Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry-Endovascular Treatment (GSR-ET) and patients from the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).

BACKGROUND AND PURPOSE: Reperfusion treatment in patients presenting with large vessel occlusion (LVO) and minor neurological deficits is still a matter of debate. We aimed to compare minor stroke patients treated with endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or IVT alone. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) and the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) between June 2015 and December 2019 were analyzed. Minor stroke was defined as National Institutes of Health Stroke Scale (NIHSS) score ≤5, and LVO as occlusion of the internal carotid, carotid-T, middle cerebral, basilar, vertebral or posterior cerebral arteries. GSR-ET and SITS-ISTR IVT-treated patients were matched in a 1:1 ratio using propensity-score (PS) matching. The primary outcome was good functional outcome at 3 months (modified Rankin Scale score 0-2). RESULTS: A total of 272 GSR-ET patients treated with EVT and IVT (age 68.6 ± 14.0 years, 43.4% female, NIHSS score 4 [interquartile range 2-5]) were compared to 272 IVT-treated SITS-ISTR patients (age 69.4 ± 13.7, 43.4% female, NIHSS score 4 [2-5]). Good functional outcome was seen in 77.0% versus 82.9% (p = 0.119), mortality in 5.9% versus 7.9% (p = 0.413), and intracranial hemorrhage in 8.8% versus 12.5% (p = 0.308) of patients in the GSR-ET versus the SITS-ISTR IVT group, respectively. In a second PS-matched analysis, 624 GSR-ET patients (IVT rate 56.7%) and 624 SITS-ISTR patients (IVT rate 100%), good outcome was more often observed in the SITS-ISTR patients (68.2% vs. 80.9%; p < 0.001), and IVT independently predicted good outcome (odds ratio 2.16, 95% confidence interval 1.43-3.28). CONCLUSIONS: Our study suggests similar effectiveness of IVT alone compared to EVT with or without IVT in minor stroke patients. There is an urgent need for randomized controlled trials on this topic.

Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination.

Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of demyelination. This led to strong astrogliosis accompanied by microgliosis and demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.

"Do you Really Believe that There is Something More?" - The Offer of Transcendental Communication by Pastoral Care Workers in German Hospices and Palliative Care Units: A Qualitative Study.

BACKGROUND: Palliative Care also encompasses the dimension of spiritual pain. Pastoral care workers and chaplains are specialists in the provision of spiritual care. Decreasing religious affiliation and increasing spiritual diversification in modern societies raise the question of the function of pastoral care. AIM: The goal of this study is to answer the question of what pastoral care workers can offer to dying residents in hospices and palliative care units. DESIGN: A qualitative interview study was designed to explore the specific perspective of pastoral care workers in a multidisciplinary environment. The study is based on differentiation theory which is particularly well adjusted to reveal differences in perspectives in so called 'holistic' care settings. The reporting follows the COREQ guidelines. SETTING: Problem centered interviews were conducted at five hospices and two palliative care units. RESULTS: Eight pastoral care workers were interviewed (5 Catholic, 3 Protestant, mean age of 58 years). The analysis of the interviews revealed three major themes: (A) Self-positioning in relation to the organization, (B) Offering conversations to patients and relatives, (C) Performing religious rituals. Minor themes were: mediating conflicts between patients, relatives and staff, sensing moods in silence with patients and organizing workshops for staff. CONCLUSION: In modern hospice care, pastoral care workers routinely address the problem of making death more tangible and of answering the unanswerable question of what comes afterwards. Through this, they support dying residents in hospices and palliative care units in dealing with the inexplicability of death.

Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions.

