Observing Etna volcano dynamics through seismic and deformation patterns.

Geophysical data provide the chance to investigate a volcano's dynamics; considerable information can especially be gleaned on the stress and strain patterns accompanying the internal processes and the effect of magma ascent on the main structures triggering earthquakes. Here, we analysed in detail the seismicity recorded over the last two decades on Etna volcano (southern Italy), focusing on earthquakes distribution and focal mechanism clustering; the ground deformation pattern affecting the volcanic edifice with the inflation and deflation phases was also examined. Analysed data were compared in order to shed light on possible relationships with the volcanic activity and to better understand the internal dynamics of the volcano over time. Significant steps during or shortly before major eruptions in the seismic strain release and ground deformation temporal series highlight a straightforward relationship between seismicity occurring at shallow level, inflation/deflation and volcanism. Furthermore, at depths greater than 5-7 km, down to about 20 km, the orientation of the P- and T-axes clearly indicate the existence of a pressure source in the central part of the volcano. All the results underline that the stress field related to the volcano plumbing system interferes with the regional field, partly overriding it.

Targeting Cell-Specific Molecular Mechanisms of Innate Immunity in Atherosclerosis.

Mechanisms of innate immunity contribute to inflammation, one of the major underlying causes of atherogenesis and progression of atherosclerotic vessel disease. How immune cells exactly contribute to atherosclerosis and interact with molecules of cholesterol homeostasis is still a matter of intense research. Recent evidence has proposed a potential role of previously underappreciated cell types in this chronic disease including platelets and dendritic cells (DCs). The pathophysiology of atherosclerosis is studied in models with dysfunctional lipid homeostasis and several druggable molecular targets are derived from these models. Specific therapeutic approaches focussing on these immune mechanisms, however, have not been successfully introduced into everyday clinical practice, yet. This review highlights molecular insights into immune processes related to atherosclerosis and potential future translational approaches targeting these molecular mechanisms.

[COVID-19 in Routine Rheumatologic Care]. / COVID-19 in der rheumatologischen Routineversorgung.

Since the first case of coronavirus infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and the associated COVID-19 (corona virus disease 2019) it has become a worldwide pandemic. This leads to persistent and far-reaching consequences for the health system and society as a whole. Our patients with inflammatory rheumatic diseases were initially considered to be at high risk of contracting SARS-CoV­2, especially if they were on immunosuppressive and/or immunomodulatory therapy (DMARD). It was assumed that a severe COVID-19 course could occur in case of infection. Although PCR diagnosis is generally considered the gold standard for early diagnosis of active infection with SARS-CoV­2, it has been shown that it should not always be used to confirm the diagnosis of COVID-19. Therefore, complementary antibody testing for SARS-CoV­2 could be useful in cases of clinical suspicion and negative PCR for diagnostic confirmation of COVID-19, even retrospectively. Apparently, patients with inflammatory rheumatic disease and under DMARD therapy are not particularly at risk in case of SARS-CoV­2 infection. Whether this is due to better hygiene measures or increased contact restrictions of patients with underlying inflammatory rheumatic disease, or whether ongoing DMARD therapy offers some protection against a severe course of COVID-19, is still to be clarified. The important questions about the tolerability and efficacy of COVID-19 vaccination have yet to be answered. In summary, there is still a clear need for research to better advise our patients.

Platelets and vascular inflammation of the brain.

UNLABELLED: There is emerging evidence that platelets have an important role in inflammation beyond their involvement in hemostasis. Platelets can contribute to inflammatory reactions via crosstalk both with immune cells and endothelial cells. Inflamed vessels are characterized by the presence of activated endothelial cells. These activated endothelial cells upregulate receptors necessary for leukocyte recruitment, but also for the adhesion of platelets. Subsequently, immune cells can bind to platelets through adhesion receptors presented on the platelet surface, thus supporting leukocyte recruitment to the vessel wall. There are several neurological diseases associated with vascular inflammation including multiple sclerosis (MS) and stroke. Increased markers of platelet activation could be demonstrated in patients suffering from MS compared to healthy individuals. Reports from murine models indicate that platelets may be of importance for disease progression and severity by mediating leukocyte recruitment as one potential underlying mechanism. Blocking platelet function disease severity was considerably ameliorated. Moreover, processes of tissue remodelling may be influenced by platelet derived mediators. Whether a role of platelets for vascular inflammation can be extrapolated to further neurological diseases will have to be investigated in further in depth experimental and clinical trials. CONCLUSION: Platelets and platelet associated mechanisms may offer novel starting points to understand neurovascular diseases from a different point of view and to develop novel approaches to access the disease.

