Search Results (3,043)

Inflammation plays a pivotal role in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury, highlighting inflammation suppression as a critical therapeutic strategy. The inflammatory response is largely mediated through Toll-like receptor 4 (TLR4), a transmembrane signal receptor whose expression is upregulated by Heat Shock Protein Family A Member 8 (HSPA8). Here, we investigated whether SEM1, a subunit of the 26S proteasome, interacts with HSPA8 and attenuates TLR4-mediated inflammation. Our results demonstrate that SEM1 expression is downregulated following myocardial I/R. Overexpression of SEM1 alleviated cardiac injury and dysfunction, inhibited myocardial inflammation, and downregulated HSPA8 expression in the I/R-injured heart. Co-IP assays confirmed a strong physical interaction between SEM1 and HSPA8, while the precise molecular mechanism responsible for SEM1-induced downregulation of HSPA8 remains to be fully elucidated. Mechanistically, SEM1 suppressed the activation of the TLR4/MyD88/NF-κB signaling pathway. Collectively, these findings identify SEM1 as a novel regulator that protects against myocardial I/R injury via its association with HSPA8 and inhibition of the TLR4-mediated inflammatory cascade, offering a promising therapeutic target for this condition. Full article

Background/Objectives: Posterolateral meniscocapsular detachment represents a potentially underrecognized component of knee trauma in patients with anterior cruciate ligament (ACL) injury. Altered rotational kinematics in ACL-deficient knees may increase stress on posterolateral corner structures. Although an association between ACL tears and posterolateral abnormalities has been reported, the true diagnostic performance of magnetic resonance imaging (MRI) for these lesions remains incompletely defined. This study aimed to evaluate the diagnostic accuracy of MRI for posterolateral meniscocapsular detachment in patients with confirmed ACL injury, to describe associated meniscal tears, and to assess the association between lateral tibial plateau bone marrow edema, age, and sex with the presence of detachment. Methods: In this retrospective study, 117 knee MRI examinations (1.5 T and 3 T) of patients with native ACL rupture or ACL graft failure were reviewed. Two readers independently assessed posterolateral meniscocapsular detachment. Ramp lesions, other meniscal tears and lateral compartment bone marrow edema were evaluated in consensus. Arthroscopy served as the reference standard. Diagnostic performance and inter-observer agreement were calculated. Detachment was considered present only when both readers independently identified the lesion. Results: MRI demonstrated high specificity (90.8%; 95% CI: 83.7–95.5%) for posterolateral meniscocapsular detachment, and promising sensitivity (87.5%; 95% CI: 47.3–99.7%) based on a small number of confirmed cases (n = 8); this estimate should be interpreted with caution given the wide confidence interval. One arthroscopically confirmed lesion was missed, and false-positive findings were limited. MRI also showed good diagnostic performance for ramp lesions and other associated meniscal tears, assessed as secondary endpoints. Lateral tibial plateau bone marrow edema, age, and sex were not significantly associated with detachment. Conclusions: Routine MRI shows high specificity and promising, although preliminary, sensitivity for detecting posterolateral meniscocapsular detachment in ACL-injured knees; given the small number of confirmed cases, this estimate warrants confirmation in larger cohorts. Careful multiplanar assessment and detailed anatomical knowledge are essential to optimize detection. Accurate preoperative MRI characterization may help guide surgical planning and reduce the risk of missed posterolateral meniscocapsular pathology at arthroscopy. Full article

Since emerging in late 2019, SARS-CoV-2 has caused over 7 million deaths globally and remains a public health concern. Understanding SARS-CoV-2 pathogenesis is vital, especially as factors like environmental exposures are still poorly understood. Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BP), found in pollutants like cigarette smoke, diesel exhaust, and charcoal-broiled steaks, are known to injure the lungs. We aimed to evaluate if BP exacerbates SARS-CoV-2 pathogenesis in a mouse model of disease. One day following intranasal administration of BP (20 mg/kg) or vehicle control, we infected male and female K18-hACE2 mice with ancestral SARS-CoV-2 and assessed lung viral load, weight change, clinical scores, immune cell recruitment, and survival in the presence and absence of BP exposure. We found that BP-exposed mice had decreased survival compared to mock-exposed mice. Additionally, BP did not alter innate or adaptive immune cell populations in the lungs of SARS-CoV-2-infected mice. These findings suggest that PAH exposure exacerbates severe COVID-19 outcomes by unknown mechanisms, highlighting the need to further explore environmental impacts on SARS-CoV-2 infection. Full article

