Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Nonviral gene transfer into primary cultures of human and porcine mesothelial cells.

International audienceDue to their abundance and accessibility, mesothelial cells may be suitable tools for recombinant reagent expression by gene transfer. Genetically modified porcine mesothelial cells (PMCs) may have the potential for the treatment of vascular diseases in humans. We studied the effect of various transfection reagents on the primary culture of PMCs and human mesothelial cells (HMCs). The cells were transfected with a plasmid encoding a reporter gene (luciferase or green fluorescent protein [GFP]) under the control of the cytomegalovirus promoter. Transfection was achieved using cationic lipids (DOSPER and DOTAP) or calcium phosphate/deoxyribonucleic acid coprecipitation or Fugene 6. Results showed that Fugene 6 was the most efficient and reproducible transfection reagent with both PMCs and HMCs. With Fugene 6, luciferase activity in PMCs (1.5 x 10(8) relative light units [RLU]/10(6) cells) was at least 2.5-fold higher than with the other transfection reagents, and it was 100-fold higher than in HMCs. However, the proportion of transfected cells expressing GFP was only 1%. These preliminary findings open up new avenues for developing experimental studies on the use of genetically modified PMCs

Increased IGM and IGG anti-NEU5GC antibodies in infectious mononucleosis (IMN): link with multiple sclerosis (MS)?

International audienceIntroduction: Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease which displays an autoimmune component at its overt clinical stage. Among etiological hypotheses, the potential initiating role of EBV in the disease has been raised following works linking EBNA levels and the risk of MS occurrence [1] showing a linkage between the occurrence of IMN and MS. Our hypothesis is that a vigorous production of anti-Neu5Gc in IMN (as indirectly measured by Paul-Bunnell Davidson reaction) may induce brain blood barrier alterations when the EBV primo-infection is contemporary of an extraordinary high frequency of EBV committed T cells and of circulating EBV+ memory B cells[2]. Our aim was to measure anti-Neu5Gc IgG and IgM levels during the IMN and to investigate whether levels of anti-NeuGc could be also increased in MS. Material and Methods: Sera from 49 patients with overt IMN were collected from the University Hospital of Grenoble and Nantes. The gender ratio was 22F/ 27M. The age average was 24 years (range: 7- 65). Two cohorts of EBV negative individuals (n= 45) and healthy individuals (n= 120) were used as controls. A second cohort of 46 patients with proven MS was collected from the University Hospital of Nantes. The gender ratio was 30F/ 16M. The age average was 48 years (range: 22-73). This cohort contained 30 patients presenting a Remitting Relapsing (RR) form (65.2%) and 16 with a Secondary or Primary Progressive (SP-PP) one (34.7%). A cohort of healthy individuals (n= 37) matched for gender and age was used as controls. On these samples, we performed two Elisa [3][4] to quantify anti-Neu5Gc IgG and IgM antibodies. Results: We showed a highly significant increase in anti-Neu5Gc IgM in IMN patients in comparison to EBV negative controls (0.82±0.16 vs. 0.15±0.05 ng/ul; p<0.0001). Anti-Neu5Gc IgG were also, though less dramatically, increased (3.64±0.6 vs. 2.78±0.57ng/ul; p=0.04). The values obtained in IMN differed significantly to healthy individuals (0.82±0.16 vs. 0.2±0.03 ng/ul;p<0.0001 for IgM and 3.63±0.6 vs. 2.74±0.3 ng/ul; p= 0.01 for IgG). The levels of anti-α1-3Gal epitopes, an other type of «xeno» antibody against a sugar not synthesized by normal individuals were also increased during IMN (12.4±1.1 vs. 9.67±1.46 ng/ul for EBV negative controls and vs. 11.7±3.4 ng/ul for healthy individuals; p<0.0001 for both). We found neither increase in anti-Neu5gc antibodies in this small MS patient cohort (p=0.8 for IgM and p=0.84 for IgG), nor in RR or SP-PP subgroups. We found no correlation between the anti-Neu5Gc titers and age or gender of IMN or MS patients, or of healthy individuals. Conclusion: Despite the fact that EVB does not express Neu5Gc, anti-Neu5Gc antibodies are strongly increased in IMN patients, suggesting that uptake of Neu5Gc from dietary sources by EBV infected cells induces them to become more immunogenic during the acute disease. However our data did not evidence higher anti-Neu5Gc antibodies in established MS

Résistances — À l'horizon — Représenter la diversité dans la cité — Oser

Ce numéro 75 des Cahiers victoriens et édouardiens rassemble sept communications effectuées lors du colloque annuel de la Sfeve qui s’est tenu à l’université de Dijon en janvier 2010 et qui s’intitulait « Résistances », six communications données lors du 50e congrès de la SAES qui s’est tenu à Lille en mai 2010 et qui s’intitulait « À l’horizon », une communication du colloque de la Sfeve de Cergy en janvier 2011 sur le thème « Représenter la diversité dans la cité » et enfin deux communications effectuées lors du 51e congrès de la SAES de mai 2011 intitulé « Oser » accueilli par Paris III . L’ensemble des articles a été recueilli par le professeur Laurent Bury, président de la Sfeve. This issue of Cahiers victoriens et édouardiens is a collection of articles based upon papers given on four occasions: seven papers from the annual Sfeve conference which was held in Dijon in January 2010 and was entitled ‘Resistance’, six papers from the 50th SAES conference which was held in Lille in May 2010 named ‘On the horizon’, one paper from the Sfeve conference which was held in Cergy in January 2010 and was entitled ‘Representing diversity in the city’ as well as two papers from the 51st SAES conference which was held in Paris III in May 2011 named ‘Daring’. The volume is edited by Professor Laurent Bury, President of the Société française des études victoriennes et édouardiennes (Sfeve)