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.

Predicting neurological recovery after traumatic spinal cord injury by time-resolved analysis of monocyte subsets.

Monocytes and lymphocytes elicit crucial activities for the regenerative processes after various types of injury. The survival of neurons exposed to mechanical and oxidative stress after traumatic spinal cord injury depends on a multitude of factors. In this study, we sought to evaluate a correlation between remission after traumatic spinal cord injury and the dynamics of monocyte subsets in respect to the lymphocytes' responsive potential, cytokine expression, patterns of trace element concentration and clinical covariates. We examined prospectively 18 (three female, 15 male) patients after traumatic spinal cord injury. Blood samples were drawn at admission and 4 h, 9 h, 12 h, 1 and 3 days as well as 1 and 2 weeks and 1, 2 and 3 months after the trauma. Analysis of cytokines (CCL2, IL-10, enolase 2, CXCL12, TGF-ß1, TGF-ß2) was performed using a multiplex cytokine panel. Plasma trace element concentrations of selenium, copper and zinc were determined by total reflection X-ray fluorescence analysis; neopterin, selenoprotein P (SELENOP) and ceruloplasmin (CP) by enzyme-linked immunosorbent assay; and selenium binding protein 1 (SELENBP1) by luminometric immunoassay. The responsive potential of lymphocytes was assessed using transformation tests. The monocyte subsets (classical, intermediate, and non-classical) and expression of CD14, CD16, CXCR4 and intracellular IL-10 were identified using a multi-colour flow cytometry analysis. The dynamics of the cluster of intermediate CD14-/CD16+/IL10+/CXCR4int monocytes differed significantly between patients with an absence of neurological remission (G0) from those with an improvement (G1) by 1 or 2 American Spinal Injury Association Impairment Scale (AIS) steps (Kruskal-Wallis Test, P = 0.010, G0 < G1, AIS+: 1 < G1, AIS+: 2) in the first 24 h. These dynamics were associated inversely with an increase in enolase and SELENBP1 14 days after the injury. In the elastic net regularized model, we identified an association between the increase of a subpopulation of intermediate CD14-/CD16+/IL10+/CXCR4int monocytes and exacerbated immune response within 24 h after the injury. These findings were reflected in the consistently elevated response to mitogen stimulation of the lymphocytes of patients with significant neurological remission. Early elevated concentrations of CD14-/CD16+/IL10+/CXCR4int monocytes were related to higher odds of CNS regeneration and enhanced neurological remission. The cluster dynamics of CD14-/CD16+/IL10+/CXCR4int monocytes in the early-acute phase after the injury revealed a maximum of prognostic information regarding neurological remission (mean parameter estimate: 0.207; selection count: 818/1000 repetitions). We conclude that early dynamics in monocyte subsets allow a good prediction of recovery from traumatic spinal cord injury.

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.

Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker.

SARS-CoV-2 infections cause the current coronavirus disease (COVID-19) pandemic and challenge the immune system with ongoing inflammation. Several redox-relevant micronutrients are known to contribute to an adequate immune response, including the essential trace elements zinc (Zn) and selenium (Se). In this study, we tested the hypothesis that COVID-19 patients are characterised by Zn deficiency and that Zn status provides prognostic information. Serum Zn was determined in serum samples (n = 171) collected consecutively from patients surviving COVID-19 (n = 29) or non-survivors (n = 6). Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study were used for comparison. Zn concentrations in patient samples were low as compared to healthy subjects (mean ± SD; 717.4 ± 246.2 vs 975.7 ± 294.0 µg/L, P < 0.0001). The majority of serum samples collected at different time points from the non-survivors (25/34, i.e., 73.5%) and almost half of the samples collected from the survivors (56/137, i.e., 40.9%) were below the threshold for Zn deficiency, i.e., below 638.7 µg/L (the 2.5th percentile in the EPIC cohort). In view that the Se status biomarker and Se transporter selenoprotein P (SELENOP) is also particularly low in COVID-19, we tested the prevalence of a combined deficit, i.e., serum Zn below 638.7 µg/L and serum SELENOP below 2.56 mg/L. This combined deficit was observed in 0.15% of samples in the EPIC cohort of healthy subjects, in 19.7% of the samples collected from the surviving COVID-19 patients and in 50.0% of samples from the non-survivors. Accordingly, the composite biomarker (SELENOP and Zn with age) proved as a reliable indicator of survival in COVID-19 by receiver operating characteristic (ROC) curve analysis, yielding an area under the curve (AUC) of 94.42%. We conclude that Zn and SELENOP status within the reference ranges indicate high survival odds in COVID-19, and assume that correcting a diagnostically proven deficit in Se and/or Zn by a personalised supplementation may support convalescence.

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.

Selenium and copper status - potential signposts for neurological remission after traumatic spinal cord injury.

INTRODUCTION: Traumatic Spinal Cord Injury (TSCI) is a severe incident resulting in loss of motor and sensory function caused by complex pathological mechanisms including massive oxidative stress and extensive inflammatory processes. The essential trace elements selenium (Se) and copper (Cu) play crucial roles as part of the antioxidant defense. HYPOTHESIS: Remission after TSCI is associated with characteristic dynamics of early changes in serum Cu and Se status. STUDY DESIGN: Single-center prospective observational study. PATIENTS AND METHODS: Serum samples from TSCI patients were analyzed (n = 52); 21 recovered and showed a positive abbreviated injury score (AIS) conversion within 3 months (G1), whereas 21 had no remission (G0). Ten subjects with vertebral fractures without neurological impairment served as control (C). Different time points (at admission, and after 4, 9, 12, and 24 h) were analyzed for total serum Se and Cu concentrations by total reflection X-ray fluorescence, and for Selenoprotein P (SELENOP) and Ceruloplasmin (CP) by sandwich ELISA. RESULTS: At admission, CP and SELENOP concentrations were higher in the remission group (G1) than in the non-remission group (G0). Within 24 h, there were marginal changes in Se, SELENOP, Cu and CP concentrations in the groups of controls (C) and G0. In contrast, these parameters decreased significantly in G1. Binary logistic regression analysis including Cu and Se levels at admission in combination with Se and CP levels after 24 h allowed a prediction for potential remission, with an area under the curve (AUC) of 87.7% (CI: 75.1%-100.0%). CONCLUSION: These data indicate a strong association between temporal changes of the Se and Cu status and the clinical outcome after TSCI. The dynamics observed may reflect an ongoing redistribution of the trace elements in favor of a better anti-inflammatory response and a more successful neurological regeneration.