Background/Objectives: Clinical outcomes after traumatic brain injury (TBI) remain difficult to predict, highlighting the need for more sensitive diagnostic and prognostic biomarkers, particularly in polytrauma. This study aimed to identify TBI-specific proteomic signatures in plasma and extracellular vesicles (EV)-enriched fractions of critically injured trauma patients. Methods: Seventy-five severely injured adult trauma patients (ISS ≥ 16) were included: isolated severe TBI (TBI; AIS_head ≥ 4, other AIS ≤ 1, n = 23), polytrauma with TBI (PT-TBI; AIS_head ≥ 4, n = 22), and polytrauma without TBI (PT; AIS_head = 0, n = 30). 24 age- and sex-matched healthy volunteers served as controls. Neat plasma and EV-enriched fractions were profiled using HPLC-MS/MS. Differentially expressed proteins (DEP) were analyzed bioinformatically, and associations with clinical parameters were assessed using Spearman’s correlation. Results: The EV-enriched plasma fraction yielded more DEPs than neat plasma (846 vs. 258). Most DEPs were linked to polytrauma, with plasma reflecting metabolism and EVs showing translation and protein catabolism signatures. Among TBI-context proteins, EV-associated NRCAM and AQR and plasma IGHV1-69D, MASP1, PON1, and IGFBP7 remained significantly associated with TBI after adjustment for confounder. Notably, only EV-associated proteins correlated with injury-related clinical parameters. AQR negatively correlated with GCS (r = −0.51, p < 0.0001), while elevated NRCAM, AQR, and plasma MASP1 were associated with neurological deterioration and neurosurgical intervention. Conclusions: EV-enriched plasma proteomics enhances biomarker discovery in polytrauma, revealing distinct pathways and greater sensitivity than whole plasma. While most changes reflect systemic injury, EV-associated NRCAM and AQR, along with plasma MASP1, show TBI-specific associations with neurological status, highlighting their potential as candidate TBI biomarkers for further study. Full article

Background/Objectives: Neuropathic pain (NP) after traumatic spinal cord injury (SCI) is highly prevalent, markedly impairs quality of life, and remains difficult to treat because available therapies show limited efficacy and may cause relevant adverse effects. Because oxidative stress and glutamate-mediated excitotoxicity contribute to central sensitization after SCI, this study evaluated the antinociceptive and antioxidant effects of dapsone (DDS), N-acetylcysteine (NAC), and their combination in rats with SCI. An isobolographic analysis was also performed to determine the pharmacodynamic interaction between the two drugs. Methods: Female Wistar rats with SCI that developed stimulus-dependent hypersensitivity from day 15 after injury were treated once daily for 7 days with DDS (1.5–12.5 mg/kg, i.p.), NAC (9.3–75 mg/kg, i.p.), or 1:1 fixed-ratio combinations. Mechanical allodynia and hyperalgesia were assessed with Von Frey filaments, whereas lipid peroxidation (LP) and reduced glutathione (GSH) were quantified in injured spinal cord tissue. Results: DDS and NAC produced dose-dependent antinociceptive effects, with DDS being more potent than NAC in both endpoints. The individual ED₅₀ values were 4.92 and 33.47 mg/kg for allodynia, and 4.06 and 27.74 mg/kg for hyperalgesia, for DDS and NAC, respectively. The DDS/NAC combination showed synergistic interactions in allodynia (ED₅₀ = 7.45 mg/kg vs. Zadd = 19.19 mg/kg; γ = 0.388) and hyperalgesia (ED₅₀ = 4.21 mg/kg vs. Zadd = 15.90 mg/kg; γ = 0.265), with stronger synergism in hyperalgesia. Combined treatment also improved LP and GSH levels. Conclusions: These findings indicate that DDS and NAC exert complementary actions and that their combination produces a synergistic antinociceptive effect associated with diminished oxidative stress after SCI. Full article

