Efanesoctocog alfa elicits functional clot formation that is indistinguishable to that of recombinant factor VIII.

BACKGROUND: Factor VIII (FVIII) binding to endogenous von Willebrand factor (VWF) has constrained half-life extension of recombinant FVIII (rFVIII) products for hemophilia A. Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a novel fusion protein designed to decouple FVIII from VWF in circulation and maximize half-life prolongation by XTEN® polypeptides and Fc fusion. FVIII, VWF, and platelets interact to achieve normal hemostasis. Thus, bioengineered FVIII replacement products, such as efanesoctocog alfa, require comprehensive assessment of their hemostatic potential. OBJECTIVES: We compared functional clot formation and injury-induced platelet accumulation between efanesoctocog alfa and rFVIII. PATIENTS/METHODS: The hemostatic potential of efanesoctocog alfa and rFVIII were assessed by measuring their dose-dependent effects on in vitro fibrin generation in hemophilic plasma and in vivo injury-induced platelet accumulation using intravital microscopy and repeat saphenous vein laser-induced injuries in hemophilia A mice. RESULTS: Equal concentrations of efanesoctocog alfa or rFVIII (up to 1 IU/ml) added to plasma from patients with hemophilia A elicited similar kinetics for dose-dependent fibrin polymerization between factor products. In the presence of tissue plasminogen activator (tPA), clots formed had similar stability between products. Single intravenous doses (50, 100, or 150 IU/kg) of efanesoctocog alfa or rFVIII shortly before repeat saphenous vein laser-induced injuries increased platelet accumulation over time in a dose-dependent manner in hemophilia A mice. Platelet deposition kinetics were similar between products. CONCLUSIONS: Equivalent doses of efanesoctocog alfa and rFVIII had similar efficacy in promoting fibrin clot formation and injury-induced platelet accumulation. The hemostatic potential of efanesoctocog alfa was indistinguishable from that of rFVIII.

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and ßS-globin. Kinetic studies with MetAP2 show that ßS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood-derived erythroid progenitor 2 cells shows more extensive modification of α-globin than ß-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on ßS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor-treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2-affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.

Solid peripheral tumor leads to systemic inflammation, astrocyte activation and signs of behavioral despair in mice.

Prevalence of depression is higher in patients with cancer than in the general population. Sustained systemic inflammation has been associated with depressive behavior and it has been reported that depressed patients commonly display alterations in their immune system. We previously showed that cancer in mice induces a systemic environment that promotes neutrophil activation and leukocytosis. We thus hypothesized that the peripheral systemic response to a solid tumor leads to endothelial activation, which may promote inflammatory changes in the brain with behavioral consequences. Using the Lewis lung carcinoma (LLC) model, we show that tumor growth induces a progressive increase in peripheral inflammation as observed by elevated interleukin-6 (IL-6). In behavioral studies, tumor-bearing mice showed no sign of motor, coordination or short term working memory deficits as assessed by rotarod, balance-beam, and novel object recognition tests. However, there was an impairment in the grip strength test and interestingly, an anxious and despair-like phenotype in the elevated plus-maze, and tail suspension tests, respectively. Immunostaining of perfused brains revealed fibrin accumulation in the vasculature with some leakage into the parenchyma, a process known to activate endothelial cells. Taken together, our results suggest that the inflamed and prothrombotic systemic environment created by the growth of a peripherally-located solid tumor induces endothelial activation, accumulation of fibrin in the brain and astrocyte activation, perhaps leading to depressive-like behavior.

Thalamic and hippocampal volume associated with memory functions in multiple sclerosis.

OBJECTIVES: Although multiple sclerosis (MS) has long been considered to primarily affect white matter, it is now recognized that cognitive deficits in MS are also related to neocortical, thalamic and hippocampal damage. However, the association between damage to these structures and memory deficits in MS is unclear. This study examines whether MS patients with cognitive impairment have a reduction of hippocampal and/or thalamic volumes compared to cognitively intact patients, and whether these volume reductions correlate with various aspects of memory function. METHODOLOGY: Volumetric MRI measures of thalamus and hippocampus of forty-one patients with MS were performed. The patients were divided in two groups depending on the presence or absence of cognitive impairment, based on their neuropsychological tests scores. RESULTS: Right hippocampal volume was found to be associated with learning, and the left thalamic volume was found to predict performance in verbal memory. Cognitively impaired patients had a tendency to have a reduced left thalamic volume compared to cognitively intact patients. CONCLUSIONS: This study does not support a direct relationship between hippocampal atrophy and verbal memory. These results add to the growing evidence of the involvement of thalamus in cognitive impairment in MS and its association with verbal memory deficits.

Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer.

Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

Prospective memory impairment in multiple sclerosis: a review.

OBJECTIVE: Multiple sclerosis (MS) is a progressive disease of the central nervous system affecting information processing speed, episodic memory, attention, and executive functions. MS patients also often report prospective memory (PM) failures that directly impact their functional autonomy, including professional and social life. The purpose of this paper was to review the literature concerning the assessment and remediation of PM deficits in MS. METHOD: The literature pertaining to PM impairment in MS was carefully reviewed using PubMed, PsyINFO, and Google Scholar, as well as cross-references from the articles published on this topic. Since PM rehabilitation in MS patients is still in its infancy, this review mainly focuses on studies that have directly assessed PM through various measures including questionnaires, standardized clinical tests, and experimental procedures. CONCLUSION: This literature review confirms the presence of PM deficits in MS patients, even in the early stages of the disease. A further need for controlled studies on PM assessment and PM interventions in patients with MS is stressed.

Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma.

There is an emerging interest in the diverse functions of neutrophil extracellular traps (NETs) in a variety of disease settings. However, data on circulating NETs rely largely upon surrogate NET markers such as cell-free DNA, nucleosomes, and NET-associated enzymes. Citrullination of histone H3 by peptidyl arginine deiminase 4 (PAD4) is central for NET formation, and citrullinated histone H3 (H3Cit) is considered a NET-specific biomarker. We therefore aimed to optimize and validate a new enzyme-linked immunosorbent assay (ELISA) to quantify the levels of H3Cit in human plasma. A standard curve made of in vitro PAD4-citrullinated histones H3 allows for the quantification of H3Cit in plasma using an anti-histone antibody as capture antibody and an anti-histone H3 citrulline antibody for detection. The assay was evaluated for linearity, stability, specificity, and precision on plasma samples obtained from a human model of inflammation before and after lipopolysaccharide injection. The results revealed linearity and high specificity demonstrated by the inability of detecting non-citrullinated histone H3. Coefficients of variation for intra- and inter-assay variability ranged from 2.1 to 5.1% and from 5.8 to 13.5%, respectively, allowing for a high precision. Furthermore, our results support an inflammatory induction of a systemic NET burden by showing, for the first time, clear intra-individual elevations of plasma H3Cit in a human model of lipopolysaccharide-induced inflammation. Taken together, our work demonstrates the development of a new method for the quantification of H3Cit by ELISA that can reliably be used for the detection of NETs in human plasma.

ADAMTS13 Deficiency Worsens Colitis and Exogenous ADAMTS13 Administration Decreases Colitis Severity in Mice.

BACKGROUND: Inflammatory bowel disease (IBD) affects 1.6 million people in the United States. IBD is associated with an increased risk of thrombosis, which rises with disease activity. The pathogenesis of IBD and its increased thrombotic risk is not completely understood. Ultra large von Willebrand factor (ULVWF) multimers are secreted from activated endothelium, leading to recruitment of platelets and leukocytes. A disintegrin and metalloproteinase with thrombospondin type I repeats motif 13 (ADAMTS13) cleaves highly adhesive ULVWF into smaller, less bioactive, multimers, releasing them into circulation. Mice deficient in ADAMTS13 (ADAMTS13-/-) have heightened inflammatory and thrombotic responses. OBJECTIVES: We hypothesized that upon colitis induction, ADAMTS13-/- mice would have more severe symptoms compared with wild-type (WT) mice, and rhADAMTS13 administration to mice with colitis would improve their condition. RESULTS: Dextran sodium sulfate-induced colitis was worse in ADAMTS13-/- mice than WT. ADAMTS13-/- showed increased weight loss, worse anemia, and increased clinical and histologic colitis severity, compared with WT mice. ADAMTS13-/- mice had increased VWF release, with accumulation at inflamed colonic sites. Also, the majority of mice showed one or more submucosal colonic thrombi. ADAMTS13 deficiency worsened colitis and propagated intestinal inflammation, most likely through increased platelet-leukocyte recruitment by VWF. Treatment of WT mice with rhA-DAMTS13 decreased colitis severity without worsening anemia. Additionally, several immune-mediated chronic murine colitis models, and inflamed colon tissue specimens from IBD patients, showed increased VWF release at inflamed sites, suggesting a generalizability of our findings. CONCLUSION: Measuring VWF/ADAMTS13 levels could have clinical utility. When applicable, the administration of ADAMTS13, in addition to primary treatment, may improve outcomes for IBD patients.

