Damm F.,Institute Gustave Roussy |
Damm F.,French Institute of Health and Medical Research |
Damm F.,University Paris - Sud |
Nguyen-Khac F.,Service dHematologie Biologique |
And 8 more authors.
Leukemia | Year: 2012
Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. © 2012 Macmillan Publishers Limited All rights reserved.
Bouligand J.,Assistance Publique Ho pitaux de Paris |
Bouligand J.,French Institute of Health and Medical Research |
Bouligand J.,University Paris - Sud |
Delemer B.,Center Hospitalier Robert Debre |
And 19 more authors.
PLoS ONE | Year: 2010
Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11b-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension. © 2010 Bouligand et al.
Schmidt M.,Groupe Hospitalier Pitie Salpetriere |
Schmidt M.,University Pierre and Marie Curie |
Demoule A.,Groupe Hospitalier Pitie Salpetriere |
Demoule A.,University Pierre and Marie Curie |
And 10 more authors.
Critical Care Medicine | Year: 2011
Objectives: Ensuring the comfort of intensive care unit patients is crucial. Although control of pain has been extensively addressed in this setting, data on dyspnea in mechanically ventilated patients are scant. The objective of this study was to assess the prevalence of dyspnea in mechanically ventilated patients, identify its clinical correlates, and examine its impact on clinical outcomes. Design: Prospective 6-month observational study. Setting: Two medical intensive care units within university hospitals. Participants: Intubated or tracheotomized patients who were mechanically ventilated for >24 hrs. We enrolled 96 patients (age, 61 ± 18 yrs; Simplified Acute Physiology Score II 43 [interquartile range, 31-60]) as soon as they could answer symptom-related questions. Dyspnea was evaluated on a "yes-no" basis; if yes, it was followed by a visual analog scale and descriptor choice ("air hunger" and/or "respiratory effort"). Pain and anxiety were also assessed by visual analog scales. Interventions: Ventilator settings adjustment in dyspneic patients. Measurements and Main Results: Forty-five patients (47%) reported dyspnea (respiratory effort in seven cases, air hunger in 15, both in 16, and neither of these in seven). Dyspneic and nondyspneic patients did not differ in terms of age, Simplified Acute Physiology Score II, indication for mechanical ventilation, respiratory rate, clinical examination, chest radiograph, or blood gases. Dyspnea was significantly associated with anxiety (odd ratio [OR], 8.84; 95% confidence interval [CI], 3.26-24.0), assist-control ventilation (OR, 4.77; 95% CI, 1.60-4.3), and heart rate (OR, 1.33 per 10 beats/min; 95% CI, 1.02-1.75). Adjusting ventilator settings improved dyspnea in 35% of patients. Successful extubation within 3 days was significantly less frequent in patients whose dyspnea failed to recede after adjusting ventilator settings (five [17%] vs. 27 [40%]; p = .034). Conclusions: Dyspnea is frequent, intense, and strongly associated with anxiety in mechanically ventilated patients. It can be sensitive to ventilator settings and seems to be associated with delayed extubation. © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Lucet J.-C.,Bichat Claude Bernard University Hospital |
Lucet J.-C.,University Paris Diderot |
Bouadma L.,Bichat Claude Bernard University Hospital |
Zahar J.-R.,University of Paris Descartes |
And 10 more authors.
Critical Care Medicine | Year: 2010
Background: Scheduled replacement of central venous catheters and, by extension, arterial catheters, is not recommended because the daily risk of catheter-related infection is considered constant over time after the first catheter days. Arterial catheters are considered at lower risk for catheter-related infection than central venous catheters in the absence of conclusive evidence. Objectives: To compare the daily risk and risk factors for colonization and catheter-related infection between arterial catheters and central venous catheters. Methods: We used data from a trial of seven intensive care units evaluating different dressing change intervals and a chlorhexidine-impregnated sponge. We determined the daily hazard rate and identified risk factors for colonization using a marginal Cox model for clustered data. Results: We included 3532 catheters and 27,541 catheter-days. Colonization rates did not differ between arterial catheters and central venous catheters (7.9% [11.4/1000 catheter-days] and 9.6% [11.1/1000 catheter-days], respectively). Arterial catheter and central venous catheter catheter-related infection rates were 0.68% (1.0/1000 catheter-days) and 0.94% (1.09/1000 catheter-days), respectively. The daily hazard rate for colonization increased steadily over time for arterial catheters (p =.008) but remained stable for central venous catheters. Independent risk factors for arterial catheter colonization were respiratory failure and femoral insertion. Independent risk factors for central venous catheter colonization were trauma or absence of septic shock at intensive care unit admission, femoral or jugular insertion, and absence of antibiotic treatment at central venous catheter insertion. Conclusions: The risks of colonization and catheter-related infection did not differ between arterial catheters and central venous catheters, indicating that arterial catheter use should receive the same precautions as central venous catheter use. The daily risk was constant over time for central venous catheter after the fifth catheter day but increased significantly over time after the seventh day for arterial catheters. Randomized studies are needed to investigate the impact of scheduled arterial catheter replacement. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.