In multiple sclerosis (MS), gray matter pathology is characterized by less pronounced inflammation when compared with white matter lesions. Although regional differences in the cytoarchitecture may account for these differences, the amount of myelin debris in the cortex during a demyelinating event might also be contributory. To analyze the association between myelin debris levels and inflammatory responses, cortical areas with distinct and sparse myelination were analyzed for micro- and astrogliosis before and after cuprizone-induced demyelination in mice. In postmortem tissue of MS patients, leucocortical lesions were assessed for the type and level of inflammation in the cortical and white matter regions of the lesion. Furthermore, mice were injected intracerebrally with myelin-enriched debris, and the inflammatory response analyzed in white and grey matter areas. Our studies show that the magnitude of myelin loss positively correlates with microgliosis in the cuprizone model. In MS, the number of MHC class II expressing cells is higher in the white compared with the grey matter part of leucocortical lesions. Finally, direct application of myelin debris into the corpus callosum or cortex of mice induces profound and comparable inflammation in both regions. Our data suggest that myelin debris is an important variable in the inflammatory response during demyelinating events. Whether myelin-driven inflammation affects neuronal integrity remains to be clarified.

Rescue Revascularisation in Acute Internal Carotid Artery Occlusion with a Super Extended Time Window of More than 48 hours.

Methods: We present the case of a 71-year-old Caucasian male "minor stroke" patient with LVO, good collateral flow via the ophthalmic artery, receiving rescue MT following clinical deterioration after >48 hours. NIHSS and modified Rankin scale (mRS) were used for follow-up and modified treatment in cerebral infarction (mTICI) score for angiographic results. Results: Excellent angiographic result (mTICI 3) and clinical improvement were achieved (NIHSS preintervention 18, on discharge 2 points). 90-day follow-up showed excellent outcome (mRS 1). Conclusions: Late intervention MT should be encouraged when clinical deficit exceeds infarct demarcation. Standardized identification based on clinical and imaging data is required to target critical patients with LVO and low NIHSS, favouring a primary intervention.

Health-related and socio-economic burden of the COVID-19 pandemic in Vienna.

Previous pandemics have rarely affected everyone equally and, so far, the COVID-19 pandemic is no exception. Emerging evidence has shown that incidence rate, hospitalisation rate, and mortality due to COVID-19 are higher among people in lower socio-economic position (SEP). In addition, first investigations indicate that not everyone is equally affected by this pandemic's collateral public health damage. Using a stratified random sample of 1,004 participants living in Vienna, a Central European city with approximately 1.9 million inhabitants, this study analysed the distribution of 10 adverse health-related and socio-economic outcomes attributable to the COVID-19 pandemic across socio-economic strata. To this end, we estimated differences in the incidence rate of these outcomes by SEP and each of its indicators using zero-inflated Poisson and logistic regression models, adjusted for age and gender. Data were collected during first lockdown measures between 27 April and 17 May 2020. Differences in the incidence rate between the two lowest and two highest SEP groups were clearly visible. Participants in the lowest SEP category had a 32.96% higher incidence rate (IRR = 1.333 [95% CI: 1.079-1.639]), and participants in the second lowest SEP category had a 44.69% higher incidence rate (IRR = 1.447 [95% CI: 1.190-1.760]) compared with participants in the highest SEP category. In sum, 6 out of 10 adverse COVID-19-related outcomes were, to a greater or lesser extent, disproportionately experienced by Viennese residents in lower SEP. Inequalities were most visible between income groups and for the outcomes job loss, worsening of the financial situation, and worse mental health. These results strengthen and extend the current evidence on the unequally distributed burden of the COVID-19 pandemic. In light of effect heterogeneity across SEP indicators, we encourage future investigators to pay increased attention to their operationalisation of SEP. Such awareness will help to correctly identify those in most urgent need of supportive polices.

The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells.

Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.

Rapid Diagnosis of Central Nervous System Scedosporiosis by Specific Quantitative Polymerase Chain Reaction Applied to Formalin-Fixed, Paraffin-Embedded Tissue.

