Demographics and Comorbidities of United States Service Members with Combat-Related Lower Extremity Limb Salvage.

Introduction: This retrospective study describes the demographics and injury characteristics of a recently identified cohort of US Service members with combat-related lower extremity limb salvage (LS).

Methods: US Service members with combat trauma were identified from the Expeditionary Medical Encounter Database and Military Health System Data Repository and stratified into primary amputation (PA), LS, and non-threatened limb trauma (NTLT) cohorts based on ICD-9 codes. Disparities in demographic factors and injury characteristics were investigated across cohorts and within the LS cohort based on limb retention outcome.

Effects of Adjunct Antifibrotic Treatment within a Regenerative Rehabilitation Paradigm for Volumetric Muscle Loss.

The use of a rehabilitation approach that promotes regeneration has the potential to improve the efficacy of pro-regenerative therapies and maximize functional outcomes in the treatment of volumetric muscle loss (VML). An adjunct antifibrotic treatment could further enhance functional gains by reducing fibrotic scarring. This study aimed to evaluate the potential synergistic effects of losartan, an antifibrotic pharmaceutical, paired with a voluntary wheel running rehabilitation strategy to enhance a minced muscle graft (MMG) pro-regenerative therapy in a rodent model of VML.

Evaluating the potential use of functional fibrosis to facilitate improved outcomes following volumetric muscle loss injury.

Volumetric muscle loss (VML) was defined as the frank loss of skeletal muscle tissue with associated chronic functional deficits. Significant effort has been dedicated to developing approaches for treating VML injuries, most of which have focused on stimulating regeneration of the affected musculature via a variety of approaches (e.g.

Necroptosis in the Pathophysiology of Disease.

Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated.

Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia.

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1α). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1α. We have previously found that transforming growth factor-β (TGFβ) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFβ/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs).

A crosstalk between TGF-β/Smad3 and Wnt/β-catenin pathways promotes vascular smooth muscle cell proliferation.

Rationale: Endovascular interventions performed for atherosclerotic lesions trigger excessive vascular smooth muscle cell (SMC) proliferation leading to intimal hyperplasia. Our previous studies show that following endovascular injury, elevated TGF-β/Smad3 promotes SMC proliferation and intimal hyperplasia. Furthermore in cultured SMCs, elevated TGF-β/Smad3 increases the expression of several Wnt genes.

TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.

Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signaling protein Smad3 ∶ 1) are up-regulated following vascular injury, 2) together drive smooth muscle cell (SMC) proliferation and migration and 3) enhance the development of intimal hyperplasia.