Epidemiology, Pathophysiology, and Treatment Strategies of Concussions: A Comprehensive Review.

A concussion is a particular manifestation of a traumatic brain injury, which is the leading cause of mortality and disabilities across the globe. The global prevalence of traumatic brain injury is estimated to be 939 instances per 100,000 individuals, with approximately 5.48 million people per year experiencing severe traumatic brain injury. Epidemiology varies amongst different countries by socioeconomic status with diverse clinical manifestations. Additionally, classifying concussions is an ambiguous process as clinical diagnoses are the only current classification method, and morbidity rates differ by demographic location as well as populations examined. In this article, we critically reviewed the pathophysiology of concussions, classification methods, treatment options available including both pharmacologic and nonpharmacologic intervention methods, etiologies as well as global etiologic differences associated with them, and clinical manifestations along with their associated morbidities. Furthermore, analysis of the current research regarding the incidence of concussion based traumatic brain injuries and future directions are discussed. Investigation on the efficacy of new therapeutic-related interventions such as exosome therapy and electromagnetic field stimulation are warranted to properly manage and treat concussion-induced traumatic brain injury.

Therapeutic Potential of Targeting p27kip1 in Plaque Vulnerability.

Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.

Pulmonary Fibrosis and Diabetes Mellitus: Two coins with the same face.

Idiopathic pulmonary fibrosis (IPF) constitutes a long-term disease with a complex pathophysiology composed of multiple molecular actors that lead to the deposition of extracellular matrix, the loss of pulmonary function and ultimately the patient's death. Despite the approval of pirfenidone and nintedanib for the treatment of the disease, lung transplant is the only long-term solution to fully recover the respiratory capacity and gain quality of life. One of the risk factors for the development of IPF is the pre-existing condition of diabetes mellitus. Both, IPF and diabetes mellitus, share similar pathological damage mechanisms, including inflammation, endoplasmic reticulum stress, mitochondrial failure, oxidative stress, senescence and signaling from glycated proteins through receptors. In this critical review article, we provide information about this interrelationship, examining molecular mediators that play an essential role in both diseases and identify targets of interest for the development of potential drugs. We review the findings of clinical trials examining the progression of IPF and how novel molecules may be used to stop this process. The results highlight the importance of early detection and addressing multiple therapeutic targets simultaneously to achieve better therapeutic efficacy and potentially reverse lung fibrosis.

Transcriptomic Analysis of Gene Expression and Effect of Electromagnetic Field in Brain Tissue after Traumatic Brain Injury.

Traumatic brain injury (TBI) due to a direct blow or penetrating injury to the head damages the brain tissue and affects brain function. Primary and secondary damage to the brain tissue increases disability, morbidity, and mortality and costs millions of dollars in treatment. Injury to the brain tissue results in the activation of various inflammatory and repair pathways involving many cellular and molecular factors. Increased infiltration of immune cells to clear the debris and lesion healing, activation of Schwann cells, myelination, oligodendrocyte formation, and axonal regeneration occur after TBI to regenerate the tissue. However, secondary damage to brain tissue results in behavioral symptoms. Repair and regeneration are regulated by a complex cascade involving various cells, hormones, and proteins. A change in the expression of various proteins due to altered gene expression may be the cause of impaired repair and the sequelae in TBI. In this pilot study, we used a Yucatan miniswine model of TBI with and without electromagnetic field (EMF) stimulation and investigated the differential gene expression between injured and non-injured cortex tissues. We found several differentially expressed genes including INSC, TTR, CFAP126, SEMA3F, CALB1, CDH19, and SERPINE1. These genes are associated with immune cell infiltration, myelination, reactive oxygen species regulation, thyroid hormone transportation, cell proliferation, and cell migration. There was a time-dependent effect of EMF stimulation on the gene and protein expression. The findings support the beneficial effect of EMF stimulation in the repair process following TBI.

