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Background: Access to reperfusion therapies in patients with large vessel occluding acute ischemic stroke demands process reorganization and optimization. Neurovascular networks are being built up to provide 24/7 endovascular stroke therapy service. In times of an increasingly complex stroke rescue chain little is known about patients' and their relatives' treatment awareness.Methods: All patients, who received any kind of acute reperfusion treatment between January and August 2017 in the university hospital Aachen, and their proxies, were included in the survey. Patients were either primarily or secondarily transferred.Results: For all questions regarding stroke treatment patients and their caregivers provided concurring answers. 40% of both patients and caregivers did not understand the treatment that was performed. Finally, patients who perceived on their own that stroke detection was delayed had significantly longer onset to door times than patients who did not have this impression.Conclusions: This study showed that patients' and proxies' answers correlated significantly. In case of patients' unavailability extrapolation of treatment satisfaction from answers by proxies might be permitted. High percentages of patients and caregivers do not understand relevant information, possibly due to limits of communication in an emergency setting or deficits in communication during the hospital stay. More emphasis should be laid on providing further information during the hospital stay. [ABSTRACT FROM AUTHOR]

Estrogens modulate the immune system and possess anti-inflammatory properties. In line, immune cells express a variety of estrogen receptors (ER) including ER-alpha and -beta. In the present study, we examined the influence of 17beta-estradiol (E2) serum concentrations on blood leukocyte composition and their ex vivo polarization/activation status by FACS analysis in sub-fertile human females under controlled ovarian stimulation (COS). Using a set of cell-type and polarization-specific markers, we demonstrate that increased 17ß-estradiol (E2) serum concentrations yield an overall increase in leukocytes, neutrophils and monocytes but decreased lymphocytes. There was a clear ratio shift towards an increase in M2 monocytes with a protective quality and an increase in T-helper cells compared to a decrease in cytotoxic T-cells. These data support experimental findings and clinical trials, i.e. related to multiple sclerosis and other autoimmune-related diseases, that have shown a down-regulation of CD8(+) T cells and up-regulation of T-regulatory cells. Further studies have to pinpoint to which extent the immune system/-responsiveness of otherwise healthy female patients is affected by medium-term systemic E2 variations. [ABSTRACT FROM AUTHOR]

Microglial cells are the primary mediators of the CNS immune defense system and crucial for shaping inflammatory responses. They represent a highly dynamic cell population which is constantly moving and surveying their environment. Acute brain damage causes a local attraction and activation of this immune cell type which involves neuron-to-glia and glia-to-glia interactions. The prevailing view attributes microglia a “negative” role such as defense and debris elimination. More topical studies also suggest a protective and “positive” regulatory function. Estrogens and progestins exert anti-inflammatory and neuroprotective effects in the CNS in acute and chronic brain diseases. Recent work revealed that microglial cells express subsets of classical and non-classical estrogen and progesterone receptors in a highly dynamic way. In this review article, we would like to stress the importance of microglia for the spreading of neural damage during hypoxia, their susceptibility to functional modulation by sex steroids, the potency of sex hormones to switch microglia from a pro-inflammatory M1 to neuroprotective M2 phenotype, and the regulation of pro- and anti-inflammatory properties including the inflammasome. We will further discuss the possibility that the neuroprotective action of sex steroids in the brain involves an early and direct modulation of local microglia cell function. This article is part of a Special Issue entitled ‘Sex steroids and brain disorders’. [ABSTRACT FROM AUTHOR]

Highlights: [•] We describe the susceptibility of murine microglia to hypoxia. [•] The absence of oxygen regulates the secretory and phagocytic function of microglia. [•] Estrogen and progesterone abrogate hypoxia-induced expression of pro-inflammatory cytokines. [•] Sex steroids induce the switch of a pro-inflammatory M1 to a more protective M2 microglia phenotype. [ABSTRACT FROM AUTHOR]

