Large granular lymphocyte leukemia (LGL) in a child with hyper IgM syndrome and autoimmune hemolytic anemia

We describe a female with a history of autosomal recessive hyper-IgM (HIGM) syndrome along with a history of autoimmune hemolytic anemia and intermittent lymphadenopathy. She subsequently developed neutropenia, lymphocyostosis and mild thrombocytopenia. Flow cytometry of the peripheral blood revealed the presence of a marked predominance of cytotoxic T lymphocytes, shown to be clonal, with concomitant natural killer (NK) antigen expression. She responded to weekly methotrexate therapy. Pediatr Blood Cancer 2008;50:142–145. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57398/1/20902_ftp.pd

Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up

Background Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. Methods EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. Conclusion GSK’s post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E’s benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa

Avortement et contraception vus à travers Population, 1970-1981

Lamy Marie-Laurence. Avortement et contraception vus à travers Population, 1970-1981. In: Revue française de sociologie, 1982, 23-3. La libéralisation de l'avortement, sous la direction de Paul Ladrière. pp. 519-526

Moulin du milieu - Niort (catalogue de l’exposition, 17 juin 2017 au 31 déc. 2018)

National audienceLe projet de construction d’un bassin d’orage, d’une superficie de 1 300 m2, est localisé au centre de la ville de Niort sur une ancienne île de la Sèvre niortaise, au pied des remparts médiévaux de la ville et du double donjon du XIIe siècle, en face d’une des entrées de l’enceinte et du port médiéval. Ce port, appelé le grenier, devenu inaccessible en raison de son ensablement progressif et de l’implantation de moulins est abandonné à la fin de la guerre de Cent Ans. En amont de la création, par la Communauté d’Agglomération de Niort, du bassin pour récupérer les eaux pluviales et usées, une fouille archéologique préventive a été réalisée du 5 août au 27 novembre 2009, par une équipe de l’INRAP sous la houlette substantielle d’Annie Bolle, archéologue. La fouille se situe sur l’emplacement du moulin du Milieu, secteur de déploiement d’activités économiques de Niort dès le XIIIe siècle jusqu’en 1964. Cette fouille a permis d’identifier quelques évolutions, essentiellement les dernières occupations du moulin dans ses différents états de transformation, d’aménagements jusqu’à son abandon et sa destruction dans le courant du xxe siècle et dans ses fonctions : activités artisanales et industrielles qui se sont succédées (meunerie, chamoiserie, filature, mégisserie, fonderie, faïencerie…).La fouille du moulin du Milieu est un exemple rare en Poitou-Charentes d’archéologie industrielle. L’exposition Moulin du Milieu - Niort restitue l’histoire de ce moulin et un pan de l’activité industrieuse de la ville de Niort ; elle explore les mutations sociales et architecturales d’un site, patrimoine industriel