Nathalie Gault

NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia

TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1–expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1–LMO–Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.

Clinical spectrum and outcomes of patients with encephalitis requiring intensive care.

Our aim was to characterize the clinical profile, temporal changes and outcomes of patients with severe encephalitis.

Self-controlled designs in pharmacoepidemiology involving electronic healthcare databases: a systematic review

BackgroundObservational studies are widely used in pharmacoepidemiology. Several designs can be used, in particular self-controlled designs (case-crossover and self-controlled case series). These designs offer the advantage of controlling for time-invariant confounders, which may not be collected in electronic healthcare databases. They are particularly useful in pharmacoepidemiology involving healthcare database. To be valid, they require the presence of some characteristics (key validity assumptions), and in such situations, these designs should be preferred. We aimed at describing the appropriate use and reporting of the key validity assumptions in self-controlled design studies.MethodsArticles published between January 2011 and December 2014, and describing a self-controlled study design involving electronic healthcare databases were retrieved. The appropriate use (fulfilment of key assumptions) was studied in terms of major (abrupt onset event, rare or recurrent event, and intermittent exposure) and minor assumptions (those for which the design can be adapted).ResultsAmong the 107 articles describing a self-controlled design, 35/53 (66%) case-crossover studies, and 48/55 (87%) self-controlled case series fulfilled the major validity assumptions for use of the design; 4/35 and 14/48 respectively did not fulfill the minor assumptions. Overall, 31/53 (58%) case-crossover studies and 34/55 (62%) self-controlled case series fulfilled both major and minor assumptions. The reporting of the methodology or the results was appropriate, except for power calculation.ConclusionsSelf-controlled designs were not appropriately used in34% and 13% of the articles we reviewed that described a case-crossover or a self-controlled case series design, respectively. We encourage better use of these designs in situations in which major validity assumptions are fulfilled (i.e., for which they are recommended), accounting for situations for which the design can be adapted.

Macrophage production and activation are dependent on TRIM33

The tripartite motif (TRIM) family of proteins plays important roles in innate immunity and antimicrobial infection. None of these proteins has been shown to directly regulate transcription of genes in monocyte/macrophage except TRIM33 that we have recently shown to be a macrophage specific transcriptional inhibitor of Ifnb1. Using ChIP-seq analyses, we now report that TRIM33 is bound to two fold more genes in immature than in mature myeloid cell lines. When located near the same genes, TRIM33 is bound to different sequences in the two cell lines suggesting a role of TRIM33 in both immature and mature myeloid cells. Accordingly, expression of TRIM33 in immature myeloid cells is necessary for efficient production of small peritoneal macrophages, monocytes and bone marrow derived macrophage (BMDM) and TRIM33 targets a subset of genes involved in the inflammatory response only in mature myeloid cells. Functionally, this targeting is associated with impaired repression of pathways regulating the late phases of lipopolysaccharide (LPS) activation of BMDM and a high sensitivity to LPS in vivo when the trim33 gene is inactivated in mature myeloid cells. These findings pinpoint TRIM33 as an important transcriptional actor of monocyte/macrophage mediated inflammation.

Repeated lumbar puncture in adults with pneumococcal meningitis: An observational study

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Ventilator-associated pneumonia due to carbapenem-resistant Gram-negative bacilli in an intensive care unit without carbapenemase-producing Enterobacteriaceae or epidemic Acinetobacter baumannii

Abstract Risk factors for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacilli (CR-GNB) have rarely been evaluated in intensive care units (ICU) without epidemic carbapenemase-producing Acinetobacter baumannii or Enterobacteriaceae. We addressed this issue in a cohort of 141 patients (previous antimicrobial exposure, n = 131) with a first episode of VAP in a medico-surgical ICU. Twenty-six VAP (18.4%) involved a CR-GNB (Pseudomonas aeruginosa, n = 14, Stenotrophomonas maltophilia, n = 11, and A. baumannii, n = 1), without previous carbapenem exposure in 12 (46.1%) cases. GNB resistant to all β-lactams except carbapenems were equally isolated in CR-GNB VAP (co-infections, 23%) and other episodes (30%). Previous exposure to aminoglycosides (odds ratio (OR) 1.14 per day, 95% confidence interval (CI) 1.02–1.30, p = 0.02) and the number of antimicrobial classes used before VAP (OR 1.38 per class, 95% CI 1.10–1.73, p = 0.006) were the only independent predictors of CR-GNB. These results suggest that the empirical use of a carbapenem–colistin combination should be evaluated in late-onset VAP following broad-spectrum antimicrobial exposure.

Underuse of self-controlled designs in pharmacoepidemiology in electronic healthcare databases: a systematic review.

The self‐controlled (SC) designs offer the advantage of inherently controlling for time‐invariant confounders, which may not be collected in electronic healthcare databases. To be valid, the design requires that some characteristics must be present. Recommendations for their use have been published in 2012, which encourage their implementation when these key characteristics are valid. We aimed at describing the potentially missed opportunities for the use of SC in pharmacoepidemiological studies on electronic healthcare databases.

Impact d’un livret thérapeutique sur la qualité des prescriptions médicamenteuses des résidents d’EHPAD

OBJECTIVE Elderly with several pathologies are usually treated with many drugs, and are exposed to a majored risk of drug-induced adverse effects. A network of local nursing homes (EHPAD) in the south Seine-Saint-Denis area (France) created a geriatric drug guidelines to improve the quality of the drugs prescriptions. This study assesses the conformity of prescriptions in elderly patients prior and after the distribution of the booklet. METHODS This before and after design study focused on the drug prescriptions for patients in eight EHPAD followed for two randomly given days in 2012 (n = 503) and 2013 (n = 334). The geriatric drug guidelines included a list of medicines suitable for the elderly (conformity list) and recommendations for prescription and monitoring. Data collection was conducted from medical records and interviews with coordinators doctors and nursing staff in nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS Median age, weight and creatinine level were respectively 88 years, 61.0 kg, and 74.9 μmol/L (prior) and 88 years, 59.6 kg, and 77.0 μmol/L (after). Median times of latest serum creatinine dosage were 112 days (prior) and 108 days (after). The median number of prescribed drugs was 8 per resident during the two period of study. The conformity rate of prescription was better prior the distribution of the guidelines, respectively 87.5% and 80.0% (p<10⁻³). The average formal quality score was better after the distribution of the booklet increasing form 4.23 to 4.40 points (p<10⁻⁴). For high risk inducing drugs, monitoring was prescribed in 34.2% (prior) and 32.4% (after). CONCLUSIONS This study shows that the drug geriatric guidelines does not improve prescription conformity and monitoring for high risk drugs, but it does significantly improve the median formal quality score.