Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation.

Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF-deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1ß, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-ß, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS.

A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease.

Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small-molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T-cell activation in the periphery were noted. From these studies, we conclude that a small-molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS.

Disease-modifying capability of murine Flt3-ligand DCs in experimental autoimmune encephalomyelitis.

Dendritic cells (DCs) bridge the innate and adaptive immune response, are uniquely capable of priming naïve T cells, and play a critical role in the initiation and regulation of autoimmune and immune-mediated disease. At present, in vivo expansion of DC populations is accomplished primarily through the administration of the recombinant human growth factor fms-like tyrosine kinase 3 ligand (hFL), and in vitro DCs are generated using cytokine cocktails containing GM-CSF +/- IL-4. Although hFL has traditionally been used in mice, differences in amino acid sequence and biological activity exist between murine FL (mFL) and hFL, and resultant DC populations differ in phenotype and immunoregulatory functional capabilities. This study developed and characterized mFL-generated DCs and determined the therapeutic capability of mFL DCs in the autoimmune disease experimental autoimmune encephalomyelitis (EAE). Our findings demonstrate that mFL and hFL expand splenic DCs equally in vivo but that mFL-expanded, splenic DCs more closely resemble normal, resting, splenic DCs. In addition, a novel method for generating mFL-derived bone marrow-derived DCs (BM-DCs) was developed, and comparison of mFL with hFL BM-DCs found mFL BM-DCs to be less mature (i.e., lower MHC Class II, CD80, and CD86) than hFL BM-DCs. These immature mFL DCs up-regulated costimulatory molecules in response to maturation stimuli LPS and TNF-alpha. Mature mFL BM-DCs were immunogenic and exacerbated the clinical disease course of EAE.

ACC/AHA Versus ESC Guidelines for Diagnosis and Management of Peripheral Artery Disease: JACC Guideline Comparison.

Peripheral artery disease is a common yet underdiagnosed cause of morbidity worldwide. Significant recent advances in management have resulted in new guideline creation for the diagnosis and management of peripheral artery disease in the United States and Europe. Here, we analyze each set of guidelines with special attention to those areas where the 2 groups disagree. Both groups emphasize the importance of risk factor reduction, including smoking cessation, lipid lowering, blood pressure management, and glucose control. The U.S. guidelines place additional attention on lifestyle factors, including regular physical activity and supervised exercise. The European guidelines offer a number of recommendations for revascularization in patients with limb-threatening ischemia. Both agree that more evidence is needed to understand which patients are at highest risk for tissue loss. A consistent charge to each committee fostering a similar approach to available data and more randomized studies would align recommendations across both organizations.

A New Educational Framework to Improve Lifelong Learning for Cardiologists.

Lifelong learning is essential for the practicing cardiologist. Present lifelong learning mechanisms are stagnant and at risk for not meeting the needs of currently practicing cardiologists. With the increasing burden of cardiovascular disease, growing complexity of patient care, and ongoing pressures of nonclinical responsibilities, educational programming must evolve to meet the demands of the contemporary cardiovascular professional. A paradigm shift, replete with modern and practical educational tools, is needed in the lifelong learning armamentarium. Emerging evidence of novel educational strategies in graduate medical education supports the promise of broader application of these tools to different stages of professional life. In this commentary from the Fellows-in-Training Section Leadership Council, the authors propose 3 novel educational tools-personalized learning, adaptive learning, and the flipped classroom-to improve lifelong learning to meet the educational needs of fellows-in-training to practicing cardiologists alike.

An Automated System for Categorizing Transthoracic Echocardiography Indications According to the Echocardiography Appropriate Use Criteria.

The Echocardiography Appropriate Use Criteria (EAUC) are a set of indications for transthoracic echocardiography (TTE) developed to guide physician decision making around ordering of TTE. In this study, an automated rule-based method for processing "indications" listed within TTE reports and classification into one of the major EAUC categories was developed and validated against a clinician-annotated reference standard. The system performed at a comparable level to trained physicians allowing for the automated classification of more than 30,000 TTE indications from a public database in less than ten minutes. The most common indication for TTE was Valvular assessment closely followed by General. Hypertension/Heart Failure/Cardiomyopathy, Acute, and Cardiac Structure assessment each contributed more than ten percent within this patient population. These results suggest potential for automated approaches for tracking appropriate use of TTE, as well as guide the development of systems for prospectively identifying when TTE use is recommended.

2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.

Mitral regurgitation (MR) is a complex valve lesion that can pose significant management challenges for the cardiovascular clinician. This Expert Consensus Document emphasizes that recognition of MR should prompt an assessment of its etiology, mechanism, and severity, as well as indications for treatment. A structured approach to evaluation based on clinical findings, precise echocardiographic imaging, and when necessary, adjunctive testing, can help clarify decision making. Treatment goals include timely intervention by an experienced heart team to prevent left ventricular dysfunction, heart failure, reduced quality of life, and premature death.

Improving the Appropriate Use of Transthoracic Echocardiography: The Echo WISELY Trial.

BACKGROUND: Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA). OBJECTIVES: This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers. METHODS: The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs. RESULTS: One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 ± 89.3 vs. 85.4 ± 111.4; p = 0.83). CONCLUSIONS: An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101).

The Supply and Demand of the Cardiovascular Workforce: Striking the Right Balance.

As the burden of cardiovascular disease in the United States continues to increase, uncertainty remains on how well-equipped the cardiovascular workforce is to meet the challenges that lie ahead. In a time when health care is rapidly shifting, numerous factors affect the supply and demand of the cardiovascular workforce. This Council Commentary critically examines several factors that influence the cardiovascular workforce. These include current workforce demographics and projections, evolving health care and practice environments, and the increasing burden of cardiovascular disease. Finally, we propose 3 strategies to optimize the workforce. These focus on cardiovascular disease prevention, the effective utilization of the cardiovascular care team, and alterations to the training pathway for cardiologists.

Memory cells specific for myelin oligodendrocyte glycoprotein (MOG) govern the transfer of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an inflammatory disease of the CNS mediated by CD4(+) T cells directed against myelin antigens. Experimental autoimmune encephalomyelitis (EAE) is induced by immunization with myelin antigens like myelin oligodendrocyte glycoprotein (MOG). We have explored the transfer of EAE using MOG(35-55)-specific TCR transgenic (2D2) T cells. Unsorted 2D2 Th1 cells reliably transferred EAE. Further, we found that CD44(hi)CD62L(lo) effector/memory CD4(+) T cells are likely responsible for the disease transfer due to the up-regulation of CD44. Given the importance of MOG in MS pathogenesis, mechanistic insights into adoptively transferred EAE by MOG-specific Th1 cells could prove valuable in MS research.