Serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase and myeloperoxidase in ischemic stroke

Background and aims: Matrix metalloproteinase (MMP)-8 and myeloperoxidase (MPO) may contribute to cerebral damage in acute ischemic stroke. We tested the hypothesis that levels of MPO, MMP-8 and the ratio between MMP-8 and its regulator, tissue inhibitor of metalloproteinase (TIMP-1), are increased in acute ischemic stroke and its etiologic subgroups and they correlate with stroke severity. Methods: In a cross-sectional case-control study, serum concentrations of MMP-8, MPO and TIMP-1 were assessed within 24 h after admission in 470 first-ever ischemic stroke patients and 809 age-and sex-matched controls, randomly selected from the population. Odds ratios (OR) per decade of log transformed dependent variables were calculated and adjusted for age, sex and vascular risk factors. Results: Levels of MMP-8 (OR 4.9; 95% CI 3.4-7.2), MMP-8/TIMP-1 ratio (3.0; 2.2-4.1) and MPO (6.6; 4.0-11.0) were independently associated with ischemic stroke. MMP-8 levels differed between etiologic stroke subgroups (p = 0.019, ANOVA), with higher levels in cardioembolic stroke and stroke due to large vessel disease, and lower levels in microangiopathic stroke. MMP-8, MMP-8/TIMP-1 ratio and MPO (p <0.001) concentrations showed positive associations with stroke severity independent of stroke etiology. Conclusions: Concentrations of serum neutrophil markers are increased after ischemic stroke and associate with stroke severity and etiology. The value of these biomarkers in diagnostics and prognostics is worth being evaluated. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Association between infectious burden, socioeconomic status, and ischemic stroke

Background and aims: Infectious diseases contribute to stroke risk, and are associated with socioeconomic status (SES). We tested the hypotheses that the aggregate burden of infections increases the risk of ischemic stroke (IS) and partly explains the association between low SES and ischemic stroke. Methods: In a case-control study with 470 ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population, antibodies against the periodontal microbial agents Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, against Chlamydia pneumonia, Mycoplasma pneumoniae (IgA and IgG), and CagA-positive Helicobacter pylori (IgG) were assessed. Results: IgA seropositivity to two microbial agents was significantly associated with IS after adjustment for SES (OR 1.45 95% CI 1.01-2.08), but not in the fully adjusted model (OR 1.32 95% CI 0.86-2.02). By trend, cumulative IgA seropositivity was associated with stroke due to large vessel disease (LVD) after full adjustment (OR 1.88, 95% CI 0.96e3.69). Disadvantageous childhood SES was associated with higher cumulative seropositivity in univariable analyses, however, its strong impact on stroke risk was not influenced by seroepidemiological data in the multivariable model. The strong association between adulthood SES and stroke was rendered nonsignificant when factors of dental care were adjusted for. Conclusions: Infectious burden assessed with five microbial agents did not independently contribute to ischemic stroke consistently, but may contribute to stroke due to LVD. High infectious burden may not explain the association between childhood SES and stroke risk. Lifestyle factors that include dental negligence may contribute to the association between disadvantageous adulthood SES and stroke. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

Serum lipopolysaccharide neutralizing capacity in ischemic stroke.

Introduction Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. Materials and methods The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. Results LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (beta = -0.68, p Conclusion Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.Peer reviewe

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series

To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies.We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic.We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects.Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Low self-reported sports activity before stroke predicts poor one-year-functional outcome after first-ever ischemic stroke in a population-based stroke register

Background: Physical activity (PA) is associated with lower risk of stroke. We tested the hypothesis that lack of pre-stroke PA is an independent predictor of poor outcome after first-ever ischemic stroke. Methods: We assessed recent self-reported PA and other potential predictors for loss of functional independence - modified Rankin Scale (mRS) &gt; 2 - one year after first-ever ischemic stroke in 1370 patients registered between 2006 and 2010 in the Ludwigshafen Stroke Study, a population-based stroke registry. Results: After 1 year, 717 (52.3%) of patients lost their independence including 251 patients (18.3%) who had died. In multivariate logistic regression analysis lack of regular PA prior to stroke (Odds Ratio (OR) 1.7, Confidence Interval (CI) 1.1–2.5), independently predicted poor outcome together with higher age (65–74: OR 1.7; CI 1.1–2.8, 75–84 years: OR 3.3; CI 2.1–5.3; ≥85 years OR 14.5; CI 7.4–28.5), female sex (OR 1.5; CI 1.1–2.1), diabetes mellitus (OR 1.8; CI 1.3–2.5), stroke severity (OR 1.2; CI 1.1–1.2), probable atherothrombotic stroke etiology (OR 1.8; CI 1.1–2.8) and high leukocyte count (&gt; 9.000/mm3; OR 1.4; CI 1.0–1.9) at admission. Subclassifying unknown stroke etiology, embolic stroke of unknown source (ESUS; n = 40, OR 2.2; CI 0.9–5.5) tended to be associated with loss of independence. Conclusion: In addition to previously reported factors, lack of PA prior to stroke as potential indicator of worse physical condition, high leukocyte count at admission as indicator of the inflammatory response and probable atherothrombotic stroke etiology might be independent predictors for non-functional independence in first-ever ischemic stroke

Evolutionary conservations, changes of circadian rhythms and their effect on circadian disturbances and therapeutic approaches

The circadian rhythm is essential for the interaction of all living organisms with their environments. Several processes, such as thermoregulation, metabolism, cognition and memory, are regulated by the internal clock. Disturbances in the circadian rhythm have been shown to lead to the development of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). Interestingly, the mechanism of the circadian rhythms has been conserved in many different species, and misalignment between circadian rhythms and the environment results in evolutionary regression and lifespan reduction. This review summarises the conserved mechanism of the internal clock and its major interspecies differences. In addition, it focuses on effects the circadian rhythm disturbances, especially in cases of ADHD, and describes the possibility of recombinant proteins generated by eukaryotic expression systems as therapeutic agents as well as CRISPR/Cas9 technology as a potential tool for research and therapy. The aim is to give an overview about the evolutionary conserved mechanism as well as the changes of the circadian clock. Furthermore, current knowledge about circadian rhythm disturbances and therapeutic approaches is discussed

Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22)=3.26, p=0.004), ZT24 (t(22)=− 2.66, p=0.015), ZT28 (t(20)=− 2.14, p=0.045) and Per3 at ZT8 (t(22)=− 4.27, p<0.001) and ZT12 (t(22)=− 2.61, p=0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to evenness; similar as prevalent in ADH

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design

Background: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. Key hypotheses/aims: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. Design: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case–control study enrolling patients aged 18–49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient– control pairs enrolled by the end of 2018. Summary: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019