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Background:Vasculopathy, microvascular endothelial cell dysfunction, platelet activation, and interstitial lung disease (ILD) are hallmarks of systemic sclerosis (SSc). Recently, extramedullary thrombopoiesis, involving the adaptation of megakaryocytes (Mks) to stress conditions, has been described in infectious and inflammatory contexts. Activated Mks and platelets both release extracellular vesicles (EVs) and mitochondria. Little is known about Mks activation in SSc.Objectives:We investigated whether Mks-derived EVs, detectable in the blood and amenable to analysis in vitro and in vivo, can provide insights into the state of Mk activation in SSc.Methods:We examined 35 SSc patients and 25 age- and sex-matched healthy donors (HD). EVs were assessed in platelet-free plasma by flow cytometry, and EVs were purified through sequential ultracentrifugation[1,2]. In vitro experiments involved evaluating mitochondria transfer to microvascular primary lung endothelial cells, while lung histology was assessed post-EVs transfer in NSG mice, known for their receptiveness to human tissues.Results:Mks-derived EVs and platelet-derived EVs, containing or lacking mitochondria, accumulated in the plasma of SSc patients (see Table 1). The concentration of both total Mks-EVs and mitochondria-containing Mks-EVs was significantly higher in SSc patients with ILD (see Figure 1). Encapsulation into EVs seemed to enhance the horizontal transfer of mitochondria to nucleated cells. In vivo experiments demonstrated that the injection of SSc-EVs, but not purified mitochondria, rapidly induced lung fibrosis.Table 1.*: P<0.05 vs healthy donors; #: P<0.05 vs patients with ILDConclusion:The accumulation of plasma Mks-derived EVs may serve as an indicator of lung involvement in SSc patients. Further investigations are needed to understand whether extramedullary Mks indeed contribute to the natural history of the disease.REFERENCES:[1] Manfredi AA; et al. Platelet Phagocytosis via P-selectin Glycoprotein Ligand 1 and Accumulation of Microparticles in Systemic Sclerosis. Arthritis Rheumatol. 2022. 10.1002/art.41926.[2] Maugeri N; et al. Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis. Sci Transl Med. 2018; 10. 10.1126/scitranslmed.aao3089.Acknowledgements:This project is funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS.Disclosure of Interests:None declared.

BackgroundPlatelet extracellular vesicles (Plt-EVs) expressing the damage-associated molecular pattern prototypic signal, high mobility group box 1 (HMGB1), accumulate in the blood of patients with systemic sclerosis (SSc) and per se promote autoimmunity, fibrosis and vascular inflammation [1, 2]. A poorly understood defect in critical players in sprouting angiogenesis, angiopoietins and the angiopoietin receptor, TIE2 is also an hallmark of SSc. Normal neutrophils respond to angiopoietin 1 and other stimuli by undergoing activation and upregulating the Tie2 expression [3].ObjectivesWe reasoned that HMGB1 could be a putative candidate signal supporting neutrophils Tie2 overexpression, as it plays a critical role in neutrophil activation and is present as an EV-associated bioactive molecule in the blood of SSc patients[1, 2].MethodsNeutrophil Tie2 expression was assessed in the blood of 39 patients with SSc and 43 healthy donors (HD) sex- aged matched, by flow cytometry and confirmed by immunogold at electron microscopy. Tie2 expression was determined in freshly purified normal neutrophils stimulated with Plt-EVs from SSc patients or from HD or stimulated with rHMGB1 in vitro. Moreover Plt-EVs purified from the plasma of SSc patients or from HD were injected in the tail vein of NSG mice (that are receptive to human tissues). 18 hours after injection the expression of Tie2 of neutrophils in blood and lung histology were analyzed. Box A and low molecular weight heparin (LMWH) have been used as HMGB1 antagonists in vitro and in vivo.ResultsMost SSc neutrophils express Tie2 (84.7±2.4% vs 8.3±1.1% in HD; p <0.0001) regardless of the extent of systemic inflammation. HMGB1 and Plt-EV expressing HMGB1 purified from the plasma of patients with SSc induced up-regulation of TIE2 in vitro. Tie2 induction was abrogated by Box A and LMWH. Plt-EVs from SSc patients (but not from the plasma of HD) injected in immune-deficient NSG mice dramatically upregulated Tie2 neutrophil expression. Neutrophil Tie2 upregulation abated in the presence of HMGB1 inhibitors, BoxA and LMWH. Immunohistochemitry revealed lung fibrosis associated with massive infiltration by Tie2+ neutrophils. Neutrophil ablation by liposome-encapsulated clodronate prevented SSc Plt-EV-induced lung fibrosis, thus causally linking neutrophil activation, Tie2 neutrophil-expressing pulmonary infiltration and tissue remodelling.ConclusionOur data highlight the role of the platelet HMGB1/neutrophil axis in SSc vascular inflammation and fibrosis.References[1]Manfredi AA; et al. Platelet Phagocytosis via P-selectin Glycoprotein Ligand 1 and Accumulation of Microparticles in Systemic Sclerosis. Arthritis Rheumatol. 2021. 10.1002/art.41926.[2]Maugeri N; et al. Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis. Sci Transl Med. 2018; 10. 10.1126/scitranslmed.aao3089.[3]Burnett A et al. Angiopoietin-1 enhances neutrophil chemotaxis in vitro and migration in vivo through interaction with CD18 and release of CCL4. Sci Rep. 2017; 7: 2332. 10.1038/s41598-017-02216-y.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

