B7 ligands (CD80 and CD86), expressed by professional antigen presenting cells (APCs), activate the main costimulatory receptor CD28 on T cells in
trans
. However, in peripheral tissues, APCs ...expressing B7 ligands are relatively scarce. This raises the questions of whether and how CD28 costimulation occurs in peripheral tissues. Here, we report that CD8
+
T cells displayed B7 ligands that interacted with CD28 in
cis
at membrane invaginations of the immunological synapse, as a result of membrane remodeling driven by phosphoinositide-3-kinase (PI3K) and sorting-nexin-9 (SNX9).
Cis
-B7:CD28 interactions triggered CD28 signaling through protein-kinase-C-theta (PKCθ) and promoted CD8
+
T cell survival, migration and cytokine production. In mouse tumor models, loss of T cell-intrinsic
cis
-B7:CD28 interactions decreased intratumoral T cells and accelerated tumor growth. Thus, B7 ligands on CD8
+
T cells can evoke cell autonomous CD28 costimulation in
cis
in peripheral tissues, suggesting
cis
-signaling as a general mechanism for boosting T cell functionality.
Classically, B7 ligands on antigen presenting cells (APC) activate the T cell costimulatory receptor, CD28. Zhao et al. reveal that B7 on T cells can activate CD28 in
cis
at endocytosis-associated membrane curvatures. This cis-signaling promotes anti-tumor T cell responses and explains how T cells sustain functionality in APC-sparse tissues.
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an ...in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Background Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients with atrial fibrillation yet have incompletely characterized factors associated with failure to ...treat and subsequent outcomes in contemporary practice. Methods Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the association between OAC non-use and subsequent outcomes over 2.5 years. Results Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC non-recipients, 1846 (83.8%) had a CHA₂DS₂-VASc score > 2. Factors independently associated with OAC non-use included atrial fibrillation type (paroxysmal odds ratio (OR) 0.73, 95% confidence interval (CI) 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent OR 0.35, 0.25-0.49; reference = new-onset), left atrial diameter enlargement (mild OR 0.80, 0.66-0.97, moderate 0.58, 0.47-0.73, severe 0.53, 0.42-0.68; reference=normal diameter) and age > 80 years (OR 1.04, 95% CI 1.02-1.08). Untreated patients had a higher risk of death (adjusted hazard ratio (HR) 1.22, 95% CI 1.05-1.41), a lower bleeding risk (adjusted HR 0.35, 95% CI 0.15-0.81) and a nonsignificant trend toward higher risk of stroke/non-central nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54). Conclusions A majority of atrial fibrillation patients not treated with an OAC in current community practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are associated with non-treatment. Untreated patients are at increased risk for adverse outcomes.
Abstract Pediatric heart failure (HF) is an important cause of morbidity and mortality in childhood. This article presents guidelines for the recognition, diagnosis, and early medical management of ...HF in infancy, childhood, and adolescence. The guidelines are intended to assist practitioners in office-based or emergency room practice, who encounter children with undiagnosed heart disease and symptoms of possible HF, rather than those who have already received surgical palliation. The guidelines have been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and are accompanied by practical Recommendations for their application in the clinical setting, supplemented by online material. This work does not include Recommendations for advanced management involving ventricular assist devices, or other device therapies.
Rho GTPases play critical roles in cell proliferation and cell death in many species. As in animal cells, cells of the budding yeast Saccharomyces cerevisiae undergo regulated cell death under ...various physiological conditions and upon exposure to external stress. The Rho5 GTPase is necessary for oxidant-induced cell death, and cells expressing a constitutively active GTP-locked Rho5 are hypersensitive to oxidants. Yet how Rho5 regulates yeast cell death has been poorly understood. To identify genes that are involved in the Rho5-mediated cell death program, we performed two complementary genome-wide screens: one screen for oxidant-resistant deletion mutants and another screen for Rho5-associated proteins. Functional enrichment and interaction network analysis revealed enrichment for genes in pathways related to metabolism, transport, and plasma membrane organization. In particular, we find that ATG21, which is known to be involved in the CVT (Cytoplasm-to-Vacuole Targeting) pathway and mitophagy, is necessary for cell death induced by oxidants. Cells lacking Atg21 exhibit little cell death upon exposure to oxidants even when the GTP-locked Rho5 is expressed. Moreover, Atg21 interacts with Rho5 preferentially in its GTP-bound state, suggesting that Atg21 is a downstream target of Rho5 in oxidant-induced cell death. Given the high degree of conservation of Rho GTPases and autophagy from yeast to human, this study may provide insight into regulated cell death in eukaryotes in general.
