Gravity sedimentation reveals functionally and morphologically different platelets in human blood.

In contrast to red blood cells, platelets float rather than sediment when a column of blood is placed in the gravitational field. By the analogy of erythrocyte sedimentation (ESR), it can be expressed with the platelet antisedimentation rate (PAR), which quantitates the difference in platelet count between the upper and lower halves of the blood column after 1 h of 1 g sedimentation. Venous blood samples from 21 healthy subjects were analyzed for PAR. After a 1-h sedimentation, the upper and lower fractions of blood samples were analyzed for platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and high-fluorescence IPF (H-IPF). The mechanisms behind platelet flotation were explored by further partitioning of the blood column, time-dependent measurements of platelet count and comparison with ESR. The structure and function of the platelets were assessed by electron microscopy (EM) and atomic force microscopy (AFM), and platelet aggregometry, respectively. Platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation. The area under the curve (AUC) of the whole blood adenosine diphosphate (ADP) aggregation curves showed significant differences between the upper and lower samples (p < .005). AUC in the upper samples of 38% of healthy subjects exceeded the top of the normal range (53-122) suggesting that ascending platelets show an intensified ADP-induced aggregability ex vivo. H-IPF was significantly higher in the upper samples (p < .05). EM and AFM revealed that platelets in the upper samples were larger in volume and contained 1.6 times more alpha granules compared to platelets in the lower samples. Our results indicate that antisedimentation is able to differentiate platelet populations based on their structural and functional properties. Therefore, PAR may be a suitable laboratory parameter in various thromboinflammatory disorders.

It is less known that platelets do not sediment in response to gravitational force but float on the top of the blood column. This phenomenon is called antisedimentation, the rate of which, however, can be different, yet this feature has not been widely studied and used in clinical practice or diagnosis. We tested the idea that antisedimentation of platelets from venous blood samples can be a potential biomarker. We have found that platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation and after 1-h upper and lower fractions develop. Interestingly, the aggregation curves showed significant differences between the upper and lower samples, suggesting that the ascending platelets show ex vivo hyperaggregability. Electron and atomic force microscopy revealed that platelets in the upper samples were larger in volume and contained more alpha granules than platelets in the lower samples. Subsequently, antisedimentation can be used to differentiate platelet populations based on their structural and functional properties; thus, it may be a promising biomarker for various thromboinflammatory disorders.

The Difference in Serum Metabolomic Profiles between the Good and Poor Outcome Groups at 3 Months in the Early and Late Phases of Aneurysmal Subarachnoid Hemorrhage.

We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified Rankin score: 0-3 vs. poor = mRS 4-6). We collected serum samples from 46 aSAH patients at 24 (D1) and 168 (D7) hours after injury for analysis by liquid chromatography-mass spectrometry. Ninety-six different metabolites were identified. Groups were compared using multivariate (orthogonal partial least squares discriminant analysis), univariate, and receiving operator characteristic (ROC) methods. We observed a marked decrease in serum homocysteine levels at the late phase (D7) compared to the early phase (D1). At both D1 and D7, mannose and sorbose levels were notably higher, alongside elevated levels of kynurenine (D1) and increased 2-hydroxybutyrate, methyl-galactoside, creatine, xanthosine, p-hydroxyphenylacetate, N-acetylalanine, and N-acetylmethionine (all D7) in the poor outcome group. Conversely, levels of guanidinoacetate (D7) and several amino acids (both D1 and D7) were significantly lower in patients with poor outcomes. Our results indicate significant changes in energy metabolism, shifting towards ketosis and alternative energy sources, both in the early and late phases, even with adequate enteral nutrition, particularly in patients with poor outcomes. The early activation of the kynurenine pathway may also play a role in this process.

Acute Phase Protein Orosomucoid (Alpha-1-Acid Glycoprotein) Predicts Delayed Cerebral Ischemia and 3-Month Unfavorable Outcome after Aneurysmal Subarachnoid Hemorrhage.

