Abraham, fin de l'éthique ? Une méditation

(Résumé de l'ouvrage) Les trois grandes religions monothéistes se partagent un même ancêtre: Abraham. Pour les juifs, il est le Juste; les chrétiens voient en lui le Père des croyants et les musulmans le nomment Ami de Dieu. Il n'y a donc pas un discours sur Abraham, mais une multitude de lectures des textes fondamentaux et superbes qui racontent le destin d'Abraham dans la Bible. Dans ce livre, on propose quelques relectures du personnage et de son accueil dans l'histoire. Les auteurs permettent ainsi de redonner à la figure emblématique d'Abraham une jeunesse oh! combien nécessaire. Auteurs: Thomas Römer, David Banon, Jean-Daniel Kaestli, Daniel Marguerat, Jean-Claude Basset, Thierry de Saussure, Bernard Reymond, Denis Müller, Pierre Gisel, Abraham Segal.

Naissances vaudoises 1993-1994: caractéristiques et facteurs de risque pour une affection chronique: rapport EDEN no 1

Une cohorte de 6477 nouveau-nés de mères résidant dans le Canton du Vaud a été recrutée pendant une année (1993-1994) dans les 18 maternités vaudoises et celle de Châtel-St-Denis. L'objectif de l'étude EDEN (Etude du DEveloppement des Nouveau-nés) est de calculer l'incidence et la prévalence des affections chroniques de toute étiologie et pour toutes les catégories de poids de naissance, à 18 mois et à 4 ans. Ce rapport présente la méthode de l'étude et l'état de santé à la naissance. Cinq critères de sélection non exclusifs ont permis de cibler un groupe de nouveau-nés à haut risque de développer une affection chronique (12% des nouveau-nés, n=760): (1) le petit poids de naissance (n=408, 6.5% des naissances vivantes); (2) une malformation congénitale ou une maladie génétique (n=157, 2.4% des naissances vivantes); (3) une affection susceptible de devenir chronique liée à une utilisation importante des services de soins au cours de la petite enfance (n=61, 0.9% des naissances vivantes); (4) le transfert aux soins intensifs (n=287, 4.4% des naissances vivantes); (5) des difficultés sociales importantes (n=105, 1.6% des naissances vivantes). Le taux d'acceptation de l'étude par les parents est bon (90%). En tout 5.9% des enfants étaient prématurés et 2.2 pour mille sont décédés à < ou = à 7 jours de vie. Selon les indicateurs à disposition, le réseau vaudois répond efficacement aux besoins en soins obstétricaux et néonatals La durée moyenne du séjour hospitalier était de 7 jours, avec des variations importantes. L'influence néfaste du tabagisme pendant la grossesse se manifeste par un doublement du risque de poids de naissance < ou = à 2500g chez les fumeuses; 24% des femmes ont fumé pendant leur grossesse, pour les trois quarts jusqu'à l'accouchement. Un grand potentiel de prévention subsiste dans ce domaine. L'examen des enfants à 18 mois, terminé fin mai 1996, ainsi que celui des 4 ans, permettront de valider les critères de sélection à la naissance comme indicateurs précoces de problèmes de santé chroniques dans la petite enfance. Les nouveaux cas d'affection chronique seront alors signalés par les pédiatres et les médecins spécialistes. [Auteurs, p. 9]

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.

The Original Risk: Over-Theologizing Ethics and Under-Theologizing Sin

The project of articulating a theological ethics on the basis of liturgical anthropology is bound to fail if the necessary consequence is that one has to quit the forum of critical modern rationality. The risk of Engelhardt's approach is to limit rationality to a narrow vision of reason. Sin is not to be understood as the negation of human holiness, but as the negation of divine holiness. The only way to renew theological ethics is to understand sin as the anthropological and ethical expression of the biblical message of the justification by faith only. Sin is therefore a secondary category, which can only by interpreted in light of the positive manifestation of liberation, justification, and grace. The central issue of Christian ethics is not ritual purity or morality, but experience, confession and recognition of our own injustice in our dealing with God and men.

