Sécularisation et humanisation dans les institutions hospitalières chrétiennes

status: publishe

Adult Vaccination for Pneumococcal Disease: a Comparison of the National Guidelines in Europe

Pneumococcal disease constitutes a major global health problem. Adults aged over 50 years and younger adults with specific chronic health conditions are at risk for invasive pneumococcal disease, associated with substantial morbidity and mortality. In Europe, two vaccine types are used in adults for pneumococcal immunization: pneumococcal polysaccharide vaccine (PPV23) and pneumococcal conjugate vaccine (PCV13). To provide an overview and to compare the national guidelines for pneumococcal immunization for adults in Europe. In November 2016, national guidelines on pneumococcal vaccination for adults of 31 European countries were obtained by Google search, the website of European Centre for Disease Prevention and Control, and contacting public health officials. In our analysis, we distinguished between age-based and risk-based guidelines. In October 2017, we used the same method to retrieve guideline updates. We observed great variability regarding age, risk groups, vaccine type, and use of boosters. In age-based guidelines, vaccination is mostly recommended in adults aged over 65 years using PPV23. Boosters are generally not recommended. An upper age limit for vaccination is reported in three countries. In the immunocompromised population, vaccination with both vaccines and administration of a booster is mostly recommended. In the population with chronic health conditions, there is more heterogeneity according vaccine type, sequence, and administration of boosters. Asplenia is the only comorbidity for which all countries recommend vaccination. The great variability in European pneumococcal vaccination guidelines warrants European unification of the guidelines for better control of pneumococcal disease.status: accepte

Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis

Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.publisher: Elsevier articletitle: Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis journaltitle: Cell Metabolism articlelink: http://dx.doi.org/10.1016/j.cmet.2013.11.008 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved.status: publishe

The role of fatty acid beta-oxidation in lymphangiogenesis

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.status: publishe

Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.status: publishe

Role of PFKFB3-Driven Glycolysis in Vessel Sprouting

Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.publisher: Elsevier articletitle: Role of PFKFB3-Driven Glycolysis in Vessel Sprouting journaltitle: Cell articlelink: http://dx.doi.org/10.1016/j.cell.2013.06.037 content_type: article copyright: Copyright © 2013 Elsevier Inc. All rights reserved.status: publishe