The pathophysiology and consequences of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) remain incompletely understood. This study aims to investigate the role of orosomucoid (ORM) in aSAH, its potential as a marker for assessing the extent of EBI-induced damage, and its correlation with delayed cerebral ischemia (DCI) and functional recovery over a 3-month period. We collected serum specimens 72 h post-aSAH to measure ORM levels. The study included 151 aSAH patients and 105 healthy subjects. The serum ORM levels within the patient cohort significantly exceeded those in the control group (p < 0.001). The ORM value showed significant correlation with the admission WFNS (p < 0.0001) and mFS scores (p < 0.05). Substantially elevated serum ORM levels at 72 h post-aSAH were detected among patients experiencing DCI, as well as those with poor functional outcomes after 3 months (p = 0.009 and p < 0.001). Binary logistic regression analyses revealed that serum ORM at 72 h post-SAH was independently associated with DCI and 3-month functional outcome after adjusting for confounders. The early stage events of aSAH influence the level of ORM. ORM serves as a marker for assessing the extent of damage during EBI and is linked to the occurrence of DCI as well as unfavorable long-term functional outcomes.

Different Kinetics of Serum ADAMTS13, GDF-15, and Neutrophil Gelatinase-Associated Lipocalin in the Early Phase of Aneurysmal Subarachnoid Hemorrhage.

Growth differentiation factor 15 (GDF-15), neutrophil gelatinase-associated lipocalin (NGAL), and ADAMTS13 have previously been implicated in the pathophysiological processes of SAH. In the present study, we aim to examine their role in the early period of SAH and their relationship to primary and secondary outcomes. Serum samples were collected at five time periods after SAH (at 24 h (D1), at 72 h (D3), at 120 h (D5), at 168 h (D7) and at 216 h (D9), post-admission) and) were measured by using MILLIPLEX Map Human Cardiovascular Disease (CVD) Magnetic Bead Panel 2. We included 150 patients with SAH and 30 healthy controls. GDF-15 levels at D1 to D9 were significantly associated with a 3-month unfavorable outcome. Based on the ROC analysis, in patients with a good clinical grade at admission (WFNS I-III), the GDF-15 value measured at time point D3 predicted a 3-month unfavorable outcome (cut-off value: 3.97 ng/mL, AUC:0.833, 95%CI: 0.728-0.938, sensitivity:73.7%, specificity:82.6%, p < 0.001). Univariate binary logistic regression analysis showed that serum NGAL levels at D1-D5 and ADAMTS13 levels at D7-D9 were associated with MVS following SAH. GDF-15 is an early indicator of a poor 3-month functional outcome even in patients with mild clinical conditions at admission.

Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

The prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH) is heavily influenced by the development of delayed cerebral ischemia (DCI), but the adequate and effective therapy of DCI to this day has not been resolved. Multiplex serum biomarker studies may help to understand the pathophysiological processes underlying DCI. Samples were collected from patients with aSAH at two time points: (1) 24 h (Day 1) and (2) 5−7 days after ictus. Serum concentrations of eotaxin, FGF-2, FLT-3L, CX3CL1, Il-1b, IL-4, IP-10, MCP3, and MIP-1b were determined using a customized MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A multiplex assay. The functional outcome was defined by the modified Rankin scale (favorable: 0−2, unfavorable: 3−6) measured on the 30th day after aSAH. One-hundred and twelve patients with aSAH were included in this study. The median level of CX3CL1 and MCP-3 measured on Days 5−7 were significantly higher in patients with DCI compared with those without DCI (CX3CL1: with DCI: 110.5 pg/mL, IQR: 82−201 vs. without DCI: 82.6, 58−119, p = 0.036; and MCP-3: with DCI: 22 pg/mL (0−32) vs. without DCI: 0 (0−11), p < 0.001). IP-10, MCP-3, and MIP-1b also showed significant associations with the functional outcome after aSAH. MCP-3 and CX3CL1 may play a role in the pathophysiology of DCI.

