Bordeaux University Hospital Center

Bordeaux, France

Bordeaux University Hospital Center

Bordeaux, France
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Sagnier S.,Bordeaux University Hospital Center
Stroke | Year: 2017

BACKGROUND AND PURPOSE—: Several markers of poststroke cognitive impairment have been reported. The role of brain cortical volume remains uncertain. The aim of this study was to evaluate the influence of brain cortical volume on cognitive outcomes using a voxel-based morphometry approach in subjects without prestroke dementia. METHODS—: Ischemic stroke patients were prospectively recruited 24 to 72 hours post-stroke (M0). Cognition was evaluated at M0, 3 months, and 1 year (M12) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo’s cancellation task. A 3-T brain magnetic resonance imaging was performed at M0. Grey matter (GM) was segmented using Statistical Parametric Mapping 12 software. Association between global GM volume and cognitive score slopes between M0 and M12 was evaluated using a linear mixed model. Correlations between focal GM volumes and changes in cognitive performance were evaluated using Statistical Parametric Mapping 12. RESULTS—: Two-hundred forty-eight patients were included (mean age 65±SD 14 years old, 66% men). Global GM volume was significantly associated with changes in Montreal Cognitive Assessment scores (β=0.01; P=0.04) and in the number of errors on the Zazzo’s cancellation task (β=−0.02; P=0.04) independently of other clinical/radiological confounders. Subjects with lower GM volumes in the left fronto-temporo-insular cortex were more vulnerable to transient Montreal Cognitive Assessment and Isaacs set test impairment. Subjects with lower GM volumes in right temporo-insular cortex, together with basal ganglia, were more vulnerable to transient cognitive impairment on the Zazzo’s cancellation task. CONCLUSIONS—: Smaller cortical volumes in fronto-temporo-insular areas measured 24 to 72 hours post-stroke are associated with cognitive vulnerability in the subacute stroke phase. © 2017 American Heart Association, Inc.

Chronic aortic aneurysms are permanent and localized dilations of the aorta that remain asymptomatic for long periods of time but continue to increase in diameter before they eventually rupture. Left untreated, the patients prognosis is dismal, since the internal bleeding of the rupture brings about sudden death. Although successful treatment cures the disease, the risky procedures can result in paraplegia from spinal cord ischaemia or even death, particularly for aneurysms extending from the thoracic to the abdominal aorta and thus involving many segmental arteries to the spinal cord, i.e. thoracoabdominal aortic aneurysms of Crawford type II. Although various strategies have achieved a remarkable decrease in the incidence of paraplegia, it is still no less than 10 to 20%. However, it has been found that the deliberate occlusion of the segmental arteries to the paraspinous collateral network finally supplying the spinal cord does not increase rates of permanent paraplegia. A therapeutic option, minimally invasive segmental artery coil embolization has been devised which proceeds in a staged way to occlude groups of arteries under highly controlled conditions after which time must be allowed for arteriogenesis to build a robust collateral blood supply. PAPA-ARTiS is a phase II trial to demonstrate that a staged treatment approach can reduce paraplegia and mortality dramatically. It can be expected to have both a dramatic impact on the individual patients quality of life if saved from a wheelchair, and also upon financial systems through savings in; 1) lower costs in EU health care; 2) lower pay-outs in disability insurance (est. at 500k in Year 1), and; 3) loss of economic output from unemployment. Approx. 2500 patients a year in Europe undergo these high risk operations with a cumulative paraplegia rate of over 15%; therefore >100M per year in costs can be avoided and significantly more considering the expected elimination of type II endoleaks.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.1.3-3 | Award Amount: 7.70M | Year: 2013

