Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos

AbstractWe have previously shown that hepcidin transgenic embryos are severely anemic and die around birth. Here, we report that embryonic hepcidin transgene expression decreases transferrin receptor 1 (TfR1) mRNA level in placenta, as shown by cDNA microarray analysis and quantitative RT-PCR, by a mechanism which is independent of placenta iron content and iron responsive element/iron regulatory protein (IRE/IRP) activity. On the contrary, iron injections into pregnant mothers result in increased placenta iron and ferritin content, and reduced IRE binding activity of IRP1 leading to decreased TfR1 mRNA level. Taken together, these results suggest that hepcidin action on placenta is mostly through transcriptional downregulation of the iron uptake machinery

Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity.

L'article final de l'éditeur contient 9 pages. Le manuscrit accepté contient 32 pages.International audienceMutations of the TMPRSS6 gene, which encodes Matriptase-2, are responsible for iron-refractory iron-deficiency anemia. Matriptase-2 is a transmembrane protease that downregulates hepcidin expression. We report one frameshift (p.Ala605ProfsX8) and four novel missense mutations (p.Glu114Lys, p.Leu235Pro, p.Tyr418Cys, p.Pro765Ala) found in IRIDA patients. These mutations lead to changes in both the catalytic and noncatalytic domains of Matriptase-2. Analyses of the mutant proteins revealed a reduction of autoactivating cleavage and the loss of N-Boc-Gln-Ala-Arg-p-nitroanilide hydrolysis. This resulted either from a direct modification of the active site or from the lack of the autocatalytic cleavage that transforms the zymogen into an active protease. In a previously described transfection assay measuring the ability of Matriptase-2 to repress the hepcidin gene (HAMP) promoter, all mutants retained some, if not all, of their transcriptional repression activity. This suggests that caution is called for in interpreting the repression assay in assessing the functional relevance of Matriptase-2 substitutions. We propose that Matriptase-2 activity should be measured directly in the cell medium of transfected cells using the chromogenic substrate. This simple test can be used to determine whether a sequence variation leading to an amino acid substitution is functionally relevant or not

Austrittsrezepte: pharmazeutische Interventionen in der Offizin

Die Versorgungskontinuität oder Continuity of Care stellt eine grosse Herausforderung im Gesundheitsbereich dar. Der Spitalaustritt ist ein heikler Schritt mit Optimierungsbedarf, um eine angemessene Arzneimittelsicherheit zu gewährleisten. Die Apotheke der Spitäler der Region Ost-Waadtland (Pharmacie des Hôpitaux de l’Est Lémanique; PHEL), die Offizinapotheker:innen der Waadt- länder Riviera und das Riviera-Chablais Spital, Waadt-Wallis (Hôpital Riviera- Chablais; HRC) haben eine Studie durchgeführt, um den Versorgungs- übergang beim Spitalaustritt zu beurteilen. Vorschläge, wie die pharma-zeutische Betreuung optimiert werden könnte, liegen auf dem Tisch.La continuité des soins représente un enjeu de santé majeur, et la sortie d’hôpital est une étape délicate qui a besoin d’être optimisée pour assurer une sécurité médicamenteuse adéquate. Une étude pour évaluer la transition des soins lors de la sortie d’hôpital a été réalisée par la Pharmacie des Hôpitaux de l’Est Lémanique (PHEL), les pharmaciens d’officine de la Riviera vaudoise et l’Hôpital Riviera-Chablais,Vaud-Valais (HRC). Avec à la clé des suggestions pouvant optimiser le suivi pharmaceutique

Pharmaceutical interventions on hospital discharge prescriptions: Prospective observational study highlighting challenges for community pharmacists

