The C242T polymorphism of the NAD(P)H oxidase p22(phox) subunit is associated with an enhanced risk for cerebrovascular disease at a young age

Background and Purpose: Oxidative stress has been proposed as a major contributing factor for vascular disease, that acts independently from its participation in predisposing disorders such as diabetes and arterial hypertension. A functionally relevant C242T polymorphism of the CYBA gene encoding the NAD(P)H oxidase p22(phox) subunit, is supposed to lead to an abnormal reduction in the generation of reactive oxygen species in vascular smooth-muscle and endothelial cells. Methods: We investigated the p22(phox) C242T single-nucleotide polymorphism by polymerase chain reaction in consecutive patients with ischemic stroke or transient ischemic attack under the age of 50 (n = 161) and in population-based control subjects (n = 136). Results: Homozygosity for the T variant was associated with an enhanced risk for cerebral ischemia (odds ratio 3.85, confidence interval 1.39-10.64) after adjusting for classical risk factors. Risk for cerebral ischemia was not increased in heterozygous subjects. Conclusion: The p22(phox) C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis. Copyright (C) 2008 S. Karger AG, Basel

Childhood and adult social conditions and risk of stroke

Background: Socioeconomic conditions may strongly influence the risk of stroke. We tested the hypotheses that indexes of social status in different life periods including childhood are inversely associated with stroke risk and that there is a cumulative effect of social conditions during lifetime on the risk of stroke. Furthermore, we investigated whether social advancement compared to the parental generation is associated with reduced stroke risk. Methods: In a case-control study, we assessed parental professional status, highest school degree, professional education and the last professional activity in 370 consecutive patients with ischemic or hemorrhagic stroke or transient ischemic attack [TIA; age 60.7 +/- 12.8 years (mean +/- standard deviation); 31.1% women] and 370 age-and sex-matched control subjects randomly selected from the general population of the same area. Results: Higher level of school exams [odds ratio (OR) 0.58, 95% confidence interval (CI) 0.39-0.86], university or polytechnic high school degrees (OR 0.39, 95% CI 0.24-0.63), nonmanual (last or current) professional activity (OR 0.51, 95% CI 0.37-0.71) and father’s nonmanual professional activity (OR 0.64, 95% 0.43-0.97) were associated with a lower risk of stroke/TIA. Adjustment for vascular risk factors including current smoking and alcohol consumption reduced the strength of these associations and rendered them nonsignificant except for university or polytechnic high school degrees (OR 0.49, 95% CI 0.27-0.87). Additional adjustment for regular sports activity further attenuated the association between academic degrees and risk of stroke/TIA (OR 0.56, 95% CI 0.31-1.02). A score summarizing 4 lifetime social indexes was not independently associated with stroke risk (OR 0.67, 95% CI 0.39-1.16). Social advancement as assessed by changes from paternal manual work to nonmanual work in the index generation was more common among control subjects (23.5%) than patients (15.3%; p = 0.0097), but such advancement was not independently associated with stroke/TIA after adjustment for all covariables (OR 0.82, 95% CI 0.50–1.33). Conclusions: Socioeconomic conditions were inversely linked to the risk of stroke/TIA. These associations were strongly influenced by lifestyle factors such as smoking, alcohol consumption and mainly sports activity. Stroke preventive strategies may have a particularly large potential if they focus on such lifestyle habits in socially disadvantaged groups. Copyright © 2012 S. Karger AG, Base

Increased Expression of Cell-Cell Signaling Genes by Stimulated Mononuclear Leukocytes in Patients with Previous Atherothrombotic Stroke A Whole Genome Expression Profile Study

Background/Aims: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. Methods: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. Results: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell-cell signaling. Conclusion: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell-cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result. Copyright (C) 2009 S. Karger AG, Base

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

Etiology, risk factors and sex differences in ischemic stroke in the Ludwigshafen stroke study, a population-based stroke registry

Background: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. Methods: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST ( Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. Results: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 8 12.6 years) than men (n = 299; 69.7 8 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20–1.56) than in women (1.12; 95% CI 0.97–1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), smallartery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and ‘probable atherothrombotic stroke’ (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p 85 years) was detected. Conclusions: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men

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

Socioeconomic decline and advancement within and between generations and the risk of stroke - a case-control study

Background: Disadvantageous socioeconomic conditions (SEC) in both childhood and adulthood increase the risk of stroke. We investigated whether intergenerational and lifetime social advancement decreases and/or social descent increases stroke risk. Methods: In a case-control study with 466 patients with first-ever ischemic stroke and 807 controls randomly selected from the general population, we compared paternal profession to subjects’ professional education in adolescence and their last profession in adulthood. Furthermore, we constructed a socioeconomic risk score for childhood (based on paternal and maternal profession and occupation, familial, living and material conditions), adolescence (based on highest school degree and professional education), and adulthood (based on last profession, periods of unemployment, and marital status), and compared subjects´ positions at different life stages. Odds ratios were derived based on conditional logistic regression conditioning on age and sex only, after adjustment for medical and lifestyle risk factors, and after additional adjustment for socioeconomic risk score values. Results: Intergenerational upward mobility between paternal profession and subject’s professional education was associated with lower ischemic stroke risk independent of medical and lifestyle risk factors (odds ratio (OR) 0.58; 95% confidence interval (CI) 0.41–0.81) and after additional adjustment for socioeconomic conditions in all three life stages (OR 0.67; 95% CI 0.45–0.99). Advancement between fathers´ profession and subject’s last profession was associated with reduced odds of stroke after adjustment for risk factors (OR 0.65; 95% CI 0.47–0.89), but not significantly after additional adjustment for SEC (OR 0.77; 95% CI 0.52–1.13). Social descent between adolescence and adulthood indicated by the transition into a more disadvantageous tertile of socioeconomic risk score was associated with increased odds of stroke after adjustment for all risk factor (OR 2.93; 95% CI 1.21–7.13). Analyses by sex revealed mostly similar results in men and women with only few potential differences. Conclusions: Our study results indicate that aspects of social downward mobility during adulthood may be associated with increased risk of stroke, whereas intergenerational upward mobility may be linked to a lower stroke risk. If confirmed by future studies, such results may help to focus stroke prevention measures at high risk populations

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

University education and cervical artery dissection

We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.Peer reviewe