The goal of SYMPATH is to advance clinical development of therapeutic vaccines targeting -synuclein (aSyn)-driven neurodegenerative diseases (ND). It addresses Parkinsons disease (PD) and multiple system atrophy (MSA), two synucleopathies, for which no causal therapy exists. Ultimately, both lead to patient disability and death, which along with patient number (PD) and age of onset (MSA, PD) define their high medical need status. The proposed programme focuses on 2 vaccine candidates, PD01A and PD03A, delivered by the innovative AFFITOME technology. Both are peptide-protein conjugate vaccines and first-in-class candidates. They were selected to elicit antibodies neutralizing aSyn but sparing compensatory -synuclein. Pre-clinical evaluation confirmed their disease-modifying activity in various models. The unprecedented clinical approach, called TANDEM strategy, uses the synergy resulting from applying 2 vaccine candidates in 2 complementary indications linked through their pathology. TANDEM PD/MSA capitalizes on (i) excellent clinical research centres and their associated national/European networks, (ii) platform methods assessing aSyn species as candidate biomarkers and (iii) preliminary clinical experience with PD01A, the first aSyn targeting vaccine ever tested in humans. Its core is formed by 2 phase I studies testing PD01A in MSA and PD03A in PD/MSA. Importantly, trial design (duration, endpoints, vaccine dose and schedule) will ensure collection of initial biomarker data connecting clinical results of PD- and MSA trajectories. SYMPATH defines the logical next development step of both AFFITOPE vaccine candidates for synucleopathies and generates information/material (biobank) rendering them more amenable to rational drug development. Successful completion of the programme promises reaching aSyn pathology with an active vaccine as a causal therapy for PD/MSA, thus advancing one or both candidates as prime targets for product development and investment.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-15-2015 | Award Amount: 6.34M | Year: 2015

Stroke is the second leading cause of death in the world population. When not fatal, stroke often results in disability, due to motor and cognitive impairments, and secondary health problems affecting not only patients but also their families. Building on emerging preclinical and pilot clinical evidences, RESSTORE will focus on the clinical assessment of regenerative cell therapy to improve stroke recovery and patients quality of life. RESSTORE European multicentre randomised phase IIb will explore, for the first time, the efficacy (functional recovery) and safety of intravenous infusion of allogenic adipose tissue derived mesenchymal stem cells (ADMSCs) in 400 stroke patients. Therapeutic effects of ADMSCs will be assessed and monitored in patients using clinical rating scales, multimodal MRI and novel blood biomarkers. Additionally, the societal value and cost-effectiveness of ADMSCs-based regenerative therapy will be evaluated through health economics and predictive in silico simulations. Complementary ancillary animal studies will support the clinical trial by defining i) if the treatment response can be further enhanced by intensive rehabilitation, ii) the contribution of co-morbidities and iii) the mechanism(s) underlying the therapeutic effect. The European regenerative therapy capacities (France, Spain, Finland, United Kingdom and Czech Republic), developed in RESSTORE will cover the full value chain in the field (large scale GMP cell production, clinical testing, biomarkers discovery, understanding of the restoring mechanisms, modelling, biobanking, economic studies, exploitation and communication plan). RESSTORE will thus surely contribute, together with the workforce trained in the context of the programme, to improve its public and private (SME) competitiveness and increase the attractiveness of Europe as a reference location to develop and clinically assess new innovative therapeutic options for brain diseases.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.2.4.2-3 | Award Amount: 15.68M | Year: 2010

The initiation and perpetuation of atrial fibrillation (AF) can be regarded as a complication of a progressive transformation of the structure and functional properties of the atria. This transformation is the result of complex and multiple changes at the molecular, cellular and organ levels which interact to form the basis for proarrhythmic mechanisms in AF. Numerous individual and environmental factors are probably involved in this profound transformation process in the atria. Therefore, we believe that progress in the diagnostics, prevention and treatment of AF requires highly integrative research from the molecule to bedside and from specific signaling pathways and electrophysiological mechanisms to population based studies. A consortium was formed providing this variety of expertises and has identified central research objectives for improvements in AF prevention and therapy. In 5 work packages focusing on basic research, new biomarkers for AF and therapeutic targets will be identified. We will study mechanisms of conduction disturbances in the atria, explore new ion channel targets for treatment of AF, identify specific alterations in the atria depending on the underlying heart disease, and evaluate beneficial effects of organ-protective compounds. Within two clinically oriented work packages the clinical application of these findings will be tested. The predictive value of diagnostic tools like serum biomarkers, 3D reconstruction of atrial conduction patterns based on high resolution body surface ECGs, and echocardiographic markers will be studied in large scale population studies. The new therapeutic targets will be explored in smaller prove-of-principle clinical trials (substrate oriented ablation, new pharmacological targets, and local gene delivery).

