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Shock (Augusta, Ga.) Sep 2023Excessive blood loss in the prehospital setting poses a significant challenge and is one of the leading causes of death in the United States. In response, emergency... (Review)
Review
Excessive blood loss in the prehospital setting poses a significant challenge and is one of the leading causes of death in the United States. In response, emergency medical services (EMS) have increasingly adopted the use of tranexamic acid (TXA) and calcium chloride (CaCl 2 ) as therapeutic interventions for hemorrhagic traumas. Tranexamic acid functions by inhibiting plasmin formation and restoring hemostatic balance, while calcium plays a pivotal role in the coagulation cascade, facilitating the conversion of factor X to factor Xa and prothrombin to thrombin. Despite the growing utilization of TXA and CaCl 2 in both prehospital and hospital environments, a lack of literature exists regarding the comparative effectiveness of these agents in reducing hemorrhage and improving patient outcomes. Notably, Morgan County Indiana EMS recently integrated the administration of TXA with CaCl 2 into their treatment protocols, offering a valuable opportunity to gather insight and formulate updated guidelines based on patient-centered outcomes. This narrative review aims to comprehensively evaluate the existing evidence concerning the administration of TXA and CaCl 2 in the prehospital management of hemorrhages, while also incorporating and analyzing data derived from the co-administration of these medications within the practices of Morgan County EMS. This represents the inaugural description of the concurrent use of both TXA and CaCl 2 to manage hemorrhages in the scientific literature.
Topics: Humans; Tranexamic Acid; Calcium Chloride; Antifibrinolytic Agents; Hemorrhage; Emergency Medical Services
PubMed: 37477447
DOI: 10.1097/SHK.0000000000002177 -
International Journal of Molecular... Dec 2023Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable... (Review)
Review
Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable the selective reabsorption of sodium ions, which is a process critical for controlling blood pressure, electrolyte balance, and overall fluid volume. ENaC activity is finely controlled through proteolytic activation, a process wherein specific enzymes, or proteases, cleave ENaC subunits, resulting in channel activation and increased sodium reabsorption. This regulatory mechanism plays a pivotal role in adapting sodium transport to different physiological conditions. In this review article, we provide an in-depth exploration of the role of proteolytic activation in regulating ENaC activity. We elucidate the involvement of various proteases, including furin-like convertases, cysteine, and serine proteases, and detail the precise cleavage sites and regulatory mechanisms underlying ENaC activation by these proteases. We also discuss the physiological implications of proteolytic ENaC activation, focusing on its involvement in blood pressure regulation, pulmonary function, and intestinal sodium absorption. Understanding the mechanisms and consequences of ENaC proteolytic activation provides valuable insights into the pathophysiology of various diseases, including hypertension, pulmonary disorders, and various gastrointestinal conditions. Moreover, we discuss the potential therapeutic avenues that emerge from understanding these mechanisms, offering new possibilities for managing diseases associated with ENaC dysfunction. In summary, this review provides a comprehensive discussion of the intricate interplay between proteases and ENaC, emphasizing the significance of proteolytic activation in maintaining sodium and fluid balance in both health and disease.
Topics: Epithelial Sodium Channels; Proteolysis; Serine Endopeptidases; Serine Proteases; Sodium
PubMed: 38139392
DOI: 10.3390/ijms242417563 -
Thrombosis Journal Sep 2023Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in...
BACKGROUND
Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined.
METHODS
Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed.
RESULTS
The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6-12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion.
CONCLUSION
The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion.
PubMed: 37674235
DOI: 10.1186/s12959-023-00536-w -
Neuroscience Mar 2024The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by... (Review)
Review
The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.
Topics: Humans; Tissue Plasminogen Activator; Fibrinolysin; Ischemic Stroke; Endothelial Cells; Brain Ischemia; Brain; Fibrinolytic Agents
PubMed: 37574107
DOI: 10.1016/j.neuroscience.2023.08.011 -
Acta Neurologica Belgica Apr 2024Alzheimer's disease (AD) is the most common type of dementia associated with amyloid beta (Aβ) deposition. Dysfunction of the neuronal clearance pathway promotes the... (Review)
Review
Alzheimer's disease (AD) is the most common type of dementia associated with amyloid beta (Aβ) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aβ. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aβ; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aβ. Progressive increase of Aβ level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aβ by reducing Aβ clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aβ. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aβ. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology.