Increased level of LIGHT/TNFSF14 is associated with survival in aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Multiple cytokines have been implicated in aneurysmal subarachnoid hemorrhage (aSAH), but tumor necrosis factor superfamily 14 (LIGHT/TNFSF14) and oncostatin-M (OSM) have not been previously explored. AIMS OF THE STUDY: The primary objective of this study was to examine the relationship between TNFSF14 and OSM levels and survival. Our secondary goal was to investigate a potential association between these markers and the incidence of delayed cerebral ischemia (DCI). MATERIALS & METHODS: We consecutively recruited 60 patients with a clinical diagnosis of aSAH. LIGHT/TNFSF14 and OSM serum concentrations were determined by ELISA. The primary endpoint was survival at Day 30, while development of DCI was assessed as secondary outcome. RESULTS: Patients had significantly higher levels of both markers than the control group (median of LIGHT: 18.1 pg/ml vs. 7 pg/ml; p = 0.01; median of OSM: 10.3 pg/ml vs. 2.8 pg/ml, p < 0.001). Significantly lower serum level of LIGHT/TNFSF14 was found in nonsurviving patients (n = 9) compared with survivors (n = 51; p = 0.011). Based on ROC analysis, serum LIGHT/TNFSF14 with a cutoff value of >7.95 pg/ml predicted 30-day survival with a sensitivity of 71% and specificity of 78% (Area: 0.763; 95% CI: 0.604-0.921, p = 0.013). In addition, it was also a predictor of DCI with a sensitivity of 72.7% and a specificity of 62.5% (AUC: 0.702; 95% CI: 0.555-0.849, p = 0.018). Based on binary logistic regression analysis, LIGHT/TNFSF14 was found to be independently associated with 30-day mortality, but not with DCI. CONCLUSION: In this cohort, a higher serum level of LIGHT/TNFSF14 was associated with increased survival of patients with aSAH.

Detection of silent cerebral microcirculatory abnormalities in patients with manifest ischemic coronary disease: a perfusion brain MRI study combined with dipyridamole stress.

OBJECTIVES: Intravenous dipyridamole (DP) can induce transient perfusion abnormalities in the heart but also the brain indicated by brain SPECT. L-arginine can regulate the vascular tone via nitric oxide (NO). Therefore, we examined cerebral blood volume (CBV) by perfusion MRI and L-arginine level before and after DP stress in patients, who developed transient neurological signs, and compared these to unaffected patients. DESIGN: A total of nine patients with ischemic coronary disease after myocardial perfusion scintigraphy were selected for this prospective pilot study. Four had DP-induced transient mild neurologic signs during myocardial perfusion scintigraphy, while five had no neurological signs. By using perfusion MRI in both groups in a second stage, we examined CBV in identical areas of the two hemispheres before and during DP stress. Besides, pre-and post-stress L-arginine serum levels were also analyzed by high-performance liquid chromatography. Trial registration: NCT03688815. RESULTS: CBV in the sensory-motor area at baseline was significantly higher in patients with DP-induced transient neurological signs compared to patients without signs (p = 0.028). Intravenous DP normalized the higher perfusion by decreasing CBV, and also increased serum L-arginine level (p = 0.001). CONCLUSIONS: Intravenous DP changed the CBV accompanied by a systemic elevation of L-arginine: this indicates a direct vasorelaxing effect on brain vessels, and an indirect vasodilator effect through L-arginine release presumably via NO. In areas with decreased CBV before DP, such double effects caused transient neurological symptoms presumably due to steal phenomenon. Therefore, intravenous DP may have a potential to identify patients with high risk for cerebral ischemia.

Increased serum level of high sensitivity troponin T even prior to surgery can predict adverse events during carotid endarterectomy.

OBJECTIVES: Perioperative stress affects the outcome of carotid endarterectomy performed under regional anesthesia. Here we aimed to explore the temporal profile of the stress marker cortisol and its relationship to high-sensitivity troponin-T, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and S100B as an indicator of blood-brain barrier alteration in the systemic circulation. METHODS: Prospective part of the study: a total of 31 patients with significant carotid stenosis scheduled for carotid endarterectomy in regional anesthesia were enrolled. Follow-up part of the study and retrospective analysis of the outcome: each patient was followed up to five years and morbidity as well as mortality data were collected from an electronic database. Blood samples from each patient were serially taken; prior to surgery (T1), at the time of reperfusion (T2), 24 h (T3) and 72 h later postoperatively (T4), then the plasma concentration of each biomarker was measured. Besides, the clinical and surgical factors and perioperative adverse events were recorded. RESULTS: More positive correlations were found between: the early change of S100B (T2-T1) and late change in plasma cortisol level (T4-T3) (r = 0.403; p < 0.05); the early change of cortisol (T2-T1) and the early postoperative change of plasma matrix metalloproteinase-9 level (T3-T2) (r = 0.432; p = 0.01); the plasma concentration of tissue inhibitor of metalloproteinase-1 at 24 postoperative hours and the late change in plasma high-sensitivity troponin-T level (T4-T3) (r = 0.705; p < 0.001). Five patients needed an intraoperative shunt in whom the high-sensitivity troponin-T was elevated even prior to surgery, but definitive stroke never occurred. Plasma matrix metalloproteinase-9 concentration at reperfusion independently predicted the five-year mortality with a cut-off value of 456 ng/ml (sensitivity: 86%, specificity: 84%, area 0.887, p = 0.002). CONCLUSIONS: A higher intraoperative change in S100B level reflecting carotid endarterectomy induced acute silent brain ischemia was associated with more pronounced post-operative change of cortisol. An early elevation of cortisol was found to be associated with a delayed increase of matrix metalloproteinase-9. Importantly, an increased high-sensitivity troponin-T even prior to carotid endarterectomy may predict clamp intolerance, and elevated matrix metalloproteinase-9 at reperfusion suggests a poor outcome.