Objectives: The prognosis of patients with acute ischemic stroke (AIS) essentially depends on both prompt diagnosis and appropriate treatment. Endovascular stroke therapy (EST) proved to be highly efficient in the treatment of emergent large vessel occluding (ELVO) strokes in the anterior circulation. To achieve a timely diagnosis, a robust combination of few and simple signs to identify ELVOs in AIS patients applicable by paramedics in the prehospital triage is worthwhile.Materials and Methods: This retrospective single-center study included 904 AIS patients (324 ELVO, 580 non-ELVO) admitted between 2010 and 2015 in a tertiary stroke center. We re-evaluated two symptoms based on NIHSS items, gaze deviation and hemiparesis of the limbs ("Gaze deviation and Paresis Score, GPS") for the pre-hospital prediction of ELVO.Results: A positive GPS AIS in patients predicted ELVO with a sensitivity of 0.89, specificity = 0.97, positive predictive value (PPV) = 0.95, negative predictive value (NPV) = 0.94 and diagnostic odds ratio (DOR) = 34.25 (CI: 20.75-56.53). The positive Likelihood-ratio (LR+) was 29.67, the negative Likelihood ratio (LR-) 0.11. NIHSS of patients with positive GPS (gaze palsy NIHSS ≥ 0, Motor arm NIHSS ≥2 and Motor leg NIHSS ≥2) was markedly higher compared to negative GPS patients (p < 0.001).Conclusions: The GPS proved to be similarly accurate in detecting ELVO in the anterior circulation of AIS patients and even more specific than other published clinical scores. Its simplicity and clarity might enable non-neurological medical staff to identify ELVO AIS patients with high certainty in a preclinical setting. [ABSTRACT FROM AUTHOR]

Abstract: Sex steroids are neuroprotective following traumatic brain injury or during neurodegenerative processes. In a recent short-term study, we have shown that 17β-estradiol (E) and progesterone (P) applied directly after ischemia reduced the infarct volume by more than 70%. This protection might primarily result from the anti-inflammatory effects of steroids. Here, we focus on the long-term neuroprotection by both steroids with respect to the infarct volume, functional recovery, and vessel density in the penumbra. The application of E/P during the first 48h after stroke (transient middle cerebral artery occlusion, tMCAO) revealed neuroprotection after two weeks. The infarct area was reduced by 70% and motor activity was preserved compared to placebo-treated animals. Blood vessel density in the penumbra using immunohistochemistry for von Willebrand factor showed increased vessel density after tMCAO which was not affected by hormones. Expression of vascular endothelial growth factor (VEGF) and its receptor (R1) was increased at 24h after tMCAO and up-regulated by E/P but not changed 14 days after stroke. These findings suggest that the neuroprotective potency of both steroids is sustained and persists for at least two weeks. Besides anti-inflammatory and anti-apoptotic actions, angiogenesis in the damaged area appears to be initially affected early after ischemia and is manifested up to two weeks. This article is part of a Special Issue entitled ‘Neurosteroids’. [Copyright &y& Elsevier]