Increased Oxidative Stress and Decreased Sirtuin-3 and FOXO3 Expression Following Carotid Artery Intimal Injury in Hyperlipidemic Yucatan Microswine.

Hypercholesterolemia is a major risk factor for atherosclerosis as oxidized-low-density lipoproteins (ox-LDL) contribute to the formation of foam cells and inflammation. Increased immune cell infiltration and oxidative stress induce instability of a plaque. Rupture of the unstable plaque precipitates adverse ischemic events. Since reactive oxygen species (ROS) play a critical role in plaque formation and vulnerability, regulating ROS generation may have therapeutic potential. Sirtuins, specifically sirtuin-3 (SIRT3), are antigenic molecules that can reduce oxidative stress by reducing mitochondrial ROS production through epigenetic modulation. Lack of SIRT3 expression is associated with dysregulation of ROS and endothelial function following high-fat high-cholesterol diet. SIRT3 deacetylates FOXO3a (Forkhead transcription factor O subfamily member 3a) and protects mitochondria against oxidative stress which can lead to even further protective anti-oxidizing properties. This study was designed to investigate the association between hyperlipidemia, intimal injury, chronic inflammation, and the expression of NAD-dependent deacetylase SIRT-3, FOXO3, antioxidant genes, and oxidative stress in carotid arteries of hypercholesterolemic Yucatan microswine. We found that intimal injury in hypercholesterolemic state led to increased expression of oxidative stress, inflammation, neointimal hyperplasia, and plaque size and vulnerability, while decreasing anti-oxidative regulatory genes and mediators. The findings suggest that targeting the SIRT3-FOXO3a-oxidative stress pathway will have therapeutic significance.

Modulation of Inflammatory Response by Electromagnetic Field Stimulation in Traumatic Brain Injury in Yucatan Swine.

Traumatic brain injury is a leading cause of disability and death worldwide and represents a high economic burden for families and national health systems. After mechanical impact to the head, the first stage of the damage comprising edema, physical damage, and cell loss gives rise to a second phase characterized by glial activation, increased oxidative stress and excitotoxicity, mitochondrial damage, and exacerbated neuroinflammatory state, among other molecular calamities. Inflammation strongly influences the molecular events involved in the pathogenesis of TBI. Therefore, several components of the inflammatory cascade have been targeted in experimental therapies. Application of Electromagnetic Field (EMF) stimulation has been found to be effective in some inflammatory conditions. However, its effect in the neuronal recovery after TBI is not known. In this pilot study, Yucatan miniswine were subjected to TBI using controlled cortical impact approach. EMF stimulation via a helmet was applied immediately or two days after mechanical impact. Three weeks later, inflammatory markers were assessed in the brain tissues of injured and contralateral non-injured areas of control and EMF-treated animals by histomorphometry, immunohistochemistry, RT-qPCR, Western blot, and ELISA. Our results revealed that EMF stimulation induced beneficial effect with the preservation of neuronal tissue morphology as well as the reduction of inflammatory markers at the transcriptional and translational levels. Immediate EMF application showed better resolution of inflammation. Although further studies are warranted, our findings contribute to the notion that EMF stimulation could be an effective therapeutic approach in TBI patients.

Stem Cell-Derived Cardiomyocyte-Like Cells in Myocardial Regeneration.

Myocardial infarction results in the significant loss of cardiomyocytes (CMs) due to the ischemic injury following coronary occlusion leading to impaired contractility, fibrosis, and ultimately heart failure. Stem cell therapy emerged as a promising regenerative strategy to replenish the otherwise terminally differentiated CM to restore cardiac function. Multiple strategies have been applied to successfully differentiate diverse stem cell populations into CM-like phenotypes characterized by the expression status of signature biomarkers and observable spontaneous contractions. This article discusses the current understanding and applications of various stem cell phenotypes to drive the differentiation machinery toward CM-like lineage. Impact Statement Ischemic heart disease (IHD) extensively affects a large proportion of the population worldwide. Unfortunately, current treatments for IHD are insufficient to restore cardiac effectiveness and functionality. A growing field in regenerative cardiology explores the potential for stem cell therapy following cardiovascular ischemic episodes. The thorough understanding regarding the potential and shortcomings of translational approaches to drive versatile stem cells to cardiomyocyte lineage paves the way for multiple opportunities for next-generation cardiac management.

