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Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF 3 -7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF 3 -7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aleksandra Rutkowska has patent #EP24191137.9 pending to n/a. Bartosz Karaszewski has patent #EP24191137.9 pending to n/a. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The differences in vascular risk factors' and stroke burden across Europe are notable, however there is limited understanding of the influence of socioeconomic environment on the quality of secondary prevention and outcome after acute ischemic stroke., Patients and Methods: In this observational multicenter cohort study, we analyzed baseline characteristics, reperfusion treatment, outcome and secondary prevention in patients with acute ischemic stroke from three tertiary-care teaching hospitals with similar service population size in different socioeconomic environments: Bern/CH/ n  = 293 (high-income), Gdansk/PL/ n  = 140 (high-income), and Lutsk/UA/ n  = 188 (lower-middle-income)., Results: We analyzed 621 patients (43.2% women, median age = 71.4 years), admitted between 07 and 12/2019. Significant differences were observed in median BMI (CH = 26/PL = 27.7/UA = 27.8), stroke severity [(median NIHSS CH = 4(0-40)/PL = 11(0-33)/UA = 7(1-30)], initial neuroimaging (CT:CH = 21.6%/PL = 50.7%/UA = 71.3%), conservative treatment (CH = 34.1%/PL = 38.6%/UA = 95.2%) (each p  < 0.001), in arterial hypertension (CH = 63.8%/PL = 72.6%/UA = 87.2%), atrial fibrillation (CH = 28.3%/PL = 41.4%/UA = 39.4%), hyperlipidemia (CH = 84.9%/PL = 76.4%/UA = 17%) (each p  < 0.001) and active smoking (CH = 32.2%/PL = 27.3%/UA = 10.2%) ( p  < 0.007). Three-months favorable outcome (mRS = 0-2) was seen in CH = 63.1%/PL = 50%/UA = 59% (unadjusted- p  = 0.01/adjusted- p CH-PL/CH-UA = 0.601/0.981), excellent outcome (mRS = 0-1) in CH = 48.5%/PL = 32.1%/UA = 27% (unadjusted- p  < 0.001/adjusted- p CH-PL/CH-UA = 0.201/0.08 and adjusted-OR CH-UA = 2.09). Three-months mortality was similar between groups (CH = 17.2%/PL = 15.7%/UA = 4.8%) (unadjusted- p  = 0.71/adjusted- p CH-PL/CH-UA = 0.087/0.24). Three-months recurrent stroke/TIA occurred in CH = 3.1%/PL = 10.7%/UA = 3.1%, adjusted- p /OR CH-PL = 0.04/0.32). Three-months follow-up medication intake rates were the same for antihypertensives. Statin/OAC intake was lowest in UA = 67.1%/25.5% (CH = 87.3%/39.2%/unadjusted- p  < 0.001/adjusted- p CH-UA = 0.02/0.012/adjusted-OR CH-UA = 2.33/2.18). Oral intake of antidiabetics was lowest in CH = 10.8% (PL = 15.7%/UA = 16.1%/unadjusted- p  = 0.245/adjusted- p CH-PL/CH-UA = 0.061/0.002/adjusted-OR CH-UA = 0.25). Smoking rates decreased in all groups during follow-up., Discussion and Conclusion: Substantial differences in presentation, treatment and secondary prevention measures, are linked to a twofold difference in adjusted 3-months excellent outcome between Switzerland and Ukraine. This underscores the importance of socioeconomic factors that influence stroke outcomes, emphasizing the necessity for targeted interventions to address disparities in treatment and secondary prevention strategies., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MRH reports grants from SITEM Research Funds and the. Swiss Heart Foundation, outside the sumbitted work and grants from the Swiss National Science Foundation partly related to the submitted work. KA reports grants from the Swiss National Science Foundation, partly related to the submitted work. All other co-authors report no disclosures directly related to this manuscript.