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.2.2-1;HEALTH.2011.2.4.3-1 | Award Amount: 7.63M | Year: 2012

The prevalence of diabetes in people 65 years approaches 25% (40% of all patients with diabetes are > 65 years). This number will increase 4-fold in people > 70 years in 2050. Diabetes results in a high personal and social health burden, and a significant public health burden in terms of rising healthcare costs. Diabetes is associated with increased functional decline in older people and may explain up to 20% of their excess risk of disability. Our project focuses on the use of interventions to improve functional status and enhance quality of life. This is justified because there has been a lack of intervention studies in this population and improvements in function and well-being may be of more clinical benefit in older patients than attention to metabolic control alone. The MID-FRAIL STUDY is a Phase IIb open randomized clinical trial to evaluate the effectiveness of a multi-modal intervention (optimizing medical management, resistance-based exercise program and educational/nutritional intervention) in 1,704 frail or pre-frail subjects 70 years with T2D to prevent functional decline and maintain or improve quality of life and its associated costs. This approach is original (both the intervention and outcomes are unique for studies in diabetes), relevant (it concerns 25% of people with diabetes), pertinent and feasible. The project is highly aligned with objectives pursued by two topics of this call: investigator-driven clinical trials in elderly populations (HEALTH 2011 2.2.2-1) and in diabetes complications (HEALTH.2011.2.4.3-1). The study aims to demonstrate a reduction of 20% in that risk, which will mean an annual prevention of around 700,000 incident cases of some disability in old people, with a major impact on global quality of life and financial costs. This is especially true in older women. Three research-intensive SMEs will play a leading role in this project and it also has the support of Diabetes UK, a major patient and family advocacy organisation

Lafitte M.,Bordeaux University Hospital Center
European journal of preventive cardiology | Year: 2013

After an acute coronary syndrome (ACS), optimal medical therapy (OMT) has been shown to be effective in reducing subsequent cardiovascular (CV) events. However, even in populations that reach recommended secondary prevention goals, there is a subset of patients that experience subsequent CV events. To identify biological or clinical predictors of residual risk of CV events in post-ACS patients receiving OMT. A total of 990 post-ACS patients benefited from OMT (optimized treatment during the acute and chronic post-ACS phase, along with a therapeutic and dietary education programme). Traditional CV risk factors and atheroma disease markers (intima-media thickness measurement, carotid atheroma, peripheral arterial disease (PAD) measured by ankle brachial index, and the number of coronary arteries with a >50% stenosis) were evaluated at 3 months post ACS. Cardiovascular events were recorded at follow up. At 20-month follow up, >80% of the patients reached the recommended secondary prevention goals. In this population, diabetes was the only CV risk factor significantly associated with CV events in multivariate analysis including traditional risk factors (HR 1.61, p = 0.017). In multivariate analyses including CV risk factors and atheroma disease markers, only PAD remained significantly associated with CV events (HR 1.83, p = 0.04). The number of vascular beds involved was associated with poorer prognosis (HR for disease in 3-vascular-beds 3.85, p = 0.001, using disease in 1-vascular-bed as a reference group). In post-ACS patients with OMT, atheroma burden is a powerful prognostic marker of recurrent CV events, while diabetes remains the only independent marker of CV events among traditional CV risk factors.

