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In a previous study from our group, argon has shown to significantly attenuate brain injury, reduce brain inflammation and enhance M 2 microglia/macrophage polarization until 7 days after ischemic stroke. However, the long-term effects of argon have not been reported thus far. In the present study, we analyzed the underlying neuroprotective effects and potential mechanisms of argon, up to 30 days after ischemic stroke. Argon administration with a 3 h delay after stroke onset and 1 h after reperfusion demonstrated long-term neuroprotective effect by preserving the neurons at the ischemic boundary zone 30 days after stroke. Furthermore, the excessive microglia/macrophage activation in rat brain was reduced by argon treatment 30 days after ischemic insult. However, long-lasting neurological improvement was not detectable. More sensorimotor functional measures, age- and disease-related models, as well as further histological and molecular biological analyses will be needed to extend the understanding of argon’s neuroprotective effects and mechanism of action after ischemic stroke.

Background In recent years, argon has been shown to exert neuroprotective effects in an array of models. However, the mechanisms by which argon exerts its neuroprotective characteristics remain unclear. Accumulating evidence imply that argon may exert neuroprotective effects via modulating the activation and polarization of microglia/macrophages after ischemic stroke. In the present study, we analyzed the underlying neuroprotective effects of delayed argon application until 7 days after reperfusion and explored the potential mechanisms. Methods Twenty-one male Wistar rats underwent transient middle cerebral artery occlusion or sham surgery randomly for 2 h using the endoluminal thread model. Three hours after transient middle cerebral artery occlusion induction and 1 h after reperfusion, animals received either 50% vol Argon/50% vol O 2 or 50% vol N 2 /50% vol O 2 for 1 h. The primary outcome was the 6-point neuroscore from 24 h to d7 after reperfusion. Histological analyses including infarct volume, survival of neurons (NeuN) at the ischemic boundary zone, white matter integrity (Luxol Fast Blue), microglia/macrophage activation (Iba1), and polarization (Iba1/Arginase1 double staining) on d7 were conducted as well. Sample size calculation was performed using nQuery Advisor + nTerim 4.0. Independent t test, one-way ANOVA and repeated measures ANOVA were performed, respectively, for statistical analysis (SPSS 23.0). Results The 6-point neuroscore from 24 h to d7 after reperfusion showed that tMCAO Ar group displayed significantly improved neurological performance compared to tMCAO N 2 group ( p  = 0.026). The relative numbers of NeuN-positive cells in the ROIs of tMCAO Ar group significantly increased compared to tMCAO N 2 group ( p  = 0.010 for cortex and p  = 0.011 for subcortex). Argon significantly suppressed the microglia/macrophage activation as revealed by Iba1 staining ( p  = 0.0076) and promoted the M2 microglia/macrophage polarization as revealed by Iba1/Arginase 1 double staining ( p  = 0.000095). Conclusions Argon administration with a 3 h delay after stroke onset and 1 h after reperfusion significantly alleviated neurological deficit within the first week and preserved the neurons at the ischemic boundary zone 7 days after stroke. Moreover, argon reduced the excessive microglia/macrophage activation and promoted the switch of microglia/macrophage polarization towards the anti-inflammatory M2 phenotype. Studies making efforts to further elucidate the protective mechanisms and to benefit the translational application are of great value.

Background Key functions of Ca 2+ signaling in rodent microglia include monitoring the brain state as well as the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca 2+ dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca 2+ signal properties of human microglia remain unknown. Methods We developed a novel genetically-encoded ratiometric Ca 2+ indicator, targeting microglial cells in the freshly resected human tissue, organotypically cultured tissue slices and analyzed in situ ongoing Ca 2+ signaling of decades-old microglia dwelling in their native microenvironment. Results The data revealed marked compartmentalization of Ca 2+ signals, with signal properties differing across the compartments and resident morphotypes. The basal Ca 2+ levels were low in ramified and high in ameboid microglia. The fraction of cells with ongoing Ca 2+ signaling, the fraction and the amplitude of process Ca 2+ signals and the duration of somatic Ca 2+ signals decreased when moving from ramified via hypertrophic to ameboid microglia. In contrast, the size of active compartments, the fraction and amplitude of somatic Ca 2+ signals and the duration of process Ca 2+ signals increased along this pathway.

