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      Tissue sodium content is elevated in the skin and subcutaneous adipose tissue in women with lipedema

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          Abstract

          Objective

          To test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema.

          Methods

          Participants with lipedema (n=10) and control (n=11) volunteers matched for biological sex, age, body-mass-index, and calf circumference were scanned noninvasively with 3.0T sodium and conventional proton MRI. Standardized tissue sodium content was quantified in skin, subcutaneous adipose tissue (SAT), and calf muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume ratio between groups (significance: two-sided p≤0.05).

          Results

          Skin ( p=0.01) and SAT ( p=0.04) sodium content were elevated in lipedema (skin: 14.9±2.9 mmol/L; SAT: 11.9±3.1 mmol/L) relative to control (skin: 11.9±2.0 mmol/L; SAT: 9.4±1.6 mmol/L) participants. Relative fat volume in the calf was elevated in lipedema (1.2±0.48 ratio) relative to control (0.63±0.26 ratio, p<0.001) participants. Skin sodium content was directly correlated with fat-to-water volume ratio (Spearman’s-rho=0.54, p=0.01).

          Conclusions

          Internal metrics of tissue sodium and adipose content are elevated in patients with lipedema potentially providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity.

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          Most cited references25

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          Pain assessment.

          Pain usually is the major complaint of patients with problems of the back, thus making pain evaluation a fundamental requisite in the outcome assessment in spinal surgery. Pain intensity, pain-related disability, pain duration and pain affect are the aspects that define pain and its effects. For each of these aspects, different assessment instruments exist and are discussed in terms of advantages and disadvantages. Risk factors for the development of chronic pain have been a major topic in pain research in the past two decades. Now, it has been realised that psychological and psychosocial factors may substantially influence pain perception in patients with chronic pain and thus may influence the surgical outcome. With this background, pain acceptance, pain tolerance and pain-related anxiety as factors influencing coping strategies are discussed. Finally, a recommendation for a minimum as well as for a more comprehensive pain assessment is given.
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            Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.

            The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
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              Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.

              Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection.
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                Author and article information

                Journal
                101264860
                32902
                Obesity (Silver Spring)
                Obesity (Silver Spring)
                Obesity (Silver Spring, Md.)
                1930-7381
                1930-739X
                25 November 2017
                27 December 2017
                February 2018
                27 June 2018
                : 26
                : 2
                : 310-317
                Affiliations
                [1 ]Department of Radiology and Radiological Science, Vanderbilt University Medical Center, Nashville, TN, USA
                [2 ]Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
                [3 ]Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA
                [4 ]Dayani Center for Health and Wellness, Vanderbilt University Medical Center, Nashville, TN, USA
                [5 ]Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
                [6 ]Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
                [7 ]Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
                [8 ]Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, USA
                Author notes
                [* ]Corresponding author: Rachelle Crescenzi, PhD, Vanderbilt University Institute of Imaging Science, 1161 21 st Avenue South, Nashville, TN 37232, USA, rachelle.crescenzi@ 123456vanderbilt.edu
                Article
                NIHMS920419
                10.1002/oby.22090
                5783748
                29280322
                1fadfb0a-bf23-403d-94c0-6d29061c3cb9

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                Medicine
                obesity,diagnosis,imaging,radiology,body composition
                Medicine
                obesity, diagnosis, imaging, radiology, body composition

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