Background: Hemorrhagic transformation (HT) in acute ischemic stroke is likely to occur in patients treated with intravenous thrombolysis (IVT) and may lead to neurological deterioration and symptomatic intracranial hemorrhage (sICH). Despite the complex inclusion and exclusion criteria for IVT and some useful tools to stratify HT risk, sICH still occurs in approximately 6% of patients because some of the risk factors for this complication remain unknown., Objective: This study aimed to explore whether there are any differences in circulating microRNA (miRNA) profiles between patients who develop HT after thrombolysis and those who do not., Methods: Using qPCR, we quantified the expression of 84 miRNAs in plasma samples collected prior to thrombolytic treatment from 10 individuals who eventually developed HT and 10 patients who did not. For miRNAs that were downregulated (fold change (FC) <0.67) or upregulated (FC >1.5) with p < 0.10, we investigated the tissue specificity and performed KEGG pathway annotation using bioinformatics tools. Owing to the small patient sample size, instead of multivariate analysis with all major known HT risk factors, we matched the results with the admission NIHSS scores only., Results: We observed trends towards downregulation of miR-1-3p, miR-133a-3p, miR-133b and miR-376c-3p, and upregulation of miR-7-5p, miR-17-3p, and miR-296-5p. Previously, the upregulated miR-7-5p was found to be highly expressed in the brain, whereas miR-1, miR-133a-3p and miR-133b appeared to be specific to the muscles and myocardium., Conclusion: miRNA profiles tend to differ between patients who develop HT and those who do not, suggesting that miRNA profiling, likely in association with other omics approaches, may increase the current power of tools predicting thrombolysis-associated sICH in acute ischemic stroke patients. This study represents a free hypothesis-approach pilot study as a continuation from our previous work. Herein, we showed that applying mathematical analyses to extract information from raw big data may result in the identification of new pathophysiological pathways and may complete standard design works., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stańczak, Wyszomirski, Słonimska, Kołodziej, Jabłoński, Stanisławska-Sachadyn and Karaszewski.)

Acidosis is one of the hallmarks of demyelinating central nervous system (CNS) lesions in multiple sclerosis (MS). The response to acidic pH is primarily mediated by a family of G protein-coupled proton-sensing receptors: OGR1, GPR4 and TDAG8. These receptors are inactive at alkaline pH, reaching maximal activation at acidic pH. Genome-wide association studies have identified a locus within the TDAG8 gene associated with several autoimmune diseases, including MS. Accordingly, we here found that expression of TDAG8, as opposed to GPR4 or OGR1, is upregulated in MS plaques. This led us to investigate the expression of TDAG8 in oligodendrocytes using mouse and human in vitro and in vivo models. We observed significant upregulation of TDAG8 in human MO3.13 oligodendrocytes during maturation and in response to acidic conditions. However, its deficiency did not impact normal myelination in the mouse CNS, and its expression remained unaltered under demyelinating conditions in mouse organotypic cerebellar slices. Notably, our data revealed no expression of TDAG8 in primary mouse oligodendrocyte progenitor cells (OPCs), in contrast to its expression in primary human OPCs. Our investigations have revealed substantial species differences in the expression of proton-sensing receptors in oligodendrocytes, highlighting the limitations of the employed experimental models in fully elucidating the role of TDAG8 in myelination and oligodendrocyte biology. Consequently, the study does not furnish robust evidence for the role of TDAG8 in such processes. Nonetheless, our findings tentatively point towards a potential association between TDAG8 and myelination processes in humans, hinting at a potential link between TDAG8 and the pathophysiology of MS and warrants further research., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Caratis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Currently, clinical trials of DMTs strive to determine their effect on neuroinflammation and neurodegeneration. We aimed to determine the impact of currently used DMTs on brain atrophy and disability in RRMS. The main goal of this review is to evaluate the neuroprotective potential of MS therapy and assess its impact on disability., Methods: We performed a systematic analysis of clinical trials that used brain atrophy as an outcome or performed post hoc analysis of volumetric MRI parameters to assess the neuroprotective potential of applied therapies. Trials between 2008 and 2019 that included published results of brain parenchymal fraction (BPF) change and brain volume loss (BVL) in the period from baseline to week 96 or longer were considered., Results: Twelve from 146 clinical trials met the inclusion criteria and were incorporated into the analysis. DMTs that presented a large reduction in BVL also exhibited robust effects on clinical disability worsening, e.g., alemtuzumab with a 42% risk reduction in 6-month confirmed disability accumulation ( p = 0.0084), ocrelizumab with a 40% risk reduction in 6-month confirmed disability progression ( p = 0.003), and other DMTs (cladribine and teriflunomide) with moderate influence on brain atrophy were also associated with a marked impact on disability worsening. Dimethyl fumarate (DEFINE) and fingolimod (FREEDOMS I) initially exhibited significant effect on BVL; however, this effect was not confirmed in further clinical trials: CONFIRM and FREEDOMS II, respectively. Peg-IFN- β 1a shows a modest effect on BVL and disability worsening., Conclusion: Our results show that BVL in one of the components of clinical disability worsening, together with other variables (lesion volume and annualized relapse rate). Standardization of atrophy measurement technique as well as harmonization of disability worsening and progression criteria in further clinical trials are of utmost importance as they enable a reliable comparison of neuroprotective potential of DMTs., Competing Interests: BK received independent (investigator initiated, project leader) grants from Siemens and Nutricia; is a member of an Astra Zeneca advisory board working on standard use of a new therapy for anticoagulant associated intracranial haemorrhage; provided content-independent lectures funded by Astra Zeneca, Biogen, Novartis, Medtronic, Boehringer Ingelheim, Servier, Angels Initiative; and was/is an investigator in clinical trials founded by Baxalta, Roche, Novartis, Astra Zeneca. MC was an investigator in clinical trials founded by Novartis, Teva, Biogen, Sanofi, and Serono. The authors JK and AW declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Magdalena Chylińska et al.)

Purpose: Wake-up stroke constitutes up to 1/4 of all ischaemic strokes; however, its pathomechanisms remain largely unknown. Although low nocturnal blood flow may be the underlying cause, little is known about blood pressure (BP) characteristic of wake-up stroke patients. The aim of our study was to look for differences in BP variables between wake-up stroke and known-onset stroke patients and to seek BP indices which could distinguish wake-up stroke patients from other stroke patients., Materials and Methods: In the study, we included ischaemic stroke patients in whom office BP measurement and Ambulatory BP monitoring (ABPM) were recorded at day 7, after acute hypertensive response. The daytime period was defined as the interval from 6 a.m. to 10 p.m. From ABPM, we obtained parameters of BP variability. Additionally, we calculated the BP percentage differences defined as (supine office BP-average daytime BP)/average daytime BP for systolic, diastolic, and mean blood pressure. We calculated analogous indices for night-time. The univariate and multivariate relationships between BP variables and wake-up stroke were analysed., Results: Among the recruited 120 patients (aged 61.6 ± 12.3; 88 [73%] males; the baseline National Institutes of Health stroke scale score 4 [3-8]), 36 (30%) had wake-up stroke. In a univariate analysis, the systolic and mean daytime and night-time BP differences were significantly lower in patients with wake-up stroke [(-1.92 (-11.55 to 3.95) vs 4.12 (-2.48 to 11.31), p  = 0.006 and -6.20 (-12.32 to 7.42) vs 2.00 (-6.86 to 11.65), p  = 0.029 for daytime, respectively; 0.00 (-9.79 to 11.82) vs 9.84 (0.00 to 18.25), p  = 0.003 and 0.51 (-8.49 to 12.08) vs 7.82 (-2.47 to 20.39), p  = 0.026, for night-time, respectively]. After adjustment for possible confounders, the systolic BP difference remained significantly associated with wake-up stroke (odds ratio = 0.96, 95% confidence interval = 0.92-1.00, p  = 0.039)., Conclusion: The subacute office-ambulatory BP difference including the dynamic (systolic BP), but not static BP component was independently associated with wake-up stroke.

Background: Adenosine deaminase (ADA) via two isoenzymes, ADA1 and ADA2, regulates intra- and extracellular adenosine concentrations by converting it to inosine. In the central nervous system (CNS), adenosine modulates the processes of neuroinflammation and demyelination that together play a critical role in the pathophysiology of multiple sclerosis (MS). Except for their catalytic activities, ADA isoenzymes display extra-enzymatic properties acting as an adhesion molecule or a growth factor., Aims: This study aimed to explore the distribution and activity of ADA1 and ADA2 in the plasma and the CSF of MS patients as well as in the human brain microvascular endothelial cells (HBMEC), human brain vascular pericytes and human astrocytes., Methods and Results: The enzyme assay following reverse phase-high performance liquid chromatography (HPLC) analysis was used to detect the ADA1 and ADA2 activities and revealed an increased ratio of ADA1 to ADA2 in both the plasma and the CSF of MS patients. Plasma ADA1 activity was significantly induced in MS, while ADA2 was decreased in the CSF, but significance was not reached. The brain astrocytes, pericytes and endothelial cells revealed on their surface the activity of ADA1, with its basal level being five times higher in the endothelial cells than in the astrocytes or the pericytes. In turn, ADA2 activity was only observed in pericytes and endothelial cells. Stimulation of the cells with pro-inflammatory cytokines TNFα/IL17 for 18 h decreased intracellular nucleotide levels measured by HPLC only in pericytes. The treatment with TNFα/IL17 did not modulate cell-surface ATP and AMP hydrolysis nor adenosine deamination in pericytes or astrocytes. Whereas in endothelial cells it downregulated AMP hydrolysis and ADA2 activity and upregulated the ADA1, which reflects the ADA isoenzyme pattern observed here in the CSF of MS patients., Conclusion: In this study, we determined the impaired distribution of both ADA isoenzymes in the plasma and the CSF of patients with MS. The increased ADA1 to ADA2 ratio in the CSF and plasma may translate to unfavorable phenotype that triggers ADA1-mediated pro-inflammatory mechanisms and decreases ADA2-dependent neuroprotective and growth-promoting effects in MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kutryb-Zajac, Kawecka, Caratis, Urbanowicz, Braczko, Furihata, Karaszewski, Smolenski and Rutkowska.)

Background: Peak width of Skeletonized Mean Diffusivity (PSMD), as a novel marker of white matter (WM) microstructure damage, is associated with cognitive decline in several WM pathologies (i.e., small vessel disorders). We hypothesized that markers combining alterations in whole WM could be associated with cognitive dysfunction in relapsing-remitting multiple sclerosis (RRMS) patients., Methods: We used PSMD based on tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) magnetic resonance (MR) scans. We investigated RRMS patients (n = 73) undergoing interferon beta (IFN-β) therapy. In this cross-sectional study, we investigated the association between neuropsychological data and clinical and MRI variables: PSMD, WM hypointensities, and normalized brain volume (NBV)., Results: In our cohort, 37 (50.7%) patients were recognized as cognitively impaired (CI) and 36 (49.3%) patients were cognitively normal (CN). In regression analysis, PSMD was a statistically significant contributor in the California Verbal Learning Test (CVLT) list A (p = 0.04) and semantic fluency (p = 0.036). PSMD (p < 0.001, r 2  = 0.35), NBV (p = 0.002, r 2  = 2.6) and WM hypointensities (p < 0.001, r 2  = 0.40) were major contributors to upper extremity disability (9HPT) in the CN subgroup. A significant contributor in the majority of neuropsychological measures was education attainment., Conclusion: We investigated PSMD as a new parameter of WM microstructure damage that is a contributor in complex cognitive tasks, CVLT performance, and semantic fluency. PSMD was a statistically significant contributor to upper extremity disability (9HPT) together with WM hypointensities and NBV. Education attainment proved to be relevant in the majority of cognitive domains. Further studies are needed to estimate PSMD relevance as a marker of CI in MS., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The main and well-defined complication of intravenous administration of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is symptomatic intracranial hemorrhage (sICH). However, rtPA might also be connected with the formation of cerebral microbleeds (CMBs), located remotely from the ischemic lesions, that may remain clinically silent. This association might be important because the load of CMBs has been associated with cognitive impairment. We investigated whether administration of rtPA in AIS results in the appearance of new CMBs and if the initial load of CMBs is associated with hemorrhagic transformation., Methods: A total of fifty-nine consecutive patients with AIS treated with rtPA underwent MRI including T2 * -weighted Echo Planar Imaging (T2 * -EPI) shortly before and 7-9 days after rtPA administration. We calculated the load of new CMBs located outside the MR diffusion restriction area in the follow-up imaging and assessed hemorrhagic transformation with ECASS-II scoring., Results: A total of forty-nine patients were included for the final analysis. On initial T2 * -EPI-GRE, 37 baseline microbleeds (CMBs) were observed in 14 patients (28.6%). On follow-up T2 * -EPI-GRE amount of CMBs increased to a total number of 103. New CMBs were found in 5 (14.3%) of 35 patients without and in 9 (64.3%) of 14 with any baseline CMBs. Multiple logistic regression analysis indicated that presence of baseline CMBs (risk ratio [RR] 5.95, 95% CI 2.69-13.20, p < 0.001) and lower platelets level (risk ratio [RR] 0.992, 95% CI 0.986-0.998, p = 0.007) were independently associated with new CMBs. The baseline load of CMBs was not associated with the risk of hemorrhagic transformation., Conclusion: In this study, new CMBs were found in nearly 30% of patients with AIS on the 7-9 days after rtPA treatment. Baseline CMBs correlated with a higher risk of new CMBs appearing after the rtPA treatment, independently of other factors. At the same time, in our sample, baseline CMBs did not correlate with an increased risk of hemorrhagic transformation. Since the associations between the CMBs load and cognitive impairment have already been proved, further studies are warranted to investigate possible associations between the thrombolytic treatment of patients with AIS, mainly those with baseline CMBs, and the risk of earlier cognitive decline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jabłoński, Gójska-Grymajło, Ossowska, Szurowska, Wyszomirski, Rojek and Karaszewski.)

Background: Changes of the coagulation system are promoted by serious infectious or noninfectious diseases, surgical procedures, and exogenous substances, including drugs. This study aimed to assess the effect of methylprednisolone pulses on selected parameters of the coagulation system., Methods: The study group consisted of patients suffering from multiple sclerosis, thyroid orbitopathy, or sudden sensorineural hearing loss. 48 patients and 20 healthy volunteers were examined. The hemostatic parameters: activity of coagulation factors (VIII, IX, and XI), antithrombin activity, protein C and S activity, and concentration of soluble tissue factor were analyzed at baseline and after 3 g and 5 g of methylprednisolone administration., Results: A statistically significant increase was noted in the activity of all the studied plasma coagulation factors, plasma coagulation inhibitors (except protein S activity), and the concentration of soluble tissue factor after methylprednisolone administration., Conclusion: The glucocorticoids administered in the intravenous pulses of methylprednisolone shift the balance toward thromboembolic complications., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Przemysław Kłosowski et al.)

Introduction: Since the turn of the century, epidemiological studies have shown an increase in stroke hospitalisation rates among young adults in contrast to a decline in rates seen among the older population. The aim of the present study was to investigate the trends of stroke hospitalisation rates and case fatality ratios (CFR) over the decade starting in 2010 in different age groups of the Polish population., Material and Methods: The patients were identified on the basis of the Polish National Health Fund that gathers all the data of the Hospital Discharge Registry as well as the National Cause of Death Registry of patients with stroke who were hospitalised between 2010 and 2019 and who were diagnosed according to the International Classification of Diseases - Tenth Revision (ICD-10) with haemorrhagic stroke (HS; codes I61* and I62*) and ischaemic stroke (IS; codes I63*)., Results: From a total nationwide cohort of 799,132 stroke patients (86.2% with IS and 13.8% with HS) treated between 2010 and 2019, a group of 22,329 patients (2.79%) aged 18-44 years was selected, among whom 69.6% had IS and 30.4% had HS. We documented a statistically significant increase in the IS hospitalisation rate in young adults alongside a decrease of this rate in those aged > 64. Among young adults with IS, the highest increase (p = 0.001) was observed for those aged 35-44 in 2019 (up to 39.2), and was significant each year starting from 2017 (2017-2019: p < 0.01). In the case of HS, the annual number of patients did not change significantly. In 2019 (compared to 2010), a decrease in 30-day, 90-day and 1-year CFR was noted in all age groups of patients with IS and HS. Stroke aetiology of IS was diagnosed in 60% of patients. More than 40% of patients with IS were discharged with the diagnosis of stroke of unspecified cause., Conclusions: In the case of IS, opposite trends of hospitalisation rates in younger and older age groups were documented, with the highest increase of IS in patients aged 35-44. A decline in CFR was observed for both IS and HS in all age groups.

Intravenous recombinant tissue plasminogen activator (rtPA) is, besides mechanical thrombectomy, the highest class evidence based reperfusion treatment of acute ischemic stroke (AIS). The biggest concern of the therapy is symptomatic intracranial hemorrhage (sICH), which occurs in 3-7% of all treated patients, and is associated with worse functional outcome. Finding a method of the powerful identification of patients at highest risk of sICH, in order to increase the percentage of stroke patients safely treated with rtPA, is one of the most important challenges in stroke research. To address this problem, we designed a complex project to identify blood, neuroimaging, and clinical biomarkers combined for prospective assessment of the risk of rtPA-associated ICH. In this paper we present results of blood proteomic and peptide analysis of pilot 41 AIS patients before rtPA administration (the test ICH group, n = 9 or the controls, without ICH, n = 32). We demonstrated that pre-treatment blood profiles of 15 proteins differ depending on whether the patients develop rtPA-associated ICH or not. SWATH-MS quantification of serum or plasma proteins might allow for robust selection of blood biomarkers to increase the prospective assessment of rtPA-associated ICH over that based solely on clinical and neuroimaging characteristics., (© 2021. The Author(s).)

Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin ( CP ) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.

Selected and basic indicators of acute ischaemic stroke care in Poland are reported cross-regionally based on the analysis of claims data of the National Health Fund (NFZ) in 2017, the most reliable source of healthcare funding in the country, being a single public payer. For research purposes, a selection algorithm based on the diagnosis coded as I63 according to the International Classification of Diseases (ICD-10) was used to identify all ischaemic stroke patients in the claims database provided by the NFZ. Stroke units and other centres providing treatment for acute ischaemic stroke patients were examined. The analysis showed marked differences between provinces in terms of stroke unit treatment availability. The crude and standardised rates of acute ischaemic stroke admissions to stroke units varied between provinces. Moreover, substantial differences were observed for the thrombolysis implementation rate, access to rehabilitation, hospital stay and early prognosis. As the leading cause of disability and the second leading cause of death in developed countries, stroke requires a well-organised, evidence-based healthcare system provided for both acute treatment and rehabilitation. Continuous monitoring of healthcare is crucial to identify weaknesses and areas for improvement.

Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Ischemic stroke (IS) still constitutes a serious problem for public health worldwide. The data on its burden in Poland before 2009 is limited and came only from a few metropolitan areas., The Aims of the Study Were: To assess temporal trends in the hospital admissions, treatment, and outcomes of IS in Poland in 2009-2013, to identify risk factors for IS mortality and to compare the results with other countries., Methods: The data from the Polish Stroke Registry were analyzed. The data concerned all subjects hospitalized due to IS (classified according to the ICD10 classification as I63.0-I63.9) as primary diagnosis in Poland in 2009-2013. Temporal trends in treatment and outcome were analyzed. Hospital admissions rates as well as case fatality and 12-month mortality rates were calculated., Results: Altogether, 360,556 patients (47.5% of males) were hospitalized due to IS in Poland in 2009-2013. The median of age was 75 years, IQR 18 (Women 78, IQR 14 vs. Men 70, IQR 17; p  < 0.001). The hospital admissions age-standardized annual rate for IS in Poland in 2013 was 8% lower than in 2009 (169 vs. 157/100,000; p for trend < 0.001). In-hospital case fatality has slightly decreased (from 13.6% in 2009 to 12.9% in 2013; p for trend < 0.001). One-year posthospital mortality rate has not changed (19.3% in 2009 and 2013). The percentage of IS subjects treated with intravenous thrombolysis was low but increased from 1.7% in 2009 to 6.3% in 2013 ( p for trend <0.001)., Conclusion: Since 2009, Poland has had national epidemiological data on the hospital admissions, treatment, and outcomes in IS. The data indicate a slow improvement of in-hospital survival and suggest the need for better stroke prevention and further dissemination of reperfusion therapy.

Introduction: Acute basilar artery occlusion (BAO) results in strokes characterized by poor outcome. Intravenous and intraarterial thrombolysis with rt-PA (IV rt-PA and IA rt-PA, respectively) and mechanical thrombectomy (MT) are the most commonly used techniques to treat BAO, but their efficacy remains unclear. Unlike in previous papers, we compared all three methods of the treatment in a single work, including an update of meta-analysis regarding each of the three therapeutic approaches with recent trials., Methods: We systematically reviewed all original studies testing the efficacy of any of the three basic methods of BAO treatment dated up to the end of Jan 2017., Results: The final analysis included 31 studies that summarized 1358 patients. These subjects were organized into three therapeutic groups: IV rt-PA, IA rt-PA±IV rt-PA, MT±IV rt-PA±IA rt-PA. The weighted pooled estimates of a favorable outcome (mRS 0-2) were 32.57% (95% CI 16.44-51.03%/I 2 =67.5%, p=0.0795) in the first group, 22.56% (95% CI 16.85-28.79%/I 2 =52.1%, p=0.027) in the second group, and 37.04% (95% CI 32.27-41.92%/I 2 =32%, p=0.0895) in the third group. The Q-test subgroup analysis revealed the statistical superiority of MT±IV rt-PA±IA rt-PA over IA rt-PA±IV rt-PA (mRS 0-2: p=0.0003, mRS 6: p=0.0010) and over any rt-PA administration (either IV rt-PA or IA rt-PA±IV rt-PA) (mRS 0-2: p=0.0006, mRS 6: p=0.0056)., Conclusions: Current data on the effects of the three basic approaches of the treatment of BAO are insufficient to generate high-class EBM guidelines. MT seems to be the most effective method of the treatment of acute BAO. The efficacy of IV or IA thrombolytic therapy in this indication remains unclear., (Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Objectives: Mechanical thrombectomy (MT) is not reimbursed by the Polish public health system. We present a description of 5 years of experience with MT in acute stroke in Comprehensive Stroke Centers (CSCs) in Poland., Methods and Results: We retrospectively analyzed the results of a structured questionnaire from 23 out of 25 identified CSCs and 22 data sets that include 61 clinical, radiological and outcome measures., Results: Most of the CSCs (74%) were founded at University Hospitals and most (65.2%) work round the clock. In 78.3% of them, the working teams are composed of neurologists and neuro-radiologists. All CSCs perform CT and angio-CT before MT. In total 586 patients were subjected to MT and data from 531 of them were analyzed. Mean time laps from stroke onset to groin puncture was 250±99min. 90.3% of the studied patients had MT within 6h from stroke onset; 59.3% of them were treated with IV rt-PA prior to MT; 15.1% had IA rt-PA during MT and 4.7% - emergent stenting of a large vessel. M1 of MCA was occluded in 47.8% of cases. The Solitaire device was used in 53% of cases. Successful recanalization (TICI2b-TICI3) was achieved in 64.6% of cases and 53.4% of patients did not experience hemorrhagic transformation. Clinical improvement on discharge was noticed in 53.7% of cases, futile recanalization - in 30.7%, mRS of 0-2 - in 31.4% and mRS of 6 in 22% of cases., Conclusion: Our results can help harmonize standards for MT in Poland according to international guidelines., (Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Pyrexia soon after stroke is associated with severe stroke and poor functional outcome. Few studies have assessed brain temperature after stroke in patients, so little is known of its associations with body temperature, stroke severity, or outcome. We measured temperatures in ischemic and normal-appearing brain using (1)H-magnetic resonance spectroscopy and its correlations with body (tympanic) temperature measured four-hourly, infarct growth by 5 days, early neurologic (National Institute of Health Stroke Scale, NIHSS) and late functional outcome (death or dependency). Among 40 patients (mean age 73 years, median NIHSS 7, imaged at median 17 hours), temperature in ischemic brain was higher than in normal-appearing brain on admission (38.6°C-core, 37.9°C-contralateral hemisphere, P=0.03) but both were equally elevated by 5 days; both were higher than tympanic temperature. Ischemic lesion temperature was not associated with NIHSS or 3-month functional outcome; in contrast, higher contralateral normal-appearing brain temperature was associated with worse NIHSS, infarct expansion and poor functional outcome, similar to associations for tympanic temperature. We conclude that brain temperature is higher than body temperature; that elevated temperature in ischemic brain reflects a local tissue response to ischemia, whereas pyrexia reflects the systemic response to stroke, occurs later, and is associated with adverse outcomes.

Background: Pyrexia after stroke (temperature ≥37.5°C) is associated with poor prognosis, but information on timing of body temperature changes and relationship to stroke severity and subtypes varies., Methods: We recruited patients with acute ischemic stroke, measured stroke severity, stroke subtype and recorded four-hourly tympanic (body) temperature readings from admission to 120 hours after stroke. We sought causes of pyrexia and measured functional outcome at 90 days. We systematically summarised all relevant previous studies., Results: Amongst 44 patients (21 males, mean age 72 years SD 11) with median National Institute of Health Stroke Score (NIHSS) 7 (range 0-28), 14 had total anterior circulation strokes (TACS). On admission all patients, both TACS and non-TACS, were normothermic (median 36.3°C vs 36.5°C, p=0.382 respectively) at median 4 hours (interquartile range, IQR, 2-8) after stroke; admission temperature and NIHSS were not associated (r(2)=0.0, p=0.353). Peak temperature, occurring at 35.5 (IQR 19.0 to 53.8) hours after stroke, was higher in TACS (37.7°C) than non-TACS (37.1°C, p<0.001) and was associated with admission NIHSS (r(2)=0.20, p=0.002). Poor outcome (modified Rankin Scale ≥3) at 90 days was associated with higher admission (36.6°C vs. 36.2°C p=0.031) and peak (37.4°C vs. 37.0°C, p=0.016) temperatures. Sixteen (36%) patients became pyrexial, in seven (44%) of whom we found no cause other than the stroke., Conclusions: Normothermia is usual within the first 4 hours of stroke. Peak temperature occurs at 1.5 to 2 days after stroke, and is related to stroke severity/subtype and more closely associated with poor outcome than admission temperature. Temperature-outcome associations after stroke are complex, but normothermia on admission should not preclude randomisation of patients into trials of therapeutic hypothermia.

In stressful situations, many animals release alarm pheromones to warn conspecifics of impending danger. The authors sought to establish experimental conditions for a larger study aimed at identifying alarm pheromones emitted by the rat. They placed rats in a specially designed chamber and exposed them to aversive tactile, visual and acoustic stimuli over the course of a few days. The researchers observed rats' behavior and analyzed air samples taken from their immediate environment under the following conditions: (i) when rats were unstressed; (ii) immediately after rats were exposed to aversive stimuli; and (iii) when rats were left alone in the chamber after being conditioned to fear imminent aversive stimuli. Stressed rats emitted several substances that are known to function as alarm pheromones in insects. When previously unstressed control rats were exposed to these same substances, they had a distinct behavioral fear response.

A comprehensive two-dimensional capillary liquid chromatographic (2D LC) method has been established for determination of neuropeptides in rat brain tissue. Rats were exposed to different levels of stress before sacrificing and the aim of this study was to design a powerful separation and detection technique capable of characterizing differences between cerebral neuropeptide expression as a function of stress level. Rat brain samples were homogenized and subjected to clean-up by solid-phase extraction (SPE) on both a reversed-phase (C(18)) and a weak cation-exchange (CBA) cartridge. The samples were divided in two fractions (A and B) depending on retention on the CBA column. Subsequently, 50 microL of the sample were injected on to a strong cation exchanger (SCX) at a mobile phase pH of 3, which enabled preconcentration of positively charged compounds. The trapped compounds were eluted using step gradients of ammonium formate in water-ACN (90:10, v/v). Before enrichment in the second dimension, the eluate from the first dimension was diluted with water containing 0.1% TFA. The compounds eluting from the first dimension were trapped in the second dimension using a dual precolumn system consisting of two short capillary columns packed with Kromasil C(18), 10 microm particles. Subsequently, the trapped compounds were backflushed on to a 10 cm long, 320 microm I.D. analytical column packed with Kromasil C(18) 3.5 microm particles, on which they were efficiently separated. Detection was performed using an ion-trap mass spectrometer (ITMS) in both the MS and the MS-MS mode. Comparison of base-peak chromatograms (BPC) from MS analysis of stressed and non-stressed rats clearly revealed several differences in neuropeptide expression. The MS-MS data obtained combined with Mascot software were employed for peptide identification.