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Neutrophils release the serine proteases neutrophil elastase and cathepsin G, which have microbicidal activity and thereby contribute to the innate immune response. Steffen Massberg et al . now show that these neutrophil serine proteases, in association with extracellular nucleosomes, can also promote coagulation and thrombosis within large blood vessels. In a mouse model of systemic bacterial infection, these proteases spurred intravascular coagulation in the microcirculation of the liver, limiting bacterial tissue invasion. These findings point to a role for thrombosis in antimicrobial defense. Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo . The serine proteases and extracellular nucleosomes enhance tissue factor– and factor XII–dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

Von Willebrand factor (VWF) is the carrier protein of the anti-haemophilic Factor VIII (FVIII) in plasma. It has been reported that the infusion of FVIII concentrate in haemophilia A patients results in lowered VWF plasma levels. However, the impact of F8-deficiency on VWF plasma levels in F8-/y mice is unresolved. In order to avoid confounding variables, we back-crossed F8-deficient mice onto a pure C57BL/6J background and analysed VWF plasma concentrations relative to C57BL/6J WT (F8+/y) littermate controls. F8-/y mice showed strongly elevated VWF plasma concentrations and signs of hepatic inflammation, as indicated by increased TNF-α, CD45, and TLR4 transcripts and by elevated macrophage counts in the liver. Furthermore, immunohistochemistry showed that expression of VWF antigen was significantly enhanced in the hepatic endothelium of F8-/y mice, most likely resulting from increased macrophage recruitment. There were no signs of liver damage, as judged by glutamate-pyruvate-transaminase (GPT) and glutamate-oxalacetate-transaminase (GOT) in the plasma and no signs of systemic inflammation, as white blood cell subsets were unchanged. As expected, impaired haemostasis was reflected by joint bleeding, prolonged in vitro clotting time and decreased platelet-dependent thrombin generation. Our results point towards a novel role of FVIII, synthesized by the liver endothelium, in the control of hepatic low-grade inflammation and VWF plasma levels.

Aim: The aim of this research was to study the effect of rabbit hemorrhagic disease virus (RHDV) on the host immune response by examining the cellular composition/pathology of lymphoid organs and serum levels of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Materials and Methods: Nine adult rabbits were inoculated with 1 ml of 10% infected liver homogenate, and three rabbits served as controls. The rabbit hemorrhagic disease (RHD)-induced animals were studied on 3 consecutive days post-infection. Diagnosis of RHD was made through routine hemagglutination tests and the polymerase chain reaction. Blood smears and tissue samples from bone marrow (BM), spleen, lymph nodes, and liver were analyzed for cell composition and cytopathology. Serum levels of TNF-α and IFN-γ were measured by enzyme-linked immunosorbent assay. Results: RHD showed a decreased absolute cell count of blood as well as lymph nodes, spleen, and BM cell populations with marked left shift. This was seen as a progressive rise in immature and blast cells. Quantitative cellular changes were accompanied by an increase in specific inflammatory cytokines. Immunocytopathological alterations were evidenced by: Vacuolized, hyperactivated tissue macrophages, finding of Dohle bodies in neutrophils, and activated lymphocytes with increased nuclear-cytoplasmic ratio. Cytoplasmic eosinophilic viral inclusions found in tissue (liver, spleen, and BM) macrophages were shown for the 1st time in RHD. Megakaryocytic emperipolesis was a common feature of RHD. Conclusion: These studies suggest that RHDV induces pathology in leukocytes due to hyperactivation with left shift (toward immature stages of the different cell lineages). Macrophages are increased in number and show an expressed cytopathic effect often accompanied by viral eosinophilic cytoplasmic inclusions. They also developed a secretory activation (increased levels of pro-inflammatory cytokines). Keywords: cytopathology, emperipolesis, eosinophilic viral inclusions, immune response, macrophages, rabbit hemorrhagic disease virus.

ObjectivesHydroxychloroquine (HCQ) has been used for decades to treat patients with rheumatic diseases, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis or the antiphospholipid syndrome (APS). We hypothesise that HCQ might target endosomal NADPH oxidase (NOX), which is involved in the signal transduction of cytokines as well as antiphospholipid antibodies (aPL).MethodsFor in vitro experiments, monocytic cells were stimulated with tumour necrosis factor α (TNFα), interleukin-1β (IL-1β) or a human monoclonal aPL and the activity of NOX was determined by flow cytometry. The expression of genes known to be induced by these stimuli was quantified by quantitative reverse transcription PCR. Live cell imaging was performed by confocal laser scanning microscopy. Finally, the effects of HCQ on NOX-induced signal transduction were analysed in an in vivo model of venous thrombosis.ResultsHCQ strongly reduces or completely prevents the induction of endosomal NOX by TNFα, IL-1β and aPL in human monocytes and MonoMac1 cells. As a consequence, induction of downstream genes by these stimuli is reduced or abrogated. This effect of HCQ is not mediated by direct interference with the agonists but by inhibiting the translocation of the catalytic subunit of NOX2 (gp91phox) into the endosome. In vivo, HCQ protects mice from aPL-induced and NOX2-mediated thrombus formation.ConclusionsWe describe here a novel mechanism of action of HCQ, that is, interference with the assembly of endosomal NOX2. Since endosomal NOX2 is involved in many inflammatory and prothrombotic signalling pathways, this activity of HCQ might explain many of its beneficial effects in rheumatic diseases including the APS.