Role of sirtuins in attenuating plaque vulnerability in atherosclerosis.

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

Biomechanical Forces in the Tissue Engineering and Regeneration of Shoulder, Hip, Knee, and Ankle Joints.

Tear on the tendon, ligament and articular cartilage of the joints do not heal by itself and new modalities of treatment are required to address the need for full restoration of joint functions. Accompanied by degenerative diseases, the healing of these tissues does not occur naturally and hence requires surgical interventions, but with associated morbidity. Tissue engineering strategies are now focusing on the effective incorporation of biomechanical stimulation by the application of biomechanical forces relevant to the tissue of interest to regenerate and engineer functional tissues. Bioreactors are being continuously developed to accomplish this goal. Although bioreactors have been developed, the advancement in the field of biomaterial, basic science, and cell engineering warrant further refinement for their effective use. In this article we reviewed the application of biomechanical forces in the tissue engineering and regeneration of the joints such as rotator cuff of shoulder, ball and socket joint of the hip, articular cartilage of knee, and the ankle joints.

Discovery of Potential RAGE inhibitors using Receptor-Based Pharmacophore Modeling, High Throughput Virtual Screening and Docking Studies.

Receptor for Advanced Glycation End products (RAGE) is a transmembrane receptor that can bind to various endogenous and exogenous ligands and initiate the inflammatory downstream signaling pathways. So far RAGE has been involved in various disorders including cardiovascular and neurodegenerative diseases, cancer, and diabetes. Blocking the interactions between RAGE and its ligands is a therapeutic approach to treat these conditions. In this context, we effectively utilized the receptor-based-pharmacophore modeling to discover structurally diverse molecular compounds having potential to effectively bind with RAGE. Two pharmacophore models were developed on V-domain of RAGE using Phase application of Schrodinger suite. The developed pharmacophoric features were used for screening of 1.8 million drug-like molecules downloaded from ChEMBL database. The molecules were scrutinized according to their molecular weight as well as clogP values. Phase screening was performed to find out the molecules that matched the developed pharmacophoric features that were further selected to analyze their binding modes using high-throughput virtual screening, extra precision docking studies and MM-GBSA ΔG binding calculations. These analyses provided ten hit RAGE inhibitory molecules that can bind to two different shallow binding sites on the V-domain of RAGE. Among the obtained compounds two compounds ChEMBL501494 and ChEMBL4081874 were found with best binding free energies that proved their receptor-ligand complex stability within their respective binding cavity on RAGE. Therefore, these molecules could be utilized for further designing and optimizing the future class of potential RAGE inhibitors.

Hyperlipidemia Lowers the Biomechanical Properties of Rotator Cuff Tendon.

Infraspinatus tendon is the most affected tendon of the rotator cuff, being an important posterior component of the shoulder joint. Hyperlipidemia is a predisposing factor in the progression of rotator cuff tears and retear. We studied the effect of hyperlipidemia on the biomechanical properties of rotator cuff tendons. The infraspinatus tendon of the rotator cuff from hyperlipidemic swine were collected and tested for ultimate tensile strength (UTS) and modulus of elasticity. Dynamic mechanical analysis was performed to examine viscoelastic properties. The findings revealed no significant difference in UTS but had significantly lower modulus of elasticity in the infraspinatus tendon of the hyperlipidemic group compared to the control group. Moreover, differences in the dynamic modulus, storage modulus, and loss modulus were not statistically significant between the hyperlipidemic and control swine. There was no difference in water content between the groups but the hyperlipidemic group had fatty infiltration aiding the initial decrease in mechanical properties. These findings suggest an association between fat deposition and early changes in the biomechanical properties of the tendons in the shoulder rotator cuff in hyperlipidemic state.

