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Background: Clinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4 + T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides., Methods: EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP 139-151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG 35-55 (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4 + , CD4 + CD25 - and CD4 + CD25 + T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed., Findings: This experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFβ, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3 + regulatory T cells (T reg cells) in vivo., Interpretation: We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific T reg cells. These findings have overcome the drawbacks of long and repeated depletion of CD4 + T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FUND: This research was supported by the Intramural Research Program of the NIH, NIDCR., (Copyright © 2019. Published by Elsevier B.V.)

Bydureon is a new galenic formulation (long-acting release) of exenatide, the first agonist of Glucagon-Like Peptide-1 (GLP-1) receptors having been commercialized for the management of type 2 diabetes. The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot, which allows one injection per week instead of two injections per day with the initial formulation of exenatide (Byetta). The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin (HbA(1c)), with a similar weight loss but a better digestive tolerance profile (less nausea and vomiting after treatment initiation), compared with the twice daily 10 microg exenatide. When compared to other glucose-lowering agents, once weekly exenatide is more efficacious than sitagliptin, pioglitazone or basal insulin (glargine or detemir), with the advantage of producing weight loss and lowering arterial blood pressure. It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring, two advantages compared with insulin therapy. Bydureon is currently only reimbursed in Belgium after failure of and in addition to metformin-sulfonylurea combination.

The interest of the scientific community for cell penetrating peptides (CPP) has been growing exponentially for these last years, and the list of novel CPP is increasing. These peptides are powerful tools for the delivery of cargoes to their site of action. Indeed, several drugs that cannot translocate through the cell plasma membrane have been successfully delivered into cells when grafted to a CPP. Various cargoes have been linked to CPP, such as oligonucleotides, pharmacologically active drugs, contrast agents for imaging, or nanoparticles as platforms for multigrafting purposes… This review illustrates the fabulous potential of CPP and the diversity of their use, but their most interesting application appears their future clinical use for the treatment of various pathological conditions., (© 2011 médecine/sciences - Inserm / SRMS.)

We report the first case of a 33-year-old woman with multiple sclerosis, who developed a livedo-like dermatitis after injection of Copolymere-1. This disease is characterized by the development of acute violent pain during or immediately after injection, and a livedo-like plaque followed by necrosis corresponding to an arterial ischemia by vasospasm or thrombosis. Early treatment with vasoactive and anticoagulation agents is required. Surgery may be necessary.

Aim: To evaluate the risks and the significance of the use of an anti-GPIIb/IIIa, in this case Eptifibatide, during angioplasty following presumed failure of thrombolysis in the acute phase of myocardial infarction., Method: Patients thrombolyzed following MI < 6 hours. Presumed failure of reperfusion with full dose thrombolysis. Analysis evaluated the success of angioplasty associated with anti-GPIIb/IIIa treatment and the hospital phase outcome., Results: 41 consecutive patients, 32 male (78%) and 9 female (22%), were included. Infarction concerned the anterior region in 22 cases (54%) and inferior in 19 cases (46%). Fibrinolysis was performed using Alteplase in 28 patients (68%) and Reteplase in 13 patients (32%). Radial access was performed in 32 cases (78%). All of the patients received Eptifibatide with a bolus then infusion from their admission to the haemodynamic suite, on average 1 h 30 after the start of thrombolytic treatment. A total of 49 stents were implanted in 41 patients. A flux of TIMI 3 was obtained in 37 patients (90.2%). TIMI 2 in 2 patients (4.9%) and no reflow in 2 patients (4.9%). Four counter-pulsions by intra-aortic balloon were necessary (9.8%) for cardiogenic shock. No decrease in TIMI flux was observed after the angioplasty procedure. The main complications were a death from cardiogenic shock in one patients (2.4%), a non-fatal digestive tract haemorrhage in 2 cases (4.9%) and a single femoral haematoma requiring transfusion., Conclusion: The initial results were encouraging: high success rates, rare vascular complications, a probable consequence of the radial approach. The association of an anti-GPIIb/IIIa, Eptifibatide, therefore appears achievable during angioplasty with the positioning of a coronary endoprosthesis following the presumed failure of full dose thrombolysis.

