CD43 Functions as an E-Selectin Ligand for Th17 Cells In Vitro and Is Required for Rolling on the Vascular Endothelium and Th17 Cell Recruitment during Inflammation In Vivo.

Endothelial E- and P-selectins mediate lymphocyte trafficking in inflammatory processes by interacting with lymphocyte selectin ligands. These are differentially expressed among different T cell subsets and function alone or in cooperation to mediate T cell adhesion. In this study, we characterize the expression and functionality of E-selectin ligands in Th type 17 lymphocytes (Th17 cells) and report that CD43 functions as a Th17 cell E-selectin ligand in vitro that mediates Th17 cell rolling on the vascular endothelium and recruitment in vivo. We demonstrate Th17 cells express CD44, P-selectin glycoprotein ligand (PSGL)-1, and CD43. Few PSGL-1(-/-)CD43(-/-) Th17 cells accumulated on E-selectin under shear flow conditions compared with wild-type cells. CD43(-/-) Th17 cell accumulation on E-selectin was impaired as compared with wild-type and PSGL-1(-/-), and similar to that observed for PSGL-1(-/-)CD43(-/-) Th17 cells, indicating that CD43 alone is a dominant ligand for E-selectin. Notably, this finding is Th17 cell subset specific because CD43 requires cooperation with PSGL-1 in Th1 cells for binding to E-selectin. In vivo, Th17 cell recruitment into the air pouch was reduced in CD43(-/-) mice in response to CCL20 or TNF-α, and intravital microscopy studies demonstrated that CD43(-/-) Th17 cells had impaired rolling on TNF-α-treated microvessels. Furthermore, CD43(-/-) mice were protected from experimental autoimmune encephalomyelitis and had impaired recruitment of Th17 cells in the spinal cord. Our findings demonstrate that CD43 is a major E-selectin ligand in Th17 cells that functions independent of PSGL-1, and they suggest that CD43 may hold promise as a therapeutic target to modulate Th17 cell recruitment.

Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.

BACKGROUND: Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. METHODS: Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. FINDINGS: Median clopidogrel exposure time was 1.07 years (IQR 0.28-3.0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (eight vs four events; HR 6.02 [1.81-20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3.00 [1.27-7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81-9.02], p=0.0006). INTERPRETATION: The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction.

Impact of emergency department management of atrial fibrillation with amiodarone on length of stay. A propensity score analysis based on the URGFAICS registry.

OBJECTIVE: Amiodarone is a widely used drug in the emergency department (ED) for control of atrial fibrillation, but it has a delayed onset of action and slow metabolism, leading to longer length of ED stay. The aim of this study was to compare the length of ED stay of atrial fibrillation patients who were treated with or without amiodarone. METHODS: We undertook a multicenter, observational, cohort study of the URGFAICS registry of older adults with atrial fibrillation who presented to five Spanish EDs and compared patients who had received amiodarone with those who had not. Afterward, we performed a propensity score matched analysis of atrial fibrillation to determine the ED length of stay related to amiodarone. RESULTS: Of the 1199 patients included in the registry, 225 patients (18.8%) were treated with amiodarone while 974 (81.2%) were not. We performed a univariate study depending on amiodarone administration followed by propensity score calculation according to the 14 statistically different features found previously and six significant variables, obtaining 150 patients (75 for each group) suitable for the analysis. The length of ED stay was analyzed using box plot, with a P <0.001 in the crude analysis and P = 0.012 after propensity score matching and using survival curves for the analysis of prolonged ED stay, with a log rank <0.001 in the crude analysis and log rank 0.021 after the propensity score-matched analysis. CONCLUSION: Amiodarone is associated with longer length of ED stay until discharge independently of the baseline characteristics of the patients.

Not All Nonverbal Tasks Are Equally Nonverbal: Comparing Two Tasks in Bilingual Kindergartners With and Without Developmental Language Disorder.

Purpose This study investigates the interaction of language ability status, cultural experience, and nonverbal cognitive skill performance in Spanish-English bilinguals with typical development (TD) and developmental language disorder (DLD). Method One hundred sixty-nine Spanish-English bilingual kindergartener's scores on the Symbolic Memory and Cube Design subtests from the Universal Nonverbal Intelligence Test (Bracken & McCallum, 1998) were analyzed by language ability (TD vs. DLD). Results t tests and analysis of variance showed bilingual children with TD and DLD performed comparably to the Universal Nonverbal Intelligence Test norming sample on the cube design task, while children with DLD had significantly lower performance on the symbolic memory task. Conclusion These results suggest that cultural experience minimally impacted performance for bilingual children with typically developing language. Bilingual children with DLD were differentially impacted on symbolic memory, a task that is verbally mediated despite nonverbal administration and performance. Findings are discussed within the Cattell-Horn-Carroll theory of cognitive abilities.

Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure.

BACKGROUND: Despite the emerging association between heart failure (HF) and inflammation, the role of T cells, major players in chronic inflammation, has only recently begun to be explored. Whether T-cell recruitment to the left ventricle (LV) participates in the development of HF requires further investigation to identify novel mechanisms that may serve for the design of alternative therapeutic interventions. METHODS AND RESULTS: Real-time videomicroscopy of T cells from nonischemic HF patients or from mice with HF induced by transverse aortic constriction revealed enhanced adhesion to activated vascular endothelial cells under flow conditions in vitro compared with T cells from healthy subjects or sham mice. T cells in the mediastinal lymph nodes and the intramyocardial endothelium were both activated in response to transverse aortic constriction and the kinetics of LV T-cell infiltration was directly associated with the development of systolic dysfunction. In response to transverse aortic constriction, T cell-deficient mice (T-cell receptor, TCRα(-/-)) had preserved LV systolic and diastolic function, reduced LV fibrosis, hypertrophy and inflammation, and improved survival compared with wild-type mice. Furthermore, T-cell depletion in wild-type mice after transverse aortic constriction prevented HF. CONCLUSIONS: T cells are major contributors to nonischemic HF. Their activation combined with the activation of the LV endothelium results in LV T-cell infiltration negatively contributing to HF progression through mechanisms involving cytokine release and induction of cardiac fibrosis and hypertrophy. Reduction of T-cell infiltration is thus identified as a novel translational target in HF.

Las mujeres siguen siendo las principales cuidadoras de pacientes dependientes / Women are still the main caregivers of dependent patients

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Ischemic stroke in the setting of chronic immune thrombocytopenia in an elderly patient--a therapeutic dilemma.

Chronic immune thrombocytopenia (ITP) carries a poor prognosis in the elderly patients. Increasing evidence proposes that a subgroup of patients with chronic ITP may be more susceptible to ischemic stroke. An 84-year-old Caucasian man with multiple ischemic stroke risk factors presented with acute onset of slurred speech, confusion, and unsteady gait. Physical examination and neurologic imaging were consistent with a new left thalamic infarct. Platelet counts ranged between 40 000 × 10(9)/L and 65 000 × 10(9) /L. Antiplatelet therapy for his newly acquired stroke was not initiated considering his low platelet counts and for mildly symptomatic thrombocytopenia, and the patient was discharged home. Both hematologic and neurologic guidelines for the management of chronic ITP and stroke have contradictory goals. Although anticoagulation is mandated in acute stroke, ITP causes low platelet counts that increase bleeding complications.