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Nearly 6 million Americans suffer from heart failure. Increased fibrosis contributes to functional decline of the heart that leads to heart failure. Previously, we identified a mechanosensitive protein, small proline-rich repeat 3 (SPRR3), in vascular smooth muscle cells of atheromas. In this study, we demonstrate SPRR3 expression in cardiac fibroblasts which is induced in activated fibroblasts following pressure-induced heart failure. Sprr3 deletion in mice showed preserved cardiac function and reduced interstitial fibrosis in vivo and reduced fibroblast proliferation and collagen expression in vitro. SPRR3 loss resulted in reduced activation of Akt, FAK, ERK, and p38 signaling pathways, which are coordinately regulated by integrins and growth factors. SPRR3 deletion did not impede integrin-associated functions including cell adhesion, migration, or contraction. SPRR3 loss resulted in reduced activation of PDGFRβ in fibroblasts. This was not due to the reduced PDGFRβ expression levels or decreased binding of the PDGF ligand to PDGFRβ. SPRR3 facilitated the association of integrin β1 with PDGFRβ and subsequently fibroblast proliferation, suggesting a role in PDGFRβ-Integrin synergy. We postulate that SPRR3 may function as a conduit for the coordinated activation of PDGFRβ by integrin β1, leading to augmentation of fibroblast proliferation and matrix synthesis downstream of biomechanical and growth factor signals. © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.We present the case of a worker with occupational exposure to a pyrethroid insecticide who acutely developed nontransient third-degree heart block. In 2000, a 57-year-old male truck driver on his delivery route was accidentally exposed to pyrethroid insecticide being sprayed for West Nile virus containment. Both the driver and his vehicle were coated with the spray. The exposure was prolonged because he did not change his clothes until after his shift ended and he used the same contaminated truck for a week. Within days, he presented with a third-degree heart block, for which he was emergently treated, and a pacemaker was placed. He had no past history of arrhythmias. In the weeks thereafter, he also developed reactive airway dysfunction syndrome (RADS). In the second decade following the exposure, the patient replaced his pacemaker, confirming the permanent nature of his heart block. In addition to the persistence of his exposure-related RADS, he developed restrictive lung disease and was diagnosed with pulmonary interstitial fibrosis in the absence of established risk factors. Pamapimod The patient died in October 2019 from respiratory illness. Most previous reports of pyrethroid-related disorders are limited to acute exposures, in which transient symptoms predominate. To our knowledge, this is the first report of an exposed worker experiencing permanent third-degree heart block, as well as persistent respiratory findings, as possible short- and long-term sequelae of pyrethroid exposure. © 2020 Wiley Periodicals, Inc.BACKGROUND Chronic spontaneous urticaria (CSU) is defined as the spontaneously appearing weals and/or angioedema for more than 6 weeks. Dietary habits can modulate the pathogenesis of CSU. However, dietary intakes of nutrients or food in CSU patients, compared with healthy controls, have not been examined in quality and quantity. METHODS We evaluated dietary habits in adult Japanese patients with chronic spontaneous urticaria using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. The severity of CSU was evaluated using the Urticaria Control Test. RESULTS Japanese CSU patients showed higher body mass indices, higher intakes of eggs, vegetables other than green/yellow vegetables/mushrooms/algae, cholesterol, folic acid, dietary fibres, vitamin D, vitamin K, Cu, Fe, Pi, Ca, Mg, Na and salt, and lower intake of alcohol, compared to controls. The logistic regression analysis showed that CSU was associated with high body mass index and high intake of eggs. The intake of beverages was higher in uncontrolled CSU patients (Urticaria Control Test ≦11 points) than in controlled patients. The logistic regression analysis showed that uncontrolled CSU was associated with high intake of beverages. The intake of coffee, caffeine-rich and non-alcohol beverage, in uncontrolled CSU patients was higher than that in controlled patients. CONCLUSIONS Chronic spontaneous urticaria was associated with high body mass index and high intake of eggs. Uncontrolled CSU was associated with high intake of beverages. Further studies should elucidate the relationships of these results with the development or exacerbation of CSU. © 2020 The Australasian College of Dermatologists.The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1flx/flx ) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally and reproduced successfully. Following Grem1 depletion the mice became unwell and were euthanised (at 7-13 days). Post mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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