Distinguishing Swine Flu (H1N1) from COVID-19: Clinical, Virological, and Immunological Perspectives.

This article provides an in-depth examination on the differences between the influenza A strain, H1N1 (also called Swine Flu) and Covid-19 focusing on the immune response and clinical symptoms. Flu symptoms due to influenza A strain, H1N1, were initially discovered in 2009. This variant of influenza A is believed to have emerged through reassortment, a process where the resulting virus inherits gene segments from each of its parental viruses. This reassortment event has resulted in a variant with altered characteristics, potentially affecting the level of immunity in humans. The symptoms of this strain typically manifest 1-4 days after exposure and include fever, cough, sore throat, runny/stuffy nose, body aches, fatigue, and gastrointestinal symptoms such as diarrhea. The transmission dynamics of this new variant, including human-to-human transmission, are still under investigation by health authorities. Individuals with weakened immune systems are generally more susceptible to severe illness. Risk factors associated with swine flu can include older adults, young children, pregnant women, and individuals with obesity. Historical variants of swine flu, such as the 2015 variant in India, have been associated with significant case numbers and deaths, often due to respiratory failure. Since the epidemic of Covid-19 due to SARS-CoV2 in early 2020, several symptoms of COVID-19 and swine flu overlap. In this article, we critically reviewed the differences and similarities in the immune response and clinical symptoms due to H1N1 virus and SARS-CoV2 in human.

A Review of Hematological Complications and Treatment in COVID-19.

COVID-19, caused by SARS-CoV-2, and its variants have spread rapidly across the globe in the past few years, resulting in millions of deaths worldwide. Hematological diseases and complications associated with COVID-19 severely impact the mortality and morbidity rates of patients; therefore, there is a need for oversight on what pharmaceutical therapies are prescribed to hematologically at-risk patients. Thrombocytopenia, hemoglobinemia, leukopenia, and leukocytosis are all seen at increased rates in patients infected with COVID-19 and become more prominent in patients with severe COVID-19. Further, COVID-19 therapeutics may be associated with hematological complications, and this became more important in immunocompromised patients with hematological conditions as they are at higher risk of hematological complications after treatment. Thus, it is important to understand and treat COVID-19 patients with underlying hematological conditions with caution. Hematological changes during COVID-19 infection and treatment are important because they may serve as biomarkers as well as to evaluate the treatment response, which will help in changing treatment strategies. In this literature review, we discuss the hematological complications associated with COVID-19, the mechanisms, treatment groups, and adverse effects of commonly used COVID-19 therapies, followed by the hematological adverse events that could arise due to therapeutic agents used in COVID-19.

Karyopherins in the Remodeling of Extracellular Matrix: Implications in Tendon Injury.

Rotator Cuff Tendinopathies (RCT) are debilitating conditions characterized by alterations in the extracellular matrix (ECM) of the shoulder tendon, resulting in pain, discomfort, and functional limitations. Specific mediators, including HIF-1α, TGF-ß, MMP-9 and others have been implicated in the morphological changes observed in the tendon ECM. These mediators rely on karyopherins, a family of nuclear proteins involved in nucleo-cytoplasmic transport; however, the role of karyopherins in RCT remains understudied despite their potential role in nuclear transport mechanisms. Also, the understanding regarding the precise contributions of karyopherins in RCT holds great promise for deciphering the underlying pathophysiological mechanisms of the disease and potentially fostering the development of targeted therapeutic strategies. This article critically discusses the implications, possibilities, and perspectives of karyopherins in the pathophysiology of RCT.

Biomarkers to monitor the prognosis, disease severity, and treatment efficacy in coronary artery disease.

