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IntroductionClassical deep learning research requires lots of centralised data. However, data sets are often stored at different clinical centers, and sharing sensitive patient data such as brain images is difficult. In this manuscript, we investigated the feasibility of federated learning, sending models to the data instead of the other way round, for research on brain magnetic resonant images of people with multiple sclerosis (MS).MethodsUsing transfer learning on a previously published brain age model, we trained a model to decode performance on the symbol digit modalities test (SDMT) of patients with MS from structural T1 weighted MRI. Three international centers in Brussels, Greifswald and Prague participated in the project. In Brussels, one computer served as the server coordinating the FL project, while the other served as client for model training on local data (n=97). The other two clients were Greifswald (n=104) and Prague (n=100). Each FL round, the server sent a global model to the clients, where its fully connected layer was updated on the local data. After collecting the local models, the server applied a weighted average of two randomly picked clients, yielding a new global model.ResultsAfter 22 federated learning rounds, the average validation loss across clients reached a minimum. The model appeared to have learned to assign SDMT values close to the mean with a mean absolute error of 9.04, 10.59 and 10.71 points between true and predicted SDMT on the test data sets of Brussels, Greifswald and Prague respectively. The overall test MAE across all clients was 10.13 points.ConclusionFederated learning is feasible for machine learning research on brain MRI of persons with MS, setting the stage for larger transfer learning studies to investigate the utility of brain age latent representations in cognitive decoding tasks.

The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy.From 3-T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver-operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients.Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p lt; 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p lt; 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p lt; 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p lt; 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67-0.91]) in discriminating between MSE and MS patients.High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS.

Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and functional interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

BACKGROUND AND PURPOSE: Data from neuro-imaging techniques allow us to estimate a brain's age. Brain age is easily interpretable as 'how old the brain looks' and could therefore be an attractive communication tool for brain health in clinical practice. This study aimed to investigate its clinical utility by investigating the relationship between brain age and cognitive performance in multiple sclerosis (MS). METHODS: A linear regression model was trained to predict age from brain magnetic resonance imaging volumetric features and sex in a healthy control dataset (HC_train, n = 1673). This model was used to predict brain age in two test sets: HC_test (n = 50) and MS_test (n = 201). Brain-predicted age difference (BPAD) was calculated as BPAD = brain age minus chronological age. Cognitive performance was assessed by the Symbol Digit Modalities Test (SDMT). RESULTS: Brain age was significantly related to SDMT scores in the MS_test dataset (r = -0.46, p

Introduction: Organ preservation through ex-vivo normothermic perfusion (EVNP) with albumin-derived perfluorocarbon-based artificial oxygen carriers (A-AOCs) consisting of albumin-derived perfluorodecalin-filled nanocapsules prior to transplantation would be a promising approach to avoid hypoxic tissue injury during organ storage. Methods: The kidneys of 16 rats underwent EVNP for 2 h with plasma-like solution (5% bovine serum albumin, Ringer-Saline, inulin) with or without A-AOCs in different volume fractions (0%, 2%, 4%, or 8%). Cell death was determined using TdT-mediated dUTP-biotin nick end labeling (TUNEL). Aspartate transaminase (AST) activity in both perfusate and urine as well as the glomerular filtration rate (GFR) were determined. The hypoxia inducible factors 1α and 2α (HIF-1α und -2α) were quantified in tissue homogenates. Results: GFR was substantially decreased in the presence of 0%, 2%, and 8% A-AOC but not of 4%. In accordance, hypoxia-mediated cell death, as indicated by both AST activity and TUNEL-positive cells, was significantly decreased in the 4% group compared to the control group. The stabilization of HIF-1α and 2α decreased with 4% and 8% but not with 2% A-AOCs. Conclusion: The dosage of 4% A-AOCs in EVNP was most effective in maintaining the physiological renal function.