Prospective memory in multiple sclerosis: The impact of cue distinctiveness and executive functioning.

OBJECTIVE: Prospective memory (PM), the ability to remember to do something at the appropriate time in the future, is crucial in everyday life. One way to improve PM performance is to increase the salience of a cue announcing that it is time to act. Multiple sclerosis (MS) patients often report PM failures and there is growing evidence of PM deficits among this population. However, such deficits are poorly characterized and their relation to cognitive status remains unclear. To better understand PM deficits in MS patients, this study investigated the impact of cue salience on PM, and its relation to retrospective memory (RM) and executive deficits. METHODS: Thirty-nine (39) MS patients were compared to 18 healthy controls on a PM task modulating cue salience during an ongoing general knowledge test. RESULTS: MS patients performed worse than controls on the PM task, regardless of cue salience. MS patients' executive functions contributed significantly to the variance in PM performance, whereas age, education and RM did not. Interestingly, low- and high-executive patients' performance differed when the cue was not salient, but not when it was, suggesting that low-executive MS patients benefited more from cue salience. CONCLUSIONS: These findings add to the growing evidence of PM deficits in MS and highlight the contribution of executive functions to certain aspects of PM. In low-executive MS patients, high cue salience improves PM performance by reducing the detection threshold and need for environmental monitoring.

Priming of neutrophils toward NETosis promotes tumor growth.

Neutrophils play a major role in cancer biology and both pro- and antitumoral functions of tumor-infiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation.

INTRODUCTION: Large elevations of high sensitive Troponin T (hsTnT) in ischemic stroke patients is associated with a poor outcome. In a pilot study we found a high prevalence of malignancies among these patients. Since neutrophil extracellular traps (NETs) have been linked to cancer-associated thrombosis, we hypothesized that the concomitant cerebral and myocardial ischemia could be the result of a NET-induced hypercoagulable state. MATERIALS AND METHODS: Clinical assessments, plasma analyses and autopsies with histopathology (in cases of in-hospital mortality) were performed on ischemic stroke patients with high elevations of hsTnT (N=12) and normal hsTnT (N=19). RESULTS: Patients with hsTnT elevation had an unexpectedly higher prevalence of cancer (p=0.002), half of which were diagnosed post-mortem. Autopsies of these patients revealed widespread myocardial, cerebral and pulmonary microthrombosis with H3Cit in thrombi. A pro-coagulant state and an increase of the NET specific marker citrullinated histone H3 (H3Cit) was found in plasma of patients with elevated hsTnT compared to patients with normal levels (p<0.001). Plasma analyses in cancer patients showed even higher H3Cit levels (p<0.001), and an increase in granulocyte colony-stimulating factor, known to prime neutrophils towards NETosis. H3Cit correlated positively with thrombin-antithrombin complex (p=0.004) and soluble P-selectin (p<0.001), further linking NETosis to the pro-thrombotic state. CONCLUSIONS: The high prevalence of known or occult cancer in our study suggests that cancer-associated arterial microthrombosis may be underestimated. By linking the thrombosis to NETs, we suggest markers of NETosis that could aid in revealing cancer in arterial microthrombosis as well as arterial microthrombosis in cancer.

Role of executive functions in prospective memory in multiple sclerosis: Impact of the strength of cue-action association.