The Role of Magnesium in the Secondary Phase After Traumatic Spinal Cord Injury. A Prospective Clinical Observer Study.

In the secondary injury phase after traumatic spinal cord injury (TSCI), oxidative stress and neuroinflammatory responses at the site of injury constitute crucial factors controlling damage extent and may serve as potential therapeutic targets. We determined Magnesium (Mg) serum concentration dynamics in context with the potential of neurological remission in patients with TSCI as Mg is suspected to limit the production of reactive oxygen species and reduce lipid peroxidation. A total of 29 patients with acute TSCI were enrolled, and blood samples were drawn over 3 months at 11 time-points and Mg quantification was performed. Patients were divided into those with (G1, n = 18) or without neurological remission (G0, n = 11). Results show a slight drop in Mg level during the first 4 h after injury, then remained almost unchanged in G1, but increased continuously during the first 7 days after injury in G0. At day 7 Mg concentrations in G1 and G0 were significantly different (p = 0.039, G0 > G1). Significant differences were detected between patients in G1 that presented an AIS (ASIA Impairment Scale) conversion of 1 level versus those with more than 1 level (p = 0.014, G1 AIS imp. = +1 > G1 AI imp. > +1). Low and decreasing levels of Mg within the first 7 days are indicative of a high probability of neurological remission, whereas increasing levels are associated with poor neurological outcome.

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.

Circulating levels of selenium-binding protein 1 (SELENBP1) are associated with risk for major adverse cardiac events and death.

OBJECTIVE: Selenium-binding protein 1 (SELENBP1) is an intracellular protein with variable expression in response to cellular stress. As the selenium (Se) status is affected by inflammation and hypoxia, we hypothesized that SELENBP1 contributes to disease-specific Se metabolism. To test this hypothesis, a quantitative assay was developed and used to monitor SELENBP1 in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: SELENBP1 was expressed, antibodies were generated and a luminometric immuno assay (LIA) was established and characterized. Serum samples were collected from controls (n = 37) and patients (n = 85) admitted to the Chest Pain Unit with suspected ACS. Blood samples were available from time of first medical contact in the ambulance, at admission to hospital, and after 2, 4, 6 and 12-36 h. RESULTS: Circulating SELENBP1 was close to limit of detection in healthy controls and elevated in patients with suspected ACS. SELENBP1 was unrelated to other biomarkers of myocardial damage such as troponin T or aspartate aminotransferase. Serum SELENBP1 enabled a categorization of patients on first medical contact as either high-risk or low-risk for major adverse cardiac events (MACE) or death, when using 0.8 nmol/l as threshold. The odds-ratios (OR) for MACE and death were OR = 11 (95% CI: 2-49, p = 0.0022) and OR = 12 (2-74, p = 0.014), respectively. CONCLUSIONS: Until now, SELENBP1 was mainly considered as an intracellular protein involved in Se metabolism and redox control. Our data indicate that SELENBP1 constitutes a circulating biomarker for cardiac events categorizing patients with suspected ACS at first medical contact into high-risk or low-risk for MACE and death, independent from and complimentary to current biomarkers.

Relation of selenium status to neuro-regeneration after traumatic spinal cord injury.

INTRODUCTION: The trace element selenium (Se) is crucial for the biosynthesis of selenoproteins. Both neurodevelopment and the survival of neurons that are subject to stress depend on a regular selenoprotein biosynthesis and sufficient Se supply by selenoprotein P (SELENOP). HYPOTHESIS: Neuro-regeneration after traumatic spinal cord injury (TSCI) is related to the Se status. STUDY DESIGN: Single-centre prospective observational study. PATIENTS AND METHODS: Three groups of patients with comparable injuries were studied; vertebral fractures without neurological impairment (n = 10, group C), patients with TSCI showing no remission (n = 9, group G0), and patients with remission developing positive abbreviated injury score (AIS) conversion within 3 months (n = 10, group G1). Serum samples were available from different time points (upon admission, and after 4, 9 and 12 h, 1 and 3 days, 1 and 2 weeks, and 1, 2 and 3 months). Serum trace element concentrations were determined by total reflection X-ray fluorescence, SELENOP by ELISA, and further parameters by laboratory routine. RESULTS: Serum Se and SELENOP concentrations were higher on admission in the remission group (G1) as compared to G0. During the first week, both parameters remained constant in C and G0, whereas they declined significantly in the remission group. Similarly, the concentration changes between admission and 24 h were most pronounced in this group of recovering patients (G1). Binary logistic regression analysis including the delta of Se and SELENOP within the first 24 h indicated an AUC of 90.0% (CI: 67.4%-100.0%) with regards to predicting the outcome after TSCI. CONCLUSION: A Se deficit might constitute a risk factor for poor outcome after TSCI. A dynamic decline of serum Se and SELENOP concentrations after admission may reflect ongoing repair processes that are associated with higher odds for a positive clinical outcome.