The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased - and, under conditions of decreased platelet adhesion, PDI inhibition reduced - fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet-secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury.

We report the synthesis of iron oxide nanoparticles using solution combustion synthesis, focusing on the controlled manipulation of material characteristics, such as particle size, phase composition, and magnetic properties, by applying external inert gas pressure. It was shown that variation of nitrogen gas pressure in the reactor in the range 0.1 to 1.1 MPa changed the time-temperature history of the process and resulted in the gradual change of phase composition of the fabricated materials along the FeO → FeO∙Fe 2 O 3  → Fe 2 O 3 route. The particle size varied in the 50–400 nm range, with a maximum for powder synthesized at a pressure of 0.25 MPa. For magnetic fluid hyperthermia, the critical parameter is specific loss power. It was demonstrated that this parameter can be optimized by gas pressure variation. The maximum specific loss power measured under conditions suitable for magnetic hyperthermia (magnetic field 33.5 mT and frequency 259.6 kHz) appears to be 174 W/g. The proposed innovative approach is an effective tool for controlling the synthesis of various nanoparticles with desired properties. Highlights Inert gas pressure controls material’s structure fabricated by solution combustion synthesis. A raise in gas pressure leads to a vary in phase composition along the FeO → Fe 3 O 4 → Fe 2 O 3 line. The particle size alters in 50–400 nm range with minimum for that made at a pressure of 1.1 MPa. The specific loss power under magnetic hyperthermia conditions was as high as 174 W/g. The innovative approach can be used for synthesis of various nanoparticles with desired properties.

Which treatment strategy for MTT would be most effective and provide the best possible prognosis in this case? * A. Surgery * B. Chemotherapy * C. Chemotherapy and radiotherapy * D. Combination chemotherapy with surgery and/or radiation therapy Advertisement CORRECT ANSWER: * D. Combination chemotherapy with surgery and/or radiation therapy Discussion Malignant peripheral nerve sheath tumor (MPNST), also known as malignant schwannoma or neurogenic sarcoma, is a rare form of soft tissue sarcoma (STS) that develops from Schwann cells or pluripotent cells of the neural crest, constituting peripheral nerve branches or sheaths of peripheral nerve fibers.1 MPNST represents approximately 5% of all STS.2 In turn, MTT is a histological subtype of MPNST, in which malignant Schwann cells coexist with malignant rhabdomyoblasts.2,3 MTT accounts for less than 10% of MPNST.4,5 MTT is a highly aggressive tumor that most often affects patients aged less than 35 years, although it is very rare in pediatric patients.6 The prognosis is poor; 5-year survival rate among children ranges between 5% and 20%.2 The disease occurs equally among males and females.7 MTT may originate in different parts of the body, affecting extremities, head, neck, or trunk. Forty-three months after diagnosis, the child was still in remission.15 However, this is the only case report available noting successful treatment without surgical resection, so the effect of this chemotherapy/radiotherapy approach remains uncertain and thus cannot be recommended for MTT treatment. [...]chemo- and radiotherapies were followed by stem cell transplantation, and the contribution of stem cell transplantation to the outcome is questionable. If complete resection of the tumor is considered feasible, patients with MTT often undergo surgery in combination with adjuvant chemotherapy and/or postoperative radiation therapy.8,10 Postoperative chemotherapy and radiation therapy to the primary site can improve the chances of survival.7,9,10 In 2020, Ailing Zhao, MD, and colleagues compared the survival rates of children treated by different modalities and demonstrated that the rates were significantly improved for children who received postoperative therapies, vs those who had surgery alone.7 However, enlarged tumors and metastatic lesions limit the efficacy of surgery followed by adjuvant therapy. According to the data available in the literature, for children who received combination treatment of surgery, chemotherapy, and radiation therapy, the overall survival (OS) is 15 months (range, 8-22 months), and the 5-year OS rate is about 30%.7 Analyzing all these data leads us to conclude that the most effective treatment option is likely to be a combination of neoadjuvant chemotherapy, including ifosfamide/doxorubicin, followed by complete resection