Topics: Humans; Alzheimer Disease; Tissue Plasminogen Activator; Amyloid beta-Peptides; Neuroserpin; Fibrinolysin; Plasminogen Activator Inhibitor 1; Plasminogen
PubMed: 37917293
DOI: 10.1007/s13760-023-02403-x -
Biochimica Et Biophysica Acta.... Feb 2024PLAU is known as a selected serine protease converting plasminogen to plasmin. The role of PLAU in the development of pan-cancer, especially bladder urothelial carcinoma...
BACKGROUND
PLAU is known as a selected serine protease converting plasminogen to plasmin. The role of PLAU in the development of pan-cancer, especially bladder urothelial carcinoma (BLCA) remains unclear.
METHOD
A variety of online tools and cancer databases, including TCGA, GETx, HPA database, GSCALite, UALCAN, ESTIMATE, CIBERSORT, ssGSEA algorithms and SangerBox website, were applied to investigate the associations between PLAU expression and prognosis, genetic alterations, pathway activation, and tumor immunity in pan-cancer. Through cBioPortal and STITCH platforms, the oncogenic role of PLAU and related targeting medicines in BLCA were also explored. We verified the expression of PLAU in pan-cancer cells and its function in bladder cancer cell lines using wet-lab experiments.
RESULTS
PLAU expression levels were significantly higher in most cancer tissues. PLAU had a certain accuracy in the diagnosis of various types of cancers (90 % AUC > 0.700). In BLCA, PLAU has abundant methylated sites and showed statistical differences in clinical features. PLAU was involved in tumor immune infiltration, and especially positively correlated with neutrophil infiltration. High-expressed PLAU indicated poorer prognosis in the BLCA patients receiving Atezolizumab. A high mRNA and protein expression levels of PLAU were observed in pan-cancer cell lines, especially BLCA cells. Knockdown of PLAU inhibited the invasive, proliferative, and aggressive phenotypes of bladder cancer cells. Immunohistochemical staining validated PLAU's higher expression in BLCA tissues than in adjacent non-cancerous tissues. And overexpression of PLAU was associated with more advanced TNM stage, and high infiltrating depth.
CONCLUSION
Our study revealed that PLAU can serve as a potential therapeutic target and prognostic marker for various malignancies, especially BLCA.
Topics: Humans; Algorithms; Carcinoma, Transitional Cell; Neutrophil Infiltration; Prognosis; Urinary Bladder Neoplasms
PubMed: 38000776
DOI: 10.1016/j.bbadis.2023.166965 -
The Science of the Total Environment Nov 2023For effective implementation of the wastewater-based epidemiology (WBE) approach, real-time quantification of markers in wastewater is critical for data acquisition... (Meta-Analysis)
Meta-Analysis Review
For effective implementation of the wastewater-based epidemiology (WBE) approach, real-time quantification of markers in wastewater is critical for data acquisition before data interpretation, dissemination, and decision-making. This can be achieved by using biosensor technology, but whether the quantification/detection limits of different types of biosensors comply with the concentration of WBE markers in wastewater is unclear. In the present study, we identified promising protein markers with relatively high concentrations in wastewater samples and analyzed biosensor technologies that are potentially available for real-time WBE. The concentrations of potential protein markers in stool and urine samples were obtained through systematic review and meta-analysis. We examined 231 peer-review papers to collect information regarding potential protein markers that can enable us to achieve real-time monitoring using biosensor technology. Fourteen markers in stool samples were identified at the ng/g level, presumably equivalent to ng/L of wastewater after dilution. Moreover, relatively high average concentrations of fecal inflammatory proteins were observed, e.g., fecal calprotectin, clusterin, and lactoferrin. Fecal calprotectin exhibited the highest average log concentration among the markers identified in stool samples with its mean value being 5.24 [95 % CI: 5.05, 5.42] ng/g. We identified 50 protein markers in urine samples at the ng/mL level. Uromodulin (4.48 [95 % CI: 4.20, 4.76] ng/mL) and plasmin (4.18 [95 % CI: 3.15, 5.21] ng/mL) had the top two highest log concentrations in urine samples. Furthermore, the quantification limit of some electrochemical- and optical-based biosensors was found to be around the femtogram/mL level, which is sufficiently low to detect protein markers in wastewater even after dilution in sewer pipes.
Topics: Humans; Wastewater; Wastewater-Based Epidemiological Monitoring
PubMed: 37419365
DOI: 10.1016/j.scitotenv.2023.165304 -
CEN Case Reports Nov 2023Infection-related glomerulonephritis (IRGN) is one of the most common causes of acute kidney injury (AKI). Positive glomerular staining of the nephritis-associated...