The study aims to provide data on authors’ gender distribution with special attention on publications from Europe. Articles (October 2019–March 2020) published in three representative neurosurgical journals (Acta Neurochirurgica, Journal of Neurosurgery, Neurosurgery) were analyzed with regard to female participation. Out of 648 publications, 503 original articles were analyzed: 17.5% (n = 670) of the 3.821 authors were female, with 15.7% (n = 79) females as first and 9.5% (n = 48) as last authors. The lowest ratio of female first and last authors was seen in original articles published in the JNS (12.3%/7.7% vs. Neurosurgery 14.9%/10.6% and Acta 23.0/11.5%). Articles originated in Europe made up 29.8% (female author ratio 21.1% (n = 226)). Female first authorship was seen in 20.7% and last authorship in 10.7% (15.3% and 7.3% were affiliated to a neurosurgical department). The percentages of female authorship were lower if non-original articles (n = 145) were analyzed (11.7% first/4.8% last authorships). Female participation in editorial boards was 8.0%. Considering the percentages of European female neurosurgeons, the current data are proportional. However, the lack of female last authors, the discrepancy regarding non-original articles and the composition of the editorial boards indicate that there still is a structural underrepresentation and that females are limited in achieving powerful positions.

The poor translational success rate of preclinical stroke research may partly be due to inaccurate modelling of the disease. We provide data on transient middle cerebral artery occlusion (tMCAO) experiments, including detailed intraoperative monitoring to elaborate predictors indicating experimental success (ischemia without occurrence of confounding pathologies). The tMCAO monitoring data (bilateral cerebral blood flow, CBF; heart rate, HR; and mean arterial pressure, MAP) of 16 animals with an ‘ideal’ outcome (MCA-ischemia), and 48 animals with additional or other pathologies (subdural haematoma or subarachnoid haemorrhage), were checked for their prognostic performance (receiver operating characteristic curve and area under the curve, AUC). Animals showing a decrease in the contralateral CBF at the time of MCA occlusion suffered from unintended pathologies. Implementation of baseline MAP, in addition to baseline HR (AUC, 0.83, 95% c.i. 0.68 to 0.97), increased prognostic relevance (AUC, 0.89, 95% c.i. 0.79 to 0.98). Prediction performance improved when two additional predictors referring to differences in left and right CBF were considered (AUC, 1.00, 95% c.i. 1.0 to 1.0). Our data underline the importance of peri-interventional monitoring to verify a successful experimental performance in order to ensure a disease model as homogeneous as possible.

Recently aside from the \"classic\" endovascular monofilament perforation technique to induce experimental subarachnoid hemorrhage (SAH) a modification using a tungsten wire advanced through a guide tube has been described. We aim to assess both techniques for their success rate (induction of SAH without confounding pathologies) as primary endpoint. Further, the early tissue lesion pattern as evidence for early brain injury will be analyzed as secondary endpoint. Sprague Dawley rats (n=39) were randomly assigned to receive either Sham surgery (n=4), SAH using the \"classic\" technique (n=18) or using a modified technique (n=17). Course of intracranial pressure (ICP) and regional cerebral blood flow (rCBF) was analyzed; subsequent pathologies were documented either 6 or 24 h after SAH. Hippocampal tissue samples were analyzed via immunohistochemistry and western blotting. SAH-induction, regardless of confounding pathologies, was independent from type of technique (p=0.679). There was no significant difference concerning case fatality rate (classic: 40%; modified: 20%; p=0.213). Successful induction of SAH without collateral ICH or SDH was possible in 40% with the classic and in 86.7% with the modified technique (p=0.008). Peak ICP levels differed significantly between the two groups (classic: 94 +/- 23 mmHg; modified: 68 +/- 19 mmHg; p=0.003). Evidence of early cellular stress response and activation of apoptotic pathways 6 h after SAH was demonstrated. The extent of stress response is not dependent on type of technique. Both tested techniques successfully produce SAH including activation of an early stress response and apoptotic pathways in the hippocampal tissue. However, the induction of SAH with less confounding pathologies was more frequently achieved with the modified tungsten wire technique.

Introduction The established neuroprotective property of the sex steroid precursor dehydroepiandrosterone-sulfate (DHEAS) has not yet been investigated in the context of aneurysmal subarachnoid hemorrhage (aSAH). The influence of DHEAS on inflammatory response resulting in modulation of interleukin 6 (IL-6) synthesis has been shown. Here, we evaluate DHEAS serum levels after aSAH (day 0–14) and levels of IL-6 related to functional outcome at discharge and at six months. Methods A complete data set (DHEAS and IL-6 serum levels for days 0, 1, 4, 7, 10 and 14 after aSAH) and outcome assessment at discharge according to modified Rankin Scale score (mRS) was available for 53 patients of the initially screened cohort ( n = 109). Outcome assessment six months after aSAH was obtained from 41 patients. Logarithmized levels of DHEAS and IL-6 were related to dichotomized functional outcome either assessed at discharge or at six months. A mixed between-within subjects ANOVA was applied for statistical analysis (SPSS 21.0). Results DHEAS and IL-6 levels across time were related to functional outcome. Regarding outcome assessment at discharge and at six months after aSAH, DHEAS levels (transformed to square root for statistical purposes) were considerably higher in patients with favorable outcome (mRS 0–2) ( p = .001; p = .020). Inversely, in patients with favorable outcome either at discharge or six months after aSAH, lower IL-6 levels (logarithmized for statistical purposes) were observed across time (both p < .001). Conclusion We provide new evidence that DHEAS is associated with protective properties resulting in improvement of functional outcome after aSAH, possibly by influencing the inflammatory response after aSAH shown in the decreasing IL-6 serum levels. But the results for outcome six months after SAH are limited due to a high drop-out rate.