The aim of this study is to analyze the long-term quality of life after surgery of cavernoma. A monocentric retrospective study was conducted on 69 patients with cavernoma treated microsurgically between 2000 and 2016. The eloquence was adopted from Spetzler-Martin definition. A most recent follow-up was elicited between 2017 and 2019, in which the quality of life (QoL) was evaluated with the Short Form-12 questionnaire (SF12). Forty-one lesions were in eloquent group (EG), 22 in non-eloquent group (NEG), 3 in orbit, and 3 in the spinal cord. Postoperative worsening of the modified Rankin scale (mRS) occurred in 19.5% of cases in EG versus 4.5% in NEG. After a mean follow-up of 6.5 years (SD 4.6), the neurological status was better or unchanged compared to baseline in 85.4% of EG and 100% of NEG. Regarding QoL assessment of 44 patients (EG n = 27, NEG n = 14) attended the last follow-up. Patients after eloquent cavernoma resection reported a non-inferior QoL in most SF12 domains (except for physical role) compared to NEG. However, they reported general health perception inferior to norms, which was affected by the limited physical and emotional roles. At a late follow-up, the surgical morbidity was transient in the NEG and mostly recovered in the EG. The QoL comparison between eloquent and non-eloquent cavernomas created interesting and new data after prolonged follow-up. These results add value for decision-making as well as patient counseling for future encountered cases. Preoperative evaluation of QoL is recommended for future studies to assess QoL dynamics.

ZusammenfassungAußerhalb der Regelarbeitszeit wird der Präsenzdienst in den meisten Krankenhäusern von Weiterbildungsassistenten geleistet. Sie sind gut beraten, einerseits die wichtigsten Krankheitsbilder zu kennen, die in dieser Übersichtsarbeit dargestellt werden, und andererseits die Fälle, die sie nicht lösen können, an ihren Hintergrund weiterzuleiten.

Objective To describe unique indications for covered stent grafts in trauma-associated cerebrovascular injuries. Patients Between 2006 and 2018, five patients with cerebrovascular injuries were treated with a covered stent graft. We present a retrospective analysis of technique and outcomes. Results In all cases stent deployment was successful. Endoleaks occurred in two cases requiring additional transvenous embolization of a carotid cavernous fistula (CCF) in one patient. Two cases of in-stent thrombosis were observed during intervention and 2 days postintervention in a patient with a long-segment dissection of the internal carotid artery (ICA) and another patient with a contained ICA rupture, both of which could not be prepared with dual antiplatelet therapy. Intravenous heparin and intra-arterial tirofiban dissolved in-stent thrombosis efficiently. One CCF and an iatrogenic vertebral artery injury were covered adequately with GraftMaster stent grafts. Conclusion Patient selection with regard to individual anatomy and the site of vascular lesions is essential for an uncomplicated deployment of covered stent grafts and the success of therapy. Management of dual antiplatelet therapy, anticoagulation, and an escalation of medication in cases of in-stent thrombosis require expertise, a strict therapeutic regime, and an evaluation of individual risks in polytraumatized patients.

Bovine serum albumin (BSA)-coated haemoglobin (Hb)-microcapsules prepared by co-precipitation of Hb and MnCO3may present an alternative type of artificial blood substitute. Prepared microcapsules were analysed by Scanning electron microscopy (SEM) and Respirometry, cytotoxicity was evaluated by addition of microcapsules to murine fibroblast-derived cell line L929 (American Type Culture Collection, NCTC clone 929 of strain L). The capsules come along with a mean diameter of approximately 0.6 μm and a mean volume of 1.13 ∙ 10−19L, thus an average human red blood cell with a volume of 9 ∙ 10−14L is about 800,000 times bigger. Hb-microcapsules are fully regenerable by ascorbic acid and maintain oxygen affinity because oxygen is able to pass the BSA wall of the capsules and thereby binding to the ferrous iron of the haemoglobin entity. Therefore, these microcapsules present a suitable type of potential artificial haemoglobin-based oxygen carrier (HbOC).