Disease-modifying treatments in multiple sclerosis emerged during the last few years, concerning mainly relapsing-remitting forms of the disease. They are essentially represented by beta-interferons. beta-interferons reduce relapse rate, achieving about 30 p. cent, and have an effect on brain lesions detected on MRI. They are indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis characterized by at least 2 attacks of neurological dysfunction over the preceding 2 (or 3)-year period. Questions and controversies still remain concerning dose-response effect, early initiation and duration of treatment. Copolymer, which has a different mechanism of action, also decreases frequency of relapses, and the magnitude of the clinical effect is similar to beta-interferon. Copolymer is indicated for use in patients with relapsing-remitting multiple sclerosis, having either an intolerance or a contra-indication to beta-interferon.

The aim of the work was to develop small microspheres made from a biodegradable polymer, poly(lactide-co-glycolide), in order to entrap small peptides. Microspheres prepared by a water-in-oil-in-water emulsion solvent evaporation technique displayed a mean diameter below than 10 microns and showed high encapsulation efficiency of a 33 amino acid peptide (V3 BRU). In vitro release kinetics studies showed that such microparticles could be employed for both oral immunization and controlled release. The encapsulation of a seven aminoacid peptide in the same conditions, led to a very low encapsulation efficiency. In order to increase the entrapment efficiency, two strategies were adopted: taking into account the solubility of pBC 264 at different pH, a pH gradient was created to prevent the leakage of the encapsulated peptide into the outer aqueous phase. The inner aqueous phase was maintained at basic pH where the peptide was soluble, while the external aqueous phase was acidic: ovalbumin was added during preparation to stabilize the inner emulsion. These two strategies allowed to increase significantly the encapsulation rate of pBC 264. Nevertheless, the in vitro release kinetics of the peptide were strongly influenced by the presence of ovalbumin which seems to form pores in the microsphere structure (80% of the total peptide content was released after 30 minutes). By contrast, when ovalbumin was replaced by Pluronic F 68 microspheres did not have pores, thus the release profile and the extent of the burst were much smaller. When microspheres were stereotactically implanted in the rat brain, in vivo release profiles were in good agreement with the release observed in vitro. In conclusion, these microspheres are well suited for the slow delivery of neuropeptides in the brain, a feature expected to facilitate the study of long term effects of these compounds.

The effect of the inflammatory cytokins TNF-alpha, oncostatin M and interleukine 1 (IL1) on low density lipoprotein (LDL) oxidative modification have been studied on UNA endothelial cells or U937 monocytes in culture, by measuring the end products of lipid peroxydation (TBARS) and the relative electrophoretic mobility of the particle. TNF-alpha as well as oncostatin M stimulated in a dose-dependent manner the LDL peroxidation induced either by endothelial cells or U937 monocytes, and induced an increase in the uptake of modified LDL by J774 macrophages. Both TNF-alpha and oncostatin enhanced the superoxide anion production by endothelial cells or monocytes. In contrast, IL1 did not influence LDL cellular oxidation, but increased cholesterol esterification by stimulating the Acyl coenzyme A: cholesterol-0-acyltransferase (ACAT) activity of J774 macrophages. If IL1 acts on cholesteryl ester deposition by a mechanism differing from those of TNF-alpha or oncostatin M, all the studied cytokins may increase cholesteryl ester deposition. These results point at the potential promoting action of inflammatory processes in the progress of atherogenesis.

This surveillance made possible an immediate check up for an appropriate use of guidelines, allowing an optimal usage of antimicrobial agents. It's interest at term is to document audits (yearly for example) to discuss the effectiveness of our guidelines and, if necessary, to make new therapeutic choices, proven to be effective after investigation for clinical and microbiological data. Our surveillance system can be easily investigated by the physicians. It consists in checking on a weekly sheet all the new antimicrobial therapy courses, with name of patient, age, cause of antimicrobial therapy and hospitalization, bacteria, antibiotics used, for infection, before superinfection, previous superinfection, prophylaxis. A shift in usage of antibiotics can be observed, with consequences in antimicrobial therapy and hospital hygiene.