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Cureus May 2024Compartment syndrome (CS) can occur in a variety of clinical scenarios. Reperfusion injury and tissue swelling are common causes across etiologies. Trauma is recognized...
Compartment syndrome (CS) can occur in a variety of clinical scenarios. Reperfusion injury and tissue swelling are common causes across etiologies. Trauma is recognized as a common cause, but CS is also seen after limb alignment correction for extremities. CS is a difficult diagnosis to make in any scenario. Timely diagnosis is also difficult. Correct diagnosis is inexact, with many false positives and some false negatives being the normal outcome. This case represents a scenario where it was inherently difficult to make the diagnosis. The patient was a young patient with an underlying neurodevelopmental disorder where physical and clinical examination was impossible to accomplish. Any intervention to decrease pain was also difficult and actively refused by the patient and the family. Leaving open wounds after a fasciotomy was also undesirable for wound care and infection. Previous care maps have high false-positive rates or a need for fasciotomy as the treatment arm when diagnosis is uncertain. This usually results in fasciotomy being performed in many legs without CS. These false positives and resultant prophylactic releases are costly because of protracted hospital stay, high rate of deep infection, and decreased operating room availability for other cases. The desirable tool for surgeons would be the one that decreased false positives and false negatives while ensuring diagnosis in a timely fashion for true-positive cases. Technology for monitoring continuous pressure has been shown to aid in diagnosis. In this report, we illustrate the use of a continuous pressure monitoring system in a case of a pediatric patient post-osteotomy of a lower limb presenting with unremitting pain and a difficult clinical examination.
PubMed: 38919242
DOI: 10.7759/cureus.61114 -
Drug Delivery and Translational Research Jun 2024Renal ischemia-reperfusion injury (IRI) frequently occurs following kidney transplantation, and exosomes derived from umbilical cord mesenchymal stem cells (WJ-MSC-Exos)...
Renal ischemia-reperfusion injury (IRI) frequently occurs following kidney transplantation, and exosomes derived from umbilical cord mesenchymal stem cells (WJ-MSC-Exos) have shown promise in treating IRI in transplanted kidneys. Our study delved into the potential mechanism of WJ-MSC-Exos in ameliorating IRI in transplanted kidneys, revealing that miR-19b is abundantly present in WJ-MSC-Exos. Both in vivo and in vitro experiments demonstrated that the absence of miR-19b abolished the protective effects of WJ-MSC-Exos against renal IRI. Mechanistically, miR-19b suppressed glycogen synthase kinase-3β (GSK3β) expression, thereby stabilizing PDXK protein through direct binding. Treatment with WJ-MSC-Exos led to reduced PDXK levels and enhanced pyridoxine accumulation, ultimately mitigating IRI in transplanted kidneys and I/R-induced HK2 cell apoptosis. These findings elucidate the underlying mechanism of WJ-MSC-Exos in alleviating IRI in transplanted kidneys, unveiling novel therapeutic targets for post-kidney transplantation IRI and providing a solid theoretical foundation for the clinical application of WJ-MSC-Exos in IRI treatment post-transplantation.
PubMed: 38918324
DOI: 10.1007/s13346-024-01645-3 -
Revue Neurologique Jun 2024Early identification of suspected stroke patients who might be eligible for a reperfusion strategy is a daily challenge in the management of patient referrals. The aim...
INTRODUCTION/BACKGROUND
Early identification of suspected stroke patients who might be eligible for a reperfusion strategy is a daily challenge in the management of patient referrals. The aim of this study was to evaluate the performance of a remote medical assessment in identifying patients eligible for endovascular therapy (EVT) while not eligible for intravenous thrombolysis (IVT), compared with a decision based on bedside clinico-radiological data.
METHODS
Patients admitted to the emergency department for acute neurological symptoms lasting for less than 24h were prospectively included. Assessment of the clinical severity and medical history was performed simultaneously by two vascular neurologists (VNs), one remotely using a mobile telemedicine solution (NOMADEEC), the other at the bedside. RACE score was calculated from the NIHSS score. At the end of the evaluation, both VNs quoted their treatment convictions (IVT/EVT). Final therapeutic decision following brain and vascular imaging was recorded and compared to remote and bedside predictions. The performances of three different conditions were evaluated: complete medical evaluation (NIHSS+medical history), NIHSS score alone, and RACE score alone. Remote and bedside performances were also compared. Diagnostic accuracy parameters (sensitivity, specificity, positive and negative predictive values) of each condition were estimated, along with their two-sided 95% binomial confidence intervals.
RESULTS
Out of 215 enrolled patients, 186 had a complete evaluation, 91 (54.3%) were diagnosed with an ischemic stroke or transient ischemic attack and 46 (24.7%) had an intracranial occlusion. Considering the three conditions evaluated remotely, RACE score-based decision provided the best sensitivity 54.6% [95% CI 23.4; 83.2]/specificity 80.6% [73.9; 86.2] combination. However, the complete medical evaluation had the best specificity (88.6% [82.9; 92.9] compared to RACE scores alone (P=0.038). Remote and bedside performances did not differ (κ=0.68 [0.59; 0.77]).