INTRODUCTION: Coronary Artery Disease (CAD) is a prevalent condition characterized by the presence of atherosclerotic plaques in the coronary arteries of the heart. The global burden of CAD has increased significantly over the years, resulting in millions of deaths annually and making it the leading health-care expenditure and cause of mortality in developed countries. The lack of cost-effective strategies for monitoring the prognosis of CAD warrants a pressing need for accurate and efficient markers to assess disease severity and progression for both reducing health-care costs and improving patient outcomes. AREA COVERED: To effectively monitor CAD, prognostic biomarkers and imaging techniques play a vital role in risk-stratified patients during acute treatment and over time. However, with over 1,000 potential markers of interest, it is crucial to identify the key markers with substantial utility in monitoring CAD progression and evaluating therapeutic interventions. This review focuses on identifying and highlighting the most relevant markers for monitoring CAD prognosis and disease severity. We searched for relevant literature using PubMed and Google Scholar. EXPERT OPINION: By utilizing the markers discussed, health-care providers can improve patient care, optimize treatment plans, and ultimately reduce health-care costs associated with CAD management.

Coronary artery disease is a narrowing or blockage of coronary arteries due to the formation of plaque. The main risk factors are inflammation, aging, high cholesterol, shear stress, obesity, and smoking. Narrowing of the arteries results in decreased blood supply (nutrient and oxygen) to the tissue precipitating ischemia presented as angina or myocardial infarction. During ischemic events, there occurs a change in the expression of various molecular and cellular components and increased expressions of many of these factors have been used as biomarkers to diagnose the pathology. Myoglobin, fatty acid-binding proteins, and glycogen phosphorylase isoenzyme BB are early biomarkers, troponin-T and troponin-I are late biomarkers, while creatine kinase-myocardial band is a biomarker in the first 10­12 h for the diagnosis of AMI. However, there is a need for a panel of biomarkers that can help in the prediction, prognosis, and diagnosis of disease progression (atherosclerosis), pre-ischemic and ischemic events, and post-MI periods to design the treatment strategies in a specific and sensitive manner. There is a need for cost-effective sensitive biomarkers that can prevent progression, risk stratify, predict, diagnose, and prevent MI in a timely manner. In this comprehensive review, we discuss the key markers of substantial utility for monitoring coronary artery disease progression and the efficacy of therapeutic intervention among various markers of interest.

A Swine Model of Neural Circuit Electromagnetic Fields: Effects of Immediate Electromagnetic Field Stimulation on Cortical Injury.

Background Neurologic diseases have profound disability, mortality, and socioeconomic effects worldwide. Treatment of these disorders varies but is largely limited to unique factors associated with neural physiology. Early studies have evaluated alterations in electromagnetic fields (EMF) due to neural disorders with subsequent modulation of EMF as a potential treatment modality. Swine models have begun to be evaluated as translational models in this effect. Methods EMF measurements of a Yucatan miniswine were recorded using proprietary non-contact, non-invasive induction sensors with a dual layer Mu-metal and interlaced copper mesh helmet. The swine then underwent controlled cortical impact (CCI) to simulate traumatic brain injury (TBI). Twenty minutes post-injury after surgical wound closure, the swine underwent targeted EMF signal modulation using a signal generator to stimulate the swine's injured cortical circuit using a sinusoidal wave individualized at 2.5 Hz with a 500mV positive offset at 1V. After 10 days of stimulation, settings were modified to another individualized frequency of 5.5 Hz, 500mV positive offset and 1V for stimulation. Behavioral patterns in swine were evaluated, and EMF measurements were recorded daily prior to, during, and after stimulation. Artificial intelligence (AI) models evaluated patterns in EMF signals. Histology of the stimulated swine cortex was evaluated using hematoxylin and eosin staining and pentachrome staining and compared to a control swine without stimulation and a swine that had received stimulation two days post-injury in a delayed fashion. Serial serum specimens and tissue at the time of euthanasia were obtained for assessment of neuron-specific enolase (NSE) concentration. Results Pre-operative and post-stimulation measurements demonstrated differences in patterns and activity early on. There was an identified peak at 1.6Hz, not frequently seen pre-operatively. There were convergent frequencies in both data sets at 10.5 Hz and 3.9 Hz. Plateaus and decreased variability of changes in slope were identified early in the post-injury phase. AI modeling identified early similarities in pre-operative and post-stimulation measurements through the patterns of peaks with similarities on postoperative day 10 and similarities in the valleys on postoperative day 17. Histologic specimens identified increased degrees of apoptosis and cellular death in the non-stimulated control compared to the stimulated swine. Similarly, the immediately stimulated swine had less apoptosis and increased histologic viability at the site of injury compared to the two-day delayed stimulation swine. There were increased levels of NSE noted in the stimulated swine at the site of injury compared to non-injured sites and the control swine. Conclusions Cortical function was appropriately measured through induction sensors and shielding in the form of a helmet and electromagnetic field channels. Early stimulation resulted in the early and durable recovery of neuronal circuit-driven electromagnetic field patterns. Histology identified increased viability of neurons with fewer apoptotic neurons and glial cells in stimulated swine with early stimulation identifying the best effect compared to a non-stimulated subject. This recovery identifies change and recovery at the circuit, cellular, and subcellular levels that potentiate the need for further study of EMF modulation as a treatment modality in neurological disorders.