In mast cells (MCs), the TEC family kinase (TFK) BTK constitutes a central regulator of antigen (Ag)-triggered, FcεRI-mediated PLCγ phosphorylation, Ca2+ mobilization, degranulation, and pro-inflammatory cytokine production. Less is known about the function of BTK in the context of stem cell factor (SCF)-induced KIT signaling. In bone marrow-derived MCs (BMMCs), Ag stimulation caused intense phosphorylation of BTK at Y551 in its active center and at Y223 in its SH3-domain, whereas in response to SCF only Y223 was significantly phosphorylated. Further data using the TFK inhibitor Ibrutinib indicated that BTK Y223 is phosphorylated by a non-BTK TFK upon SCF stimulation. In line, SCF-induced PLCγ1 phosphorylation was stronger attenuated by Ibrutinib than by BTK deficiency. Subsequent pharmacological analysis of PLCγ function revealed a total block of SCF-induced Ca2+ mobilization by PLC inhibition, whereas only the sustained phase of Ca2+ flux was curtailed in Ag-stimulated BMMCs. Despite this severe stimulus-dependent difference in inducing Ca2+ mobilization, PLCγ inhibition suppressed Ag- and SCF-induced degranulation and pro-inflammatory cytokine production to comparable extents, suggesting involvement of additional TFK(s) or PLCγ-dependent signaling components. In addition to PLCγ, the MAPKs p38 and JNK were activated by Ag in a BTK-dependent manner; this was not observed upon SCF stimulation. Hence, FcεRI and KIT employ different mechanisms for activating PLCγ, p38, and JNK, which might strengthen their cooperation regarding pro-inflammatory MC effector functions. Importantly, our data clearly demonstrate that analyzing BTK Y223 phosphorylation is not sufficient to prove BTK activation. Unlabelled Image • In contrast to Ag, SCF hardly induces BTK Y551 phosphorylation in BMMCs. • SCF/KIT signaling uses non-BTK TFKs for activating PLCγ1 tyrosine phosphorylation. • Synergistic quality of Ag plus SCF-induced TNF-α production is independent of BTK. • Analysis of BTK Y223 phosphorylation is not sufficient to prove BTK activation. [ABSTRACT FROM AUTHOR]

Highlights • Hypoxia impacts on the inflammasome NLRP3/ASC/caspase-1 axis in BV-2 cells and primary astroglia. • Estrogen and progesterone counteracts hypoxia-induced effects on NLRP3 and ASC. • Sex steroids fail to mitigate caspase-1 mediated IL1beta maturation. Abstract Clinical and animal model studies have demonstrated the neuroprotective and anti-inflammatory effects of 17beta-estradiol (E2) and progesterone (P) in different disease models of the central nervous system (CNS) including ischemic stroke. Inflammasomes are involved in the interleukin-1 beta (IL1beta) maturation, in particular, NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the active caspase-1 (Casp1) form. Recently, we showed that administration of E2 or P selectively regulated these components after experimental ischemic stroke in rats. Therefore, we investigated the impact of E2 and P on the NLRP3/ASC/Casp1 axis in the murine microglia-like cell line BV-2 cells and primary astrocytes after short-term in vitro hypoxia. The inflammatory cytokine IL1beta but not IL18 was increased after short-term hypoxia in astroglia and BV-2 cells. The same applied to NLPR3 and ASC. Casp1 activity was also elevated in astroglia and BV-2 cells after hypoxia. The administration of E2 or P selectively dampened IL1beta, ASC and NLRP3 expression mainly in BV-2 cells. Both steroid hormones failed to reduce Casp1 activity after hypoxia. We conclude that E2- and P-mediated anti-inflammatory mechanisms occur upstream of Casp1 through the regulation of NLRP3 and its adaptor ASC. [ABSTRACT FROM AUTHOR]

Excessive glutamate secretion leads to excitotoxicity, which has been shown to underlie neurodegenerative disorders. Excitotoxicity is in part exerted by overactivation of calpains, which promote neuronal cell death via induction of limited proteolysis of the cellular proteins p35, regulatory subunit of cyclin-dependent kinase 5, and αII-spectrin. We used primary murine neuronal cells in a model of glutamate toxicity. The protease inhibitor α 1 -antitrypsin was able to prevent glutamate toxicity as determined by MTT assay and immunofluorescence. Calpain and caspase 3 activity were reduced following α 1 -antitrypsin treatment, as assessed by calpain and caspase 3 activity assays. In addition we could observe a modulation of cleavage of the calpain/caspase substrates αII-spectrin and p35 in Western blots. In summary, α 1 -antitrypsin shows inhibitory effects on excitotoxicity of primary neurons involving the inhibition of calpain activity. The advantage of using α 1 -antitrypsin is that the substance is already in clinical use for the treatment of patients with hereditary α 1 -antitrypsin deficiency. Further experiments are required in animal models of neurodegenerative disorders to assess the suitability of this substance in patients suffering from Alzheimer's disease or Parkinson's disease. [ABSTRACT FROM AUTHOR]