Pariente B.,University Paris Diderot | Laharie D.,Bordeaux University Hospital Center
Alimentary Pharmacology and Therapeutics | Year: 2014

Background Therapeutic objectives are currently evolving in inflammatory bowel diseases (IBD) from control of symptoms towards improvement of long-term disease outcomes. In patients achieving remission, safety concerns - infections or neoplasia - and economic issues are prompting de-escalation strategies. Aim To give a complete overview of studies on de-escalating therapy in IBD. Methods A structured search in Pubmed, the Cochrane Library and EMBASE was performed using defined key words (inflammatory bowel diseases, Crohn's disease, ulcerative colitis, immunosuppressants, azathioprine, methotrexate, anti-TNF, infliximab, adalimumab, de-escalation, dose reduction, cessation, stopping, withdrawal), including full text articles and abstracts in English language. Results Eleven studies were identified, investigating cessation of immunosuppressants (IS) and/or anti-TNF treatments. Patients exposed to a combination of IS and anti-TNF have an increased risk for infections, especially due to opportunistic agent, without any clear signal for associated cancers when compared to those receiving single therapy. In patients receiving IS alone, relapse rate at 12 months following IS cessation is close to 20% and 30% in Crohn's disease (CD) and ulcerative colitis (UC) respectively. There is no study specifically evaluating anti-TNF treatment withdrawal in case of scheduled anti-TNF monotherapy in IBD. In patients receiving combination therapy with IS and infliximab (IFX) for at least 6 months, relapse rate of IFX failure following IS cessation is near to 20% at 24 months and seems to be similar in patients who maintained combination therapy. In case of anti-TNF therapy, cessation in CD patients in combo-therapy proportion of relapse is high, close to 40% and 50% over 1 year and 2 years respectively. Regarding higher risk of adverse events, some special situations - young males, pregnancy and elderly - should be managed specifically and de-escalating treatment considered. Conclusions De-escalating treatment strategy should be mainly considered in patients with high risk of severe adverse events and low relapse risk (patients in deep remission) after drug withdrawal. For these reasons, cessation of anti-TNF treatment and/or immunosuppressants should be a case by case decision in highly selected patients. © 2014 John Wiley & Sons Ltd.

Malvy D.,Bordeaux University Hospital Center
Malaria journal | Year: 2014

BACKGROUND: Parenteral artesunate is recommended as first-line therapy for severe and complicated malaria. Although its efficacy has been proven, long-term safety profile is still under evaluation. Several cases of delayed haemolytic anaemia occurred after initial clinical improvement and resolution of parasitaemia in non-immune travellers and children living in endemic areas. Reports have generated concern that this phenomenon might be related to the treatment itself, either by direct toxicity or immune-related mechanism. This is a report of the first case of autoimmune haemolytic anaemia following treatment of severe malaria initially managed with parenteral artesunate with strong indication for drug-immune related mechanism.CASE: A 17-year old Ivoirian female travelling in France presented with fever, headache and abdominal pain seven days after her arrival. Physical examination was indicative of septic shock while blood analysis showed normal haemoglobin level, but profound thrombocytopaenia and hyperlactataemia. Blood smear analysis showed Plasmodium falciparum infection with a parasitaemia of 0.8%. Severe malaria was diagnosed according to the WHO criteria. The patient was initially managed with artemether/lumefantrine combination and then parenteral artesunate for 48 hours. Empiric antibiotic course was also initiated with ceftriaxone, metronidazole, gentamycin, and then piperacillin and ciprofloxacin. At day 14, haemoglobin dropped to 4.6 g/dL with biologic features indicative of haemolysis (LDH 658 U/L, haptoglobin<0.15 g/L). At that time, parasitaemia was negative and other infections or hereditary disorders were excluded, while Coombs' direct antiglobulin test was positive for IgG and C3d. Antinuclear antibodies were absent. Further investigations evidenced drug-induced antibodies related to artesunate. It was concluded a drug-mediated autoimmune haemolytic anaemia. A corticosteroids regimen was initiated at 1 mg/kg/day. Outcome was favourable and corticosteroids were progressively tapered during two months. At present the patient's condition remains stable without recurrence of haemolytic anaemia.CONCLUSION: This is the first case of delayed haemolytic anaemia related to artesunate with a strong indication for drug-immune related mechanism. Further research is warranted to better characterize this plausible cause of post-treatment haemolysis following parenteral artesunate administration in severe malaria patients.

Bordeaux University Hospital Center | Date: 2013-04-11

The present invention relates to a nucleic acid aptamer that binds specifically to human matrix metalloproteinase 9 (h MMP-9) and its use for imaging h MMP-9 in a subject in need thereof.

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