In this article, we discuss some applications of the construction of the Apéry set of a good semigroup in N d given in (Commun Algebra 49(10):4136–4158, 2021). In particular, we study the duality of a symmetric and almost symmetric good semigroup, the Apéry set of non-local good semigroups and the Apéry set of value semigroups of plane curves.

Neutrophil activation and the generation of neutrophils extracellular traps (NETs) contribute to vascular damage and thrombosis in antiphospholipid syndrome (aPS). We reported that Low molecular weight heparin (LMWH) prevent neutrophil activation induced by P-selectin expressed by activated platelets [1, 2] and jeopardize in healthy subjects the ability of neutrophils to generate NETs and to mobilize granule contents [3]. To investigate whether LMWH, used on empirical bases to in high-risk patients, regulate neutrophil/platelet interaction in pregnant women. Here we report preliminary data from a prospective monocentric study in which the activation of platelets and neutrophils was assessed in sixteen pregnant women treated with LMWHs, with or without aPS at 12, 24 and 32 weeks of gestation. Patients were studied again when feasible after pregnancy completion. Sixteen healthy pregnant women, ten healthy women outside pregnancy and ten women with Systemic Lupus Erythematosus outside pregnancy served as controls. Platelets of pregnant healthy women were activated, as assessed by the increased expression of P-selectin and tissue factor. All patients successfully completed the pregnancy. Abnormalities were evident at the pathological assessment of the placentae despite the treatment with LMWHs. The treatment was associated with significantly reduced: i) platelet/neutrophil interaction, as assessed by heterotypic aggregates; ii) neutrophil expression of tissue factor; iii) platelet expression of the prototypic DAMP, HMGB1; iv) accumulation in the blood of byproducts of NET formation/catabolism, such as myeloperoxidase-DNA complexes. P-selectin expression was, in contrast, unaffected. The results indicate that neutrophil and platelet activation/interaction, which may reflect detrimental intravascular immune events leading to pregnancy complications, abate in patients treated with LMWHs. [1]Maugeri N et al. Prevention of platelet-polymorphonuclear leukocyte interactions: new clues to the antithrombotic properties of parnaparin, a low molecular weight heparin. Haematologica. 2005; 90(6):833-9. [2]Maugeri N et al. Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost. 2007 Jun;97(6):965-73. doi: 10.1160/th06-12-0680. [3]Manfredi AA et al. Low molecular weight heparins prevent the induction of autophagy of activated neutrophils and the formation of neutrophil extracellular traps. Pharmacol Res. 2017 Sep;123:146-156. doi: 10.1016/j.phrs.2016.08.008 NIL. None Declared.

This contribution presents a set of experimental results on fiber-reinforced innovative lightweight panels (FRIL-panels) having thickness of 12mm. These panels are prepared with a peculiar foamed concrete that has a high viscosity and cohesion in the fresh state, which makes it particularly suitable for 3D printing applications. The FRIL-panels can be used for internal partitions, external infills, and suspended ceilings of buildings as more effective solutions than conventional plasterboard ones, with better thermal insulation and acoustic absorption properties due to the internal air-void microstructure. The aim of this work is to investigate the out-of-plane resistance of FRIL-panels, prepared with a density of 800kg/m3, under displacement-controlled three-point bending tests. In view of potential use in the precast industry, the FRIL-panels were placed into an accelerated concrete curing tank so as to speed up the overall production process. Modulus of rupture, ultimate deflection and collapse mode of FRIL-panels are critically analysed and discussed.