This work aimed at the development of a stable albumin-perfluorocarbon (o/w) emulsion as an artificial oxygen carrier suitable for clinical application. So far, albumin-perfluorocarbon-(o/w) emulsions have been successfully applied in preclinical trials. Cross-linking a variety of different physical and chemical methods for the characterization of an albumin-perfluorocarbon (PFC)-(o/w) emulsion was necessary to gain a deep understanding of its specific emulsification processes during high-pressure homogenization. High-pressure homogenization is simple but incorporates complex physical reactions, with many factors influencing the formation of PFC droplets and their coating. This work describes and interprets the impact of albumin concentration, homogenization pressure, and repeated microfluidizer passages on PFC-droplet formation; its influence on storage stability; and the overcoming of obstacles in preparing stable nanoemulsions. The applied methods comprise dynamic light scattering, static light scattering, cryo- and non-cryo-scanning and transmission electron microscopies, nuclear magnetic resonance spectroscopy, light microscopy, amperometric oxygen measurements, and biochemical methods. The use of this wide range of methods provided a sufficiently comprehensive picture of this polydisperse emulsion. Optimization of PFC-droplet formation by means of temperature and pressure gradients results in an emulsion with improved storage stability (tested up to 5 months) that possibly qualifies for clinical applications. Adaptations in the manufacturing process strikingly changed the physical properties of the emulsion but did not affect its oxygen capacity.

Background: High-impact trauma frequently leads to injuries of the orbit, but literature focusing on the viscerocranium rather than the neurocranium is underrepresented. Methods: Retrospective cohort study (2006–2014) at an urban level 1 trauma center assessing the frequency and typical patterns of orbital injuries on whole-body computed tomography (WBCT) with maxillofacial multi-slice CT (MSCT) after severe trauma. (1) Screening of consecutive WBCT cases for dedicated maxillofacial MSCT. (2) Examination by two independent experts’ radiologists for (peri-/)orbital injuries. (3) Case review for trauma mechanisms. Results: 1061 WBCT were included revealing 250 (23.6%) patients with orbital injuries. Less than one-quarter (23.3%) of patients showed osseous and 9.5% showed soft tissue injuries. Combined osseous and soft tissue lesions were present in 39.2% of orbital injuries, isolated soft tissue injuries were rare. Single- or two-wall fractures of the orbit were prevalent, and the orbital floor was affected in 67% of fractures. Dislocated extraocular muscles (44.6%), deformation of the ocular globe (23.8%), and elongation of the optic nerve (12.9%) were the most frequently soft tissue findings. Vascular trauma was suspected in 15.8% of patients. Conclusions: Orbital trauma was confirmed in 23.6% of cases with suspected facial injuries after severe trauma. Concomitant soft tissue injuries should be excluded explicitly in cases with orbital fractures to prevent loss of vision or ocular motility.

Background and Purpose: T lymphocytes contribute to secondary brain damage after stroke. It has not been fully investigated whether this contribution is caused by antigen-specific or antigen-nonspecific activation of T lymphocytes. Lymphocytes from Nur77 GFP transgenic mice express a fluorescent protein upon activation via the TCR (T-cell receptor), allowing the differentiation of activation mode in a natural repertoire of immune cells and antigens. Methods: Middle cerebral artery occlusion or sham surgery was performed, and T-lymphocyte activation was analyzed by flow cytometry in the brain, spleen, and blood 16 hours, 2 days, 3 days, 4 days, and 7 days after surgery. Results: Ipsilateral hemispheric T-lymphocyte invasion peaked on day 4 poststroke. Here, we observed PD-1 (programmed cell death protein 1) expression on almost all invading T lymphocytes, while CD25 expression was low. CD25+, CD69+, or PD-1+ T lymphocytes predominantly displayed antigen-specific activation; the opposite was observed for T lymphocytes isolated from the blood. A mixed activation that favored antigen-specific activation was observed in the spleen. PD-1 was upregulated within the brain, whereas CD25 was not. Antigen-specific T lymphocytes home to the brain, while antigen-nonspecifically activated cells remain within the blood. Conclusions: Our data clearly demonstrate antigen-specific activation of T lymphocytes infiltrating ischemic brain lesions in stroke. The high expression of inhibitory PD-1 and low expression of CD25 on activated T lymphocytes in the brain most likely reflect immunosuppressive mechanisms.