Fatty Acid-Binding Protein 3 and CXC-Chemokine Ligand 16 are Associated with Unfavorable Outcome in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with activation of the inflammatory cascade contributing to unfavorable outcome and secondary complications, such as delayed cerebral ischemia (DCI). Both fatty acid-binding protein 3 (FABP3) and CXC-chemokine ligand 16 (CXCL-16) have been linked to vascular inflammation and cellular death. The authors aimed to assess the 30-day prognostic value of serum levels of FABP3 and CXCL-16 and explore their associations with DCI in aSAH patients. METHODS: A total of 60 patients with aSAH were prospectively enrolled. Sampling for markers was done at 24 hours after the index event. FABP3 and CXCL-16 serum concentrations were determined by MilliPlex multiplex immunoassay method. The primary endpoint was unfavorable outcome at Day 30 based on the modified Rankin Scale. RESULTS: Both FABP3 and CXCL-16 levels were significantly elevated in patients with unfavorable outcome compared to those with favorable outcome after aSAH (FABP3: 2133 pg/mL, IQR: 1053-4567 vs. 3773, 3295-13116; p<0.003 and CXCL-16: 384 pg/mL, 313-502 vs. 498, 456-62, p<0.001). The area under the curve (AUC) for serum CXCL-16 levels as a predictor of unfavorable outcome at Day 30 was 0.747 (95% CI =0.622-0.871; p<0.001). Based on binary logistic regression analysis, serum CXCL-16 with a cut-off level >446.7 ng/L independently predicted Day 30 unfavorable outcome with a sensitivity of 81% and a specificity of 62%. Neither CXCL-16 nor FABP3 showed a significant correlation with DCI. CONCLUSION: Early FABP3 and CXCL-16 levels are significantly associated with poor 30-day outcome in patients with aSAH.

Capability of stroke scales to detect large vessel occlusion in acute ischemic stroke - a pilot study.

BACKGROUND AND PURPOSE: Rapid changes of stroke management in recent years facilitate the need for accurate and easy-to-use screening methods for early detection of large vessel occlusion (LVO) in acute ischemic stroke (AIS). Our aim was to evaluate the ability of various stroke scales to discriminate an LVO in AIS. METHODS: We have performed a cross-sectional, observational study based on a registry of consecutive patients with first ever AIS admitted up to 4.5 hours after symptom onset to a comprehensive stroke centre. The diagnostic capability of 14 stroke scales were investigated using receiver operating characteristic (ROC) analysis. RESULTS: Area under the curve (AUC) values of NIHSS, modified NIHSS, shortened NIHSS-EMS, sNIHSS-8, sNIHSS-5 and Rapid Arterial Occlusion Evaluation (RACE) scales were among the highest (>0.800 respectively). A total of 6 scales had cut-off values providing at least 80% specificity and 50% sensitivity, and 5 scales had cut-off values with at least 70% specificity and 75% sensitivity. CONCLUSION: Certain stroke scales may be suitable for discriminating an LVO in AIS. The NIHSS and modified NIHSS are primarily suitable for use in hospital settings. However, sNIHSS-EMS, sNIHSS-8, sNIHSS-5, RACE and 3-Item Stroke Scale (3I-SS) are easier to perform and interpret, hence their use may be more advantageous in the prehospital setting. Prospective (prehospital) validation of these scales could be the scope of future studies.

Awake Sedation With Propofol Attenuates Intraoperative Stress of Carotid Endarterectomy in Regional Anesthesia.