Platelet surface expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease.

BACKGROUND: Surface expression of stromal cell-derived factor-1 (SDF-1, CXCL12) on platelets is enhanced during ischemic events and plays an important role in peripheral homing of stem cells and myocardial repair mechanisms. SDF-1 effects are mediated through CXCR4 and CXCR7. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in patients with coronary artery disease (CAD) compared with healthy controls. In this study, we investigated the prognostic role of platelet CXCR4- and CXCR7 surface expression in patients with symptomatic CAD. METHODS AND RESULTS: In a cohort study, platelet surface expression of CXCR4 and CXCR7 was measured by using flow cytometry in 284 patients with symptomatic CAD at the time of percutaneous coronary intervention (PCI). The primary combined end point was defined as all-cause death and/or myocardial infarction (MI) during 12-month follow-up. Secondary end points were defined as the single events of all-cause death and MI. We found significant differences of CXCR4 values in patients who developed a combined end point compared with event-free patients (mean MFIAUTHOR: Please define MFI at first use. 3.17 vs. 3.44, 95% confidence interval [CI] 0.09-0.45) and in patients who subsequently died (mean MFI 3.10 vs. 3.42, 95% CI 0.09-0.56). In multivariate Cox regression analysis, lower platelet CXCR4 levels were independently and significantly associated with all-cause mortality (hazard ratio 0.24, 95% CI 0.07-0.87) and the primary combined end point of all-cause death and/or MI (hazard ratio 0.30, 95% CI 0.13-0.72). CONCLUSION: These findings highlight a potential prognostic value of platelet expression CXCR4 on clinical outcomes in patients with CAD.

Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease.

OBJECTIVE: Inhibition of components of the complement system or of its receptors has been postulated as a concept for primary and secondary prevention in atherosclerosis and was applied in clinical trials. Although the anaphylatoxin-receptors C3aR and C5aR are commonly associated with inflammatory cells, in vitro studies suggested their expression also on platelets. METHODS AND RESULTS: Expression levels of C3aR and C5aR were measured by flow cytometry in a collective of 302 patients with documented coronary artery disease (CAD) including patients with stable CAD (n = 152), unstable angina (n = 54), acute myocardial infarction (AMI; Non-ST elevation myocardial infarction, n = 70, ST elevation MI, n = 26) or healthy controls (n = 21). Patients with stable CAD, unstable angina or AMI had significantly higher expression of C5aR on platelets in comparison to healthy controls (MFI 14.68 (5.2), 14.56 (5.18) and 13.34 (4.52) versus 10.68 (3.1)); p < 0.001). In contrast, the expression of C3aR on platelets was significantly enhanced in patients with stable and unstable CAD but not in patients with AMI compared to controls. While there was a strong correlation between the soluble ligands of these receptors C3a and C5a, we observed only a weak correlation with their receptors on platelets. Similarly, agonist induced aggregation (MEA, ADP, and TRAP) showed only a weak correlation with the expression level of anaphylatoxin - receptors on platelets. Of note, the expression of both anaphylatoxin-receptors on platelets strongly correlated with platelet activation as assessed with the surface activation marker P-selectin (r = 0.47, p > 0.001 for C3aR, r = 0.76 for C5aR, p < 0.001). Likewise, we observed a positive correlation of C3aR with other molecules associated with platelet activation such as SDF-1. CONCLUSION: In summary, we observed a positive correlation between the expression of anaphylatoxin-receptors C3aR and C5aR with platelet activation in patients with CAD. Further investigations are needed to study the clinical and mechanistic relevance of these findings.

Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice.

The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. Here, we hypothesised that selective blockade of the CD40L-Mac-1 interaction may also retard restenosis. We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery. Mice were randomised to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide, or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843 µm² vs 35469 ± 11870 µm²). Flow cytometry in CD40-deficient mice revealed reduced formation of platelet-granulocyte and platelet-inflammatory monocyte- aggregates. In vitro, supernatants of CD40-deficient platelet-leukocyte aggregates attenuated proliferation and increased apoptosis of smooth muscle cells. Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac-1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favorable strategy to fight restenosis.

Implications of glycoprotein VI for theranostics.