Background This study aimed to prospectively investigate patients’ satisfaction with briefings before computed tomography (CT) examinations, determine feasibility, and identify factors influencing patient satisfaction independent of patient and physician characteristics. Methods One hundred sixty patients received information by a radiologist prior to contrast-enhanced CT examinations in an open, prospective, two-center, cross-sectional study (including the introduction of the radiologist, procedure, radiation exposure, possible side effects, and alternatives). Afterwards, patients and radiologists evaluated the briefing using a standardized questionnaire. Additionally, factors such as age, socioeconomic status, inpatient/outpatient status, length of the radiologist’s professional experience, duration of the briefing, clarity of the radiologist’s explanations as perceived by patients, and the duration of communication were obtained in this questionnaire. Subsequently, three classes of influencing factors were defined and entered stepwise into a hierarchical regression. Results Patient satisfaction ratings differed significantly by type of hospitalization, perceived type of communication, and patient gender. Hierarchical regression analysis revealed that perceived clarity was the strongest predictor of patients’ satisfaction when controlling for the patient and physician characteristics. Conclusions Patients appeared to be satisfied with the briefing prior to CT examination. The mean briefing time (2 min 35 s) seemed feasible. Patients’ demographics influenced satisfaction. To improve patients’ satisfaction with briefings before contrast-enhanced CT, radiologists should aim to clarify their communication.

To examine the prevalence of the so-called bovine aortic arch variation (common origin of the brachiocephalic trunk and the left common carotid artery) in embolic stroke patients, compared with a control group. Aortic arch branching patterns were retrospectively evaluated in 474 individuals with (n = 152) and without (n = 322) acute embolic stroke of the anterior circulation. Contrast-enhanced CT scans of the chest and neck (arterial contrast phase, 1–2-mm slice thickness) were used to evaluate aortic arch anatomy. The stroke cohort included 152 patients who were treated for embolic strokes of the anterior circulation between 2008 and 2018. A total of 322 randomly selected patients who had received thoracic CT angiographies within the same time frame were included as a control group. With a prevalence of 25.7%, the bovine aortic arch variant was significantly more common among patients suffering from embolic strokes, compared with 17.1% of control patients (p = 0.039, OR = 1.67, 95%CI = 1.05–1.97). Stroke patients were more likely to show the bovine arch subtype B (left common carotid artery originating from the brachiocephalic trunk instead of the aortic arch) (10.5% vs. 5.0%, p = 0.039, OR = 2.25, 95%CI = 1.09–4.63), while subtype A (V-shaped common aortic origin of the brachiocephalic trunk and the left carotid) was similarly common in both groups. There was no significant difference regarding the frequency of other commonly observed variant branching patterns of the aortic arch. The bovine aortic arch, particularly the bovine arch subtype B, was significantly more common among embolic stroke patients. This might be due to altered hemodynamic properties within the bovine arch.

Background and Purpose— The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods— Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results— Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions— For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.

(1) Background: We aimed to compare the accuracy of after-hours CT reports created in a traditional in-house setting versus a teleradiology setting by assessing the discrepancy rates between preliminary and final reports. (2) Methods: We conducted a prospective study to determine the number and severity of discrepancies between preliminary and final reports for 7761 consecutive after-hours CT scans collected over a 21-month period. CT exams were performed during on-call hours and were proofread by an attending the next day. Discrepancies between preliminary and gold-standard reports were evaluated by two senior attending radiologists, and differences in rates were assessed for statistical significance. (3) Results: A total of 7209 reports were included in the analysis. Discrepancies occurred in 1215/7209 cases (17%). Among these, 433/7209 reports (6%) showed clinically important differences between the preliminary and final reports. A total of 335/5509 of them were in-house reports (6.1%), and 98/1700 were teleradiology reports (5.8%). The relative frequencies of report changes were not significantly higher in teleradiology. (4) Conclusions: The accuracy of teleradiology reports was not inferior to that of in-house reports, with very similar clinically important differences rates found in both reporting situations.

Objective: To analyze the long-term quality of life after surgery of cavernoma.Methods: A monocentric retrospective study was conducted on 69 patients with cavernoma treated microsurgically between 2000 and 2016. The eloquence was adopted from Spetzler-Martin definition. A most recent follow-up was elicited between 2017 and 2019, in which the quality of life (QoL) was evaluated with the Short Form-12 questionnaire (SF12).Results: 41 lesions were in eloquent group (EG), 22 in non-eloquent group (NEG), 3 in orbit and 3 in the spinal cord. Postoperative worsening of the modified Rankin scale (mRS) occurred in 19.5% of cases in EG versus 4.5% in NEG. After a mean follow-up of 6.5 years, the neurological status was better or unchanged compared to baseline in 85.4% of EG and 100% of NEG. 44 patients (EG n =27, NEG n = 14) attended the last follow-up. The EG had mostly comparable QoL results matched to NEG except for the physical role (RP). The study population when compared to the norms, did well on only half of the parameters of SF12. Yet, the general health (GH), vitality, physical (RP) and emotional roles (RE) were significantly inferior.Conclusion: At a late follow-up, the surgical morbidity was transient in the NEG and mostly recovered in the EG. Regarding QoL, Patients after eloquent cavernoma resection reported a non-inferior QoL in most SF12 domains (except for physical role) compared to NEG. However, they reported general health perception inferior to norms, which was affected by the limited physical and emotional roles.