Scedosporium (S.) apiospermum is a typical mold causing cerebral abscesses, often after near-drowning. Infections are associated with high morbidity and mortality due to diagnostic challenges including the need for prolonged incubation of cultures. In addition, histopathological differentiation from other filamentous fungi, including Aspergillus fumigatus, may not be possible, excluding early specific diagnosis and targeted therapy. Polymerase chain reaction (PCR) on tissue samples can rapidly identify fungi, leading to an earlier adequate treatment. Due to an extensive spectrum of causative fungi, broad-range PCRs with amplicon sequencing have been endorsed as the best DNA amplification strategy. We herein describe a case with brain abscesses due to S. apiospermum in a 66-year-old immunocompromised female patient. While broad-range PCR failed to identify a fungal pathogen from a cerebral biopsy demonstrating hyaline mold hyphae, specific quantitative PCR (qPCR) identified Scedosporium and ruled out Aspergillus, the most prevalent agent of central nervous system mold infection. A panel of specific qPCR assays, guided by the morphology of fungal elements in tissue or as a multiplex assay, may be a successful molecular approach to identify fungal agents of brain abscesses. This also applies in the presence of negative broad-range fungal PCR, therefore providing diagnostic and therapeutic potential for early specific management and improvement of patient clinical outcome.

Inadequate cytoplasmatic calcium signals in alveolar macrophages after cardiac surgery.

OBJECTIVE AND DESIGN: Patients undergoing cardiac surgery have an elevated risk for pulmonary complications. A dysfunction of alveolar macrophages (AM) might promote postoperative infections. Therefore intracellular calcium [Ca(2+)](i) as an important second messenger in cellular signaling was assessed in AM. MATERIALS AND METHODS: Twelve patients undergoing elective coronary artery bypass graft surgery (CABG) were enrolled in this clinical trial. After anesthesia induction and 2 h after cardiopulomary bypass (CPB) declamping, the bronchoalveolar lavage (BAL) fluid was collected preoperatively from the right middle lobe and postoperatively from the left lingula of the lung. Cell subpopulations and [Ca(2+)](i) signals were assessed via flow cytometry. To express the changes of [Ca(2+)](i) signals the Fluo4/FuraRed-Ratio was used. RESULTS: After surgery the [Ca(2+)](i) baseline in unstimulated AMs were significantly reduced (p < 0.001). A significant signal reduction after fMLP (p = 0.021) and C5a (p = 0.028) stimulation was found in FSC high AMs after surgery, even though all populations showed a trend of less responsiveness. CONCLUSION: We suggest that the reduced [Ca(2+)](i) signaling in postoperative AMs is caused by a reduced coupling to membrane channels. These preliminary data suggest an inadequate [Ca(2+)](i) signal of AM after surgery, which may contribute to a local immune dysfunction in the lung.

Perioperative indocyanine green clearance is predictive for prolonged intensive care unit stay after coronary artery bypass grafting--an observational study.

INTRODUCTION: During cardiac surgery with cardiopulmonary bypass (CPB) haemodilution occurs. Hepatic dysfunction after CPB is a rare, but serious, complication. Clinical data have validated the plasma-disappearance rate of indocyanine green (PDR ICG) as a marker of hepatic function and perfusion. Primary objective of this analysis was to investigate the impact of haemodilutional anaemia on hepatic function and perfusion by the time course of PDR ICG and liver enzymes in elective CABG surgery. Secondary objective was to define predictors of prolonged ICU treatment like decreased PDR ICG after surgery. METHODS: 60 Patients were subjected to normothermic CPB with predefined levels of haemodilution anaemia (haemotacrit (Hct) of 25% versus 20% during CPB). Hepatic function and perfusion was assessed by PDR ICG, plasma levels of aspartate aminotransferase (ASAT) and alpha-GST. Prolonged ICU treatment was defined as treatment >or= 48 hours. RESULTS: Logistic regression analysis showed that all postoperative measurements of PDR ICG (P < 0.01), and the late postoperative ASAT (P < 0.01) measurement were independent risk factors for prolonged ICU treatment. The predictive capacity for prolonged ICU treatment was best of the PDR ICG one hour after admission to the ICU. Furthermore, the time course of PDR ICG as well as ASAT and alpha-GST did not differ between groups of haemodilutional anaemia. CONCLUSIONS: Our study provides evidence that impaired PDR ICG as a marker of hepatic dysfunction and hypoperfusion may be a valid marker of prolonged ICU treatment. Additionally this study provides evidence that haemodilutional anaemia to a Hct of 20% does not impair hepatic function and perfusion. TRIAL REGISTRATION: [ISRCTN35655335].