Since the discovery and characterization of mesenchymal stem cells (MSC) some 40 years ago and the development of induced pluripotent stem cells (iPSC), opportunities to advance repair and potentially regenerate injured or diseased connective tissues of the musculoskeletal (MSK) system have been intensely investigated. While some advances have been made with some tissues, progress has not been as great as was hoped following the availability of such stem-like cells. Optimizing cell-biomaterial composites in vitro for features such as cell state or extracellular vesicle cargo, structure, composition, biomechanical integrity are likely to be only part of the story and optimizing the environments where such composites have been implanted has not received the same attention. Thus, implanting optimized or near optimized cell-biomaterial composites in acutely or chronically affected implantation sites can compromise the efficacy of such composites to effectively repair/regenerate MSK tissues. This may be due to inflammatory processes, alterations to the remaining tissues in the injury site during development of chronicity, waiting too long to repair residual tissue, or other host factors. Thus, success in realizing the potential of MSC and iPSC may depend, in significant part, on the environment at the implantation site. Further attention to optimizing the implantation site may enhance outcome success with long-term return to tissue function. Furthermore, heterogeneity in patient populations regarding natural factors influencing healing outcomes after injury may also require changes to clinical trial design to assess efficacy of cell therapies. Full article

Background: Infrared thermography (IRT) offers a non-invasive means to monitor skin temperature and physiological changes during rehabilitation. However, variability in image segmentation methods limits its broader clinical use. This study assessed the inter-rater reliability of a manual thermal image segmenatation protocol using FLIR Thermal Studio Pro™ and presents a longitudinal single-case feasibility illustration evaluating the agreement between this manual method and automatic segmentation using ThermoHuman^®. Methods: Two regions of interest (ROI) were analyzed throughout the study: the frontal knee and vastus medialis oblique (VMO). For the inter-rater reliability analysis, thermal images from 20 professional athletes were used. For the agreement analysis, 50 lower extremity thermal images were captured from a single athlete recovering from a meniscal repair over a four-month rehabilitation period. Intraclass correlation coefficients (ICC _(2,1)) were used to assess agreement and reliability. Results: Inter-rater reliability was excellent for all frontal knee measurements (ICC _(2,1) = 0.991, 0.995, and 0.964 for maximum, average, and minimum temperature, respectively) and for VMO maximum and average temperature (ICC _(2,1) = 0.967 and 0.981, respectively), with VMO minimum temperature as the exception demonstrating good reliability (ICC _(2,1) = 0.779). Excellent agreement was found between methods for all frontal knee (ICC _(2,1) = 0.967, 0.949, and 0.985) and VMO measurements (ICC _(2,1) = 0.971, 0.973, and 0.980) for maximum, average, and minimum temperature, respectively. Conclusion: Manual segmentation using FLIR Thermal Studio Pro™ provides highly reliable results across multiple subjects, supporting its use as a practical and consistent clinical tool. Furthermore, our single-case feasibility illustration suggests it provides comparable results to automatic segmentation using ThermoHuman^®, supporting its potential feasibility for accessible rehabilitation monitoring in injured athletes. Further multi-subject research is warranted to confirm the broader applicability of the agreement findings. Full article

Myocardial infarction remains a major clinical challenge because ischemic injury triggers inflammation, oxidative stress, cardiomyocyte loss, impaired vascularization, and adverse ventricular remodeling. Injectable hydrogels offer a minimally invasive and versatile strategy for post-infarction cardiac repair by providing structural support, localized bioactive delivery, and dynamic modulation of the injured myocardial microenvironment. This review highlights pathology-informed design principles for injectable hydrogels, including shear-thinning injectability, in situ gelation, tissue adhesion, modulus matching, fatigue resistance, biodegradability, and controlled bioactivity. We further discuss hydrogel-based strategies for immunomodulation, angiogenesis, fibrosis attenuation, extracellular matrix remodeling, and myocardial regeneration. Finally, translational progress and key challenges involving biosafety, scalable manufacturing, standardization and long-term efficacy are examined. This review provides a concise framework for developing next-generation injectable hydrogels for myocardial infarction repair and clinical translation. Full article

