Trace element and biomarker analyses in serum samples of patients with traumatic spinal cord injury

Hintergrund: Traumatische Rückenmarksschädigungen (TSCI) sind schwerwiegende Verletzungen, welche zum Verlust aller sensiblen und motorischen Funktionen unterhalb des Verletzungsniveaus führen können. Durch primäre und sekundäre Mechanismen wird das betroffene neuronale Gewebe massivem oxidativen Stress ausgesetzt. Die Spurenelemente Selen (Se) und Kupfer (Cu) sind von zentraler Bedeutung für die antioxidative Abwehr. Methodik: Von 2011 bis 2018 wurden in einer prospektiven Beobachtungsstudie des Querschnittzentrums Ludwigshafen von 144 Patient*innen nach TSCI klinische Daten und Blutproben zusammengetragen. Anhand der ASIA Impairment Scale (AIS) erfolgten dabei die Quantifizierung und Schweregradeinteilung (AIS A-D) der resultierenden neurologischen Defizite. Als Remission wurde eine Verbesserung des AIS Scores innerhalb von 3 Monaten definiert und die Patient*innen dementsprechend in eine Remissionsgruppe G1 und eine Nicht-Remissionsgruppe G0 eingeteilt. Als Kontrollgruppe dienten 10 Individuen mit isolierten Wirbelfrakturen ohne neurologische Defizite. Am Institut für Experimentelle Endokrinologie der Charité Universitätsmedizin Berlin erfolgten die Analysen der Spurenelemente mittels Totalreflexions-Röntgenfluoreszenzanalysen (TXRF), der Selenoprotein P (SELENOP) und Ceruloplasmin (CP) Konzentrationen mittels ELISA und des Selen-bindenden-Protein 1 (SELENBP1) durch einen Immuno-lumineszenz Assay. Zusätzlich erfolgte die Detektion eines Zytokinprofils am Universitätsklinikum Heidelberg via Multiplex-Immunoassay Verfahren. Ergebnisse: Innerhalb der ersten 24 Stunden (h) fielen die Se-Konzentrationen in der Remissionsgruppe G1 von 71,9 μg/L auf 48,3 μg/L ab, während sie in der Nicht- Remissionsgruppe G0 nahezu stabil blieben (58,5 μg/L vs. 60,6 μg/L) (ΔG1 vs. ΔG0 p = 0,044). Die SELENOP Konzentrationen sanken in G1 nach 12 h (p 0,05). Die Dynamiken der Cu-Konzentrationen divergierten nach 12 h (p < 0,001) und nach 24 h (p = 0,023). Die Analysen der CP-Konzentrationen ergaben keine Gruppenunterschiede. Die SELENBP1 Analysen zeigten sowohl im Hinblick auf das klinische Outcome (G0 vs. G1, p = 0,019) als auch in Abhängigkeit vom Ausmaß der neurologischen Beeinträchtigungen (AIS A vs. AIS B-D, p = 0.011) signifikante Unterschiede auf. Anhand binärer logistischer Regressionsanalysen wurden Vorhersagemodelle für das Remissionspotenzial ermittelt, deren Genauigkeit in Abhängigkeit der ausgewählten Parameter variiert: 90,0 % (67,4 – 100,0 %) für Se + SELENOP; 87,7 % (75,1 – 100,0 %) für Se + Cu + CP. Schlussfolgerung: Frühe Konzentrationsänderungen der Spurenelementparameter liefern diagnostische Einsichten in die Verletzungsschwere und das individuelle Remissionspotential der Patient*innen nach TSCI. Peripher reduzierte Dynamiken könnten eine für die Regenerationsprozesse vorteilhafte Umverteilung der Spurenelemente zum Ort des Verletzungsgeschehens aufzeigen.Background: Traumatic spinal cord injuries (TSCI) can lead to loss of all sensory and motor functions below the injury level. Due to primary and secondary pathophysiological mechanisms, the affected neuronal tissue is exposed to massive oxidative stress. The trace elements selenium (Se) and copper (Cu) are crucial for antioxidant defence. Methods: From 2011 to 2018, in a prospective observational study of the Paraplegic Centre Ludwigshafen, blood samples and clinical data were collected from 144 patients after TSCI. The ASIA Impairment Scale (AIS) was used to grade the accompanying neurological deficits into severity levels (AIS A-D). An improvement of the AIS within three months was defined as remission and patients accordingly divided into a remission group G1 or a non-remission group G0. Ten individuals with isolated vertebral fractures without neurological deficits served as control. Trace elements were detected by total reflection X-ray fluorescence analysis (TXRF), Selenoprotein P (SELENOP) and Ceruloplasmin (CP) by ELISA and selenium-binding-protein 1 (SELENBP1) by immunoluminescence assay at the Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin. In addition, a cytokine profile was detected at Heidelberg University Hospital via multiplex immunoassay. Results: Within the first 24 hours, Se concentrations in the remission group G1 decreased from 71,9 µg/L to 48,3 µg/L, while they remained almost stable in the non remission group G0 (58,5 µg/L vs. 60,6 µg/L) (ΔG1 vs. ΔG0 p = 0.044). These significantly divergent dynamics were also apparent Cu- analyses, after 12 hours (G1 vs. G0 p < 0.001) and after 24 hours (G1 vs. G0 p = 0.023). SELENOP concentrations decreased significantly in G1 after 12 hours (p < 0.05), whereas the differences in G0 appeared marginal (p > 0.05). The CP analyses showed no group differences. SELENBP1 analyses revealed significant differences both in terms of clinical outcome (G0 vs. G1, p = 0.019) and relation to the extent of neurological impairments (AIS A vs. AIS B-D, p = 0.011). Binary logistic regression analyses were used to determine prediction models for the remission potential. The accuracy varies depending on the selected parameters: 90.0 % (67.4 % – 100.0 %) for Se + SELENOP, 87.7 % (75.1 % – 100.0 %) for Se + Cu parameters. Conclusion: Early concentration changes of trace element parameters provide insights into the injury severity and the individual remission potential of patients after TSCI. Peripherally reduced dynamics may indicate a beneficial redistribution of trace elements to the site of injury for regeneration processes