Argon belongs to the group of noble gases, which are regarded as chemically inert. Astonishingly some of these gases exert biological properties and during the last decades more and more reports demonstrated neuroprotective and organoprotective effects. Recent studies predominately use in vivo or in vitro models for ischemic pathologies to investigate the effect of argon treatment. Promising data has been published concerning pathologies like cerebral ischemia, traumatic brain injury and hypoxic ischemic encephalopathy. However, models applied and administration of the therapeutic gas vary. Here we provide a systematic review to summarize the available data on argon’s neuro- and organoprotective effects and discuss its possible mechanism of action. We aim to provide a summary to allow further studies with a more homogeneous setting to investigate possible clinical applications of argon.

•Inflammatory response is an early and common phenomenon after aneurysmal subarachnoid hemorrhage (aSAH).•We assessed various inflammatory parameters at admission related to functional outcome at discharge and six months after aSAH.•High drop-out rate hinders interpretation for outcome six months after aSAH.•After multivariate analysis, the only remaining parameter with relevance for outcome was serum IL-6.•LIF is involved in neuroinflammatory response after aSAH. Early brain injury after aneurysmal subarachnoid hemorrhage (aSAH) comprises a pronounced neuroinflammatory reaction. Nevertheless, its relevance for functional outcome and its role as outcome predictor remains uncertain. We evaluated the relationship of various early inflammatory parameters regarding functional outcome according to the modified Rankin Scale score (mRS) at discharge (primary objective) and six months after aSAH. A total of 81 patients (63% female) with a mean age of 53.8±13.2 years were included. At admission clinical data and various inflammatory parameters in serum and – wherever applicable – cerebrospinal fluid (CSF) of patients after aSAH were assessed. Outcome was evaluated according to dichotomized mRS at discharge and six months after aSAH (unfavorable outcome: mRS 3–6). Univariate and thereafter multivariate logistic regression analyses were performed using SAS 9.2. Elevated levels of interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in serum and CSF were related to unfavorable outcome at discharge (p<0.05; univariate analyses). IL-6 remains the only parameter relevant for outcome applying a multivariate model including the relevant baseline characteristics. Six months after aSAH no significant correlation was found regarding the outcome, most likely due to the high drop-out rate (27%). A pronounced rise of LIF serum and CSF levels after aSAH was observed. Higher early IL-6 serum levels after aSAH are associated with poor outcome at discharge. In addition, involvement of LIF in the early inflammatory reaction after aSAH has been demonstrated.

Traumatic brain injury (TBI) contributes to death and disability, resulting in an enormous individual and socio-economic challenges. Despite huge efforts, there are still controversies on treatment strategies and early outcome estimation. We evaluate current randomized controlled trials (RCTs) on TBI according to their fulfillment of the CONSORT (Consolidated Statement of Reporting Trials) statement’s criteria as a marker of transparency and the quality of study planning and realization. A PubMed search for RCTs on TBI (January 2014–December 2019) was carried out. After screening of the abstracts (n = 1.926), the suitable full text manuscripts (n = 72) were assessed for the fulfillment of the CONSORT criteria. The mean ratio of consort statement fulfillment was 59% (±13%), 31% of the included studies (n = 22) complied with less than 50% of the CONSORT criteria. Citation frequency was moderately related to ratio of CONSORT item fulfillment (r = 0.4877; p < 0.0001) and citation frequency per year (r = 0.5249; p < 0.0001). The ratio of CONSORT criteria fulfillment was associated with the impact factor of the publishing journal (r = 0.6428; p < 0.0001). Essential data for study interpretation, such as sample size determination (item 7a), participant flow (item 13a) as well as losses and exclusions (item 13b), were only reported in 53%, 60% and 63%, respectively. Reporting and methodological aspects in RCTs on TBI still may be improved. Thus, the interpretation of study results may be hampered due to methodological weaknesses.