A Swine Model of Changes in the Neuronal Electromagnetic Field After Traumatic Brain Injury: A Pilot Study.

Background Traumatic brain injury (TBI) is a global cause of disability and mortality. Treatment depends on mitigation of secondary injury resulting in axonal injury, necrosis, brain dysfunction, and disruption of electrical and chemical signaling in neural circuits. To better understand TBI, translational models are required to study physiology, diagnostics, and treatments in homologous species, such as swine. Electromagnetic fields (EMFs) from altered neural circuits can be measured and historically have been reliant on expensive shielding and supercooling in magnetoencephalography. Using proprietary induction sensors, it has been found that a non-invasive, non-contact approach with an engineered Mu-metal and copper mesh-shielded helmet effectively measures EMFs. This has not yet been investigated in swine models. We wished to evaluate the efficacy of this technology to assess TBI-dependent EMF changes in swine to describe the efficacy of these sensors and this model using a gravity-dependent controlled cortical impact (CCI). Methods A Yucatan miniswine was evaluated using non-contact, non-invasive proprietary induction sensors with an engineered dual-layer Mu-metal and interlaced copper mesh helmet with sensors within EMF channels connected to a helmet. Swine EMF recordings were obtained prior to induced gravity-dependent CCI followed by post-TBI measurements. Behavioral changes and changes in EMF measurements were assessed. EMF measurements were evaluated with an artificial intelligence (AI) model. Results Differences between room "noise" EMF measurements and pre-TBI swine electromagnetic field measurements were identified. Morphological characteristics between pre-injury and post-injury measurements were noted. AI modeling differentiated pre-injury and post-injury patterns in the swine EMF. Frequently identified frequencies seen post-injury were peaks at 2.5 Hz and 6.5 Hz and a valley at 11 Hz. The AI model identified less changes in the slope and thus decreased variation of EMF measurements post-TBI between 4.5 Hz and 7 Hz. Conclusions For the first time, it was identified that cortical function in a swine can be appropriately measured using novel induction sensors and shielding isolated to a helmet and EMF channels. The swine model can be appropriately differentiated from the external noise signal with identifiably different pre-injury and post-injury EMFs. Patterns can be recognized within the post-injury EMF due to altered neural circuits that can be measured using these sensors continuously, non-invasively, and in real time.

A Swine Model of Traumatic Brain Injury: Effects of Neuronally Generated Electromagnetic Fields and Electromagnetic Field Stimulation on Traumatic Brain Injury-Related Changes.