Addictive drugs are responsible for mass killing. Neither persons with addiction nor the general populace seem conscious of the malevolence of governments and drug dealers working together. How could this be? What is the place of psychoanalysis in thinking about deaths from addiction and in responding to patients with addiction? To answer these questions, we revise concepts of SEEKING, drive, instinct, pleasure, and unpleasure as separable. We review the neurobiological mechanism of cathexis. We discuss how addictive drugs take over the will by changing the SEEKING system. We review how opioid tone in the central nervous system regulates human relationships and how this endogenous hormonal system is modified by external opioid administration. We differentiate the pleasure of relatedness from the unpleasure of urgent need including the urgent need for drugs. We show how addictive drug-induced changes in the SEEKING system diminish dopaminergic tone, reducing the motivation to engage in the pursuit of food, water, sex, sleep, and relationships in favor of addictive drugs. With this neuropsychoanalytic understanding of how drugs work, we become more confidently conscious of our ability to respond individually and socially.

This work describes a general method for the encapsulation of enzymes with albumin as wall material and the enzyme catalase as prime example. Care was taken for the preparation of biochemically active sub-micrometer particles in order to prevent oxygen toxicity induced by artificial oxygen carriers of any type. In cell culture experiments, capsules containing catalase did not exhibit any harmful activities in the absence of peroxides. In the presence of hydrogen peroxide application of low and medium dosed capsules below 0.05 vol% (final concentration 0.001 vol%) even increased the cell damaging process. However, a higher dosage of capsules (>0.05 vol%) prevented completely cellular disruption induced by 5 mM hydrogen peroxide and decreased up to 90% of cellular damage at higher peroxide concentrations. These results demonstrated that encapsulated catalase was enzymatically active and the over-all activity of prepared catalase capsules was determined to be >1900 U mL(-1) vol%(-1).

This work describes a general method for the encapsulation of enzymes with albumin as wall material and the enzyme catalase as prime example. Care was taken for the preparation of biochemically active sub-micrometer particles in order to prevent oxygen toxicity induced by artificial oxygen carriers of any type. In cell culture experiments, capsules containing catalase did not exhibit any harmful activities in the absence of peroxides. In the presence of hydrogen peroxide application of low and medium dosed capsules below 0.05 vol% (final concentration 0.001 vol%) even increased the cell damaging process. However, a higher dosage of capsules (> 0.05 vol%) prevented completely cellular disruption induced by 5 mM hydrogen peroxide and decreased up to 90% of cellular damage at higher peroxide concentrations. These results demonstrated that encapsulated catalase was enzymatically active and the over-all activity of prepared catalase capsules was determined to be > 1000 U ∙ mL−1 ∙ vol%−1.

Background Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated with a high mortality of approximately 50% to 90%. In previous studies, the single application of β-alanine or aprotinin caused an ameliorated intestinal damage but without any systemic effects. Methods To analyze the combined effect of β-alanine and aprotinin on acute ischemia and reperfusion of the small intestine, a model with anesthetized rats was used. Ischemia and reperfusion were initiated by occluding and reopening the superior mesenteric artery. After 120 min of ischemia and 180 min of reperfusion, the intestine was analyzed for tissue damage, the activity of the saccharase, and accumulation of granulocytes. In addition, systemic and metabolic as well as inflammatory parameters were measured in blood at certain points in time. Results The combination of β-alanine and aprotinin resulted in a clearly stabilized mean arterial blood pressure and blood glucose level during the reperfusion period. Furthermore, the combined administration resulted in significantly reduced tissue damage parameters, cytokine and cell-free hemoglobin concentrations in blood plasma. In addition, the damage to the small intestine was significantly attenuated, so that the animals ultimately survived the entire test period because of the administration of both substances. Conclusions Overall, the simultaneous application of both substances leads to a synergistic protection without the occurrence of undesirable side effects. The combined usage of β-alanine and aprotinin can be seen as a promising approach to inhibit the onset of acute mesenteric ischemia.

