay (Roche, Indianapolis, Ind., USA). RESULTS: The AdSOD procedure allowed SOD activity to increase by twofold to threefold for 2 to 8 days following transfection. Adenovirus-driven SOD overexpression was associated with a significant reduction of SIN-1-induced cytotoxicity on human islets (69.9 +/- 10.5% protection at 200 micromol/l and 40.5 +/- 8.9% protection at 400 micromol/l) and INS-1 cells (82.2 8.8% protection at 200 micromol/l and 31.1 +/- 5.8% protection at 400 micromol/l). Protection against increasing doses of SNAP was AdSOD dose-dependent. Transfected islets released significantly more insulin than control islets in glucose-theophylline-stimulated conditions, without or following exposure to SNAP. CONCLUSIONS/INTERPRETATION: We thus established that adenoviral-induced overexpression of Cu/Zn SOD can be beneficial to human islet endocrine function and resistance to nitric oxide cytotoxicity. These data could be relevant for the development of new strategies aimed at preventing NO-induced beta-cell damage in an islet transplantation setting.

[Local treatment during angioplasty]. / Traitement local lors de l'angioplastie.

Intracoronary thrombosis and post-angioplasty complications (acute occlusion) are now controlled. Restenosis is the principal obstacle to transluminal coronary revascularisation. The conviction of the multifactorial and focal nature of the process leading to this excessive scarring is acquired. Constrictive remodelling is now established as the main mechanism of restenosis. Failure to prevent restenosis by systemic therapy has led several groups to experiment local treatment for this problem. The object of this article is to review the different systems of local treatment at the site of angioplasty. Even if some results are encouraging, there is no solution as yet to the problem of restenosis. Although local therapy is possible, the agent(s) of choice remain(s) to be defined.

[Patients in a state of agitation at the admission service of a Rouen hospital emergency department]. / Les patients agités au service d'accueil et d'urgence du CHU de Rouen.

OBJECTIVE: To determine the incidence and causes of agitation states in patients presenting at the Rouen University Hospital emergency room and to analyze the management scheme. PATIENTS AND METHOD: A prospective study was conducted over a 9 month period in 100 consecutive patients presenting a state of agitation assessed using the Overt Aggression Scale. A pre-planned management protocol was applied. RESULTS: The incidence of states of agitation was 0.56%. There were 43 women and 57 men, mean age 33 years. Most of the agitated patients were admitted between 6 p.m. and 4 a.m. (69%). Over the 9 month period, 2 patients were admitted twice for agitation and 2 absconded. Low glucose level was the cause of agitation in 4 cases. Alcohol and/or drug use concerned 73% of the agitated patients and was the most frequently observed triggering factor (17%). Only 6% of the patients had a regular employment. Physical restraining measures and sedation were required in 86% and 84% of the cases respectively. Among 67 patients given loxapine for sedation, 2 developed acute dyskinesia and 9 low blood pressure. One out of 4 patients were referred to a psychiatric unit. CONCLUSION: Patients in a state of agitation are young, often female, and in a difficult socio-economic situation. Hypoglycemia is the main differential diagnosis. A triggering factor can often be identified. A state of agitation is not a repetitive condition but occurs as a short-lived episode in the patientís history. Such patients need rapid care to avoid further aggravation and disruption of the emergency room activity, and to prevent the patient from fleeing. Loxapine provides effective sedation but requires regular monitoring of blood pressure and can provoke acute dyskinesia in young subjects.

ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose.

The transcription of genes encoding proteins involved in the hepatic synthesis of lipids from glucose is strongly stimulated by carbohydrate feeding. It is now well established that in the liver, glucose is the main activator of the expression of this group of genes, with insulin having only a permissive role. While ADD1/SREBP-1 has been implicated in lipogenic gene expression through temporal association with food intake and ectopic gain-of-function experiments, no genetic evidence for a requirement for this factor in glucose-mediated gene expression has been established. We show here that the transcription of ADD1/SREBP-1c in primary cultures of hepatocytes is controlled positively by insulin and negatively by glucagon and cyclic AMP, establishing a link between this transcription factor and carbohydrate availability. Using adenovirus-mediated transfection of a powerful dominant negative form of ADD1/SREBP-1c in rat hepatocytes, we demonstrate that this factor is absolutely necessary for the stimulation by glucose of L-pyruvate kinase, fatty acid synthase, S14, and acetyl coenzyme A carboxylase gene expression. These results demonstrate that ADD1/SREBP-1c plays a crucial role in mediating the expression of lipogenic genes induced by glucose and insulin.

Obesity-related overexpression of fatty-acid synthase gene in adipose tissue involves sterol regulatory element-binding protein transcription factors.