BACKGROUND: Carotid endarterectomy in regional anesthesia is often associated with increased perioperative stress. We assumed that carotid endarterectomy performed under awake sedation with propofol is more beneficial to prevent such stress than alprazolam premedication only. METHODS: A total of 47 consecutive patients with significant carotid artery stenosis were enrolled into this investigation and followed up for 5 years to explore vascular complications. All operations were performed under regional anesthesia. As premedication, all patients took 0.5 mg of alprazolam 30 minutes before the procedure. After randomization, 22 patients had awake sedation with target controlled propofol infusion, and the other 25 had only premedication. Cortisol plasma levels were serially analyzed: before surgery (T1), before (T2) and after release of carotid clamp (T3), and at 2 (T4) and 24 postoperative hours (T5). Alprazolam levels were also measured before and after the surgery. RESULTS: The plasma concentration of cortisol was significantly lower in the propofol sedation group at T2 (P < 0.001), T3 (P = 0.001), and T4 (P < 0.001) than in the alprazolam-only group. Alprazolam levels did not correlate with cortisol levels at any time point. A significant positive correlation was found between the clamp time and plasma cortisol level at T3 (P = 0.018), similarly between the degree of contralateral carotid stenosis and plasma cortisol level at T3 (P = 0.03). Plasma cortisol concentration 2 hours after the operation (T4) proved to be an independent predictor of carotid restenosis during the 5-year follow-up (odds ratio: 1.67, 95% confidence interval: 1.02-2.73, P = 0.04). CONCLUSIONS: An additional intraoperative propofol sedation provides better stress relief than alprazolam-only premedication during awake carotid endarterectomy.

Detailed severity assessment of Cincinnati Prehospital Stroke Scale to detect large vessel occlusion in acute ischemic stroke.

BACKGROUND: Selecting stroke patients with large vessel occlusion (LVO) based on prehospital stroke scales could provide a faster triage and transportation to a comprehensive stroke centre resulting a favourable outcome. We aimed here to explore the detailed severity assessment of Cincinnati Prehospital Stroke Scale (CPSS) to improve its ability to detect LVO in acute ischemic stroke (AIS) patients. METHODS: A cross-sectional analysis was performed in a prospectively collected registry of consecutive patients with first ever AIS admitted within 6 h after symptom onset. On admission stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and the presence of LVO was confirmed by computed tomography angiography (CTA) as an endpoint. A detailed version of CPSS (d-CPSS) was designed based on the severity assessment of CPSS items derived from NIHSS. The ability of this scale to confirm an LVO was compared to CPSS and NIHSS respectively. RESULTS: Using a ROC analysis, the AUC value of d-CPSS was significantly higher compared to the AUC value of CPSS itself (0.788 vs. 0.633, p < 0.001) and very similar to the AUC of NIHSS (0.795, p = 0.510). An optimal cut-off score was found as d-CPSS≥5 to discriminate the presence of LVO (sensitivity: 69.9%, specificity: 75.2%). CONCLUSION: A detailed severity assessment of CPSS items (upper extremity weakness, facial palsy and speech disturbance) could significantly increase the ability of CPSS to discriminate the presence of LVO in AIS patients.

Associations between serum L-arginine and ficolins in the early phase of acute ischemic stroke - A pilot study.

INTRODUCTION: Activation of both the L-arginine and the lectin pathway contributes to the pathophysiology and the outcome of acute ischemic stroke (AIS). However, the interplay between the two systems has not yet been examined. METHODS: A total of 44 patients with AIS were recruited into this study. Serial measurement of serum L-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA), and hsCRP, ficolin-2, ficolin-3, MAP-1, MASP-3 and mannose-binding lectin (MBL) were analyzed within 6 h after onset of stroke and 72 h later. Outcomes were assessed as National Institutes of Health Stroke Scale (NIHSS) worsening by 24 h, poststroke infection, and death by 1 month. RESULTS: In the hyperacute stage of AIS, ficolin-3, MAP-1 and MBL were positively correlated with L-arginine within 6 h after onset of symptoms (p<0.05 respectively). Significantly lower ficolin-3 and MASP-3 levels were found at 72 h in patients, who developed post-stroke infection after day 4, when compared to patients without post-stroke infections (p=0.03 and p=0.009). At 72 hours, ficolin-3 levels negatively correlated with S100B (p=0.01). Ficolin-3 at 72 post-stroke hours remained an independent predictor of post-stroke infection, while only hsCRP was an independent predictor of 30-day mortality. CONCLUSION: Early consumption of ficolin-3 is associated with complications such as post-stroke infections. In the hyperacute phase of AIS, the positive correlation between ficolins and the NO donor L-arginine may reflect the protective role of L-arginine presumably by improving the cerebral microcirculation in a prothrombotic environment induced by complement activation.