Artificial blood for clinical use is not yet available therefore, we previously developed artificial oxygen carriers (capsules) and showed their functionality in vitro and biocompatibility in vivo. Herein, we assessed the functionality of the capsules in vivo in a normovolemic hemodilution rat-model. We stepwise exchanged the blood of male Wistar-rats with medium either in the presence of capsules (treatment) or in their absence (control). We investigated tissue hypoxia thoroughly through online biomonitoring, determination of enzyme activity and pancreatic hormones in plasma, histochemical and immunohistochemical staining of small intestine, heart, liver and spleen as well as in situ hybridization of kidneys. After hemodilution, treated animals show higher arterial blood pressure and have a stable body temperature. Additionally, they show a more stable pH, a higher oxygen partial pressure (pO₂), and a lower carbon dioxide partial pressure (pCO₂). Interestingly, blood-glucose-levels drop severely in treated animals, presumably due to glucose consumption. Creatine kinase values in these animals are increased and isoenzyme analysis indicates the spleen as origin. Moreover, the small intestine of treated animals show reduced hypoxic injury compared to controls and the kidneys have reduced expression of the hypoxia-inducible erythropoietin mRNA. In conclusion, our capsules can prevent hypoxic tissue damage. The results provide a proof of concept for capsules as adequate erythrocyte substitute. OA Förderung 2020

For three decades, studies have demonstrated the therapeutic efficacy of perfluorocarbon (PFC) in reducing the onset of decompression trauma. However, none of these emulsion-based preparations are accepted for therapeutic use in the western world, mainly because of severe side effects and a long organ retention time. A new development to guarantee a stable dispersion without these disadvantages is the encapsulation of PFC in nanocapsules with an albumin shell. Purpose Newly designed albumin-derived perfluorocarbon-based artificial oxygen carriers (A-AOC) are used in a rodent in vivo model as a preventive therapy for decompression sickness (DCS). Methods Thirty-seven rats were treated with A-AOC (n = 12), albumin nanocapsules filled with neutral oil (A-O-N, n = 12), or 5% human serum albumin solution (A-0-0, n = 13) before a simulated dive. Eleven rats, injected with A-AOC, stayed at normal pressure (A-AOC surface). Clinical, laboratory, and histological evaluations were performed. Results The occurrence of DCS depended on the treatment group. A-AOC significantly reduced DCS appearance and mortality. Furthermore, a significant improvement of survival time was found (A-AOC compared with A-0-0). Histological assessment of A-AOC-dive compared with A-0-0-dive animals revealed significantly higher accumulation of macrophages, but less blood congestion in the spleen and significantly less hepatic circulatory disturbance, vacuolization, and cell damage. Compared with nondiving controls, lactate and myoglobin showed a significant increase in the A-0-0- but not in the A-AOC-dive group. Conclusion Intravenous application of A-AOC was well tolerated and effective in reducing the occurrence of DCS, and animals showed significantly higher survival rates and less symptoms compared with the albumin group (A-0-0). Analysis of histological results and fast reacting plasma parameters confirmed the preventive properties of A-AOC.

Self-cleavage of proteins is an important natural process that is difficult to control externally. Recently a new mechanism for the accelerated autolysis of trypsin was discovered involving polyanionic template polymers; however it relies on unspecific interactions and is inactive at elevated salt loads. We have now developed affinity copolymers that bind to the surface of proteases by specific recognition of selected amino acid residues. These are highly efficient trypsin inhibitors with low nanomolar IC50 levels and operate at physiological conditions. In this manuscript we show how these affinity copolymers employ the new mechanism of polymer-assisted self-digest (PAS) and act as a template for multiple protease molecules. Their elevated local concentration leads to accelerated autolysis on the accessible surface area and shields complexed areas. The resulting extremely efficient trypsin inhibition was studied by SDS-PAGE, gel filtration, CD, CZE and ESI-MS. We also present a simple theoretical model that simulates most experimental findings and confirms them as a result of multivalency and efficient reversible templating. For the first time, mass spectrometric kinetic analysis of the released peptide fragments gives deeper insight into the underlying mechanism and reveals that polymer-bound trypsin cleaves much more rapidly with low specificity at predominantly uncomplexed surface areas. CA Schrader