Background and objective Traumatic brain injury (TBI) has been associated with aberrations in neural circuitry attributable to the pathology resulting in electromagnetic field (EMF) changes. These changes have been evaluated in a variety of settings including through novel induction sensors with an ultra-portable shielded helmet and EMF channels with differences identified by comparing pre-injury and post-injury states. Modulation of the EMF has undergone cursory evaluation in neurologic conditions but has not yet been fully evaluated for clinical effects in treatment. Target EMF stimulation using EMF-related changes preoperatively to postoperatively has not yet been attempted and has not been completed using induction sensor technology. Our objectives in this study were twofold: we wanted to test the hypothesis that targeted stimulation using an EMF signal generator and stimulator to abnormal thresholds identified by real-time measurement of EMFs may enable early resolution of EMF changes and treatment of the TBI as modeled through controlled cortical impact (CCI); we also aimed to assess the feasibility of attempting this using real-time measurements with an EMF shielded helmet with EMF channels and non-contact, non-invasive induction sensors with attached EMF transmitters in real-time. Methods A singular Yucatan miniswine was obtained and baseline EMF recordings were obtained. A CCI of TBI and postoperative assessment of cortical EMF in a non-invasive, non-contact fashion were completed. Alterations in EMF were evaluated and EMF stimulation using those abnormal frequencies was completed using multiple treatments involving three minutes of EMF stimulation at abnormal frequencies. Stimulation thresholds of 2.5 Hz, 3.5 Hz, and 5.5 Hz with 1 V signal intensity were evaluated using sinusoidal waves. Additionally, stimulation thresholds using differing offsets to the sine wave at -500 mV, 0 mV, and 500 mv were assessed. Daily EMF and post-stimulation EMF measurements were recorded. EMF patterns were then assessed using an artificial intelligence (AI) model. Results AI modeling appropriately identified differences in EMF signal in pre-injury, post-injury, and post-stimulation states. EMF stimulation using a positive offset of 500 mV appeared to have maximal beneficial effects in return to baseline. Similarly targeted stimulation using thresholds of 2.5 Hz and 5.5 Hz with a positive 500 mV offset at 1 V allowed for recovery of EMF patterns post-injury towards patterns seen in baseline EMF measurements on stimulation day seven (postoperative day 17). Conclusion Stimulation of neural circuits with targeted EMF in a sinusoidal pattern with targeted thresholds after measurement with induction sensors with shielding isolated to a Mu-metal and copper mesh helmet and EMF channels is efficacious in promoting neuronal circuit recovery to preoperative baselines in the TBI miniswine model. Similarly, our findings confirm the appropriateness of this translational model in the evaluation of brain neuronal circuit EMF and that preoperative and post-trauma differences can be appropriately assessed with this technology.

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation.

End-stage renal disease is a crippling diagnosis that generally requires dialysis to prolong life. To facilitate filtration of patient's blood in dialysis, surgical formation of an arteriovenous fistula (AVF) is commonly performed. Maturation of the AVF is required to allow for successful dialysis. However, AVFs commonly fail to mature, leading to the fistula closure, the necessity for another fistula site, and markedly increased morbidity and mortality. The current literature concerning molecular mechanisms associated with AVF maturation failure supports the role of inflammatory mediators involving immune cells and inflammatory cytokines. However, the role of oncostatin M (OSM), an inflammatory cytokine, and its downstream targets are not well investigated. Through inflammation, oxidative stress, and hypoxic conditions, the vascular tissue surrounding the AVF undergoes fibrosis, stenosis, and wall thickening, leading to complete occlusion and nonfunctional. In this report, first we critically review the existing literature on the role of OSM in the most common causes of early AVF failure - vascular inflammation, thrombosis, and stenosis. We next consider the potential of using OSM as a therapeutic target, and finally discuss therapeutic agents targeting inflammatory mediators involved in OSM signaling to potentiate successful maturation of the AVF.

Novel mediators regulating angiogenesis in diabetic foot ulcer healing.

A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.