Variety of Planar Fourth‐Order Fiber Orientation Tensors and Implications on Effective Elastic Stiffnesses

In this contribution, selected results from [1–3] are presented in a compact and simplified way. In addition, the variety of fiber orientation tensors is used to determine a maximum deviation of the direction-dependent Young\u27s modulus, which can arise if only second-order directional information is included in a specific meanfield homogenization. Focusing on the special case of planar fiber distributions, the variety of fiber orientation tensors identified in [1] is considered as a design space. This design space is completely explored for the orientation-averaging homogenization following [4], fixed material parameters and fixed fiber volume content. The possible directional dependence of the resulting effective stiffnesses is graphically presented using polar plots of the direction-dependent Young\u27s modulus. These polar plots are arranged on two-dimensional slices within the parameter space of planar fourth-order fiber orientation tensors. This gives a complete representation of the influence of the orientation tensor on the anisotropic stiffness tensor. Consequences of closure approximations, i.e., restriction to second-order directional information, are demonstrated and motivate measurement of fourth-order fiber orientation tensors

Selenium-Binding Protein 1 Indicates Myocardial Stress and Risk for Adverse Outcome in Cardiac Surgery

Selenium-binding protein 1 (SELENBP1) is an intracellular protein that has been detected in the circulation in response to myocardial infarction. Hypoxia and cardiac surgery affect selenoprotein expression and selenium (Se) status. For this reason, we decided to analyze circulating SELENBP1 concentrations in patients (n = 75) necessitating cardioplegia and a cardiopulmonary bypass (CPB) during the course of the cardiac surgery. Serum samples were collected at seven time-points spanning the full surgical process. SELENBP1 was quantified by a highly sensitive newly developed immunological assay. Serum concentrations of SELENBP1 increased markedly during the intervention and showed a positive association with the duration of ischemia (ρ = 0.6, p < 0.0001). Elevated serum SELENBP1 concentrations at 1 h after arrival at the intensive care unit (post-surgery) were predictive to identify patients at risk of adverse outcome (death, bradycardia or cerebral ischemia, "endpoint 1"; OR 29.9, CI 3.3-268.8, p = 0.00027). Circulating SELENBP1 during intervention (2 min after reperfusion or 15 min after weaning from the CPB) correlated positively with an established marker of myocardial infarction (CK-MB) measured after the intervention (each with ρ = 0.5, p < 0.0001). We concluded that serum concentrations of SELENBP1 were strongly associated with cardiac arrest and the duration of myocardial ischemia already early during surgery, thereby constituting a novel and promising quantitative marker for myocardial hypoxia, with a high potential to improve diagnostics and prediction in combination with the established clinical parameters

Selenium Deficiency Is Associated with Mortality Risk from COVID-19

SARS-CoV-2 infections underlie the current coronavirus disease (COVID-19) pandemic and are causative for a high death toll particularly among elderly subjects and those with comorbidities. Selenium (Se) is an essential trace element of high importance for human health and particularly for a well-balanced immune response. The mortality risk from a severe disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that this relation also applies to COVID-19. Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively. The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors. We conclude that Se status analysis in COVID patients provides diagnostic information. However, causality remains unknown due to the observational nature of this study. Nevertheless, the findings strengthen the notion of a relevant role of Se for COVID convalescence and support the discussion on adjuvant Se supplementation in severely diseased and Se-deficient patients

Zinc Concentration Dynamics Indicate Neurological Impairment Odds after Traumatic Spinal Cord Injury

Traumatic Spinal Cord Injury (TSCI) is debilitating and often results in a loss of motor and sensory function caused by an interwoven set of pathological processes. Oxidative stress and inflammatory processes are amongst the critical factors in the secondary injury phase after TSCI. The essential trace element Zinc (Zn) plays a crucial role during this phase as part of the antioxidant defense system. The study aims to determine dynamic patterns in serum Zn concentration in patients with TSCI and test for a correlation with neurological impairment. A total of 42 patients with TSCI were enrolled in this clinical observational study. Serum samples were collected at five different points in time after injury (at admission, and after 4 h, 9 h, 12 h, 24 h, and 3 d). The analysis of the serum Zn concentrations was conducted by total reflection X-ray fluorescence (TXRF). The patients were divided into two groups-a study group S (n = 33) with neurological impairment, including patients with remission (G1, n = 18) and no remission (G0, n = 15) according to a positive AIS (American Spinal Injury Association (ASIA) Impairment Scale) conversion within 3 months after the trauma; and a control group C (n = 9), consisting of subjects with vertebral fractures without neurological impairment. The patient data and serum concentrations were examined and compared by non-parametric test methods to the neurological outcome. The median Zn concentrations in group S dropped within the first 9 h after injury (964 µg/L at admission versus 570 µg/L at 9 h, p < 0.001). This decline was stronger than in control subjects (median of 751 µg/L versus 729 µg/L, p = 0.023). A binary logistic regression analysis including the difference in serum Zn concentration from admission to 9 h after injury yielded an area under the curve (AUC) of 82.2% (CI: 64.0-100.0%) with respect to persistent neurological impairment. Early Zn concentration dynamics differed in relation to the outcome and may constitute a helpful diagnostic indicator for patients with spinal cord trauma. The fast changes in serum Zn concentrations allow an assessment of neurological impairment risk on the first day after trauma. This finding supports strategies for improving patient care by avoiding strong deficits via adjuvant nutritive measures, e.g., in unresponsive patients after trauma

Serum Selenium Status as a Diagnostic Marker for the Prognosis of Liver Transplantation

The trace element selenium (Se) is taken up from the diet and is metabolized mainly by hepatocytes. Selenoprotein P (SELENOP) constitutes the liver-derived Se transporter. Biosynthesis of extracellular glutathione peroxidase (GPx3) in kidney depends on SELENOP-mediated Se supply. We hypothesized that peri-operative Se status may serve as a useful prognostic marker for the outcome in patients undergoing liver transplantation due to hepatocellular carcinoma. Serum samples from liver cancer patients were routinely collected before and after transplantation. Concentrations of serum SELENOP and total Se as well as GPx3 activity were determined by standardized tests and related to survival, etiology of cirrhosis/carcinoma, preoperative neutrophiles, lymphocytes, thyrotropin (TSH) and Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. A total of 221 serum samples from 79 transplanted patients were available for analysis. The Se and SELENOP concentrations were on average below the reference ranges of healthy subjects. Patients with ethanol toxicity-dependent etiology showed particularly low SELENOP and Se concentrations and GPx3 activity. Longitudinal analysis indicated declining Se concentrations in non-survivors. We conclude that severe liver disease necessitating organ replacement is characterized by a pronounced Se deficit before, during and after transplantation. A recovering Se status after surgery is associated with positive prognosis, and an adjuvant Se supplementation may, thus, support convalescence