Protective effects by exogenous sodium pyruvate already have been described in various experimental models of injury, among others during intestinal ischemia-reperfusion injury, hemorrhagic shock, and shock secondary to systemic inflammation (endotoxemic shock). Low doses of sodium pyruvate reduced signs of inflammation, enhanced systemic blood pressure, and ameliorated metabolic acidosis when administered in a prophylactic manner during endotoxemic shock. In the present study, we investigated whether low-dosed infusions of sodium pyruvate exhibited beneficial effects when applied therapeutically after the induction of systemic inflammation. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h over a period of 360 min to induce systemic inflammation in male Wistar rats. Sodium pyruvate (single dose 50 mg/kg × 15 min) was administered intravenously 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic/vital parameters (e.g., systemic blood pressure and breathing rate) and blood/plasma parameters (e.g., acid-base parameters; electrolytes; glucose and lactate concentration; hemolysis; aminotransferase activities; and parameters of coagulation) were determined in regular intervals. Lipopolysaccharide infusion led to metabolic acidosis, hypoglycemia, electrolyte as well as hemostatic disturbances, and hemolysis. Except for the acid-base status (amelioration of metabolic acidosis) and the plasma chloride concentration (reduction of hyperchloremia), the additional infusion of sodium pyruvate failed in significantly improving lipopolysaccharide-dependent alterations (e.g. vital, blood and plasma parameters). Protective effects of a delayed administration of the metabolizable anion pyruvate during systemic inflammation, hence, are limited to its function as alkalizer to counteract metabolic acidosis.

Johannes Jägers,1 Stephan Brauckmann,2 Michael Kirsch,1 Katharina Effenberger-Neidnicht1,3 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany; 3Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany Background: Systemic inflammation alters energy metabolism. A sufficient glucose level, however, is most important for erythrocytes, since erythrocytes rely on glucose as sole source of energy. Damage to erythrocytes leads to hemolysis. Both disorders of glucose metabolism and hemolysis are associated with an increased risk of death. The objective of the study was to investigate the impact of intravenous glucose on hemolysis during systemic inflammation.Materials and methods: Systemic inflammation was accomplished in male Wistar rats by continuous lipopolysaccharide (LPS) infusion (1 mg LPS/kg and h, 300 min). Sham control group rats received Ringer’s solution. Glucose was supplied moderately (70 mg glucose/kg and h) or excessively (210 mg glucose/kg and h) during systemic inflammation. Vital parameters (eg, systemic blood pressure) as well as blood and plasma parameters (eg, concentrations of glucose, lactate and cell-free hemoglobin, and activity of lactate dehydrogenase) were measured hourly. Clot formation was analyzed by thromboelastometry.Results: Continuous infusion of LPS led to a so-called post-aggression syndrome with disturbed electrolyte homeostasis (hypocalcemia, hyperkalemia, and hypernatremia), changes in hemodynamics (tachycardia and hypertension), and a catabolic metabolism (early hyperglycemia, late hypoglycemia, and lactate formation). It induced severe tissue injury (significant increases in plasma concentrations of transaminases and lactate dehydrogenase), alterations in blood coagulation (disturbed clot formation), and massive hemolysis. Both moderate and excessive glucose supply reduced LPS-induced increase in systemic blood pressure. Excessive but not moderate glucose supply increased blood glucose level and enhanced tissue injury. Glucose supply did not reduce LPS-induced alterations in coagulation, but significantly reduced hemolysis induced by LPS.Conclusion: Intravenous glucose infusion can diminish LPS-related changes in hemodynamics, glucose metabolism, and, more interestingly, LPS-induced hemolysis. Since cell-free hemoglobin is known to be a predictor for patient’s survival, a reduction of hemolysis by 35% only by the addition of a small amount of glucose is another step to minimize mortality during systemic inflammation. Keywords: lipopolysaccharide, sepsis, erythrocytes, red blood cells, cell-free hemoglobin, glucose metabolism