Infection-related glomerulonephritis (IRGN) is one of the most common causes of acute kidney injury (AKI). Positive glomerular staining of the nephritis-associated plasmin receptor (NAPlr) has been reported as a useful biomarker of IRGN. Although the infection can provoke acute tubulointerstitial nephritis (AIN), there are few reports of positive staining for NAPlr with AIN. We report a case of methicillin-sensitive Staphylococcus aureus (MSSA) infection-related nephritis complicated with AIN, which showed positive staining for tubulointerstitial NAPlr. The patient developed AKI and nephrotic syndrome during an intraperitoneal MSSA infection. A diagnosis of IRGN complicated by infection-related acute tubulointerstitial nephritis (IRAIN) was made based on glomerular endocapillary proliferation with tubulointerstitial infiltrating cells and tubular atrophy. Tubulointerstitial infiltrating cells were positive for NAPlr staining and plasmin activity. Treatment of the infection by antibiotics and drainage did not improve the AKI, but steroid administration improved that. NAPlr evaluation is a helpful tool for identifying causes of AIN during infection.
Topics: Humans; Glomerulonephritis; Glomerulonephritis, IGA; Nephritis; Nephritis, Interstitial; Acute Kidney Injury; Staphylococcal Infections; Immunoglobulin A
PubMed: 36920749
DOI: 10.1007/s13730-023-00782-x -
Journal of Orthopaedic Surgery and... Jul 2023Calcaneal fractures are a common orthopedic disease, account for approximately 2% of all bone fractures, and represent 60% of fractures of tarsal bones. Tranexamic acid... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Calcaneal fractures are a common orthopedic disease, account for approximately 2% of all bone fractures, and represent 60% of fractures of tarsal bones. Tranexamic acid (TXA) is a synthetic antifibrinolytic drug that competitively blocks the lysine-binding sites of plasminogen, plasmin, and tissue plasminogen activator, delaying fibrinolysis and blood clot degradation. However, the effect of TXA on patients with calcaneal surgery remains controversial. Our objective was to evaluate the effectiveness of TXA in calcaneal fractures surgeries.
METHODS
The electronic literature databases of Pubmed, Embase, and Cochrane library were searched in December 2022. The data on blood loss, the stay in the hospital, the duration of surgery, hemoglobin, hematocrit, platelet count, prothrombin time, activated partial thromboplastin time, and wound complication were extracted. The Stata 22.0 software was used for the meta-analysis.
RESULTS
Four randomized controlled studies met our inclusion criteria. This meta-analysis showed that TXA significantly reduced postoperative blood loss during the first 24 h (p < 0.001), improved the level of hemoglobin (p < 0.001) and hematocrit (p = 0.03), and reduced the risk of wound complications (p = 0.04). There was no significant difference between the two groups regarding total and intraoperative blood loss, hospital stay, duration of surgery, platelet count, activated partial thromboplastin time, and prothrombin time.
CONCLUSION
TXA significantly reduced blood loss during the first 24 h postoperatively, improved the level of hemoglobin and hematocrit, and reduced the risk of wound complications. Given the evidence, TXA can be used in patients with calcaneal fractures and had the potential benefit of blood reduction.
PROTOCOL REGISTRATION
The protocol was registered in PROSPERO (registration No. CRD42023391211).
Topics: Humans; Tranexamic Acid; Tissue Plasminogen Activator; Randomized Controlled Trials as Topic; Calcaneus; Tarsal Bones; Ankle Injuries
PubMed: 37438798
DOI: 10.1186/s13018-023-03924-0 -
Cells Mar 2024Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis... (Review)
Review
Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis frequently result in bone destruction. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-17 are known to influence bone loss by promoting the differentiation and activation of osteoclasts. Fibrinolytic factors, such as plasminogen (Plg), plasmin, urokinase-type plasminogen activator (uPA), its receptor (uPAR), tissue-type plasminogen activator (tPA), α2-antiplasmin (α2AP), and plasminogen activator inhibitor-1 (PAI-1) are expressed in osteoclasts and osteoblasts and are considered essential in maintaining bone homeostasis by regulating the functions of both osteoclasts and osteoblasts. Additionally, fibrinolytic factors are associated with the regulation of inflammation and the immune system. This review explores the roles of fibrinolytic factors in bone destruction caused by inflammation.
Topics: Humans; Urokinase-Type Plasminogen Activator; Inflammation; Osteoclasts; Osteoblasts; Bone and Bones
PubMed: 38534360
DOI: 10.3390/cells13060516