OBJECTIVES: Patients diagnosed with multiple sclerosis (MS) often report prospective memory (PM) deficits. Although PM is important for daily functioning, it is not formally assessed in clinical practice. The aim of this study was to examine the role of executive functions in MS patients' PM revealed by the effect of strength of cue-action association on PM performance. METHOD: Thirty-nine MS patients were compared to 18 healthy controls matched for age, gender, and education on a PM task modulating the strength of association between the cue and the intended action. RESULTS: Deficits in MS patients affecting both prospective and retrospective components of PM were confirmed using 2 × 2 × 2 mixed analyses of variance (ANOVAs). Among patients, multiple regression analyses revealed that the impairment was modulated by the efficiency of executive functions, whereas retrospective memory seemed to have little impact on PM performance, contrary to expectation. More specifically, results of 2 × 2 × 2 mixed-model analyses of covariance (ANCOVAs) showed that low-executive patients had more difficulty detecting and, especially, retrieving the appropriate action when the cue and the action were unrelated, whereas high-executive patients' performance seemed to be virtually unaffected by the cue-action association. CONCLUSIONS: Using an objective measure, these findings confirm the presence of PM deficits in MS. They also suggest that such deficits depend on executive functioning and can be reduced when automatic PM processes are engaged through semantic cue-action association. They underscore the importance of assessing PM in clinical settings through a cognitive evaluation and offer an interesting avenue for rehabilitation.

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor-Induced Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13(-/-) mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13(-/-) mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.

Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock.

Neutrophil extracellular traps (NETs), consisting of nuclear DNA with histones and microbicidal proteins, are expelled from activated neutrophils during sepsis. NETs were shown to trap microbes, but they also fuel cardiovascular, thrombotic, and autoimmune disease. The role of NETs in sepsis, particularly the balance between their antimicrobial and cytotoxic actions, remains unclear. Neutrophils from peptidylarginine deiminase 4-(PAD4(-/-)) deficient mice, which lack the enzyme allowing for chromatin decondensation and NET formation, were evaluated. We found that neutrophil functions involved in bacterial killing, other than NETosis, remained intact. Therefore, we hypothesized that prevention of NET formation might not have devastating consequences in sepsis. To test this, we subjected the PAD4(-/-) mice to mild and severe polymicrobial sepsis produced by cecal ligation and puncture. Surprisingly, under septic conditions, PAD4(-/-) mice did not fare worse than wild-type mice and had comparable survival. In the presence of antibiotics, PAD4-deficiency resulted in slightly accelerated mortality but bacteremia was unaffected. PAD4(-/-) mice were partially protected from lipopolysaccharide-induced shock, suggesting that PAD4/NETs may contribute to the toxic inflammatory and procoagulant host response to endotoxin. We propose that preventing NET formation by PAD4 inhibition in inflammatory or thrombotic diseases is not likely to increase host vulnerability to bacterial infections.

NETosis: a new factor in tumor progression and cancer-associated thrombosis.

Neutrophils have long been known as innate immune cells that phagocytose and kill pathogens and mount inflammatory responses protecting the host from infection. In the past decades, new aspects of neutrophils have emerged unmasking their importance not only in inflammation but also in many pathological conditions including thrombosis and cancer. The 2004 discovery that neutrophils, upon strong activation, release decondensed chromatin to form neutrophil extracellular traps (NETs), has unveiled new avenues of research. Here, we review current knowledge regarding NETs in thrombosis, with a special focus on cancer-associated thrombosis as well as their potential role in cancer growth and metastasis. We discuss the prospective use of NET-specific biomarkers, such as citrullinated histone H3 and NET inhibitors, as tools to anticipate and fight cancer-associated thrombosis. We propose that the rapid developments in the field of NETosis may provide new targets to combat the thrombotic consequences of cancer and perhaps even help to contain the disease itself.

Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice.

Deep vein thrombosis and pulmonary embolism are major health problems associated with high mortality. Recently, DNA-based neutrophil extracellular traps (NETs) resulting from the release of decondensed chromatin, were found to be part of the thrombus scaffold and to promote coagulation. However, the significance of nuclear decondensation and NET generation in thrombosis is largely unknown. To address this, we adopted a stenosis model of deep vein thrombosis and analyzed venous thrombi in peptidylarginine deiminase 4 (PAD4)-deficient mice that cannot citrullinate histones, a process required for chromatin decondensation and NET formation. Intriguingly, less than 10% of PAD4(-/-) mice produced a thrombus 48 h after inferior vena cava stenosis whereas 90% of wild-type mice did. Neutrophils were abundantly present in thrombi formed in both groups, whereas extracellular citrullinated histones were seen only in thrombi from wild-type mice. Bone marrow chimera experiments indicated that PAD4 in hematopoietic cells was the source of the prothrombotic effect in deep vein thrombosis. Thrombosis could be rescued by infusion of wild-type neutrophils, suggesting that neutrophil PAD4 was important and sufficient. Endothelial activation and platelet aggregation were normal in PAD4(-/-) mice, as was hemostatic potential determined by bleeding time and platelet plug formation after venous injury. Our results show that PAD4-mediated chromatin decondensation in the neutrophil is crucial for pathological venous thrombosis and present neutrophil activation and PAD4 as potential drug targets for deep vein thrombosis.

Value of the MoCA test as a screening instrument in multiple sclerosis.

OBJECTIVE: Since a large proportion of multiple sclerosis (MS) patients exhibit cognitive deficits, it is important to have reliable and cost-effective screening measures that can be used to follow patients effectively. the objective of this study was to evaluate the clinical value of the Montreal Cognitive Assessment (MoCA) test in detecting cognitive deficits in MS patients. METHODS: Forty-one (70.1% women, mean age 44.51 ±7.43) mildly impaired (EDSS: 2.26 ±1.87) MS patients were recruited for this study. In addition to the MoCA, they were administered the MSNQ-P (patient version) and the MSNQ-I (informant version), the bDI-FS and a comprehensive neuropsychological test battery. RESULTS: there were significant correlations between the MoCA test and the three factors derived from the neuropsychological evaluation (Executive/speed of processing, Learning, Delayed recall). the MoCA test was correlated with the MSNQ-I but only marginally with the MSNQ-P. In addition, there was no significant correlation between the MSNQ-P and the neuropsychological factors, whereas significant correlations were found between two of those factors (Learning and Delayed recall) and the MSNQ-I, suggesting that the informant version is more reliable than the patient version for the presence of cognitive deficits. CONCLUSION: the results obtained in the present study support the value of the MoCA test as a screening tool for the presence of cognitive dysfunction in MS patients, even in patients with mild functional disability (EDSS).

Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression.

Cancers prime neutrophils to release extracellular DNA traps through the systemic release of granulocyte colony-stimulating factor (G-CSF). We recently showed that these circulating neutrophil extracellular traps (NETs) promote the establishment of a pro-thrombotic state. The role of NETs in cancer biology and tumor progression may prove much more than an unfortunate side effect of cancer.

Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model.

PURPOSE: Neutrophil recruitment to the inflammatory sites is regulated by a variety of adhesion molecules including ß2 integrins. The dependency of neutrophil recruitment on ß2 integrins is variable in different tissues, but has not yet been verified in the cutaneous passive reverse Arthus reaction. We examined this question and also evaluated the impact of isoflurane on neutrophil recruitment to the skin because we previously showed in vitro that isoflurane binds and inhibits ß2 integrins. METHODS: The dependency on ß2 integrins in neutrophil recruitment to the skin in the Arthus reaction was examined using αL, αM and ß2 knockout mice. Then, we evaluated the effect of isoflurane on neutrophil recruitment to the skin. In addition, the effects of isoflurane on neutrophil binding to intercellular adhesion molecule-1 (ICAM-1), one of the ß2 integrin ligands, were studied in vitro using cell adhesion assays. RESULTS: Neutrophil recruitment to the skin in the Arthus reaction model was totally dependent on ß2 integrins, as ß2 knockout mice completely abolished it. However, the defect of only one of the ß2 integrins was not sufficient to abolish neutrophil recruitment. Isoflurane reduced neutrophil recruitment to the skin by approximately 90 %. Also, isoflurane inhibited neutrophil adhesion to ß2 integrin ligand ICAM-1. CONCLUSIONS: We demonstrated that (1) neutrophil recruitment to the skin was totally dependent on ß2 integrins, and (2) isoflurane significantly impaired neutrophil recruitment. Based on the previous studies on the contribution of other adhesion molecules in neutrophil recruitment, it is likely that isoflurane at least partially affects on ß2 integrins in this model.