Spinal cord injury often causes persistent neurological dysfunction, whereas the developing central nervous system retains greater plasticity. This study investigated whether spontaneous hindlimb motor recovery occurs after complete spinal cord transection in neonatal mice and whether such recovery is accompanied by structural remodeling of the lumbar spinal cord distal to the lesion. C57BL/6J mice underwent complete T9 spinal cord transection at postnatal day 7, and recovery was assessed by Basso Mouse Scale scoring, CatWalk gait analysis, foot-fault testing, immunofluorescence, and electromyography. Compared with adult mice subjected to the same injury, neonatal mice showed progressive partial improvement in hindlimb motor function, including locomotor performance, gait coordination, and foot placement accuracy. Meanwhile, this recovery was accompanied by preservation of lumbar motor neurons and structural changes in the local neural network. Syn⁺ coverage around lumbar motor neurons was relatively preserved in neonatal injured mice compared with adult injured mice; excitatory synaptic input remained increased, and inhibitory input showed a dynamic pattern of early increase followed by later reduction. In addition, myelin-related alterations were less severe, and motor neuron innervation of peripheral muscles (EMG) were relatively preserved in neonatal mice. The results indicate that the restoration of hindlimb motor function after complete spinal cord transection in neonatal mice is associated with structural and functional remodeling of lumbar spinal motor circuits. This includes enhanced synaptic signals around motor neurons and reorganization of the neuromuscular junction. Full article

(1) Background: This study validated the accuracy of a markerless gait analysis system, Foot4D, against the Vicon 3D motion capture system in 60 patients with ankle injuries. (2) Methods: Synchronized gait data were collected using both systems while participants walked on a treadmill at self-selected speeds. The Foot4D system employs a Vision Transformer (ViT-H/16) encoder and the SKEL parametric model for markerless 3D pose reconstruction from multi-view depth cameras. Spatiotemporal gait parameters and lower limb 3D kinematics (hip, knee, and ankle) were compared using ICC, Bland–Altman analysis, and MAE. (3) Results: All 12 spatiotemporal parameters showed good-to-excellent agreement (ICC = 0.738–0.999, MAE = 0.009–0.108 m/s). Agreement for joint kinematics decreased from proximal to distal: hip (mean ICC ≈ 0.947, MAE 1.16–1.52°), knee (mean ICC ≈ 0.921, MAE 1.17–1.75°), and ankle (mean ICC ≈ 0.839). Ankle sagittal plane ROM demonstrated good agreement (ICC = 0.857–0.911), while the frontal (ICC ≈ 0.807) and transverse (ICC ≈ 0.816–0.835) planes were at the lower bound of good agreement, with a −3.19° systematic bias in the injured ankle sagittal plane. (4) Conclusions: Foot4D is clinically reliable for spatiotemporal and proximal joint kinematic assessment, though ankle multiplanar motion measurement warrants further algorithmic optimization. Full article

Introduction: The Trauma Medical Home (TMH) randomized clinical trial tested the efficacy of a collaborative care intervention on the biopsychosocial recovery of older injured adults compared to usual care. Study enrollment occurred between 11 October 2017 and 13 October 2021 and study operations were impacted by the COVID-19 pandemic. It is important to measure the potential effects of COVID-19 on research study participants to ensure accurate reporting of results. The purpose of this secondary analysis was to compare depression and anxiety symptoms and health-related quality of life in older adults at TMH study enrollment pre-COVID-19 and during COVID-19. We hypothesized that those enrolled during COVID-19 would have worse symptoms and quality of life. Methods: This study was a secondary analysis of data from a multicenter randomized clinical trial (R01AG052493-01A1) TMH, that examined the ability of a collaborative care model to enhance the recovery of older injured adults compared to usual care. It was hypothesized that the TMH intervention would improve biopsychosocial recovery for injured older adults compared to usual care. The enrollment periods pre-COVID-19 and during COVID-19 were compared. Chi-square tests and Wilcoxon Rank Sum tests, then multivariable linear and logistic regressions were completed with SF-36 component scores and depression (PHQ-9) and anxiety (GAD-7) scores as the dependent variables, respectively. Results: A total of 429 participants were analyzed. There was no significant difference in anxiety and depression symptoms between the pre-COVID-19 and during-COVID-19 enrollment periods. Perceived limitations due to physical health problems were worse for those enrolled during COVID-19 (adjusted β = −9.8, 95% CI −18.3 to −1.4), but other health-related quality of life measures were similar between the two groups. Conclusions: These findings support the conclusion that the negative psychological impacts of the pandemic are likely due to individual factors other than age or COVID-19. These results suggest a high degree of psychological resiliency in older adults under stress. Future research should focus on the potential effects of socioeconomic status, demographic background, and level of physical functioning on psychological outcomes. Full article