Background Premature coronary heart disease and thromboembolic complications have emerged as a major cause of morbidity and mortality in patients with autoimmune rheumatic diseases. Tissue factor (TF) is a pivotal signal within the coagulation cascade that results in the thrombin generation. In turn thrombin, besides its well-characterized role as an effector of clot formation, is also a potent signal driving the activation of platelets and endothelial cells. An elevated incidence of thromboembolic events has been reported in patients with autoimmune diseases. Objectives We analyzed the TF expression on blood cells in patients with autoimmune diseases and matched healthy controls. Methods We studied a group of twelve active rheumatic patients comprising 8 females and 4 males, 45 (24-65) years old. Four patients had with reactive arthritis, two with Adult Still's disease (AOSD), three with ankylosing spondylitis (SA) and three with rheumatoid arthritis (RA). We compared results with 14 healthy donors, sex (8 female and 6 male) and age (median 47, range 27-65 years old) – matched. TF expression was analyzed in platelets, monocytes and neutrophils by flow cytometry in whole blood samples. Results are expressed as mean ± SEM. Results A strikingly higher fraction of patients blood cells expressed TF compared to healthy controls. Specifically, platelets expressing TF were the 23.6±2.0 in patients vs. 2.5±0.7% in controls. The monocyte TF expression was 19.2±4.0 in patients vs. 1.9±0.6% in controls and neutrophil TF expression was 22.3±3.3 in patients vs. 2.4±1.1% in controls. All p<0.001. We did not observe any significant association between blood cell TF expression and age, sex, actual diagnosis, disease duration or treatment. Conclusions The fraction of TF positive leukocytes and platelets was consistently higher in patients with rheumatic diseases compared with matched controls. This features is shared by patients with diseases with different pathogenesis and clinical features, such as AR, SA and AOSD. This feature could be involved in the increased thromboembolic risk associated to rheumatic conditions. References Maugeri N. et al; Srp Arh Celok Lek. 2010. Maugeri N. et al; Autoimmunity 2009. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5071

Background Cardiovascular disease is the major cause of mortality in patients with rheumatoid arthritis (RA) and it is not fully explained by traditional risk factors. Some evidence exists that RA treatment, in particular with anti-TNF agents, may reduce the disease-related cardiovascular risk. Platelet activation and the presence of platelet-leukocyte heterotypic aggregates characterize acute coronary syndromes [1, 2] and other conditions associated with increased thrombotic risk, including RA [2, 3]. TNF-alpha regulates the expression of Tissue Factor (TF), the initiator signal of the extrinsic pathway of the coagulation cascade, by neutrophils [4]. Platelets express functional TF upon activation [5]. Objectives To analyze the effect of TNF-alpha pharmacological blockade on platelet and leukocytes activation and TF expression. Methods Flow cytometry markers of platelet and leukocyte activation and the fraction of heterotypic aggregates were assessed in patients with RA (n = 42), osteoarthritis (OA, n = 12), chronic stable angina (CSA, n = 37) and age- and sex-matched healthy controls (HC, n = 70). 11 RA patients were untreated, 19 on DMARDs and 12 on anti-TNF therapy, i.e. etanercept (n = 8) or adalimumab (n = 4). Results Platelets from RA patients were activated compared to control groups, as revealed by the significant increase in P-selectin expression and by the higher fraction of circulating heterotypic aggregates. Circulating neutrophils were also significantly activated in RA. The expression of TF by circulating platelets and leukocytes was significantly higher in RA patients compared to control groups. Among RA patients, platelet P-selectin and TF expression were significantly higher in untreated patients, while patients in the anti-TNF group showed a significantly lower expression of platelet and neutrophil activation markers. Moreover, TNF treatment resulted in a significant reduction in platelet TF expression. DMARDs alone were poorly effective in reversing the activated phenotype of platelets from RA patients. Conclusions RA patients exhibit a significant platelet and leukocyte activation, resulting in their reciprocal physical interaction and in TF expression, which may contribute to the increased cardiovascular risk in these patients. Anti-TNF treatment results in a significant reduction in platelet activation and TF expression, suggesting a role of TNF-alpha pathway in the prothrombotic risk of RA patients. References Maugeri N et al. Early and transient release of leukocyte pentraxin 3 during acute myocardial infarction. J Immunol 2011. Maugeri N et al. An intense and short-lasting burst of neutrophil activation differentiates early acute myocardial infarction from systemic inflammatory syndromes. PLoS One 2012 Joseph JE et al. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001. Kambas K et al. C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol 2008. Panes O et al. Human platelets synthesize and express functional tissue factor. Blood 2007. Disclosure of Interest None Declared