Investigating attitudinal ambivalence via sequential priming: Evidence for the simultaneous and unintentional activation of opposite evaluations.

This research tested a central assumption of attitudinal ambivalence research: ambivalent attitude objects simultaneously trigger positive and negative evaluations. It further specifies at which stage this activation is likely to produce an evaluative conflict. Experiments 1 to 3 involved 2 evaluative priming paradigms, in which ambivalent stimuli served either as primes or as targets. The Ambivalent Primes Paradigm tested the degree to which the concurrent and unintentional activation of positivity and negativity influences responding to univalent targets. The Ambivalent Targets Paradigm tested the degree to which ambivalent targets entail an evaluative response conflict irrespective of prime valence. Experiments 1 and 2 revealed slower responses on ambivalent trials compared with congruent trials in both paradigms. Employing a longer stimulus onset asynchrony, Experiment 3 attested to the short-lived nature of the joint activation of opposite evaluations triggered by ambivalent primes. In contrast, the deliberate categorization of ambivalent targets was not affected by this procedural variation. Finally, by relying on a valent/neutral categorization task, Experiments 4 and 5 indicate that conflicts triggered by ambivalent stimuli occur at the response selection rather than the exposure stage. Our findings lend original empirical support to the assumption that positivity and negativity are activated simultaneously and unintentionally in ambivalent attitude objects. Moreover, the present research suggests that ambivalence generates a conflict only if the task at hand requires a univalent categorization. We discuss the extent to which the activation of ambivalent attitudes may be automatic and the implications of our findings for dual-process models of attitudes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Prediction of volume response under open-chest conditions during coronary artery bypass surgery.

INTRODUCTION: Adequate fluid loading is the first step of hemodynamic optimization in cardiac patients undergoing surgery. Neither a clinical approach alone nor conventional parameters like central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) are thought to be sufficient for recognizing fluid deficiency or overload. The aim of this study was to evaluate the suitability of CVP, PCWP, global end-diastolic volume index (GEDVI), pulse pressure variation (PPV), and stroke volume variation (SVV) for predicting changes in the cardiac index (CI) and stroke volume index (SVI) after sternotomy. METHODS: In 40 patients, CVP, PCWP, GEDVI, PPV, SVV, and the CI were measured at two points of time. One measurement was performed after inducing anesthesia and one after sternotomy. RESULTS: A significant increase in heart rate, CI, and GEDVI was observed during the study period. CVP, SVV, and PPV decreased significantly. There were no significant correlations between CVP and PCWP and changes in CI. In contrast, GEDVI, SVV, and PPV significantly correlated with CI changes. Only relative changes of GEDVI, SVV, and PPV predicted changes in SVI. CONCLUSION: During cardiac surgery and especially after sternotomy, CVP and PCWP are not suitable for monitoring fluid status. Direct volume measurement like GEDVI and dynamic volume responsive measurements like SVV and PPV may be more suitable for monitoring the volume status of patients, particularly under open-chest conditions.

Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis.

