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Objective: Improve the characterization of mechanical properties of blood clots. Parameters derived from shear wave (SW) velocity and SW amplitude spectra were determined for gel phantoms and in vitro blood clots., Methods: Homogeneous phantoms and phantoms with gel or blood clot inclusions of different diameters and mechanical properties were analyzed. SW amplitude spectra were used to observe resonant peaks. Parameters derived from those resonant peaks were related to mimicked blood clot properties. Three regions of interest were tested to analyze where resonances occurred the most. For blood experiments, 20 samples from different pigs were analyzed over time during a 110-minute coagulation period using the Young modulus, SW frequency dispersion, and SW attenuation., Results: The mechanical resonance was manifested by an increase in the number of SW spectral peaks as the inclusion diameter was reduced (P < .001). In blood clot inclusions, the Young modulus increased over time during coagulation (P < .001). Descriptive spectral parameters (frequency peak, bandwidth, and distance between resonant peaks) were linearly correlated with clot elasticity values (P < .001) with R 2  = .77 for the frequency peak, .60 for the bandwidth, and .48 for the distance between peaks. The SW dispersion and SW attenuation reflecting the viscous behavior of blood clots decreased over time (P < .001), mainly in the early stage of coagulation (first minutes)., Conclusion: The confined soft inclusion configuration favored SW mechanical resonances potentially challenging the computation of spectral-based parameters, such as the SW attenuation. The impact of resonances can be reduced by properly selecting the region of interest for data analysis., (© 2023 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Background: A growing body of evidence has shed light on the role of the hemostatic pathway and its components in the pathogenesis of multiple sclerosis (MS), particularly in enhancing and sustaining neuroinflammation. Objective: To review the clinical, experimental, and neuroimaging evidence supporting the role of different components of the hemostatic pathway in the pathogenesis of neuroinflammation in MS and discuss their translational potential as disease biomarkers and therapeutic targets. Methods: A literature search for most relevant articles from 1956 to 2020 was conducted in PubMed and Scopus. Results: Hemostasis components appear to be involved in different key events of neuroinflammation in MS including mononuclear cell diapedesis, microglia activation, and neuronal damage. Conclusion: The findings on the interplay between hemostatic and thrombotic molecular pathways in the pathogenesis of neuroinflammation in MS open new opportunities for developing novel biomarkers for disease monitoring and prognosis, as well as novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Platelet procoagulant mechanisms are emerging to be complex and important to achieving haemostasis. The mechanisms include the release of procoagulant molecules from platelet storage granules, and strong agonist‐induced expression of procoagulant phospholipids on the outer platelet membrane for tenase and prothrombinase assembly. The release of dense granule polyphosphate is important to platelet procoagulant function as it promotes the activation of factors XII, XI and V, inhibits tissue factor pathway inhibitor and fibrinolysis, and strengthens fibrin clots. Platelet procoagulant function also involves the release of partially activated factor V from platelets. Scott syndrome has provided important insights on the mechanisms that regulate procoagulant phospholipids expression on the external platelet membrane, which require strong agonist stimulation that increase cystolic calcium levels, mitochondrial calcium uptake, the loss of flippase function and activation of the transmembrane scramblase protein anoctamin 6. There have been advances in the methods used to directly and indirectly assess platelet procoagulant function in health and disease. Assessments of thrombin generation with platelet rich plasma samples has provided new insights on how platelet procoagulant function is altered in inherited platelet disorders, and how platelets influence the bleeding phenotype of a number of severe coagulation factor deficiencies. Several therapies, including desmopressin and recombinant factor VIIa, improve thrombin generation by platelets. There is growing interest in targeting platelet procoagulant function for therapeutic benefit. This review highlights recent advances in our understanding of platelet‐dependent procoagulant mechanisms in health and in bleeding disorders. [ABSTRACT FROM AUTHOR]

Background: Titanium (Ti) is one of the most popular implant materials, and its surface titanium dioxide (TiO2) provides good biocompatibility. The coagulation of blood on Ti implants plays a key role in wound healing and cell growth at the implant site; however, researchers have yet to fully elucidate the mechanism underlying this process on TiO2. Methods: This study examined the means by which blood coagulation was affected by the crystal structure of TiO2 thin films (thickness < 50 nm), including anatase, rutile, and mixed anatase/rutile. The films were characterized in terms of roughness using an atomic force microscope, thickness using an X-ray photoelectron spectrometer, and crystal structure using transmission electron microscopy. The surface energy and dielectric constant of the surface films were measured using a contact angle goniometer and the parallel plate method, respectively. Blood coagulation properties (including clotting time, factor XII contact activation, fibrinogen adsorption, fibrin attachment, and platelet adhesion) were then assessed on the various test specimens. Results: All of the TiO2 films were similar in terms of surface roughness, thickness, and surface energy (hydrophilicity); however, the presence of rutile structures was associated with a higher dielectric constant, which induced the activation of factor XII, the formation of fibrin network, and platelet adhesion. Conclusions: This study provides detailed information related to the effects of TiO2 crystal structures on blood coagulation properties on Ti implant surfaces. [ABSTRACT FROM AUTHOR]

Background: Fibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury. Purpose: To investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment. Materials and methods: Specificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables. Results: For the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p =.008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p =.006). CNS fibrin deposition corresponded to immunoinflammatory activity (R2 = 0.85, p <.001) and disability (R2 = 0.81, p <.001) in a model for MS, which suggests a clinical role for staging and monitoring. Additionally, EP2104-R showed substantially higher SNR (M ± SD, 6.6 ± 1 (EP2104-R) vs. 2.7 ± 0.4 (gadobutrol), p =.004) than clinically used contrast media, which increases sensitivity for lesion detection. Conclusions: Molecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment. [ABSTRACT FROM AUTHOR]

Dental endo-osseous implants have become a widely used treatment for replacing missing teeth. Dental implants are placed into a surgically created osteotomy in alveolar bone, the healing of the soft tissue lesion and the osseointegration of the implant being key elements to long-term success. Autophagy is considered the major intracellular degradation system, playing important roles in various cellular processes involved in dental implant integration. The aim of this review is an exploration of autophagy roles in the main cell types involved in the healing and remodeling of soft tissue lesions and implant osseointegration, post-implant surgery. We have focused on the autophagy pathway in macrophages, endothelial cells; osteoclasts, osteoblasts; fibroblasts, myofibroblasts and keratinocytes. In macrophages, autophagy modulates innate and adaptive immune responses playing a key role in osteo-immunity. Autophagy induction in endothelial cells promotes apoptosis resistance, cell survival, and protection against oxidative stress damage. The autophagic machinery is also involved in transporting stromal vesicles containing mineralization-related factors to the extracellular matrix and regulating osteoblasts' functions. Alveolar bone remodeling is achieved by immune cells differentiation into osteoclasts; autophagy plays an important and active role in this process. Autophagy downregulation in fibroblasts induces apoptosis, leading to better wound healing by improving excessive deposition of extracellular matrix and inhibiting fibrosis progression. Autophagy seems to be a dual actor on the scene of dental implant surgery, imposing further research in order to completely reveal its positive features which may be essential for clinical efficacy. [ABSTRACT FROM AUTHOR]

Diabetes is a serious threat to global health and is among the top 10 causes of death. The Diabetic foot ulcer (DFU) is among the most common and severe complications of the disease. Bacterial infections are common; therefore, timely aggressive management, using multidisciplinary management approaches is needed to prevent complications, morbidity, and mortality, particularly in view of the growing cases of antibiotic-resistant bacteria. Photobiomodulation (PBM) involves the application of low-level light at specific wavelengths to induce cellular photochemical and photophysical responses. Red and near-infrared (NIR) wavelengths have been shown to be beneficial, and recent studies indicate that other wavelengths within the visible spectrum could be helpful as well, including blue light (400–500 nm). Reports of the antimicrobial activity and susceptibility of blue light on several strains of the same bacterium show that many bacteria are less likely to develop resistance to blue light treatment, meaning it is a viable alternative to antibiotic therapy. However, not all studies have shown positive results for wound healing and fibroblast proliferation. This paper presents a critical review of the literature concerning the use of PBM, with a focus on blue light, for tissue healing and diabetic ulcer care, identifies the pros and cons of PBM intervention, and recommends the potential role of PBM for diabetic ulcer care. [ABSTRACT FROM AUTHOR]

Due to the obstruction and heterogeneity of the blood-brain barrier, the clinical treatment of glioma has been extremely difficult. Isoliquiritigenin (ISL) exhibits antitumor effects, but its low solubility and bioavailability limit its application potential. Herein, we established a nanoscale hybrid membrane-derived system composed of erythrocytes and tumor cells. By encapsulating ISL in hybrid membrane nanoparticles, ISL is expected to be enhanced for the targeting and long-circulation in gliomas therapy. We fused erythrocytes with human glioma cells U251 and extracted the fusion membrane via hypotension, termed as hybrid membrane (HM). HM-camouflaged ISL nanoparticles (ISL@HM NPs) were prepared and featured with FT-IR, SEM, TEM, and DLS particle analysis. As the results concluded, the ISL active pharmaceutical ingredients (APIs) were successfully encapsulated with HM membranes, and the NPs loading efficiency was 38.9 ± 2.99% under maximum entrapment efficiency. By comparing the IC50 of free ISL and NPs, we verified that the solubility and antitumor effect of NPs was markedly enhanced. We also investigated the mechanism of the antitumor effect of ISL@HM NPs, which revealed a marked inhibition of tumor cell proliferation and promotion of senescence and apoptosis of tumor cells of the formulation. In addition, the FSC and WB results examined the effects of different concentrations of ISL@HM NPs on tumor cell disruption and apoptotic protein expression. Finally, it can be concluded that hybridized membrane-derived nanoparticles could prominently increase the solubility of insoluble materials (as ISL), and also enhance its targeting and antitumor effect. [ABSTRACT FROM AUTHOR]

Objective: There is controversy regarding the efficacy and safety of tranexamic acid (TXA) in reducing tonsillectomy-related hemorrhage. We conducted a systematic review and meta-analysis to evaluate the prophylactic role of TXA in tonsillectomy. Methods: We searched 6 databases to identify studies that directly compare the effect of TXA versus controls in tonsillectomy patients. Standardized mean difference was applied to summate the findings across the studies. Dichotomous data were expressed as relative risk. Results: Ten studies representing a total of 111 898 patients were included. The pooled results showed a significant reduction of intraoperative blood loss by 39.02 ml (SMD = −1.05, 95% CI: −1.91 to −0.20, P =.016) and the rate of post-tonsillectomy hemorrhage (RR = 0.42, 95% CI: 0.28 to 0.65, P <.0001), with no significant difference in reduction of further intervention risk (RR = 0.78, 95% CI: 0.45 to 1.35, P =.373). Conclusions: Overall, this study indicates that TXA may reduce blood loss and frequency of post-operative hemorrhage associated with tonsillectomy. Further large, high-quality clinical trials are still needed to explore TXA's effect on post-tonsillectomy hemorrhage and the safety of its use. [ABSTRACT FROM AUTHOR]

Factor X (FX) is one of the major players in the blood coagulation cascade. Upon activation to FXa, it converts prothrombin to thrombin, which in turn converts fibrinogen into fibrin (blood clots). FXa deficiency causes hemostasis defects, such as intracranial bleeding, hemathrosis, and gastrointestinal blood loss. Herein, we have analyzed a pool of pathogenic mutations, located in the FXa catalytic domain and directly associated with defects in enzyme catalytic activity. Using chymotrypsinogen numbering, they correspond to D102N, T135M, V160A, G184S, and G197D. Molecular dynamics simulations were performed for 1.68 μs on the wild-type and mutated forms of FXa. Overall, our analysis shows that four of the five mutants considered, D102N, T135M, V160A, and G184S, have rigidities higher than those of the wild type, in terms of both overall protein motion and, specifically, subpocket S4 flexibility, while S1 is rather insensitive to the mutation. This acquired rigidity can clearly impact the substrate recognition of the mutants. [ABSTRACT FROM AUTHOR]

Abstract: Activated factor XIII (FXIIIa) catalyzes the formation of γ-glutamyl-ε-lysyl cross-links within the fibrin blood clot network. Although several cross-linking targets have been identified, the characteristic features that define FXIIIa substrate specificity are not well understood. To learn more about how FXIIIa selects its targets, a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI–TOF MS)-based assay was developed that could directly follow the consumption of a glutamine-containing substrate and the formation of a cross-linked product with glycine ethylester. This FXIIIa kinetic assay is no longer reliant on a secondary coupled reaction, on substrate labeling, or on detecting only the final deacylation portion of the transglutaminase reaction. With the MALDI–TOF MS assay, glutamine-containing peptides derived from α2-antiplasmin, Staphylococcus aureus fibronectin binding protein A, and thrombin-activatable fibrinolysis inhibitor were examined directly. Results suggest that the FXIIIa active site surface responds to changes in substrate residues following the reactive glutamine. The P−1 substrate position is sensitive to charge character, and the P−2 and P−3 substrate positions are sensitive to the broad FXIIIa substrate specificity pockets. The more distant P−8 to P−11 region serves as a secondary substrate anchoring point. New knowledge on FXIIIa specificity may be used to design better substrates or inhibitors of this transglutaminase. [Copyright &y& Elsevier]

The formation of platelet thrombi is determined by the integrin αIIbβ3-mediated interactions of platelets with fibrinogen and fibrin. Blood clotting in vivo is catalyzed by thrombin, which simultaneously induces fibrinogen binding to αIIbβ3 and converts fibrinogen to fibrin. Thus, after a short time, thrombus formation is governed by αIIbβ3 binding to fibrin fibers. Surprisingly, there is little understanding of αIIbβ3 interaction with fibrin polymers. Here we used an optical trap-based system to measure the binding of single αIIbβ3 molecules to polymeric fibrin and compare it to αIIbβ3 binding to monomeric fibrin and fibrinogen. Like αIIbβ3 binding to fibrinogen and monomeric fibrin, we found that αIIbβ3 binding to polymeric fibrin can be segregated into two binding regimes, one with weaker rupture forces of 30-60 pN and a second with stronger rupture forces >60 pN that peaked at 70-80 pN. However, we found that the mechanical stability of the bimolecular αIIbβ3-ligand complexes had the following order: fibrin polymer > fibrin monomer > fibrinogen. These quantitative differences reflect the distinct specificity and underlying molecular mechanisms of αIIbβ3-mediated reactions, implying that targeting platelet interactions with fibrin could increase the therapeutic indices of antithrombotic agents by focusing on the destabilization of thrombi rather than the prevention of platelet aggregation.

Background: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women.Methods/design: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia.Discussion: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia.Trial Registration: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018. [ABSTRACT FROM AUTHOR]

Nearly two decades ago, pathologic examination results suggested that acoustic factors, such as mid-frequency active naval military sonar (MFAS) could be the cause of acute decompression-like sickness in stranded beaked whales. Acute systemic gas embolism in these whales was reported together with enigmatic cystic liver lesions (CLL), characterized by intrahepatic encapsulated gas-filled cysts, tentatively interpreted as "gas-bubble" lesions in various other cetacean species. Here we provide a pathologic reinterpretation of CLL in odontocetes. Among 1,200 cetaceans necropsied, CLL were only observed in four striped dolphins (Stenella coeruleoalba), with a low prevalence (2%, N = 179). Together, our data strongly suggest that CLL are the result of the combination of a pre-existing or concomitant hepatic vascular disorder superimposed and exacerbated by gas bubbles, and clearly differ from acute systemic gas embolism in stranded beaked whales that is linked to MFAS. Budd-Chiari-like syndrome in dolphins is hypothesized based on the present pathologic findings. Nonetheless, further researched is warranted to determine precise etiopathogenesis(es) and contributing factors for CLL in cetaceans. [ABSTRACT FROM AUTHOR]

