Noninvasive diagnostics for extremity compartment syndrome following traumatic injury: A state-of-the-art review.

Acute compartment syndrome (ACS) is a serious medical condition that can occur following traumatic injury to an extremity. If left undiagnosed, ACS can eventuate in amputation of the limb or even death. Because of this, fasciotomy to release the pressure within the muscle and restore tissue perfusion is often performed upon suspicion of ACS, as the sequelae to fasciotomy are less severe than those associated with not performing the fasciotomy. Currently, the "gold standard" of diagnosis is based on clinical assessment of such symptoms as pain out of proportion to the injury, obvious high pressure and swelling, pain on passive stretch of the muscles in the affected compartment, and deficits in sensory and/ormotor functions. Diagnosis is often confirmed using invasive measurements of intramuscular pressure (IMP); however, controversy exists as to how direct IMP measurement should be accomplished and threshold pressures for accurate diagnosis. Because of this and the attendant issues with invasive measurements, investigators have been searching over the last 25 years for a noninvasive means to quantitatively measure IMP or perfusion to the limb. The purpose of this review is to summarize the current state of the art of noninvasive devices that could potentially be used to diagnose ACS accurately and objectively. To do this, we divide the discussion into those medical devices that primarily measure mechanical surrogates of IMP (e.g., tissue hardness or myofascial displacement) and those that primarily measure indices of tissue perfusion (e.g., tissue oxygen saturation via near-infraredspectroscopy). While near-infrared spectroscopy-basedtechnologies have shown the most promise, whether such technologies will be of diagnostic benefit await the completion of ongoing clinical trials. LEVEL OF EVIDENCE: Systematic Review, level II.

Transcriptional and Chromatin Dynamics of Muscle Regeneration after Severe Trauma.

Following injury, adult skeletal muscle undergoes a well-coordinated sequence of molecular and physiological events to promote repair and regeneration. However, a thorough understanding of the in vivo epigenomic and transcriptional mechanisms that control these reparative events is lacking. To address this, we monitored the in vivo dynamics of three histone modifications and coding and noncoding RNA expression throughout the regenerative process in a mouse model of traumatic muscle injury. We first illustrate how both coding and noncoding RNAs in tissues and sorted satellite cells are modified and regulated during various stages after trauma. Next, we use chromatin immunoprecipitation followed by sequencing to evaluate the chromatin state of cis-regulatory elements (promoters and enhancers) and view how these elements evolve and influence various muscle repair and regeneration transcriptional programs. These results provide a comprehensive view of the central factors that regulate muscle regeneration and underscore the multiple levels through which both transcriptional and epigenetic patterns are regulated to enact appropriate repair and regeneration.

Where's the Leak in Vascular Barriers? A Review.

Edema is typically presented as a secondary effect from injury, illness, disease, or medication, and its impact on patient wellness is nested within the underlying etiology. Therefore, it is often thought of more as an amplifier to current preexisting conditions. Edema, however, can be an independent risk factor for patient deterioration. Improper management of edema is costly not only to the patient, but also to treatment and care facilities, as mismanagement of edema results in increased lengths of hospital stay. Direct tissue trauma, disease, or inappropriate resuscitation and/or ventilation strategies result in edema formation through physical disruption and chemical messenger-based structural modifications of the microvascular barrier. Derangements in microvascular barrier function limit tissue oxygenation, nutrient flow, and cellular waste removal. Recent studies have sought to elucidate cellular signaling and structural alterations that result in vascular hyperpermeability in a variety of critical care conditions to include hemorrhage, burn trauma, and sepsis. These studies and many others have highlighted how multiple mechanisms alter paracellular and/or transcellular pathways promoting hyperpermeability. Roles for endothelial glycocalyx, extracellular matrix and basement membrane, vesiculo-vacuolar organelles, cellular junction and cytoskeletal proteins, and vascular pericytes have been described, demonstrating the complexity of microvascular barrier regulation. Understanding these basic mechanisms inside and out of microvessels aid in developing better treatment strategies to mitigate the harmful effects of excessive edema formation.

In vivo Monitoring of Transcriptional Dynamics After Lower-Limb Muscle Injury Enables Quantitative Classification of Healing.

Traumatic lower-limb musculoskeletal injuries are pervasive amongst athletes and the military and typically an individual returns to activity prior to fully healing, increasing a predisposition for additional injuries and chronic pain. Monitoring healing progression after a musculoskeletal injury typically involves different types of imaging but these approaches suffer from several disadvantages. Isolating and profiling transcripts from the injured site would abrogate these shortcomings and provide enumerative insights into the regenerative potential of an individual's muscle after injury. In this study, a traumatic injury was administered to a mouse model and healing progression was examined from 3 hours to 1 month using high-throughput RNA-Sequencing (RNA-Seq). Comprehensive dissection of the genome-wide datasets revealed the injured site to be a dynamic, heterogeneous environment composed of multiple cell types and thousands of genes undergoing significant expression changes in highly regulated networks. Four independent approaches were used to determine the set of genes, isoforms, and genetic pathways most characteristic of different time points post-injury and two novel approaches were developed to classify injured tissues at different time points. These results highlight the possibility to quantitatively track healing progression in situ via transcript profiling using high- throughput sequencing.

Role of phosphoinositide 3-OH kinase p110ß in skeletal myogenesis.

Phosphoinositide 3-OH kinase (PI3K) regulates a number of developmental and physiologic processes in skeletal muscle; however, the contributions of individual PI3K p110 catalytic subunits to these processes are not well-defined. To address this question, we investigated the role of the 110-kDa PI3K catalytic subunit ß (p110ß) in myogenesis and metabolism. In C2C12 cells, pharmacological inhibition of p110ß delayed differentiation. We next generated mice with conditional deletion of p110ß in skeletal muscle (p110ß muscle knockout [p110ß-mKO] mice). While young p110ß-mKO mice possessed a lower quadriceps mass and exhibited less strength than control littermates, no differences in muscle mass or strength were observed between genotypes in old mice. However, old p110ß-mKO mice were less glucose tolerant than old control mice. Overexpression of p110ß accelerated differentiation in C2C12 cells and primary human myoblasts through an Akt-dependent mechanism, while expression of kinase-inactive p110ß had the opposite effect. p110ß overexpression was unable to promote myoblast differentiation under conditions of p110α inhibition, but expression of p110α was able to promote differentiation under conditions of p110ß inhibition. These findings reveal a role for p110ß during myogenesis and demonstrate that long-term reduction of skeletal muscle p110ß impairs whole-body glucose tolerance without affecting skeletal muscle size or strength in old mice.