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Chokroverty S.,JFK Neuroscience Institute | Chokroverty S.,Seton Hall University
Sleep Medicine Clinics | Year: 2015

Restless legs syndrome (RLS) mimics cannot always be differentiated from RLS/Willis-Ekbom disease (WED) based on 4 essential criteria; hence, a fifth criterion has recently been established. RLS comorbidities may provide us important clues for understanding the neurobiology of RLS/WED. Iron-dopamine connection, hypoxia pathway activation, and dopamine-opioid interaction are important pathophysiological mechanisms in RLS; this knowledge is derived from our understanding of RLS associations with a variety of medical, neurologic, and other conditions. Clinicians must formulate an RLS differential diagnosis based on history and physical examination, but laboratory tests may sometimes be needed to arrive at a correct diagnosis. © 2015 Elsevier Inc.

Previtera M.L.,JFK Neuroscience Institute | Previtera M.L.,Seton Hall University
Cellular and Molecular Bioengineering | Year: 2014

Regulation of the immune system has been heavily investigated from a biological perspective due to the biological nature of inflammatory stimulants and pathogens. However, more studies have shown that biophysical cues generated by normal physiological events or diseases regulate the immune system. In fact, a new paradigm is emerging in which data shows that normal physiological mechanical stimuli suppress inflammation whereas pathophysiological mechanical stimuli trigger inflammation. In this review, evidence supporting this paradigm is provided. Specifically, physiological and pathophysiological mechanical stimuli are described, the effects of mechanical stimuli on innate and adaptive immune system function are discussed, and the mechanotransduction pathways that regulate white blood cell behavior are explained. By understanding both the biological and physical stimulants that regulate the immune system, novel and more effective drugs can be developed that reduce inflammation. © 2014 Biomedical Engineering Society.

Previtera M.L.,JFK Neuroscience Institute | Previtera M.L.,Seton Hall University | Peterman K.,JFK Neuroscience Institute | Shah S.,JFK Neuroscience Institute | Luzuriaga J.,JFK Neuroscience Institute
Annals of Biomedical Engineering | Year: 2015

Infiltrating leukocytes are exposed to a wide range of tissue elasticities. While we know the effects of substrate elasticity on acute inflammation via the study of neutrophil migration, we do not know its effects on leukocytes that direct chronic inflammatory events. Here, we studied morphology and motility of macrophages, the innate immune cells that orchestrate acute and chronic inflammation, on polyacrylamide hydrogels that mimicked a wide range of tissue elasticities. As expected, we found that macrophage spreading area increased as substrate elasticity increased. Unexpectedly, we found that morphology did not inversely correlate with motility. In fact, velocity of steady-state macrophages remained unaffected by substrate elasticity, while velocity of biologically stimulated macrophages was limited on stiff substrates. We also found that the lack of motility on stiff substrates was due to a lack of lipid rafts on the leading edge of the macrophages. This study implicates lipid rafts in the mechanosensory mechanism of innate immune cell infiltration. © 2014, Biomedical Engineering Society.

Previtera M.L.,JFK Neuroscience Institute | Previtera M.L.,Seton Hall University | Sengupta A.,JFK Neuroscience Institute
PLoS ONE | Year: 2015

Clinical data show that disease adversely affects tissue elasticity or stiffness. While macrophage activity plays a critical role in driving disease pathology, there are limited data available on the effects of tissue stiffness on macrophage activity. In this study, the effects of substrate stiffness on inflammatory mediator production by macrophages were investigated. Bone marrow-derived macrophages were grown on polyacrylamide gels that mimicked the stiffness of a variety of soft biological tissues. Overall, macrophages grown on soft substrates produced less proinflammatory mediators than macrophages grown on stiff substrates when the endotoxin LPS was added to media. In addition, the pathways involved in stiffness-regulated proinflammation were investigated. The TLR4 signaling pathway was examined by evaluating TLR4, p-NF-κB p65, MyD88, and p-IκBα expression as well as p-NF-κB p65 translocation. Expression and translocation of the various signaling molecules were higher in macrophages grown on stiff substrates than on soft substrates. Furthermore, TLR4 knockout experiments showed that TLR4 activity enhanced proinflammation on stiff substrates. In conclusion, these results suggest that proinflammatory mediator production initiated by TLR4 is mechanically regulated in macrophages. © 2015 Previtera, Sengupta.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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