Glycoprotein VI (GPVI), a membrane glycoprotein solely expressed in platelets and megakaryocytes, plays a critical role in thrombus formation due to collagen/GPVI-mediated platelet activation and adhesion. Recent studies have shown that surface expression of GPVI on circulating platelets is enhanced in acute cardiovascular diseases such as myocardial infarction and ischaemic stroke. Increased GPVI levels are associated with poor clinical outcome and are an early indicator for imminent myocardial infarction in patients with chest pain. The soluble form of the dimeric GPVI fusion protein (sGPVI-Fc) binds with high affinity to collagen and atherosclerotic plaque tissue. Non-invasive imaging studies with radiolabelled sGPVI-Fc show specific binding activity to vascular lesions in vivo. Further, sGPVI-Fc has been developed as a new therapeutic platelet-based strategy for lesion-directed antithrombotic therapy. This review summarises the potential of GPVI for diagnostic and therapeutic options based on novel non-invasive molecular imaging modalities to ameliorate care of patients with cardiovascular diseases.

Crosstalk between platelets and the complement system in immune protection and disease.

Platelets have a central function in repairing vascular damage and stopping acute blood loss. They are equally central to thrombus formation in cardiovascular diseases such as myocardial infarction and ischaemic stroke. Beyond these classical prothrombotic diseases, immune mediated pathologies such as haemolytic uraemic syndrome (HUS) or paroxysmal nocturnal haemoglobinuria (PNH) also feature an increased tendency to form thrombi in various tissues. It has become increasingly clear that the complement system, part of the innate immune system, has an important role in the pathophysiology of these diseases. Not only does complement influence prothrombotic disease, it is equally involved in idiopathic thrombocytopenic purpura (ITP), an autoimmune disease characterised by thrombocytopenia. Thus, there are complex interrelationships between the haemostatic and immune systems, and platelets and complement in particular. Not only does complement influence platelet diseases such as ITP, HUS and PNH, it also mediates interaction between microbes and platelets during systemic infection, influencing the course of infection and development of protective immunity. This review aims to provide an integrative overview of the mechanisms underlying the interactions between complement and platelets in health and disease.

Platelets and neurovascular inflammation.

Platelets participate in haemostasis and in thrombus formation in health and disease. Moreover, they contribute to inflammation and cooperate with immune cells in a magnitude of inflammatory/immune responses. Although the inflammatory response has been recognised to be critical in neuronal diseases such as Alzheimer's disease or multiple sclerosis and its mouse counterpart, experimental autoimmune encephalomyelitis, the participation of platelets in these diseases is poorly investigated so far. Emerging studies, however, point to an interesting crosstalk between platelets and neuroinflammation. For instance, when the integrity of the blood brain barrier is compromised, platelets may be relevant for endothelial inflammation, as well as recruitment and activation of inflammatory cells, thereby potentially contributing to central nervous tissue pathogenesis. This review summarises recent insights in the role of platelets for neurovascular inflammation and addresses potential underlying mechanisms, by which platelets may affect the pathophysiology of neurovascular diseases.

Reliability issues for a bolometer detector for ITER at high operating temperatures.

The first detector prototypes for the ITER bolometer diagnostic featuring a 12.5 µm thick Pt-absorber have been realized and characterized in laboratory tests. The results show linear dependencies of the calibration parameters and are in line with measurements of prototypes with thinner absorbers. However, thermal cycling tests up to 450 °C of the prototypes with thick absorbers demonstrated that their reliability at these elevated operating temperatures is not yet sufficient. Profilometer measurements showed a deflection of the membrane hinting to stresses due to the deposition processes of the absorber. Finite element analysis (FEA) managed to reproduce the deflection and identified the highest stresses in the membrane in the region around the corners of the absorber. FEA was further used to identify changes in the geometry of the absorber with a positive impact on the intrinsic stresses of the membrane. However, further improvements are still necessary.

Bioremediation of soil contaminated with pentachlorophenol by Anthracophyllum discolor and its effect on soil microbial community.

Bioaugmentation is a promising technology to clean up sites contaminated with recalcitrant chemicals. White-rot fungi have proven to be effective in the degradation of pentachlorophenol. Here, we report the bioremediation of soil contaminated with pentachlorophenol (PCP) by Anthracophyllum discolor and its impact on the soil microbial community. In this study three types of microcosms were established: fresh soil (C(0)), fresh soil plus wheat straw (WS(0)) and, fresh soil plus wheat straw inoculated with A. discolor (WSAD(0)). Additionally, similar treatments and a control of sterile soil spiked with PCP (C(250), WS(250) and WSAD(250)) were used to evaluate the remediation and adsorption of PCP. The PCP removal, total microbial activity, and enzymatic activities were evaluated. This study also investigated the structure of soil microbial community by denaturing gradient gel electrophoresis (DGGE), identifying some of the dominant bacterial and fungal species. The results showed that PCP was effectively degraded in soils by A. discolor and by indigenous soil microorganisms. The addition of wheat straw increased the PCP degradation and enzymatic activities. Only laccase activity was negatively affected by PCP contamination. The PCP degradation was associated with changes in microbial communities, mainly stimulation of members of bacterial phylum Proteobacteria (Xanthomonadaceae, Burkholderiaceae and Enterobacteriaceae), and fungal phylum Ascomycota and Basidiomycota. This study shows the ability of A. discolor to degrade PCP from contaminated soil, and demonstrates that agricultural residues, such as wheat straw, can be used as growth substrate by microorganisms in PCP-contaminated soil, demonstrating a great potential of autochthonous microorganisms for soil remediation.

Platelets modulate atherogenesis and progression of atherosclerotic plaques via interaction with progenitor and dendritic cells.

Platelets not only play a role in the late complications of atherosclerosis, but are also essential in its initiation, interacting with endothelial cells and leukocytes. Platelet adhesion to injured or atherosclerotic vessels is critical for the initiation of atherosclerotic lesion formation in vivo. Increasing evidence has recently highlighted the role of progenitor cells in inflammation, atherogenesis, and atheroprogression. Recruitment of progenitor and dendritic cells to sites of vascular injury is poorly understood so far. Both human progenitor and dendritic cells significantly adhere to platelets, indicating that platelets adherent to collagen or to endothelial cells can serve as a bridging mechanism directing circulating progenitor and dendritic cells to sites of impaired vasculature. Moreover, platelets regulate differentiation of progenitor cells to endothelial cells or macrophages and foam cells and modulate essential functions of dendritic cells, including their activation, differentiation and apoptosis in vitro. This review describes recent findings on platelet interaction with progenitor cells or dendritic cells and discusses potential consequences of this interaction in atherosclerosis.

Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease.

OBJECTIVE: To evaluate residual platelet activity in a consecutive cohort of patients treated with dual antiplatelet therapy after coronary stent implantation DESIGN: Prospective single-centre cohort study. SETTING: University hospital in Germany. PATIENTS: 480 patients with symptomatic coronary artery disease (n = 221 (46%) or acute coronary syndrome (ACS; n = 259 (54%) stable angina) were studied. Platelet activity was measured by collagen- (5 microg/ml) and adenosine diphosphate- (ADP; 20 micromol/l) induced platelet aggregation to assess post-treatment activity in patients treated with acetylsalicylic acid (500 mg bolus intravenously followed by 100 mg once a day) and clopidogrel (600 mg loading dose followed by 75 mg once a day) MAIN OUTCOME MEASURES: Increased residual platelet activity (IRPA) was defined if platelet aggregation was in the upper tertile of values in the patient collective. Association of epidemiological factors with IRPA was evaluated in a multivariate logistic regression analysis. RESULTS: IRPA-ADP was found in 53 patients (11.0%) and IRPA-collagen in 42 patients (8.8%). ACS was associated with IRPA independently from other factors (for IRPA-collagen: odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.2 to 4.5, p<0.05; for IRPA-ADP: OR = 2.4; 95% CI 1.3 to 4.4, p<0.01; for IRPA-ADP/collagen: OR = 4.5, 95% CI 1.2 to 16.9, p<0.05). CONCLUSIONS: The data suggest that ACS is independently associated with IRPA despite conventional antiplatelet therapy. Further studies are warranted to demonstrate the effects of intensified antiplatelet therapy for patients with acute coronary events.

[Recurrent transient ischaemic attacks in a patient with pansinusitis]. / Rezidivierende transitorische ischämische Attacken bei einer Patientin mit Pansinusitis.