Pediatric trauma accounts for 10–20% of all emergency department visits annually in the United States, and both intentional and unintentional injuries contribute significantly to the overall morbidity and mortality associated with trauma in children. Solid organ injuries are often identified, particularly in relation to blunt injury mechanisms, and can lead to serious adverse events if not diagnosed and treated expeditiously. Advancements in diagnostic tools and intervention strategies have improved outcomes for injured children. This review identifies common mechanisms for pediatric solid organ injuries, discusses advances in triage and diagnostic capabilities, and explores treatment options along with intervention innovations for these types of traumatic injuries in the pediatric population. Full article

Wallerian degeneration (WD), which occurs distal to peripheral nerve injury, is a tightly regulated process. Axonal degeneration during the onset of WD represents a self-destructive process that begins with an early phase and progresses to an execution phase characterized by fragmentation of axons and myelin sheaths. Efficient clearance of axonal and myelin debris, together with the reprogramming of Schwann cells and macrophages into a repair phenotype, constitutes a critical extrinsic prerequisite for successful axonal regeneration. In parallel, signaling molecules produced during WD trigger intrinsic responses in injured neurons that are essential for neuronal survival and the initiation of the regenerative program. This review provides an overview of the key events involved in WD, which are often studied separately, with the aim of elucidating their interrelationships and their impact on nerve regeneration. Such an integrated overview may aid in identifying molecular targets for the development of novel therapeutic strategies to enhance axonal regeneration. Full article

Spinal cord injury (SCI) is a devastating neurological disorder. The development of effective therapies to ameliorate the consequences of SCI represents a major challenge and a central priority of international biomedical research. The stromal vascular fraction (SVF) derived from adipose tissue possesses considerable functional potential. SVF is a heterogeneous mixture of cells that act synergistically. However, after local transplantation, SVF is rapidly cleared via the bloodstream, and its poor survival severely compromises therapeutic efficacy. To overcome this limitation, we employed a self-assembling peptide nanohydrogel HGF-RADA16-IKVAV (where HGF denotes the tripeptide histidine–glycine–phenylalanine) as a scaffold to enhance SVF retention and efficacy in a rat model of SCI. Implantation of SVF and HGF into the injured spinal cord demonstrated that this combined therapy significantly modulated the inflammatory response, increased neuronal survival, and promoted a denser network of axon tracts. Consequently, the SVF-encapsulated HGF hydrogel resulted in superior restoration of limb movement and reduced neuropathic pain. Proteomic analysis confirmed that the combined treatment shifted the injury-induced molecular landscape, particularly in immune and inflammatory pathways. Collectively, these findings demonstrate that this combinatorial strategy represents an effective therapeutic paradigm for SCI. Full article

Peripheral neurons have an intrinsic capacity for repair, albeit still challenging. How the nervous system responds to the cellular stress imposed by nerve injury and adjunct therapies impacts axon regeneration and functional outcomes. Here, we summarize some of the key primarily axonal and neuronal adaptive stress responses and mechanisms that underlie the ability of peripheral neurons to regenerate an axon. This includes activation of the unfolded protein response and endoplasmic reticulum membrane-associated molecules, namely Luman/CREB3, a transmembrane basic leucine zipper transcription factor that regulates the encoding of beneficial adaptive stress responses that drive the ability of an injured sensory neuron to regenerate their axon. We also highlight an emerging novel non-invasive strategy, therapeutic acute intermittent hypoxia, that imposes a level of beneficial adaptive stress that can alter gene programs induced by the injury to enhance regeneration in a manner akin to the more invasive yet highly effective electrical nerve stimulation. The ability to manipulate and significantly elevate the intrinsic adaptive stress/repair responses of injured peripheral neurons holds therapeutic promise, with accumulating evidence supporting its clinical use. Full article