Risk analysis of post-procedural intracranial hemorrhage based on STAY ALIVE Acute Stroke Registry.

BACKGROUND: Intracranial hemorrhages (ICH) are classified as symptomatic or asymptomatic according to the presence of clinical deterioration. Here, we aimed to find predictive factors of symptomatic intracranial bleeding in a registry-based stroke research. METHODS: Data of consecutive patients with acute ischemic stroke (AIS) were extracted from the prospective STAY ALIVE stroke registry. Analysis of the total population and treatment sugroups such as endovascular thrombectomy (EVT), intravenous thrombolysis (IVT), or their combination (IVT+EVT) were also done. Outcome measures were ICH, 30- and 90-day clinical outcome based on the modified Rankin Scale (mRS:0-2 as favorable outcome). The hemorrhage was captured by a non-enhanced CT of the skull within 24 h after procedure. RESULTS: A total of 355 patients (mean age: 68±11; female N=177 (49.9%); EVT n=131 (36.9%); IVT n=157 (44.2%); IVT+EVT n=67 (18.9%) were included in the analysis. The total number of ICH was 47 (13%), symptomatic (sICH) 12 (3.4%) and asymptomatic (aICH) 35 (9.9%) in the whole population. NIHSS ≥15.5 at 24 post stroke hours predicted sICH with a sensitivity of 100% and a specificity of 92% (p<0.001). Furthermore, lower age, good collateral circulation on initial CT angiography and lower NIHSS score measured at 24 h independently associated with a favorable 90-day outcome, whereas baseline NIHSS and ASPECT score were not. CONCLUSION: Although partial recanalization, ASPECT< 6, and poor collaterals were significantly associated with sICH, the only independent predictor was NIHSS ≥15.5 at 24 post stroke hours. This suggests a careful evaluation of patients with worsening NIHSS despite an adequate therapy.

Subacute Elevation of Plasma Level of Caspase-Cleaved Cytokeratin-18 is Associated with Hemorrhagic Transformation and Functional Outcome in Ischemic Stroke.

BACKGROUND: Caspase-cleaved cytokeratin-18 (CCCK-18) is an apoptosis marker. Here, we analyzed the relationship between plasma level of CCCK-18 in the acute and subacute stage of ischemic stroke and early and late functional outcome. Besides, correlation among CCCK-18 and complications, such as hemorrhagic transformation (HT) were also explored. METHODS: Plasma concentration of CCCK-18 was investigated in 54 patients at admission and poststroke 72 hours. HT was evaluated by CT scans on 24 poststroke hours. Outcome measures were assessed by modified Rankin scale at hospital discharge and 6-month later. Receiver operating characteristics (ROC) analysis was used to determine the best cut-off values of CCCK-18 as a predictor of unfavorable functional outcome. RESULTS: Significantly elevated CCCK-18 level was observed at 72 hours after onset of stroke, in nonsurviving compared to surviving patients (331 ± 191 ng/L versus 251 ± 164 ng/L, P = .01). Based on ROC analysis, the cut-off value of plasma CCCK-18 levels >223 ng/L at 72 poststroke hours predicted 6-month unfavorable stroke outcome with a sensitivity of 84.4% and a specificity of 77.3% (area under the curve: .851, 95% confidence interval = .745-.955, P < .001). The rate of complications such as HT and in-hospital infection was significantly higher in patients presented with a plasma CCCK-18 level above the cut-off value. CONCLUSIONS: The association between high serum CCCK-18 levels and unfavorable early and late stroke outcome in an unselected study population was first described here. Besides, the apoptosis marker CCCK-18 might be a predictor of further complication such as HT and in-hospital infection.