It has been long known that blood health heavily influences optimal physiological function. Abnormalities affecting the physical properties of blood have been implicated in the pathogenesis of various disorders, although the exact mechanistic links between hemorheology and clinical disease manifestations remain poorly understood. Often overlooked in current medical practice, perhaps due to the promises offered in the molecular and genetic era, the physical properties of blood which remain a valuable and definitive indicator of circulatory health and disease. Bridging this gap, the current manuscript provides an introduction to hemorheology. It reviews the properties that dictate bulk and microcirculatory flow by systematically dissecting the biomechanics that determine the non-Newtonian behavior of blood. Specifically, the impact of hematocrit, the mechanical properties and tendency of red blood cells to aggregate, and various plasma factors on blood viscosity will be examined. Subsequently, the manner in which the physical properties of blood influence hemodynamics in health and disease is discussed. Special attention is given to disorders such as sickle cell disease, emphasizing the clinical impact of severely abnormal blood rheology. This review expands into concepts that are highly topical; the relation between mechanical stress and intracellular homeostasis is examined through a contemporary cell-signaling lens. Indeed, accumulating evidence demonstrates that nitric oxide is not only transported by erythrocytes, but is locally produced by mechanically-sensitive enzymes, which appears to have intracellular and potentially extracellular effects. Finally, given the importance of shear forces in the developing field of mechanical circulatory support, we review the role of blood rheology in temporary and durable mechanical circulatory support devices, an increasingly utilized method of life support. This review thus provides a comprehensive overview for interested trainees, scientists, and clinicians. [ABSTRACT FROM AUTHOR]

Background: The aim of this research was to determine and compare the clinical efficacy of leukocyte platelet-rich fibrin (L-PRF) and advanced platelet-rich fibrin (A-PRF) in combination with coronally advanced flap (CAF) in the treatment of gingival recession defects.Methods: Systemically healthy subjects presenting with 30 Miller's class I or II gingival recession defects in maxillary anteriors and premolars, were treated with either CAF + L-PRF or CAF + A-PRF. Clinical parameters such as recession height (RH), width, probing pocket depth, clinical attachment level (CAL), keratinized tissue height (KTH), and width of attached gingiva (WAG) were measured at baseline, 3, and 6 months. Gingival biotype was evaluated at baseline and 6 months post-surgery. Mean root coverage percentage (MRC%) was evaluated at 3 and 6 months.Results: Statistically significant reduction in mean RH was observed from baseline (2.53 ± 0.74 mm, 2.63 ± 0.82 mm) to 6 months (0.87 ± 0.83 mm, 0.53 ± 0.91 mm) in CAF + L-PRF and CAF + A-PRF groups, respectively. The MRC% achieved at 6 months was 67.20 ± 32.81 in the CAF + L-PRF group and 81.66 ± 28.21 in the CAF + A-PRF group. Statistically significant gain in CAL, WAG, and KTH was observed in both therapeutic groups (p < 0.05). Intergroup analysis revealed no statistically significant differences among study parameters between groups at any time point (p > 0.05).Conclusion: Based on the findings of this study, both L-PRF and A-PRF may be suggested as viable treatment options for the management of gingival recession in maxilla. [ABSTRACT FROM AUTHOR]

For last months, humanity has faced a formidable unknown enemy, which is presented as a new coronavirus infection. Despite the fact that the causative agents of new diseases appear at a certain frequency and that the virus SARS-CoV-2 has certain common properties with its predecessors, at the moment we are dealing with a new unknown pathogenesis of the development of severe complications in patients with risk factors. A final understanding of pathological process mechanisms is the goal of the scientific community. Summarizing research data from different countries, it became obvious that in severe cases of viral infection, we are dealing with a combination of the systemic inflammatory response syndrome, disseminated intravascular coagulation and thrombotic microangiopathy (TMA). Thrombotic microangiopathy is represented by a group of different conditions in which thrombocytopenia, hemolytic anemia, and multiple organ failure occur. The article reflects the main types of TMA, pathogenesis and principles of therapy. The main participants in the process are described in detail, including the von Willebrand factor and ADAMTS-13. Based on the knowledge available, as well as new data obtained from patients with COVID-19, we proposed possible models for the implementation of conditions such as sepsis, TMA, and DIC in patients with severe new coronavirus infection. Through a deeper understanding of pathogenesis, it will be possible to develop more effective diagnosis and therapy. [ABSTRACT FROM AUTHOR]

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer's disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

To obtain modified polyurethane (PU) plates, quaternized chitosan (QuatCh; degree of substitution 50%, degree of deacetylation 87%) and unfractionated heparin (UFH) were applied in layers to the plate surfaces. The relief of the surface of the plates was studied via atomic-force microscopy (AFM). After processing, the root-mean-square roughness and the height of the unevenness of the PU profile of the plates significantly increased. The value of the contact angle of the modified PU plates decreased from 86.1° ± 11.3° to 63.2° ± 3.68°. Donor blood and the blood recalcification time test were used to assess the in vitro resistance of the PU plates to the appearance of blood clots on the surface (thromboresistance, TR). When the modified PU plates were incubated with blood for 20–180 min, the TR reached 78.43 ± 4.02–88.94 ± 1.98%. The recalcification time of human blood containing PU plates coated with QuatCh–UFH (483 ± 22.64 s for 20 min of incubation and576.5 ± 24.64 s for 40 min of incubation) significantly differed from the recalcification time of human blood containing PU plates without coating (257.5 ± 12.84 s for 20 min of incubation and 273.3 ± 16.6 s for 40 min of incubation). Thus, layer-by-layer modification of the PU plates with QuatCh and UFH led to a high resistance to the appearance of blood clots on the surface. [ABSTRACT FROM AUTHOR]