Exploration of immune competencies of viral-specific CD8+T cells in MS patients using tetramers and functional CTL assays

Introduction: Epstein-Barr Virus(EBV) has been repeatedly associatedwith multiple sclerosis (MS). Wehave previously shown that there is ahigh peripheral as well as intrathecalactivation of EBV-, but not cytomegalovirus(CMV)-specific CD8+ Tcells, early in the course of MS,strengthening the link between EBVand MS. However, the trigger of thisincreased EBV-specific CD8+ T cellresponse remains obscure. It could resultfrom a higher EBV viral load. Alternatively,it could be due to an intrinsicallydeficient EBV-specificCTL response, cytotoxic granulesmediated.Thus, we performed anin-depth study of the phenotype of exvivo EBV- and CMV-specific CD8+T cells in MS patients and control patients,assessing their cytotoxic activity.Methods:We analyzed the profileof cytotoxic granules in EBV- andCMV-specific CD8+ T cells in a cohortof 13 early MS patients, 20 lateMS, 30 other neurological diseases(OND) patients and 7 healthy controlsubjects. Ex vivo analysis of EBV- orCMV-specific CD8+ T cells was performedusing HLA class I/tetramercomplexes coupled to CCR7 andCD57 markers in conjunction withperforin, granzymes A, BandKstaining.In a sub-cohort of MS patientsand controls, cytotoxic activity ofEBV- and CMV-specific CD8+ Tcells was investigated using a functionalCFSE CTL assay. Results: UsingHLA Class I tetramers for EBVand CMV, we found that the frequencyof EBV- or CMV-specificCD8+ T cells were similar in all studysubjects. Most of EBV- and CMVspecificCD8+Tcells were highly differentiated(CCR7-) and a variousproportion expressed the exhaustionmarker CD57. MS and OND patientshad increased perforin expression inEBV-specific CD8+ T cells. Most importantly,we found that MS patientswith longer disease duration tended tohave lower CTL cytotoxicity as comparedto earlyMSpatients or controls.Conclusions: Effector EBV-specificCD8+ T cells are increased in earlyMS, however their cytotoxic granuleprofile does not seem to be fully alteredand the cytotoxic activity ofthese cells is normal. However, thecytotoxic activity of CTL decreasedin late MS patients suggesting an exhaustionof EBV-specific CD8+ Tcells possibly due to EBV reactivation.This work was supported by theSwiss National Foundation PP00B3-124893, the Swiss Society for MS,and the Biaggi Foundation to RADP.

EZH2 is essential for glioblastoma cancer stem cell maintenance.

Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management.

Cholinergic neurons of fetal rat telencephalon in aggregating cell culture respond to NGF as well as to protein kinase C-activating tumor promoters.

Serum-free aggregating cell cultures of fetal rat telencephalon treated with the potent tumor promoter phorbol 12-myristate 13-acetate (PMA) showed a dose-dependent, persistent stimulation of the enzymes choline acetyltransferase (ChAT), glutamic acid decarboxylase and glutamine synthetase. After elimination of the proliferating cells by treatment of the cultures with Ara-C (0.4 microM) only the cholinergic marker enzyme, ChAT, could be stimulated by tumor promoters. The non-promoting phorbol ester, 4 alpha-phorbol 12,13-didecanoate proved to be inactive in these cultures, whereas the potent non-phorbol tumor promoter, mezerein, produced an even greater stimulatory effect than PMA. Since PMA and mezerein are potent and specific activators of protein kinase C, the present results suggest a role for this second messenger in the development of cholinergic telencephalon neurons. Stimulation of ChAT required prolonged exposure (48 h) of the cultures to PMA and the responsiveness of the cholinergic neurons to the tumor promoters decreased with progressive cellular maturation. The cholinergic telencephalon neurons showed the same pattern of responsiveness for tumor promoters as for nerve growth factor (NGF). However, the combined treatment with NGF and either PMA or mezerein produced an additive stimulatory effect, suggesting somewhat different mechanisms of action.