In this article, we discuss some applications of the construction of the Apéry set of a good semigroup in$$\\mathbb {N}^d$$N d given in (Commun Algebra 49(10):4136–4158, 2021). In particular, we study the duality of a symmetric and almost symmetric good semigroup, the Apéry set of non-local good semigroups and the Apéry set of value semigroups of plane curves.

The primary aim was to assess both the type and degree of impact of the COVID-19 pandemic on child and family wellbeing in a cohort with neurodevelopmental disorders. This was a single time-point observational study utilizing a combination of surveys and standardized measures, which were administered to parents by researchers by telephone. The Child and Adolescent Neuropsychiatric Clinic of the Department of Clinical and Experimental Medicine, Catania University, Italy. In total, 200 caregivers completed the questionnaires on behalf of themselves and their child. They were predominantly mothers (88.00%) and primary caregivers (93.50%), with a mean age of 42.84 years (sd = 7.13). A questionnaire featured in a previous study was used to assess the impact of COVID-19 on general wellbeing, types of support, family health, home-based learning, and child behaviors. Children's diagnoses were recorded. Caregivers provided information about physical, mental, financial, and vocational wellbeing, and completed several standardised measures of mental health and well-being: the Kessler Psychological Distress Scale - K6; the General Anxiety Disorder Scale - GAD-2; and the WHO Well-being Scale - WHO-5. Overall, 58.50% of respondents agreed somewhat or strongly that their child's overall health and wellbeing had been impacted by the pandemic, while 47.74% felt that their own wellbeing as parents had been affected. Whilst home-based learning and disruption to services for children were noted as being significant, child wellbeing appeared to not be correlated with these but rather to restrictions, home isolation, and disruption to routine. Children with neurocognitive disorders and their families have been substantially impacted by the COVID-19 pandemic. It is expected that targeted resources and support services will be required in response to this increase in need.

BackgroundNeutrophils and platelets are key innate immune cells that productively interact upon activation, generating/releasing moieties that can damage the bystander tissue and prompt vasculogenesis. Successful pregnancy critically depends on a tight regulation of the latter events. Conversely pregnancy complications are associated with alteration/damage of the vasculature associated to the placenta. Blood-born tissue factor (TF) due to the expression of the moiety by platelets and leukocytes has been involved in the pro-thrombotic diathesis associated with sustained human autoimmunity, including that associated with anti-phospholipid syndrome (APS).ObjectivesTo test the modulation of parameters related to blood-born TF during normal and pathological pregnancyMethodsThe expression of TF by platelets, monocytes and neutrophils has been studied in 40 women at the 12th week of gestation (wg) including twelve healthy women, 14 patients with insulin-dependent diabetes mellitus (IDDM) and 14 patients with a previous history of pregnancy complications, six of them with APS. 30 healthy age-matched non-pregnant women served as controls. When possible, patients were studied again at least one year after the pregnancy completion. Blood samples were collected and processed as described1,2. Other features reflecting cell activation were assessed in parallel1,2.ResultsThe expression of platelet TF was significantly higher in pregnant women compared with age-matched controls. Platelet P-selectin was as well significantly up-regulated. Neutrophils circulating in all pregnant women were mildly degranulated. The content of the neutrophil secondary granules was depleted in particular in subiects with previous pregnancy complications sine causa.ConclusionsOur data support the contention that the activation of the innate immune system is a key feature of pregnancy, regardless of the presence of features of systemic or organ-specific autoimmunity. This implies an important modulation of the machinery involved in the reciprocal activation of platelets and neutrophils and in the pro-thrombotic phenotype of circulating cells. The analysis of the potential modulation of these parameters by ongoing treatment is currently being carried out.References Manfredi A & al. Ann Rheum Dis. 2016;75(8):1511–20. doi: 10.1136/annrheumdis-2015-208442.Maugeri N et al. Blood. 2011 Sep 22;118(12):3359–66. doi: 10.1182/blood-2011-02-337337. Disclosure of InterestNone declared