BACKGROUND AND AIMS: Micro-RNAs (miRNAs) have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. Therefore, in the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis. METHODS: We performed a systematic, array-based miRNA expression analysis on serum samples from patients with liver cirrhosis. In functional experiments we evaluated the relationship between alterations of miRNA serum levels and their role in distinct cellular compartments involved in hepatic cirrhosis. RESULTS: The array analysis and the subsequent confirmation by qPCR in a larger patient cohort identified significant alterations in serum levels of miR-513-3p, miR-571 and miR-652, three previously uncharacterized miRNAs, in patients with alcoholic or hepatitis C induced liver cirrhosis. Of these, miR-571 serum levels closely correlated with disease stages, thus revealing potential as a novel biomarker for hepatic cirrhosis. Further analysis revealed that up-regulation of miR-571 in serum reflected a concordant regulation in cirrhotic liver tissue. In isolated primary human liver cells, miR-571 was up-regulated in human hepatocytes and hepatic stellate cells in response to the pro-fibrogenic cytokine TGF-ß. In contrast, alterations in serum levels of miR-652 were stage-independent, reflecting a concordant down-regulation of this miRNA in circulating monocytes of patients with liver cirrhosis, which was inducible by proinflammatory stimuli like bacterial lipopolysaccharide. CONCLUSION: Alterations of miR571 and miR-652 serum levels in patients with chronic liver disease reflect their putative roles in the mediation of fibrogenic and inflammatory processes in distinct cellular compartments involved in the pathogenesis of liver cirrhosis.

Perturbation of endothelial junction proteins by Staphylococcus aureus alpha-toxin: inhibition of endothelial gap formation by adrenomedullin.

Endothelial hyperpermeability is a hallmark of an inflammatory reaction and contributes to tissue damage in severe infections. Loss of endothelial cell-cell adhesion leads to intercellular gap formation allowing paracellular fluid flux. Although Staphylococcus aureus alpha-toxin significantly contributed to staphylococci disease, little is known about its mechanism of endothelial hyperpermeability induction. Here, we demonstrate that in a model of isolated perfused rat ileum discontinuation of capillary vascular-endothelial-cadherin (VE-cadherin) was observed after bolus application of S. aureus alpha-toxin being inhibited by the endogenous peptide adrenomedullin (ADM). In vitro, alpha-toxin exposure induced loss of immunoreactivity of VE-cadherin and occludin in human cultured umbilical vein endothelial cells. Likewise, ADM blocked alpha-toxin-related junctional protein disappearance from intercellular sites. Additionally, cyclic AMP elevation was shown to stabilize endothelial barrier function after alpha-toxin application. Although no RhoA activation was noted after endothelial alpha-toxin exposure, inhibition of Rho kinase and myosin light chain kinase blocked loss of immunoreactivity of VE-cadherin and occludin as well as intercellular gap formation. In summary, stabilization of endothelial junctional integrity as indicated by interendothelial immunostaining might be an interesting approach to stabilize endothelial barrier function in severe S. aureus infections.

Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia.

OBJECTIVE: Acute respiratory failure is a significant complication of severe pneumococcal pneumonia. In a mouse model, we observed early-onset lung microvascular leakage after pulmonary infection with Streptococcus pneumoniae, and we hypothesized that the important virulence factor pneumolysin may be the direct causative agent. DESIGN: Controlled, in vivo, ex vivo, and in vitro laboratory study. SETTING: Laboratory. SUBJECTS: Female mice, 8-12 wks old. INTERVENTIONS: Ventilated and blood-free perfused murine lungs were challenged with recombinant pneumolysin via the airways as well as via the vascular bed. In addition, we analyzed the impact of pneumolysin on electrical cell impedance and hydraulic conductivity of human umbilical vein endothelial cell (HUVEC) and alveolar epithelial cell (A549) monolayers. MEASUREMENTS AND MAIN RESULTS: Aerosolized pneumolysin dose-dependently increased capillary permeability with formation of severe lung edema but did not affect pulmonary vascular resistance. Intravascular pneumolysin caused an impressive dose-dependent increase in pulmonary vascular resistance and in lung microvascular permeability. By immunohistochemistry, pneumolysin was detected mainly in endothelial cells of pulmonary arterial vessels, which concomitantly displayed strong vasoconstriction. Moreover, pneumolysin increased permeability of HUVEC and A549 monolayers. Interestingly, immunofluorescence of endothelial cell monolayers exposed to pneumolysin showed gap formation and moderate stress fiber generation. CONCLUSIONS: Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension.