Radoslaw Kazmierski

Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients

Objective: To evaluate the significance of circulating tight-junction (TJ) proteins as predictors of hemorrhagic transformation (HT) in ischemic stroke patients. Methods: We examined 458 consecutive ischemic stroke patients, 7.2% of whom had clinically evident HT. None of the patients was treated with thrombolytic drugs. Serum levels of standard markers of blood–brain barrier (BBB) breakdown (S100B, neuron-specific enolase), TJ proteins (occludin [OCLN], claudin 5 [CLDN5], zonula occludens 1 [ZO1]), and molecules involved in BBB disintegration (matrix metalloproteinase 9 and vascular endothelial growth factor [VEGF]) were assessed upon admission to the emergency department. A clinical deterioration caused by HT (cdHT) was defined as an increase of ≥4 points in the NIH Stroke Scale score in combination with a visible HT on a CT scan performed immediately after the onset of new neurologic symptoms. Results: Patients with cdHT had higher concentrations of OCLN, S100B, and the CLDN5/ZO1 ratio, and a lower level of VEGF than those without cdHT. CLDN5 levels also correlated with cdHT occurrence when estimated within 3 hours of stroke onset. We also demonstrated correlations between the levels of circulating TJ molecules and the level of S100B, which is a previously established marker of BBB disruption. Conclusions: Analyzing serum levels of TJ proteins, like CLDN5, OCLN, and CLDN5/ZO1 ratio, as well as S100B and VEGF, is an effective way to screen for clinical deterioration caused by HT in ischemic stroke patients, both within and after the IV thrombolysis time window.

Automatic Segmentation of Cerebrospinal Fluid, White and Gray Matter in Unenhanced Computed Tomography Images

RATIONALE AND OBJECTIVES Although segmentation algorithms for cerebrospinal fluid (CSF), white matter (WM), and gray matter (GM) on unenhanced computed tomographic (CT) images exist, there is no complete research in this area. To take into account poor image contrast and intensity variability on CT scans, the aim of this study was to derive and validate a novel, automatic, adaptive, and robust algorithm. MATERIALS AND METHODS Unenhanced CT scans of normal subjects from two different centers were used. The algorithm developed uses adaptive thresholding, connectivity, and domain knowledge and is based on heuristics on the shape of CT histogram. The slope of the intensity histogram corresponding to the three-dimensional largest connected region in a variable CSF intensity range is tracked to determine the critical intensity, which serves as an initial classifier of CSF-WM. Thresholds of CSF, WM, and GM are then optimally derived to minimize classification overlap. Multiple, null, and erroneous classifications are resolved by applying domain knowledge. RESULTS The ground-truth regions with the minimal partial volume effect were used to evaluate segmentation results using the statistical markers. Average sensitivity, Dice index, and specificity, respectively, for the first center were 95.7%, 97.0%, and 98.6% for CSF; 96.1%, 97.3%, and 98.8% for WM; and 95.2%, 94.3%, and 92.8% for GM. The results were consistent for the second data center. CONCLUSIONS The algorithm automatically identifies CSF, WM, and GM on unenhanced CT images with high accuracy, is robust to data from different scanners, does not require any parameter setting, and takes about 5 minutes in MATLAB to process a 512 × 512 × 30 scan. The algorithm has potential use in research and clinical applications.

Anti-inflammatory cytokines in subclinical carotid atherosclerosis

Some studies have shown correlations between selected proinflammatory factors and carotid atherosclerosis. It has not been established whether anti-inflammatory cytokines are associated with carotid intima–media thickness (IMT), an ultrasound surrogate marker of atherosclerosis. Therefore, the authors studied the relationship between the carotid IMT and serum levels of interleukin (IL)-10 and transforming growth factor-β1 in 76 subjects. They discovered that lower IL-10 levels were associated with increased mean IMT in common carotid arteries.

Common carotid artery remodeling studied by sonomorphological criteria.

Background and Purpose. Only a few attempts have been made to establish the impact of critical intima‐media thickness (IMT) on narrowing of the lumen of the common carotid artery (CCA). In the present study, sonomorphological criteria have been used to assess how intima‐media thickening in the CCA may influence the artery geometry.Methods. High‐resolution ultrasonography was employed in 233 patients (466 arteries) to quantify the selected parameters of CCA biometry: IMT, arterial lumen diameter (LD), interadventitial diameter (IAD), and outer artery diameter (OAD).Results. With an increase of CCA IMT up to the critical point of 1.2 mm, the LD showed parallel compensatory increases. Above the inflection point of 1.3 mm, the lumen became progressively narrower proportionally to the increasing IMT.Conclusion. There are limits to the compensa‐tory enlargement of the CCA lumen. Above the inflection point of CCA IMT of 1.3 mm, the artery lumen becomes progressively narrower with increasing IMT.

Association of atherosclerotic risk factors with carotid adventitial thickness assessed by ultrasonography

There is increasing evidence that adventitial inflammation may participate in atherosclerosis development. The aim of this study was to investigate which atherosclerotic risk factors correlated with carotid adventitial thickness (AT) and to compare them with those associated with carotid intima‐media thickness (IMT). We also set out to test the hypothesis that there is a significant correlation between IMT and AT in the carotid arteries.

Serum Paraoxonase/Arylesterase Activity Affects Outcome in Ischemic Stroke Patients

Background: The severity of neurological deficits arising from ischemic stroke may be related to serum redox homeostasis. The aim of this study was to estimate the effect of serum paraoxonase (PON), arylesterase (ARE) activities and conjugated dienes (CD) on patient outcome during a 1-year follow-up period. Methods: The study included 468 consecutive ischemic stroke patients (251 males, 217 females) with an average age of 67.5 ± 12.4 years. Clinical evaluation was based on vital signs, National Institutes of Health Stroke Scale (NIHSS) scored at the time of admission and on the 7th day after stroke, as well as modified Rankin scale (mRS) and Barthel index (BI) scored at 30, 90, 180 and 360 days after stroke onset. Serum PON, ARE activities and CD concentration were measured with the use of spectrophotometric methods. Results: Serum PON activity alone correlated directly with a favorable outcome during a 3-month observation period. Serum ARE activity correlated directly only with the mRS score in a 1-year observation. PON/ARE ratio showed the strongest direct correlation with favorable stroke outcome expressed by BI and inverse correlation with mRS as compared to serum PON or ARE activities assessed alone. PON/ARE affected the NIHSS score on admission (rS = –0.119, p = 0.014) and on the 7th day after stroke (rS = 0.120, p = 0.015); it also showed an association with the BI and mRS on the 30th (rS = 0.145, p = 0.007 and rS = –0.098, p = 0.049, respectively), 90th (rS = 0.147, p = 0.009, rS = –0.133, p = 0.008, respectively), as well as 180th, and 360th day after stroke. We did not find correlations between the serum CD concentration and stroke outcome. Conclusion: The PON/ARE ratio is an important predictor of ischemic stroke outcome and can be used in clinical practice rather than evaluating either PON or ARE activity alone.

Predictors of early mortality in patients with ischemic stroke

Accurate predictors of early outcome in stroke patients have a number of important applications, such as introducing secondary prevention strategies, supporting treatment decisions or designing randomized clinical trials. Surprisingly, a generally accepted, reliable and well-validated mortality-prediction model is still unavailable. This review outlines the most important predictors of in-hospital mortality that could be assessed at admission to hospital emergency room within 24 h of ischemic stroke onset. A number of factors are discussed such as nonmodifiable factors (e.g., age, gender and genetic factors); type of stroke and its severity – measured by different clinical score scales; predictive models; laboratory markers; special neuroradiological and neurophysiological tests; and comorbid conditions at admission and quality of hospital care.

Population-Based Stroke Atlas for Outcome Prediction: Method and Preliminary Results for Ischemic Stroke from CT

Background and Purpose Knowledge of outcome prediction is important in stroke management. We propose a lesion size and location-driven method for stroke outcome prediction using a Population-based Stroke Atlas (PSA) linking neurological parameters with neuroimaging in population. The PSA aggregates data from previously treated patients and applies them to currently treated patients. The PSA parameter distribution in the infarct region of a treated patient enables prediction. We introduce a method for PSA calculation, quantify its performance, and use it to illustrate ischemic stroke outcome prediction of modified Rankin Scale (mRS) and Barthel Index (BI). Methods The preliminary PSA was constructed from 128 ischemic stroke cases calculated for 8 variants (various data aggregation schemes) and 3 case selection variables (infarct volume, NIHSS at admission, and NIHSS at day 7), each in 4 ranges. Outcome prediction for 9 parameters (mRS at 7th, and mRS and BI at 30th, 90th, 180th, 360th day) was studied using a leave-one-out approach, requiring 589,824 PSA maps to be analyzed. Results Outcomes predicted for different PSA variants are statistically equivalent, so the simplest and most efficient variant aiming at parameter averaging is employed. This variant allows the PSA to be pre-calculated before prediction. The PSA constrained by infarct volume and NIHSS reduces the average prediction error (absolute difference between the predicted and actual values) by a fraction of 0.796; the use of 3 patient-specific variables further lowers it by 0.538. The PSA-based prediction error for mild and severe outcomes (mRS = [2]–[5]) is (0.5–0.7). Prediction takes about 8 seconds. Conclusions PSA-based prediction of individual and group mRS and BI scores over time is feasible, fast and simple, but its clinical usefulness requires further studies. The case selection operation improves PSA predictability. A multiplicity of PSAs can be computed independently for different datasets at various centers and easily merged, which enables building powerful PSAs over the community.

The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients

AbstractInterferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients.In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens.BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit.

The Association between Serum Matricellular Protein: Secreted Protein Acidic and Rich in Cysteine-Like 1 Levels and Ischemic Stroke Severity

BACKGROUND The role of matricellular proteins like secreted protein acidic and rich in cysteine-like 1 (SC1) has been shown in important functions in the central nervous system, including the regulation of synaptic stability with upregulation throughout axonal regeneration. The aim of this study was to determine whether SC1 is related to ischemic stroke severity. METHODS A total of 132 consecutively recruited patients admitted for acute ischemic stroke were included in this observational prospective study. Stroke severity was evaluated in the National Institutes of Health (NIHSS) scale on hospital admission. RESULTS There was a positive correlation between SC1 levels and NIHSS score (r = .22, P = .009). Compared with patients with NIHSS scores lower than 5 at admission, patients with moderate and severe stroke (NIHSS ≥ 6) had significantly higher SC1 levels: 4.84 (2.53-11.58) ng/mL versus 3.31 (1.67-8.95) ng/mL (P = .01). SC1 was an independent predictor of stroke severity at admission (adjusted odds ratio =1.25; 95% confidence interval, 1.03-1.97; P = .04). CONCLUSION SC1 levels were independently associated with ischemic stroke severity evaluated by the NIHSS.