The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Drug-resistant and immune-escape HBV mutants in HIV-infected hosts.

International audienceHIV-HBV-coinfected patients require optimal control of viral replication in order to prevent the development of severe comorbidities, such as liver cirrhosis and hepatocellular carcinoma. The genetic diversity of HBV is a poorly investigated factor of such viral replication in HIV-infected hosts. HBV genome diversity can be differentiated into two major aspects: genotypic and phenotypic. Genotypic diversity is more related to the natural history of HBV infection and genotypes are mostly determined by geographical origin of the hosts. Phenotypic diversity arises from attempts to escape from host immune surveillance (that is, precore, core and basal core promoter mutants), selection resulting from the use of treatments with weak genetic barrier (that is, pol mutants), exposure to hepatitis B immunoglobulin (that is, 'immune-escape' S gene mutants) or treatment-induced mutations from overlapping genes (that is, pol mutants inducing 'vaccine-escape' S gene mutants). pol mutations typically lead to uncontrolled viral replication, whereas S gene mutations can significantly alter hepatitis B surface antigen synthesis and reduce binding to antibodies, which renders individuals who are vaccinated or cured of HBV infection susceptible to infection. For patients coinfected with HIV, hepatitis B treatment options that aim to reduce the risk of HBV mutations from emerging must be seriously considered, not only from clinical but also public health perspectives

Syndrome de Bartter anténatal : Difficultés diagnostiques et thérapeutiques, devenir à moyen terme (A propos de 7 observations)

Le syndrome de Bartter anténatal (SBa) est une tubulopathie héréditaire rare. Il existe trois génotypes dont le mode de transmission est autosomique récessif. Les auteurs rapportent 7 observations recueillies à partir des dossiers médicaux des Centres Hospitaliers Universitaires de Lyon (4) et de Saint-Etienne (3). Ils décrivent les difficultés diagnostiques et thérapeutiques néonatales ainsi que le devenir à moyen terme de ces enfants issus de 5 familles, dont 2 consanguines. Toutes les grossesses sont compliquées d'un hydramnios précoce (moy : 24.8 semaines d'aménorrhée (SA), (Ext : 23-31). Tous les nouveaux nés sont prématurés (moy : 33.2 SA, Ext : 29-37 SA). Ils présentent un syndrome de perte de sel rénale, une alcalose métabolique hypochlorémique hypokaliémique et une hypercalciurie, ainsi qu'un hyperaldostéronisme et une activité rénine plasmatique élevée. Des apports hydriques importants sont nécessaires, en moyenne de 292.5 ml/kg/j, mais très variables d'un enfant à l'autre (Ext : 173-405, n=4), ainsi que des apports sodés élevés, en moyenne de 25.8 mmol/kg/j (Ext : 14.9-46.3, n=4). Le SBa est diagnostiqué en période néonatale dans 3 cas. Il est retenu in utero dans un cas d'une famille connue, permettant un traitement maternel par indométhacine et une prise en charge néonatale optimale. Dans les 3 autres observations, le SBa est diagnostiqué tardivement à 7, 10 et 11 ans alors que la prise en charge néonatale symptomatique à été identique. Les analyses génétiques ont confirmé le diagnostique dans tout les cas. Le traitement par inhibiteur de synthèse des prostaglandines (ISP) est commencé en période néonatale précoce dans 4 cas, avec l'indométhacine dans 3 cas et l'ibuprofen dans un cas, sans effet indésirable grave. Il entraîne une diminution nette des apports apports hydrosodés et une meilleure prise pondérale, mais n'a pas évité l'apparition précoce de la néphrocalcinose. Il est instauré bien avant que le SBa ne soit diagnostiqué dans les 3 autres cas, pour tenter de contrôler l'hypercalciurie. A la fin du suivi, tous les enfants, âgés de 2.7 à 12.7 ans, sont toujours traités pas ISP. Deux sont également sous diurétiques thiazidiques. Leur croissance staturopondérale et leur fonction rénale sont correctes. Le seul effet secondaire grave imputé à l'indométhacine est digestif (ulcère duodénal perforé). Conclusion : le SBa reste une pathologie rare qui va être évoquée chez un prématuré polyurique dans un contexte d'hydramnios. L'expression clinique est variable, la prise en charge reste intensive en période néonatale. Les symptômes ont tendance à s'atténuer après les 6 premiers mois de vie. L'efficacité du traitement par IPS est nette sur la polyurie et la croissance, mais reste limitée sur la néphrocalcinose. L'ibuprofen, utilisé chez un seul enfant, semble aussi efficace que l'indométhacine. Les inhibiteurs sélectifs de COX2 n'ont pas été essayés chez ces patients.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

"The Fact that Things Keep Going On Like This Is the Catastrophe". The Spectacularization of 9/11 Compared wil Pablo Picasso's Guernica

La spettacolarizzazione dell'attacco alle Twin Towers viene criticamente confrontato con la pittura storica Guernica di Picasso per indagare le differenze di percezione e fruizione in vista dell'evento che sta alla base delle rispettive espressioni televisive e artistiche

L'imaginaire du volcan

Quelle force naturelle pouvait, mieux que le volcan, devenir la métaphore vive de l'enthousiasme poétique ? Auteur du paysage qu'il remodèle après l'avoir détruit, sculpteur de laves autant qu'objet pittoresque, le volcan est dans la littérature un actant essentiel, un relais de l'auteur, comme le montre ce voyage dans la mémoire des représentations volcaniques

Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells

International audienceAccumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 Cancers 2018, 10, 452 2 of 17 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations

Observations of a large Dent disease cohort.

Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

International audienc