DISCUSSION/CONCLUSION
This real-life study performed in the setting of emergency demonstrates that remote medical evaluations including recording of extensive medical information and NIHSS examination to address patient's eligibility to revascularization treatment is swiftly feasible and is as effective as bedside prediction to EVT and/or IVT. Remote standardized medical evaluation might improve the decision of patients' primary orientation and avoid overcrowding of comprehensive stroke centres.
PubMed: 38918135
DOI: 10.1016/j.neurol.2024.05.006 -
Neurotherapeutics : the Journal of the... Jun 2024The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into...
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA-Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
PubMed: 38918128
DOI: 10.1016/j.neurot.2024.e00387 -
Clinical Immunology (Orlando, Fla.) Jun 2024Beta 2 glycoprotein I (B2GPI) is the major autoantigen in the antiphospholipid syndrome, an autoimmune disorder characterized by thrombotic and obstetric complications....
Beta 2 glycoprotein I (B2GPI) is the major autoantigen in the antiphospholipid syndrome, an autoimmune disorder characterized by thrombotic and obstetric complications. The autoantibodies that target beta 2 glycoprotein I are pathogenic and contribute to disease pathogenesis. The B2GPImolecule is composed of 5 domains that are numbered 1 through to 5. Autoantibodies bind mainly to domain 1 whereas the majority of the biological functions of the B2GPI molecule in diverse processes such as apoptotic cell clearance, complement regulation, lipopolysaccharide clearance, and anticoagulation have been localised to domain 5 and its unique biochemistry which is reviewed in this review article. The role of purified domain 5 peptide as a potential therapeutic agent in APS and ischemia reperfusion injury is discussed.
PubMed: 38917928
DOI: 10.1016/j.clim.2024.110282 -
Biomaterials Jun 2024Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation...
Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation after cardiac arrest (CA-ROSC). Inspired by the propensity of melanoma metastasis to the brain, B16F10 cell membranes are camouflaged on 2-methoxyestradiol (2ME2)-loaded reactive oxygen species (ROS)-triggered "Padlock" nanoparticles that are constructed by phenylboronic acid pinacol esters conjugated D-a-tocopheryl polyethylene glycol succinate (TPGS-PBAP). The biomimetic nanoparticles (BM@TP/2ME2) can be internalized, mainly mediated by the mutual recognition and interaction between CD44v6 expressed on B16F10 cell membranes and hyaluronic acid on cerebral vascular endothelial cells, and they responsively release 2ME2 by the oxidative stress microenvironment. Notably, BM@TP/2ME2 can scavenge excessive ROS to reestablish redox balance, reverse neuroinflammation, and restore autophagic flux in damaged neurons, eventually exerting a remarkable neuroprotective effect after CA-ROSC in vitro and in vivo. This biomimetic drug delivery system is a novel and promising strategy for the treatment of cerebral ischemia-reperfusion injury after CA-ROSC.
PubMed: 38917705
DOI: 10.1016/j.biomaterials.2024.122678 -
International Immunopharmacology Jun 2024Liver ischemia-reperfusion (IR) injury is an inevitable pathophysiological process in various liver surgeries. Previous studies have found that IR injury is exacerbated...
BACKGROUND
Liver ischemia-reperfusion (IR) injury is an inevitable pathophysiological process in various liver surgeries. Previous studies have found that IR injury is exacerbated in fatty liver due to significant hepatocellular damage and macrophage inflammatory activation, though the underlying mechanisms are not fully understood. In this study, we aim to explore the role and mechanism of Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling in regulating hepatocellular damage and macrophage immune response in fatty liver IR injury.
METHODS
The study used high-fat diet-induced fatty liver mice to establish an IR model, alongside an in vitro co-culture system of primary hepatocytes and macrophages. This approach was used to examine mitochondrial dysfunction, oxidative stress, mitochondrial DNA (mtDNA) release, and activation of macrophage STING (Stimulator of interferon genes) signaling. We also conducted recovery verification using H-151 (a STING inhibitor) and tBHQ (an Nrf2 activator).
RESULTS
Compared to the control group, mice on a high-fat diet demonstrated more severe liver IR injury, as evidenced by increased histological damage, elevated liver enzyme levels, and heightened inflammatory markers. The HFD group showed significant oxidative stress and mitochondrial dysfunction and damage post-IR, as indicated by elevated levels of ROS and lipid peroxidation markers, and decreased antioxidant enzyme activity. Elevated mtDNA release from hepatocytes post-IR activated macrophage STING signaling, worsening inflammation and liver damage. However, STING signaling inhibition with H-151 in vivo or employing STING knockout macrophages significantly reduced these injuries. In-depth mechanism studies have found that the transfer of Nrf2 protein into the nucleus of liver cells after IR in fatty liver is reduced. Pre-treatment with tBHQ ameliorated liver oxidative stress, mitochondrial damage and suppressed the macrophage STING signaling activation.