A growing number of patients seek medical care outside their country of residence. More mobile populations that seek access to information about international medical treatment alternatives have influenced a booming medical tourism industry. The countries engaged in medical tourism are ranging from countries with high cost of medical care like the USA and Japan to medium cost countries, like Singapore and Germany to low cost countries like India and Poland. Engaging in medical tourism by attracting patients internationally involves a process of internationalization of healthcare. Countries have commonly gone through different stages in their approach to medical tourism which has matured the industry. A first stage in the internationalization is encouraging regular travelers to consider treatment options in a destination. A second stage involves the signing of agreements with healthcare systems in countries that can remit patients abroad. A third stage is to develop an integrated organization taking patients all needs before, during and after treatment into consideration. Our study is based on more than 80 in-depth interviews as well as secondary data from countries in Europe, Asia and North America. Much lower medical treatment prices in many Asian and Latin American countries act as driving forces for medical tourism attracting Western medical tourists to seek treatment in those countries. Patienter utan gränser – Medicinturismens utmaning för svensk sjukvård

Until today, artificial oxygen carriers have not been reached satisfactory quality for routine clinical treatments. To bridge this gap, we designed albumin-derived perfluorocarbon-based nanoparticles as novel artificial oxygen carriers and evaluated their physico-chemical and pharmacological performance. Our albumin-derived perfluorocarbon-based nanoparticles (capsules), composed of an albumin shell and a perfluorodecalin core, were synthesized using ultrasonics. Their subsequent analysis by physico-chemical methods such as scanning electron-, laser scanning- and dark field microscopy as well as dynamic light scattering revealed spherically-shaped, nano-sized particles, that were colloidally stable when dispersed in 5% human serum albumin solution. Furthermore, they provided a remarkable maximum oxygen capacity, determined with a respirometer, reflecting a higher oxygen transport capacity than the competitor Perftoran®. Intravenous administration to healthy rats was well tolerated. Undesirable effects on either mean arterial blood pressure, hepatic microcirculation (determined by in vivo microscopy) or any deposit of capsules in organs, except the spleen, were not observed. Some minor, dose-dependent effects on tissue damage (release of cellular enzymes, alterations of spleen's micro-architecture) were detected. As our promising albumin-derived perfluorocarbon-based nanoparticles fulfilled decisive physico-chemical demands of an artificial oxygen carrier while lacking severe side-effects after in vivo administration they should be advanced to functionally focused in vivo testing conditions.

Purpose Hydrocephalus is caused by an imbalance of production and absorption of cerebrospinal fluid (CSF) or obstruction of its pathways, resulting in ventricular dilatation and increased intracranial pressure. Imaging plays a crucial role in the diagnosis, differential diagnosis and planning of treatment. Methods This review article presents the different types of hydrocephalus und their typical imaging appearance, describes imaging techniques, and discusses differential diagnoses of the different forms of hydrocephalus. Results and Conclusion Imaging plays a central role in the diagnosis of hydrocephalus. While magnetic resonance (MR) imaging is the first-line imaging modality, computed tomography (CT) is often the first-line imaging test in emergency patients. Key points Citation Format

Inhibition of the key enzyme for DNA quality control, i.e. PARP-1, by synthetic molecular tweezers is demonstrated via a non-competitive mechanism with an IC50 value of 3 µM. Electrophoretic mobility shift assays and molecular docking experiments point to a simultaneous inclusion of lysine side chains in the tweezers cavity and one phosphate arm to the central Zn2+ ion of the zinc finger thereby displacing DNA.Abstract Text, 800-1000 characters.

The aim of this study was to prove whether albumin-derived perfluorocarbon-based nanoparticles (capsules) can operate as a novel artificial oxygen carrier in a rat Langendorff-heart perfusion model. Hearts perfused with capsules showed increased left ventricular pressure and rate pressure product compared to hearts perfused with pure Krebs-Henseleit (KH)-buffer. The capsules prevented the myocardium from functional fail when in their absence a noxious ischemia was observed. Capsules did not change rheological properties of KH-buffer and could repeatedly reload with oxygen. This albumin-derived perfluorocarbon-based artificial oxygen carrier preserved the function of rat hearts due to the transport of oxygen in a satisfactory manner. Because of these positive results, the functionality of the applied capsules should be verified in living animals.