Transfusion-transmitted infections (TTIs), such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and treponema pallidum (TP), must be detected before blood transfusion. However, few studies have been conducted on the prevalence and accuracy of positive results in hospitalized patients. The purpose of this study was to investigate the real seroprevalence of TTIs among patients before blood transfusion and analyze the characteristics of false-positive results in Jinling Hospital, Nanjing University, China. TTI results were collected from medical records and analyzed retrospectively. Additionally, we also used confirmatory assays to verify the accuracy of positive results. The overall prevalence of TTI was 8.96%, which was related to gender and age. The real positive rates were 86.67% (HBV), 35.09% (HCV), 20.75% (HIV), and 100% (TP). Our results also showed that high-speed centrifugation can reduce the false-positive rate of HBsAg. In summary, the results demonstrated that the positive rates of TTIs in hospitalized patients are higher than those in the general population. We also confirmed the existence of false-positive results in serological screening for TTIs. The method of processing specimens through high-speed centrifugation could reduce the false-positive results of detecting antigens effectively. [ABSTRACT FROM AUTHOR]

In blood coagulation, circulating platelets and coagulation factors are crucial for the primary process because thrombi are generated by fibrin clotting with fibrinogen, thrombin, FXIIIa, and platelet activation. Therefore, strategies to reduce the activity of key coagulation factors, or interfere with their functions and delay the activation of platelets can be used as important tools to suppress excessive blood clot formation and platelet hyperactivation. This study examined the antithrombotic activity and hematological toxicity of PA, IVA, and 4-HA isolated from M. tricuspidata (Carr.) Bur in several in vitro experiments and inhibitor assays. We found that PA, IVA, and 4-HA attenuated the formation of fibrin polymers/clots and degraded the blood clots. These compounds inhibited the activities of procoagulant proteases and fibrinoligase, and prolonged the coagulation time. There was a significant reduction in platelet function and ATP or serotonin levels in thrombin-activated platelets. An inhibitor study showed that PA exhibited a mixed inhibition type for thrombin, an uncompetitive inhibition type for FXa, and a non-competitive inhibition type for FXIIIa and IVA, while 4-HA exhibited an uncompetitive inhibition type for thrombin and non-competitive inhibition type for FXa and FXIIIa. These three compounds (up to 50 μg/mL) were not toxic to blood cells. [ABSTRACT FROM AUTHOR]

Uncontrolled bleeding is a major problem in trauma and emergency medicine. While materials for trauma applications would certainly find utility in traditional surgical settings, the unique environment of emergency medicine introduces additional design considerations, including the need for materials that are easily deployed in austere environments. Ideally, these materials would be available off the shelf, could be easily transported, and would be able to be stored at room temperature for some amount of time. Both natural and synthetic materials have been explored for the development of hemostatic materials. This review article provides an overview of classes of materials used for topical hemostats and newer developments in the area of injectable hemostats for use in emergency medicine. [ABSTRACT FROM AUTHOR]

The preparation of platelet-rich fibrin (PRF) requires blood centrifugation to separate the yellow plasma from the red erythrocyte fraction. PRF membranes prepared from coagulated yellow plasma are then transferred to the defect sites to support tissue regeneration. During natural wound healing, however, it is the unfractionated blood clot (UBC) that fills the defect site. It is unclear whether centrifugation is necessary to prepare a blood-derived matrix that supports tissue regeneration. The aim of the present study was to compare lysates prepared from PRF and UBC based on bioassays and degradation of the respective membranes. We report here that lysates prepared from PRF and UBC membranes similarly activate TGF-β signaling, as indicated by the expression of interleukin 11 (IL-11), NADPH oxidase 4 (NOX-4) and proteoglycan 4 (PRG4) in gingival fibroblasts. Consistently, PRF and UBC lysates stimulated the phosphorylation and nuclear translocation of Smad3 in gingival fibroblasts. We further observed that PRF and UBC lysates have comparable anti-inflammatory activity, as shown by the reduction in lipopolysaccharide (LPS)-induced IL-6, inducible nitric oxidase synthase (iNOS) and cyclooxygenase 2 (COX-2) expression in RAW264.7 cells. Moreover, inflammation induced by Poly (1:C) HMW and FSL-1, which are agonists of Toll-like receptor (TLR) 3 and 2/6, respectively, was reduced by both PRF and UBC. PRF and UBC lysates reduced the nuclear translocation of p65 in LPS-induced RAW264.7 cells. In contrast to the similar activity observed in the bioassays, UBC membranes lack the structural integrity of PRF membranes, as indicated by the rapid and spontaneous disintegration of UBC membranes. We show here that the lysates prepared from PRF and UBC possess robust TGF-β and anti-inflammatory activity. However, visual inspection of the PRF and UBC membranes confirmed the negative impact of erythrocytes on the structural integrity of membranes prepared from whole blood. The data from the present study suggest that although both UBC and PRF have potent TGF-β and anti-inflammatory activity, UBC does not have the strength properties required to be used clinically to prepare applicable membranes. Thus, centrifugation is necessary to generate durable and clinically applicable blood-derived membranes. [ABSTRACT FROM AUTHOR]

Fibrin is the fibrous protein network that comprises blood clots; it is uniquely capable of bearing very large tensile strains (up to 200%) due to multiscale force accommodation mechanisms. Fibrin is also a biochemical scaffold for numerous enzymes and blood factors. The biomechanics and biochemistry of fibrin have been independently studied. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry? In this study, we show that mechanically induced protein structural changes in fibrin affect fibrin biochemistry. We find that tensile deformation of fibrin leads to molecular structural transitions of α-helices to β-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrin lysis. Moreover, binding of tPA and Thioflavin T, a commonly used β-sheet marker, were mutually exclusive, further demonstrating the mechano-chemical control of fibrin biochemistry. Finally, we demonstrate that structural changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to reduced αIIbβ3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and biological activity in an elegant mechano-chemical feedback loop, which possibly extends to other fibrous biopolymers. [ABSTRACT FROM AUTHOR]

Endovascular treatment with stent retriever thrombectomy is a major advancement in the standard of care in acute ischemic stroke (AIS). The modalities through which thrombi embed along stent retriever following mechanical thrombectomy (MTB) have not yet been elucidated. Using scanning electron microscopy (SEM), we analyzed the appearance of thrombi retrieved by MTB from AIS patients, when embedded into the stent retriever. We observed that the organization and structural compactness vary for compositionally different thrombi. The modalities of attachment onto the stent vary according to thrombus composition and organization. [ABSTRACT FROM AUTHOR]

Both the rate of osseointegration and its extent depend upon the characteristics of the implant surface. 12345 Depending on the surface of the implant determination of implant–bone contact area, the rate of bone formation around the implant can be done. 6 Hence, the implant surface plays an important part in multiple ways in the osseointegration process. [ABSTRACT FROM AUTHOR]

Hemostasis plays an essential role in all surgical procedures. Uncontrolled hemorrhage is the primary cause of death during surgeries, and effective blood loss control can significantly reduce mortality. For modern surgeons to select the right agent at the right time, they must understand the mechanisms of action, the effectiveness, and the possible adverse effects of each agent. Over the past decade, various hemostatic agents have grown intensely. These agents vary from absorbable topical hemostats, including collagen, gelatins, microfibrillar, and regenerated oxidized cellulose, to biologically active topical hemostats such as thrombin, biological adhesives, and other combined agents. Commercially available products have since expanded to include topical hemostats, surgical sealants, and adhesives. Silk is a natural protein consisting of fibroin and sericin. Silk fibroin (SF), derived from silkworm Bombyx mori, is a fibrous protein that has been used mostly in fashion textiles and surgical sutures. Additionally, SF has been widely applied as a potential biomaterial in several biomedical and biotechnological fields. Furthermore, SF has been employed as a hemostatic agent in several studies. In this review, we summarize the several morphologic forms of SF and the latest technological advances on the use of SF-based hemostatic agents. [ABSTRACT FROM AUTHOR]

Mechanical properties have been extensively studied in pure elastic or viscous materials; however, most biomaterials possess both physical properties in a viscoelastic component. How the biomechanics of a fibrin clot is related to its composition and the microenvironment where it is formed is not yet fully understood. This review gives an outline of the building mechanisms for blood clot mechanical properties and how they relate to clot function. The formation of a blood clot in health conditions or the formation of a dangerous thrombus go beyond the mere polymerization of fibrinogen into a fibrin network. The complex composition and localization of in vivo fibrin clots demonstrate the interplay between fibrin and/or fibrinogen and blood cells. The study of these protein–cell interactions and clot mechanical properties may represent new methods for the evaluation of cardiovascular diseases (the leading cause of death worldwide), creating new possibilities for clinical diagnosis, prognosis, and therapy. [ABSTRACT FROM AUTHOR]

Currently, it is a challenge to develop hemostatic materials with high water absorption capacity and anti-fatigue properties for quickly preventing massive hemorrhage from arteries and visceral organs. A series of polyacrylic acid/chitosan (PAA/CS) cryogels were prepared by a cryostructurization technique to improve mechanical performance and hemostatic efficiency of chitosan (CS). In this system, the chemically cross-linked PAA network was used as a framework to improve water absorption behaviors and mechanical strength. The CS network was co-blended by hydrogen bonding and electrostatic interactions, both of which synergistically promoted hemostasis. These cryogels had high porosity (>94%), rapid water absorption rate (<3 s), high blood absorption capacity (>2000%), outstanding mechanical strength, and fatigue resistance. Moreover, the results of cytotoxicity and hemolysis demonstrated that the cryogels had good biocompatibility. Notably, the PAA/CS cryogels exhibited superior whole blood coagulation ability and red blood cell and platelet adhesion ability compared to those of commercial hemostatic dressing (gauze, gelatin sponges, and CS sponges). Based on these results, mouse femoral artery hemorrhage models and liver hemorrhage models were prepared to investigate the hemostatic ability of the prepared PAA/CS cryogels. Results suggested that the hemostatic ability of PAA5/CS cryogels was superior to that of commercial hemostatic materials. Therefore, the PAA/CS cryogels showed potential application in preventing massive hemorrhage from arteries and visceral organs. [ABSTRACT FROM AUTHOR]

Bacterial plasminogen (Pg) activators generate plasmin to degrade fibrin blood clots and other proteins that modulate the pathogenesis of infection, yet despite strong homology between mammalian Pgs, the activity of bacterial Pg activators is thought to be restricted to the Pg of their host mammalian species. Thus, we found that Streptococcus uberis Pg activator (SUPA), isolated from a Streptococcus species that infects cows but not humans, robustly activated bovine but not human Pg in purified systems and in plasma. Consistent with this, SUPA formed a higher avidity complex (118-fold) with bovine Pg than with human Pg and non-proteolytically activated bovine but not human Pg. Surprisingly, however, the presence of human fibrin overrides the species- restricted action of SUPA. First, human fibrin enhanced the binding avidity of SUPA for human Pg by 4-8-fold in the presence and absence of chloride ion (a negative regulator). Second, although SUPA did not protect plasmin from inactivation by α2-antiplasmin, fibrin did protect human plasmin, which formed a 31-fold higher avidity complex with SUPA than Pg. Third, fibrin significantly enhanced Pg activation by reducing the Km (4-fold) and improving the catalytic efficiency of the SUPA complex (6-fold). Taken together, these data suggest that indirect molecular interactions may override the species-restricted activity of bacterial Pg activators; this may affect the pathogenesis of infections or may be exploited to facilitate the design of new blood clot-dissolving drugs. [ABSTRACT FROM AUTHOR]

Objective: Bacterial endocarditis is a frequent infectious cardiac disease, especially in patients with congenital or acquired heart defects. It is characterized by bacterial colonization of the heart valves and the appearance of vegetations consisting of fibrin, blood cells, and bacteria. The glycoprotein Deleted in Malignant Brain Tumors 1 is a scavenger receptor cysteine-rich protein with functions in innate immunity and epithelial differentiation. Because of the aggregating capacity of Deleted in Malignant Brain Tumors 1, we hypothesized that an up-regulation in bacterial endocarditis may be linked to the development of vegetations. Methods: Heart tissue of 19 patients with bacterial endocarditis and 10 controls without bacterial endocarditis was analyzed by immunohistochemistry. The effect of human recombinant Deleted in Malignant Brain Tumors 1 on erythrocyte aggregation was measured using an automated red blood cell aggregometer MA1. Binding of human recombinant Deleted in Malignant Brain Tumors 1 to erythrocyte membranes, platelets, fibrin, and fibrinogen was analyzed by Western blotting and enzyme-linked immunosorbent assay. Results: Deleted in Malignant Brain Tumors 1 expression was up-regulated in affected heart valves with bacterial endocarditis and limited to the colonizing bacteria on the heart valves and granulocyte-depleted fibrin/fibrinogen formations, and around localized atheromatosis. Patients with aggressive bacteria showed higher DMBT1 levels than patients with less aggressive bacteria. Human recombinant Deleted in Malignant Brain Tumors 1 aggregates erythrocytes and binds to erythrocyte membranes, platelets, and fibrin/fibrinogen. Conclusion: Deleted in Malignant Brain Tumors 1 up-regulation at sites of bacterial endocarditis, its association with platelets and fibrin/fibrinogen, and its ability to aggregate erythrocytes through binding to their membranes indicate a potential role in the development of vegetations and thrombosis. [Copyright &y& Elsevier]

Several neurodegenerative diseases are characterized by the accumulation of aggregated misfolded proteins. These pathological agents have been suggested to propagate in the brain via mechanisms similar to that observed for the prion protein, where a misfolded variant is transferred from an affected brain region to a healthy one, thereby inducing the misfolding and/or aggregation of correctly folded copies. This process has been characterized for several proteins, such as α-synuclein, tau, amyloid beta (Aβ) and less extensively for huntingtin and TDP-43. α-synuclein, tau, TDP-43 and huntingtin are intracellular proteins, and their aggregates are located in the cytosol or nucleus of neurons. They have been shown to spread between cells and this event occurs, at least partially, via secretion of these protein aggregates in the extracellular space followed by re-uptake. Conversely, Aβ aggregates are found mainly extracellularly, and their spreading occurs in the extracellular space between brain regions. Due to the inherent nature of their spreading modalities, these proteins are exposed to components of the extracellular matrix (ECM), including glycans, proteases and core matrix proteins. These ECM components can interact with or process pathological misfolded proteins, potentially changing their properties and thus regulating their spreading capabilities. Here, we present an overview of the documented roles of ECM components in the spreading of pathological protein aggregates in neurodegenerative diseases with the objective of identifying the current gaps in knowledge and stimulating further research in the field. This could potentially lead to the identification of druggable targets to slow down the spreading and/or progression of these pathologies. [ABSTRACT FROM AUTHOR]