L-arginine pathway metabolites can discriminate paroxysmal from permanent atrial fibrillation in acute ischemic stroke.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. We aimed to measure the L-arginine pathway metabolites as well as their ratios in patients with different types of AF or sinus rhythm and to explore the relationship among the markers and clinical variables in the subacute phase of acute ischemic stroke (AIS). METHODS: A total of 46 patients with AIS were prospectively enrolled. The patients were divided into three groups based on diagnosis of either sinus rhythm, paroxysmal or permanent AF. Plasma concentration of the L-arginine pathway metabolites were analyzed at post-stroke 24 hours in the three rhythm groups. Besides, clinical variables and laboratory data were recorded. RESULTS: Asymmetric dimetylarginine (ADMA) was significantly higher in patients with permanent AF compared to sinus rhythm (p<0.001). Both ADMA (p<0.001) and symmetric dimethylarginine (SDMA) (p<0.002) at 24 hours were significantly higher among patients with permanent AF compared to those with paroxysmal AF. The L-arginine/SDMA (p<0.031) ratios at 24 hours were significantly higher among patients with sinus rhythm compared to those with permanent AF. ROC analysis also revealed that plasma SDMA cut-off level over 0.639 µmol/L discriminated permanent AF from paroxysmal AF or sinus rhythm with a 90.9% sensitivity and 77.1% specificity. Neutrophil-lymphocyte ratio also showed significantly higher value in individuals with both paroxysmal and permanent AF (p=0.029). CONCLUSION: Plasma level of SDMA could discriminate permanent from paroxysmal AF in the subacute phase of ischemic stroke. In addition, an increased neutrophil-lymphocyte ratio may suggest inflammatory process in the evolution of atrial fibrillation.

Cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring: a prospective, randomized controlled trial.

BACKGROUND: We compared cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring, in the clinical setting of ear-nose-throat surgery. METHODS: One hundred twenty adult patients were randomized to four groups. In groups SEVO and SEVO+ anesthesia was maintained with sevoflurane, in group SEVO+ with additional bispectral index (BIS) and train-of-four (TOF) monitoring. In groups PROP and PROP+ anesthesia was maintained with propofol, in group PROP+ with additional BIS and TOF monitoring. RESULTS: Total cost of anesthesia per hour was greater in group SEVO+ compared to SEVO [€ 19.95(8.53) vs. 12.15(5.32), p <  0.001], and in group PROP+ compared to PROP (€ 22.11(8.08) vs. 13.23(4.23), p <  0.001]. Time to extubation was shorter in group SEVO+ compared to SEVO [11.1(4.7) vs. 14.5(3.9) min, p = 0.002], and in PROP+ compared to PROP [12.6(5.4) vs. 15.2(4.7) min, p <  0.001]. Postoperatively, arterial blood pressure returned to its initial values sooner in groups SEVO+ and PROP+. CONCLUSIONS: Our study demonstrated that the use of BIS and TOF monitoring decreased the total cost of anesthesia drugs and hastened postoperative recovery. However, in our circumstances, these were associated with higher disposables costs. Detailed cost analysis and further investigations are needed to identify patient populations who would benefit most from additional monitoring. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02920749 . Retrospectively registered (date of registration September 2016).

Relationship between Cardiac Troponin and Thrombo-Inflammatory Molecules in Prediction of Outcome after Acute Ischemic Stroke.

BACKGROUND: In patients with acute ischemic stroke (AIS) without cardiovascular complications, we investigated the association of serum concentration of cardiac troponin (high-sensitivity cardiac troponin T [hs-cTnT]) with thrombo-inflammatory markers. METHODS: Thirty-five patients with first-ever AIS were prospectively examined. Serum hs-cTnT was measured 6 and 24 hours after stroke, whereas S100B, high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand, tissue plasminogen activator (tPA), monocyte chemoattractant protein-1 (MCP-1), and P-selectin were measured 6 and 72 hours after stroke. Severity of stroke was assessed by the National Institutes of Health Stroke Scale (NIHSS) on admission, 24 hours later, and at discharge. RESULTS: Concentration of MCP-1 at 6 hours was higher in the serum of patients with worsened NIHSS by 24 hours (P = .009). Concentration of hs-cTnT at both 6 and 24 hours was higher, if NIHSS worsened by discharge (P = .026 and P = .001). A cutoff value for hs-cTnT measured at T24 greater than or equal to 9.4 predicted worsened NIHSS on discharge with a sensitivity of 81% and a specificity of 74% (area: .808, P = .002). Concentration of hs-cTnT at both 6 and 24 hours was also higher in nonsurvivors compared with survivors (P = .03, respectively), and correlated with (1) tPA levels at 6 hours (P = .001 and P = .002, respectively); (2) MCP-1 concentration at 6 hours (P = .01 and P = .015, respectively); and increased hsCRP levels at 72 hours (P = .01, respectively). Concentration of hs-cTnT at 24 hours was an independent predictor of worsened NIHSS at discharge (odds ratio: 1.58, 95% confidence interval: 1.063-2.370, P = .024). CONCLUSIONS: Elevated concentration of hs-cTnT measured 24 hours after AIS is an independent predictor of progressing neurologic deficit in patients without apparent myocardial damage, and also correlates with acute elevation of tPA and MCP-1.