Background: Transition between hospital and ambulatory care is a delicate step involving several healthcare professionals and presenting a considerable risk of drug-related problems. Objective: To investigate pharmaceutical interventions made on hospital discharge prescriptions by community pharmacists. Method: This observational, prospective study took place in 14 community pharmacies around a Swiss acute care hospital. We recruited patients with discharge prescriptions (minimum three drugs) from the internal medicine ward of the hospital. The main outcome measures were: number and type of pharmaceutical interventions made by community pharmacists, time spent on discharge prescriptions, number of medication changes during the transition of care. Results: The study included 64 patients discharged from the hospital. Community pharmacists made a total of 439 interventions; a mean of 6.9 ± 3.5 (range 1-16) interventions per patient. All of the discharge prescriptions required pharmaceutical intervention, and 61 (95%) necessitated a telephone call to the patients' hospital physician for clarifications. The most frequent interventions were: confirming voluntary omission of a drug (31.7%), treatment substitution (20.5%), dose adjustment (16.9%), and substitution for reimbursement issues (8.8%). Roughly half (52%) of all discharge prescriptions required 10-20 min for pharmaceutical validation. The mean number of medication changes per patient was 16.4: 9.6 changes between hospital admission and discharge, 2.6 between hospital discharge and community pharmacy, and 4.2 between community pharmacy and a general practitioner's appointment. Conclusion: Hospital discharge prescriptions are complex and present a significant risk of medication errors. Community pharmacists play a key role in preventing and identifying drug-related problems.</p

ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia

The presence of ETV6 deletions was investigated in 215 children with acute lymphoblastic leukemia (ALL) using the loss of heterozygosity (LOH) approach. We used four intragenic or juxtagenic microsatellite markers to detect allelic deletions. In this series of unselected patients, LOH of ETV6 markers was found in 23% of cases (6% of T-ALL and 26% of B lineage ALL) confirming that chromosome 12p12-13 deletions represent a major genetic alteration in childhood ALL, frequently missed by cytogenetic analysis. The presence of a t(12;21)(p13;q22) was studied by RT-PCR and/or FISH in a total of 134 patients (125 B lineage ALL, nine T-ALL) including 42 cases with LOH. Thirty-four out of 44 patients (77%) for whom a t(12;21) was observed displayed LOH of the ETV6 markers. When associated with a t(12;21), ETV6 is very likely to be the target of deletions as indicated by the detection of intragenic deletions in three patients. Although deletion of ETV6 and t(12;21) were associated in most patients, in eight cases (six B lineage and two T-ALL) LOH was detected at the ETV6 locus without ETV6-AML1 hybrid RNA. FISH studies conducted in five of these eight patients confirmed the absence of translocation involving ETV6. In such patients, the other allele of ETV6 could be disrupted by either a small deletion, a point mutation, or an epigenetic modification and it will be of interest to study the structure and expression of the remaining allele of ETV6 in these cases. Alternatively, a tumor suppressor gene located close to ETV6 and CDKN1B could be the target of deletions.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pasteurs des âmes, Passeurs des Arts

Les disciplines historiques ont porté un éclairage décisif sur la diversité du clergé séculier et sur sa place dans la société française d’Ancien Régime ; analysée à travers les prismes de la culture matérielle, de l’histoire sociale et politique ou de l’anthropologie religieuse, la figure du prêtre de campagne est aujourd’hui mieux cernée. Sans être totalement négligées, les recherches sur l’implication du bas clergé dans la commande artistique des temps modernes attendent cependant des approfondissements, dont cet ouvrage livre tes premières réflexions. Les prêtres étaient probablement les premiers concernés par le décor de leurs églises mais quelle était précisément la nature de leurs « participations » ? Quelques interrogations ont déjà leurs réponses : textes et documents livrent des preuves de leur immixtion dans la commande, allant de la mise en œuvre des adjudications au choix des artistes ou des ateliers, à la gestion des coûts, la sélection des matériaux, etc. Et si nous pouvons saisir la manière dont les hommes d’église s’immisçaient dans la création, l’examen des portraits qu’ils ont laissés documente conjointement la perception de leur propre condition : des guides de cortèges processionnels aux faiseurs de miracles, des célébrants d’autels aux « notables » en soutanes, ces représentations sont autant d’indices qui éclairent la vie et la culture des dites paroissiales qu’ils constituaient