Selenium-Binding Protein 1 (SELENBP1) as Biomarker for Adverse Clinical Outcome After Traumatic Spinal Cord Injury

Introduction: Traumatic spinal cord injury (TSCI) presents a diagnostic challenge as it may have dramatic consequences for the affected patient. Additional biomarkers are needed for improved care and personalized therapy. Objective: Serum selenium binding protein 1 (SELENBP1) has been detected in myocardial infarction, reflecting hypoxic tissue damage and recovery odds. As SELENBP1 is usually not detected in the serum of healthy subjects, we tested the hypothesis that it may become detectable in TSCI and indicate tissue damage and regeneration odds. Methods: In this prospective observational study, patients with comparable injuries were allocated to three groups; vertebral body fractures without neurological impairment (control "C"), TSCI without remission ("G0"), and TSCI with signs of remission ("G1"). Consecutive serum samples were available from different time points and analyzed for SELENBP1 by sandwich immunoassay, for trace elements by X-ray fluorescence and for cytokines by multiplex immunoassays. Results: Serum SELENBP1 was elevated at admission in relation to the degree of neurological impairment [graded as A, B, C, or D according to the American Spinal Injury Association (AISA) impairment scale (AIS)]. Patients with the most severe neurological impairment (classified as AIS A) exhibited the highest SELENBP1 concentrations (p = 0.011). During the first 3 days, SELENBP1 levels differed between G0 and G1 (p = 0.019), and dynamics of SELENBP1 correlated to monocyte chemoattractant protein 1, chemokine ligand 3 and zinc concentrations. Conclusion: Circulating SELENBP1 concentrations are related to the degree of neurological impairment in TSCI and provide remission odds information. The tight correlation of SELENBP1 with CCL2 levels provides a novel link between Se metabolism and immune cell activation, with potential relevance for neurological damage and regeneration processes, respectively

Selenium-Binding Protein 1 (SELENBP1) as Biomarker for Adverse Clinical Outcome After Traumatic Spinal Cord Injury

Introduction: Traumatic spinal cord injury (TSCI) presents a diagnostic challenge as it may have dramatic consequences for the affected patient. Additional biomarkers are needed for improved care and personalized therapy.Objective: Serum selenium binding protein 1 (SELENBP1) has been detected in myocardial infarction, reflecting hypoxic tissue damage and recovery odds. As SELENBP1 is usually not detected in the serum of healthy subjects, we tested the hypothesis that it may become detectable in TSCI and indicate tissue damage and regeneration odds.Methods: In this prospective observational study, patients with comparable injuries were allocated to three groups; vertebral body fractures without neurological impairment (control “C”), TSCI without remission (“G0”), and TSCI with signs of remission (“G1”). Consecutive serum samples were available from different time points and analyzed for SELENBP1 by sandwich immunoassay, for trace elements by X-ray fluorescence and for cytokines by multiplex immunoassays.Results: Serum SELENBP1 was elevated at admission in relation to the degree of neurological impairment [graded as A, B, C, or D according to the American Spinal Injury Association (AISA) impairment scale (AIS)]. Patients with the most severe neurological impairment (classified as AIS A) exhibited the highest SELENBP1 concentrations (p = 0.011). During the first 3 days, SELENBP1 levels differed between G0 and G1 (p = 0.019), and dynamics of SELENBP1 correlated to monocyte chemoattractant protein 1, chemokine ligand 3 and zinc concentrations.Conclusion: Circulating SELENBP1 concentrations are related to the degree of neurological impairment in TSCI and provide remission odds information. The tight correlation of SELENBP1 with CCL2 levels provides a novel link between Se metabolism and immune cell activation, with potential relevance for neurological damage and regeneration processes, respectively