Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice.

OBJECTIVE: The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance. METHODS AND RESULTS: Young or old Apoe-/- mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe-/- mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe-/- mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alterantibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4+CD25+ Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection. CONCLUSION: Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to Apoe-/- mice reduces atherosclerosis through the induction of a specific Treg cell response.

Poor performances of EuroSCORE and CARE score for prediction of perioperative mortality in octogenarians undergoing aortic valve replacement for aortic stenosis.

BACKGROUND AND OBJECTIVE: Although results of cardiac surgery are improving, octogenarians have a higher procedure-related mortality and more complications with increased length of stay in ICU. Consequently, careful evaluation of perioperative risk seems necessary. The aims of our study were to assess and compare the performances of EuroSCORE and CARE score in the prediction of perioperative mortality among octogenarians undergoing aortic valve replacement for aortic stenosis and to compare these predictive performances with those obtained in younger patients. METHODS: This retrospective study included all consecutive patients undergoing cardiac surgery in our institution between November 2005 and December 2007. For each patient, risk assessment for mortality was performed using logistic EuroSCORE, additive EuroSCORE and CARE score. The main outcome measure was early postoperative mortality. Predictive performances of these scores were assessed by calibration and discrimination using goodness-of-fit test and area under the receiver operating characteristic curve, respectively. RESULTS: During this 2-year period, we studied 2117 patients, among whom 134/211 octogenarians and 335/1906 nonoctogenarians underwent an aortic valve replacement for aortic stenosis. When considering patients with aortic stenosis, discrimination was poor in octogenarians and the difference from nonoctogenarians was significant for each score (0.58, 0.59 and 0.56 vs. 0.82, 0.81 and 0.77 for additive EuroSCORE, logistic EuroSCORE and CARE score in octogenarians and nonoctogenarians, respectively, P < 0.05). Moreover, in the whole cohort, logistic EuroSCORE significantly overestimated mortality among octogenarians. CONCLUSION: Predictive performances of these scores are poor in octogenarians undergoing cardiac surgery, especially aortic valve replacement. Risk assessment and therapeutic decisions in octogenarians should not be made with these scoring systems alone.

Plasticity-associated gene Krox24/Zif268 is required for long-lasting behavioral effects of cocaine.

The extracellular signal-regulated kinases (ERKs) 1/2 pathway is stimulated by drugs of abuse in striatal neurons through coincident activation of dopamine D1 and glutamate NMDA receptors and is critical for long-lasting behavioral effects of these drugs. Although regulation of transcription is a major target of ERK, the precise mechanisms by which it contributes to behavioral alterations is not known. We examined the role of Zif268, an immediate-early gene induced by drugs of abuse under the control of ERK, in behavioral responses to cocaine using knock-in mutant mice in which Zif268 was replaced by LacZ. No biochemical or behavioral differences between mutant and wild-type mice were observed in basal conditions or in acute responses to cocaine injection. In contrast, locomotor sensitization to single or repeated cocaine injections was dramatically diminished in both heterozygous and homozygous Zif268 mutant mice. Conditioned place preference in response to cocaine was prevented in Zif268-deficient mice. This effect was not attributable to a general learning deficit because the mutant mice displayed normal conditioned place preference when food was used as reward. Our results provide direct genetic evidence for the requirement of Zif268 for long-lasting association of environmental context with specific behavioral responses after short exposures to cocaine. They also underline the common molecular machinery involved in long-lasting drug-induced behavioral alterations and the formation of other types of memory.

Extended-spectrum ß-lactamase-producing Enterobacteriaceae in French nursing homes: an association between high carriage rate among residents, environmental contamination, poor conformity with good hygiene practice, and putative resident-to-resident transmission.

OBJECTIVE: We evaluated the spread of multidrug-resistant Enterobacteriaceae in 38 nursing homes (NHs) in the Centre region of France. METHODS: We conducted a multicenter prevalence study and evaluated extended-spectrum ß-lactamase- and carbapenemase-producing Enterobacteriaceae (ESBLE and CPE, respectively) colonization of 1,155 residents. The colonizing isolates were studied by randomly amplified polymorphic DNA typing. We observed hygiene practices and studied the contamination of the environment in 8 NHs. RESULTS: A total of 114 residents were ESBLE carriers (9.9%); none were CPE carriers. A total of 82.6% of the ESBLE were Escherichia coli. ESBLE colonization was associated with poor health status (P = .002), malignancy (P = .006), urinary incontinence (P = .007), fecal incontinence (P = .002), previous hospitalization (P = .033), and carbapenem treatment (P = .040). The clonal relationship between isolates within NHs suggested resident-to-resident ESBLE transmission in 15 NHs. ESBLE isolates were recovered from 6 of 232 bedrooms studied. A total of 1,533 observations revealed low rates of conformity for hand hygiene (25.7%), the use of gloves (45.9%) and protective clothing (13.3%), and waste management (46.7%). Conformity rates correlated inversely with ESBLE carriage rates. CONCLUSIONS: In most of the participating NHs, improved application of standard precautions during incontinence care is needed, and greater efforts to clean the environment of residents are required.

Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol.

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knockin mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1 (PP1), but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of PP1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.