A 31-year-old woman presented with neurological deficits after an operation for sinusitis. The cranial MRI revealed multiple ischaemic lesions. Laboratory results showed a hypereosinophilia as well as elevated creatine kinase and troponin levels. The ECG implied ST elevations, the left ventricular ejection fraction was highly reduced and the cardiac MRI was suspicious for endomyocarditis. The cardiac biopsy demonstrated the findings of Loeffler's endocarditis. In conclusion the diagnosis of hypereosinophilic syndrome was made and identified as the cause of the neurological deficits.

Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM.

BACKGROUND: Multipotent mesenchymal stromal cells (MSC) have become important tools in regenerative and transplantation medicine. Rapidly increasing numbers of patients are receiving in vitro-expanded MSC. Culture conditions typically include FSC because human serum does not fully support growth of human MSC in vitro (MSC(FCS)). Concerns regarding BSE, other infectious complications and host immune reactions have fueled investigation of alternative culture supplements. METHODS: As PDGF has long been identified as a growth factor for MSC, we tested media supplementation with platelet lysate for support of MSC proliferation. RESULTS: We found that primary cultures of BM-derived MSC can be established with animal serum-free media containing fresh frozen plasma and platelets (MSC(FFPP)). Moreover, MSC(FFPP) showed vigorous proliferation that was superior to classical culture conditions containing FCS. MSC(FFPP) morphology was equivalent to MSC(FCS), and MSC(FFPP) expressed CD73, CD90, CD105, CD106, CD146 and HLA-ABC while being negative for CD34, CD45 and surface HLA-DR, as expected. In addition to being phenotypically identical, MSC(FFPP) could efficiently differentiate into adipocytes and osteoblasts. In terms of immune regulatory properties, MSC(FFPP) were indistinguishable from MSC(FCS). Proliferation of PBMC induced by IL-2 in combination with OKT-3 or by PHA was inhibited in the presence of MSC(FFPP). DISCUSSION: Taken together, FCS can be replaced safely by FFPP in cultures of MSC for clinical purposes.

[The role of platelets for the pathophysiology of acute coronary syndromes]. / Die Rolle der Thrombozyten in der Pathophysiologie des akuten Koronarsyndroms.

Cardiovascular diseases, especially ischaemic heart disease, are actually the most frequent causes of death in the Western world and represent a central challenge for modern research and medicine. The pathophysiology of ischaemic heart disease is based upon the development and biological remodelling of atherosclerotic plaques. Mainly at late stages, but also in the early phase of atherosclerosis, rupture of the atherosclerotic plaque occurs and may lead to the clinical manifestation of acute coronary syndromes, including unstable angina pectoris, non-transmural or transmural myocardial infarction. Next to inflammation mediating cells like monocytes, platelets play an essential role at early and late stages of atherosclerotic disorders. This review summarizes the basic pathophysiological mechanism of platelet adhesion and secretion, the molecular steps involved in platelet mediated thrombus formation in the atherosclerotic microenvironment and the role of platelet accumulation in reperfused myocardium.

Effect of low molecular weight heparin on intra-abdominal metastasis in a laparoscopic experimental study.

BACKGROUND AND AIMS: Metastatization, adhesion, invasion, and growth of tumor cells involve a cascade of complex phenomena which may be affected. We investigated the effect of a low molecular weight heparin, reviparin, on intra-abdominal tumor growth and intra-abdominal metastasis in rats undergoing laparoscopy. METHODS: CC531 adenocarcinoma cells (5x10(6) cells/ml) were administered intraperitoneally to 150 Wistar Albino Glaxo rats, with 15 groups of animals each. During laparoscopy 1 ml saline containing 0.0, 0.5, 2.0,; 4.0, and 10 mg reviparin/kg b.w. was introduced intraperitoneally (i.p.), daily subcutaneously (s.c.), or combined. After 21 days the animals were killed and underwent autopsy, and the tumor weight and the number of metastases on the liver surface were determined. RESULTS: Tumor weight was significantly reduced by 4.0 and 10.0 mg/kg b.w. but not by 0.5 or 2.0 mg/kg b.w. compared to controls. Decreased metastatization was observed in all treated groups. These effects were most pronounced after the s.c. or combined i.p. and s.c. administration, whereas after a sole i.p. administration only the highest dose of 10 mg/kg b.w. induced a significant inhibition of tumor growth. CONCLUSION: Low molecular weight heparin given s.c. or in combination of i.p. lavage and s.c. injections significantly inhibits intra-abdominal tumor growth and intraperitoneal metastasis of CC531 adenocarcinoma cells in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic and also open cancer surgery.