Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Relative adrenal insufficiency and hemodynamic status in cardiopulmonary bypass surgery patients. A prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The objectives of this study were to determine the risk factors for relative adrenal insufficiency in cardiopulmonary bypass patients and the impact on postoperative vasopressor requirements.</p> <p>Methods</p> <p>Prospective cohort study on cardiopulmonary bypass patients who received etomidate or not during anesthetic induction. Relative adrenal insufficiency was defined as a rise in serum cortisol ≤ 9 μg/dl after the administration of 250 μg of consyntropin. Plasma cortisol levels were measured preoperatively, immediately before, 30, 60, and 90 minutes after the administration of cosyntropin, and at 24 hours after surgery.</p> <p>Results</p> <p>120 elective cardiopulmonary bypass patients were included. Relative adrenal insufficiency (Δcortisol ≤9 μg/dl) incidence was 77.5%. 78 patients received etomidate and 69 (88%) of them developed relative adrenal insufficiency, (<it>P </it>< 0.001). Controlling for clinical characteristics with a propensity analysis, etomidate was the only independent risk factor associated with relative adrenal insufficiency (OR 6.55, CI 95%: 2.47-17.4; <it>P </it>< 0.001). Relative adrenal insufficiency patients showed more vasopressor requirements just after surgery (<it>P </it>= 0.04), and at 4 hours after surgery (<it>P </it>= 0.01). Pre and post-test plasma cortisol levels were inversely associated with maximum norepinephrine dose (ρ = -0.22, <it>P </it>= 0.02; ρ = -0.18, <it>P </it>= 0.05; ρ = -0.21, <it>P </it>= 0.02; and ρ = -0.22, <it>P </it>= 0.02, respectively).</p> <p>Conclusions</p> <p>Relative adrenal insufficiency in elective cardiopulmonary bypass patients may induce postoperative vasopressor dependency. Use of etomidate in these patients is a modifiable risk factor for the development of relative adrenal insufficiency that should be avoided.</p

International recommendations for glucose control in adult non diabetic critically ill patients

The purpose of this research is to provide recommendations for the management of glycemic control in critically ill patients.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishedPour la Société Française d'Anesthésie-Réanimation (SFAR); Société de Réanimation de langue Française (SRLF) and the Experts grou

Prevalence and risk factor analysis of resistant Escherichia coli urinary tract infections in the emergency department.

Background: Escherichia coli (E. coli) is a frequent uropathogen in urinary tract infections (UTI). Widespread resistance to sulfamethoxazole-trimethoprim (SMX-TMP) and increasing resistance to fluoroquinolones amongst these isolates has been recognized. There are limited data demonstrating risk factors for resistance to both SMX-TMP and fluoroquinolones.Objectives: This study was conducted to assess for the prevalence of community resistance amongst E. coli isolates to SMX-TMP and levofloxacin in ambulatory patients discharged from the emergency department (ED).Methods: Adults presenting for evaluation and discharged from the ED with a diagnosis of an E. coli UTI were retrospectively reviewed. Utilizing demographic and clinical data the prevalence of E. coli resistance and risk factors associated with SMX-TMP- and fluoroquinolone-resistant infection were determined. Results: Among the 222 patients, the mean rates of E. coli susceptibility to levofloxacin and SMX-TMP were 82.4% and 72.5%, respectively. Significant risk factors for resistance to SMX-TMP included prior antibiotic use (p=0.04) and prior diagnosis of UTI (p= 0.01). Significant risk factors for resistance to levofloxacin included: male gender, age, presence of hypertension, diabetes, chronic respiratory disease, nursing home resident, previous antibiotic use, previous diagnosis of UTI, existence of renal or genitourinary abnormalities, and prior surgical procedures (p <0.05 for all comparisons). The number of hospital days prior to initial ED evaluation (p<0.001) was determined to be a predictive factor in hospital and ED readmission. Conclusions: These results suggest that conventional approaches to monitoring for patterns of susceptibility may be inadequate. It is imperative that practitioners develop novel approaches to identifying patients with risk factors for resistance. Identification of risk factors from this evaluation should prompt providers to scrutinize the use of these agents in the setting of patients presenting with an uncomplicated UTI in the ED