Background and Purpose: The ability of attenuation value of the non-hypodense region of hematoma in non-contrast computed tomography (NCCT) for predicting hematoma expansion (HE) remains unclear. Our purpose is to explore this relationship. Methods: Two cohorts of patients were collected for analysis. The region where we measured hematoma attenuation values was limited to the non-hypodense region that was not adjacent to the normal brain tissue on NCCT. The critical attenuation value was derived via receiver operating characteristic (ROC) curve analysis in the derivation cohort and its predictive ability was validated in the validation cohort. Independent relationships between predictors, such as critical attenuation value of the non-hypodense region and HE were analyzed using the least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic analysis. Results: The results showed that the attenuation value <64 Hounsfield units (HU) was independently associated with HE [odds ratio (OR), 4.118; 95% confidential interval (CI), 1.897–9.129, p < 0.001] and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and area under the curve (AUC) for predicting HE were 36.11%, 81.71%, 1.97, 0.78, 44.8%, 75.7%, and 0.589, respectively. Conclusions: Our research explored and validated the relationship between the attenuation value of the non-hypodense region of hematoma and HE. The attenuation value < 64 HU was an appropriate indicator of early HE. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) affects the occurrence and prognosis of acute ischemic stroke (AIS). However, the impact of diabetes on thrombus characteristics is unclear. The relationship between the composition and ultrastructure of clots and DM with admission hyperglycemia was investigated.Methods: Consecutive patients with AIS who underwent endovascular thrombus retrieval between June 2017 and May 2021 were recruited. The thrombus composition and ultrastructure were evaluated using Martius scarlet blue stain and scanning electron microscopy. Clot perviousness was evaluated via thrombus attenuation increase on computed tomography angiography (CTA) versus non-contrast CT. Patients with admission hyperglycemia DM (ahDM) and those without DM (nonDM) were compared in terms of thrombus composition, ultrastructure, and perviousness.Results: On admission, higher NIHSS scores (17 vs. 12, respectively, p = 0.015) was evident in ahDM patients. After the 90-day follow-up, the rates of excellent outcomes (mRS 0-1) were lower in patients with ahDM (16.6%, p = 0.038), but functional independence (mRS 0-2) and handicapped (mRS 3-5) were comparable between patients with ahDM and nonDM. The outcome of mortality was higher in patients with ahDM (33.3%, p = 0.046) than in nonDM patients. Clots in patients with ahDM had more fibrin (39.4% vs. 25.0%, respectively, p = 0.007), fewer erythrocyte components (21.2% vs. 41.5%, respectively, p = 0.043), equivalent platelet fraction (27.7% vs. 24.6%, respectively, p = 0.587), and higher WBC counts (4.6% vs. 3.3%, respectively, p = 0.004) than in nonDM patients. The percentage of polyhedral erythrocytes in thrombi was significantly higher in ahDM patients than in nonDM patients (68.9% vs. 45.6%, respectively, p = 0.007). The proportion of pervious clots was higher in patients nonDM than in patients with ahDM (82.61% vs. 40%, respectively, p = 0.026).Conclusion: Patients with ahDM presented with greater stroke severity on admission and poorer functional outcomes after 3 months. Clots in patients with ahDM had more fibrin, leucocytes, and fewer erythrocyte components than in patients nonDM. The content of polyhedral erythrocytes and impervious clots proportion were significantly higher in thrombi of patients with AIS and ahDM. Further research is required to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Noncontrast computed tomography (NCCT) markers for hematoma expansion (HE) in intracerebral hemorrhage (ICH) are difficult to be found in small ICHs, of which can also expand. We aimed to investigate whether there were size-related differences in the prevalence of NCCT markers and their association with HE. Methods: This retrospective analysis of prospectively collected stroke registry included 267 consecutive patients with ICH who underwent baseline NCCT within 12 h of onset. Qualitative NCCT markers, including heterogeneous density and irregular shape, were assessed. Hematoma density, defined as mean Hounsfield unit of hematoma, and hematoma volume were measured by semiautomated planimetry. Hematoma volume was categorized as small (≤ 10 ml) and large (> 10 ml). Associations of NCCT markers with HE were analyzed using multivariable logistic regression analyses. The model performances of NCCT markers and hematoma density were compared using receiver operating characteristic curves. Results: Hematoma expansion occurred in 29.9% of small ICHs and 35.5% of large ICHs. Qualitative NCCT markers were less frequently observed in small ICHs. Heterogeneous density, irregular shape, and hematoma density were associated with HE in small ICH (adjusted odds ratios [95% confidence interval] 3.94 [1.50–10.81], 4.23 [1.73–10.81], and 0.72 [0.60–0.84], respectively), and hematoma density was also related to HE in large ICH (0.84 [0.73–0.97). The model performance was significantly improved in small ICHs when hematoma density was added to the baseline model (DeLong's test, p = 0.02). Conclusions: The prevalence of NCCT markers and their association with HE differed according to hematoma volume. Quantitative hematoma density was associated with HE, regardless of hematoma size. [ABSTRACT FROM AUTHOR]

Fibrin is widely used in vascular tissue engineering. Typically, fibrin polymerization is initiated by adding exogenous thrombin. In this study, we proposed a protocol for the preparation of completely autologous fibrin without the use of endogenous thrombin and compared the properties of the prepared fibrin matrix with that obtained by the traditional method. Fibrinogen was obtained by ethanol precipitation followed by fibrin polymerization by adding either exogenous thrombin and calcium chloride (ExThr), or only calcium chloride (EnThr). We examined the structure, mechanical properties, thrombogenicity, degradation rate and cytocompatibility of fibrin matrices. Factor XIII (FXIII) quantitative assay was performed by ELISA, and FXIII activity was assessed by SDS-PAGE detection of γ-γ cross-links. The results show that network structure of EnThr fibrin was characterized by thinner fibers. The EnThr fibrin matrices had higher strength, stiffness and resistance to proteolytic degradation compared to ExThr fibrin. EnThr fibrin matrices exhibited less thrombogenicity in vitro than ExThr, and retained high cytocompatibility. Thus, the proposed approach has several advantages over the traditional method, namely the fabrication of a completely autologous coating material that has better mechanical properties, higher resistance to proteolysis and lower thrombogenicity. [ABSTRACT FROM AUTHOR]

Objectives The pathophysiology of chronic wounds typically involves redox imbalance and inflammation pathway dysregulation, often with concomitant microbial infection. Endogenous antioxidants such as glutathione and tocopherols are notably reduced or absent, indicative of significant oxidative imbalance. However, emerging evidence suggests that polyphenols could be effective agents for the amelioration of this condition. This review aims to summarise the current state of knowledge surrounding redox imbalance in the chronic wound environment and the potential use of polyphenols for the treatment of chronic wounds. Key findings Polyphenols provide a multi-faceted approach towards the treatment of chronic wounds. Firstly, their antioxidant activity allows direct neutralisation of harmful free radicals and reactive oxygen species, assisting in restoring redox balance. Upregulation of pro-healing and anti-inflammatory gene pathways and enzymes by specific polyphenols further acts to reduce redox imbalance and promote wound healing actions, such as proliferation, extracellular matrix deposition and tissue remodelling. Finally, many polyphenols possess antimicrobial activity, which can be beneficial for preventing or resolving infection of the wound site. Summary Exploration of this diverse group of natural compounds may yield effective and economical options for the prevention or treatment of chronic wounds. [ABSTRACT FROM AUTHOR]