Abstract Background Few longitudinal studies have delineated the association between traditional cardiovascular risk factors and development of aortic stenosis (AS). Objectives The authors examined ...the association between traditional cardiovascular risk factors and incident severe AS in a large, unselected elderly population. Methods This observational cohort study used multiple linked health care population-based databases of individuals older than 65 years on April 1, 2002, without prior valvular disease, coronary artery disease, heart failure, cardiac arrhythmia, cerebrovascular disease, congenital heart disease, or admissions with cardiac symptoms. The relationship between hypertension (HTN), diabetes, dyslipidemia, and incident severe AS requiring hospitalization or surgical or interventional treatment was examined. Results Among 1.12 million individuals followed for a median of 13 years, 20,995 subjects developed severe AS. Overall absolute incidence was 144 per 100,000 person-years (169 and 127 per 100,000 person-years in men and women, respectively). In cause-specific hazard models, HTN (adjusted hazard ratio HR: 1.71; 95% confidence interval CI: 1.66 to 1.76), diabetes (HR: 1.49; 95% CI: 1.44 to 1.54), and dyslipidemia (HR: 1.17; 95% CI: 1.14 to 1.21) were all significantly associated with increased risk of developing severe AS (all p < 0.001). There was a positive dose-response relationship between the number and duration of cardiac risk factors and risk of AS. In the Fine-Gray model, all 3 risk factors were independently associated with a higher incidence of AS. The population-attributable risk of AS associated with 3 cardiac risk factors was 34.4% (95% CI: 32.8 to 36.0). Conclusions HTN, diabetes, and dyslipidemia have independent and dose-response associations with incident AS in an unselected population of older individuals, and together accounted for approximately one-third of the incidence of severe AS.
Abstract Background context Adolescent idiopathic scoliosis (AIS) is associated with low bone mass that could persist into early adulthood and is an important prognostic factor for curve progression. ...Previous studies were confined to areal bone mineral density measurement that was a two-dimensional investigation for a three-dimensional structure. Evaluation of volumetric BMD (vBMD) and other bone quality parameters are important for gaining in-depth understanding of the etiopathogenesis of AIS. Purpose The objective of this study was to carry out direct in vivo measurement of bone quality in AIS using high-resolution peripheral quantitative computed tomography (HR-pQCT) and compare the correlation of bone quality with osteopenia between AIS and control subjects. Study design/setting A case-control study. Patient sample Newly diagnosed AIS girls (n=112) and non-AIS girls (n=115) between 11 and 13 years. Outcome measures Areal bone mineral density of bilateral femoral necks and HR-pQCT of the nondominant distal radius were performed. Methods Areal bone mineral density of femoral necks was measured by dual-energy X-ray absorptiometry. Subjects were classified into the osteopenic (Z score less than or equal to −1) and nonosteopenic (Z score more than −1) groups. Bone quality parameters, including bone morphometry, trabecular bone microarchitecture, and vBMD, were measured by HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland). Results In AIS, the osteopenic group had lower measurements in cortical area, cortical thickness, average vBMD, compact bone vBMD, trabecular vBMD, trabecular bone volume to tissue volume ratio, and trabecular thickness compared with nonosteopenic AIS subjects. In contrast, among the non-AIS controls, the osteopenic group had lower measurements only in bone morphometry, average vBMD, and compact bone vBMD but not in trabecular vBMD and all other trabecular bone microarchitecture parameters. Conclusions This is the first study using HR-pQCT to compare the correlation of bone quality with osteopenia in AIS and non-AIS subjects. It provides new insights and highlights the unique bone quality profile with predominant changes in the trabecular compartment in association with osteopenia being notably only detected in the AIS subjects. Further studies in this area are warranted for defining the metabolic nature and biomechanical sequelae of derangement in bone mass and bone quality and their roles in the etiopathogenesis of AIS.
The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing ...elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery.
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