Elevated lipogenesis is a key determinant of exaggerated fat deposition in adipose tissue of obese Zucker rats. We previously delineated a region in the fatty-acid synthase promoter, which was responsible for obesity-related overexpression of the fatty-acid synthase (FAS) gene, by negatively regulating the activity of the downstream promoter in lean but not obese rat fat cells. The present study aimed to identify the transcriptional factors acting on this target region. First, functional analysis of mutated FAS promoter constructs in transiently transfected lean and obese rat adipocytes showed that the activity of the obesity-related region relied on the presence of a transcriptionally inactive sterol regulatory element at -150, which counteracted activation through the downstream E-box. Adenovirus-mediated overexpression of a dominant negative form of adipocyte determination and differentiation factor 1 (ADD1) was used to neutralize endogenous ADD1/ sterol regulatory element-binding protein (SREBP) transcriptional activity in fat cells, by producing inactive dimers unable to bind target DNA. With this system, we observed that overexpression of FAS in obese rat adipocytes was ADD1/SREBP-dependent. SREBP isoforms expression was assessed in lean and obese rat fat cells and showed no differences in the level of ADD1/SREBP1 mRNA. In addition, equivalent amounts of immunoreactive ADD1/SREBP1 were found in nuclear extracts from lean and obese rat fat cells. In contrast, immunoreactive SREBP2, which was very low in nuclear extracts from lean rats, was induced in obese rat fat cells. Finally, using in vitro binding studies, we showed that SREBP2 was able to displace ADD1/SREBP1 binding from the sterol regulatory element (SRE) site. Thus, we propose a mechanism for obesity-related overexpression of FAS gene in rat adipocyte. ADD1/SREBP1-activated transcription proceeding from the E-box motif is counterbalanced by a negative SRE site acting by limiting the availability of ADD1/SREBP1 in normal fat cells. The negative effect of this site is abolished in obese rat adipocyte nuclei where SREBP2 is induced and can substitute for ADD1/SREBP1 binding to the inactive SRE. These results provide evidence for the implication of SREBPs in the dysregulation of adipocyte metabolism characteristic of the obese state.

Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets.

Susceptibility of pancreatic islets to oxidant stress may affect islet viability and contribute to primary non function of allo- or xenogenic grafts. We investigated the influence of overexpression of catalase (CAT) on the viability of human, porcine and rat islets, as well as INS-1 beta-cell line. Islets were transfected with a replication-deficient adenovirus vector containing human CAT cDNA under the control of the adenovirus major late promoter (AdCAT) or a vector containing no foreign gene (AdNull) and used as a control. Oxidant stress was induced 48 h later by xanthine oxidase-hypoxanthine (XO 25 mU/ml, HX 0.5 mmol/l) or hydrogen peroxide (100 or 250 micromol/l). Islet cell viability was assessed 72 h after CAT transfer by 4-[3-(4-Idophenyl)-2-(4 nitrophenyl)-2H-5-tetrazolio]-1,2,benzene disulphonate (WST-1) test. Baseline catalase activity was three to fourfold lower in porcine than in human islets. CAT activity was reproducibly increased 2.5- to 7-fold in AdCAT infected islets, at least for 13 days. Overall, AdCAT conferred on human and pig islets a protection of 26.1 +/- 6.1 and 21.2 +/- 9.8% on XOHX injury and 35.4 +/- 4.2 and 57.9 +/- 10.5% on H2O2 stress. Similarly, rat islet cells and INS-1 cells were protected on XOHX stress by 17.8 +/- 2.3 and 30.8 +/- 8.7%, respectively. AdNull had no effect. Basal and stimulated insulin secretion was preserved in AdCAT-transfected human islets despite a XOHX challenge. This study validates adenovirus-mediated catalase gene transfer as a realistic approach to reduce non specific inflammation effects on human or porcine islet grafts. Moreover the relevance of defense mechanisms, previously suggested in human islets, is here illustrated in porcine islets.

Gene therapy for oxidant injury-related diseases: adenovirus-mediated transfer of superoxide dismutase and catalase cDNAs protects against hyperoxia but not against ischemia-reperfusion lung injury.

Hyperoxia and ischemia-reperfusion cause profound lung cellular damage mediated, in part, by generation of oxygen radicals. We hypothesized that gene therapy can be used to overcome oxidant injury by augmenting intracellular antioxidant enzymes. Adult rats were injected intratracheally with an adenovirus (Ad) vector encoding human superoxide dismutase (CuZn-SOD) or catalase cDNA, a mixture of both Ad vectors, or a control Ad vector containing no exogenous gene. Expression of human catalase and CuZn-SOD was demonstrated 3 days later in distal lung epithelial cells and alveolar macrophages, using ELISA and immunochemistry. After exposure to 100% O2 for 62 hr, survival was greater in rats injected with the catalase and/or SOD Ad vectors than in control rats. Ischemia-reperfusion injury was evaluated in the isolated perfused lung model. Overexpression of SOD worsened ischemia-reperfusion injury. Interestingly, concomitant overexpression of catalase prevented this adverse effect, but did not protect against ischemia-reperfusion injury. We conclude that Ad-mediated transfer to lungs of both catalase and SOD cDNAs protects from pulmonary O2 toxicity. Absence of protection against ischemia-reperfusion using intratracheal Ad injections may be related to the lack of endothelial protection, despite epithelial expression of catalase and SOD.