CONCLUSIONS
Our study reveals a novel mechanism where the interaction between hepatocellular damage and macrophage inflammation intensifies liver IR injury in fatty liver. Enhancing Nrf2 activation to protect mitochondrial from oxidative stress damage and inhibiting macrophage STING signaling activation emerge as promising strategies for clinical intervention in fatty liver IR injury.
PubMed: 38917524
DOI: 10.1016/j.intimp.2024.112515 -
American Journal of Physiology.... Jun 2024Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. hepatic machine perfusion (MP) is an emerging organ preservation technique...
Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically-based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT . Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multi-drug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; ) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for hepatic MP and fit a 6-parameter version of this model to control time course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only 3 unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT and found the mean estimated value for each parameter and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of for MRP2 at 30 min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during MP.
PubMed: 38917324
DOI: 10.1152/ajpgi.00048.2024 -
Cardiovascular Drugs and Therapy Jun 2024Noninvasive remote ischemic preconditioning (RIPC) is a practical, acceptable, and feasible conditioning technique reported to provide cardioprotection in myocardial...
OBJECTIVES
Noninvasive remote ischemic preconditioning (RIPC) is a practical, acceptable, and feasible conditioning technique reported to provide cardioprotection in myocardial ischemia-reperfusion injury (MIRI). It has been well-reported that quercetin possesses antioxidant and anti-inflammatory properties. This study investigates the modification of the cardioprotective response of RIPC by quercetin.
METHODS
Adult Wistar rats were randomized into 12 groups of six animals each. MIRI was induced by subjecting the isolated hearts of Wistar rats to global ischemia for 30 min, succeeded by reperfusion of 120 min after mounting on the Langendorff PowerLab apparatus. Hind limb RIPC was applied in four alternate cycles of ischemia and reperfusion of 5 min each by tying the pressure cuff before isolation of hearts.
RESULTS
MIRI was reflected by significantly increased infarct size, LDH-1, and CK-MB, TNF-α, TBARS, and decreased GSH, catalase, and hemodynamic index, and modulated Nrf2. Pretreatment of quercetin (25 and 50 mg/kg; i.p.) significantly attenuated the MIRI-induced cardiac damage and potentiated the cardioprotective response of RIPC at the low dose. Pretreatment of ketamine (10 mg/kg; i.p.), an mTOR-dependent autophagy inhibitor, significantly abolished the cardioprotective effects of quercetin and RIPC.
CONCLUSIONS
The findings highlight the modification of the cardioprotective effect of RIPC by quercetin and that quercetin protects the heart against MIRI through multiple mechanisms, including mTOR-dependent activation of autophagy and Nrf-2 activation.
PubMed: 38916838
DOI: 10.1007/s10557-024-07595-9 -
Drug Design, Development and Therapy 2024Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether...
Short-Term Preconditioning with Insulin and Glucose Efficiently Protected the Kidney Against Ischemia-Reperfusion Injury via the P-AKT-Bax-Caspase-3 Signaling Pathway in Mice.
OBJECTIVE
Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether preconditioning with insulin and glucose protects the kidney against ischemia-reperfusion injury (IRI).
METHODS
Kidney IRI was performed in C57BL/6 mice by clamping the renal vessels for 30 min, followed by reperfusion for 24 h. A total subcutaneous 0.1 unit of insulin along with 10% glucose in drinking water was treated on the mice for 24 h before kidney IRI. The kidney function and injuries were investigated through the determination of BUN and Cr in blood plasma, as well as the apoptosis and the expression of P-AKT, BAX, and caspase-3 in the kidneys. The role of P-AKT in insulin-treated IRI kidneys was tested using an AKT inhibitor. The effects of the preconditional duration of insulin and glucose on IRI kidneys were investigated by expanding the treatment duration to 1, 3, and 6 days.
RESULTS
Preconditioning with insulin and glucose protected the kidney against IRI as manifested by a decrease in creatinine and BUN and a reduction of kidney tubular injury. The protection effect was mediated by P-AKT-BAX-caspase-3 signaling pathway resulting in suppression of apoptotic cell death. An AKT inhibitor partially reversed the protective effects of preconditional insulin. The preconditional duration for 1, 3, and 6 days had no differences in improving kidney functions and pathology.
CONCLUSION
A short-term preconditioning with insulin and glucose protected the kidney from IRI through the activation of p-AKT and subsequent reduction of BAX-caspase-3-induced apoptosis. The short-term precondition provides a practicable strategy for protecting the kidney against predictable IRI, such as kidney transplant and major surgical operations with high risk of hypotension.
Topics: Animals; Reperfusion Injury; Proto-Oncogene Proteins c-akt; Mice; Mice, Inbred C57BL; Signal Transduction; Insulin; Male; Caspase 3; Glucose; bcl-2-Associated X Protein; Kidney; Apoptosis
PubMed: 38915866
DOI: 10.2147/DDDT.S465836