C-reactive protein in the detection of post-stroke infections: systematic review and individual participant data analysis.

We conducted a systematic review and individual participant data meta-analysis to explore the role of C-reactive protein (CRP) in early detection or prediction of post-stroke infections. CRP, an acute-phase reactant binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, thereby activating complement and promoting phagocytosis by macrophages. We searched PubMed up to May-2015 for studies measuring CRP in stroke and evaluating post-stroke infections. Individual participants' data were merged into a single database. CRP levels were standardized and divided into quartiles. Factors independently associated with post-stroke infections were determined by logistic regression analysis and the additional predictive value of CRP was assessed by comparing areas under receiver operating characteristic curves and integrated discrimination improvement index. Data from seven studies including 699 patients were obtained. Standardized CRP levels were higher in patients with post-stroke infections beyond 24 h. Standardized CRP levels in the fourth quartile were independently associated with infection in two different logistic regression models, model 1 [stroke severity and dysphagia, odds ratio = 9.70 (3.10-30.41)] and model 2 [age, sex, and stroke severity, odds ratio = 3.21 (1.93-5.32)]. Addition of CRP improved discrimination in both models [integrated discrimination improvement = 9.83% (0.89-18.77) and 5.31% (2.83-7.79), respectively], but accuracy was only improved for model 1 (area under the curve 0.806-0.874, p = 0.036). In this study, CRP was independently associated with development of post-stroke infections, with the optimal time-window for measurement at 24-48 h. However, its additional predictive value is moderate over clinical information. Combination with other biomarkers in a panel seems a promising strategy for future studies.

Serum L-arginine and dimethylarginine levels in migraine patients with brain white matter lesions.

Background/Aim Migraine is a risk factor for the formation of silent brain white matter lesions (WMLs) that are possibly ischemic in nature. Although dysfunction of the L-arginine/nitric oxide (NO) pathway has been associated with oxidative stress and endothelial dysfunction in migraine, its role in WML development has not been specifically investigated. Thus, this prospective study aimed to measure the serum concentrations of the NO substrate L-arginine, the NO synthase inhibitor asymmetric dimethylarginine (ADMA), and the L-arginine transport regulator symmetric dimethylarginine (SDMA) in migraine patients in a headache-free period. Methods All participants underwent MR imaging to assess for the presence of WMLs on fluid-attenuated inversion recovery imaging. Altogether 109 migraine patients (43 with lesions, 66 without lesions) and 46 control individuals were studied. High-performance liquid chromatography was used to quantify L-arginine, ADMA and SDMA serum concentrations. Migraine characteristics were investigated, and participants were screened for risk factors that can lead to elevated serum ADMA levels independent of migraine. Results Migraine patients and controls did not differ in regard to vascular risk factors. Migraineurs with WMLs had a longer disease duration ( p < 0.001) and a higher number of lifetime headache attacks ( p = 0.005) than lesion-free patients. Higher L-arginine serum levels were found in both migraine subgroups compared to controls ( p < 0.001). Migraine patients with WMLs showed higher ADMA concentrations than lesion-free patients and controls ( p < 0.001, for both). In migraineurs, the presence of WMLs, aura and increasing age proved to be significant predictors of increased ADMA levels ( p = 0.008, 0.047 and 0.012, respectively). SDMA serum levels of lesional migraineurs were higher than in nonlesional patients ( p < 0.001). The presence of lesions and increasing age indicated an increased SDMA level ( p = 0.017 and 0.001, respectively). Binary logistic regression analysis showed that ADMA level ( p = 0.006), increasing age ( p = 0.017) and the total number of lifetime migraine attacks ( p = 0.026) were associated with an increased likelihood of exhibiting WMLs. There was no significant effect of age on ADMA and SDMA concentrations in controls. Conclusions Elevated ADMA levels may impact the pathogenesis of migraine-related WMLs by influencing cerebrovascular autoregulation and vasomotor reactivity. Higher SDMA concentrations may indirectly influence NO synthesis by reducing substrate availability. Elevated L-arginine serum levels might reflect an increased demand for NO synthesis.