Hyperthermia in Human Ischemic and Hemorrhagic Stroke: Similar Outcome,Different Mechanisms

Hyperthermia is a predictor of poor outcome in ischemic (IS) and intracerebral hemorrhagic (ICH) stroke. Our aim was to study the plausible mechanisms involved in the poor outcome associated to hyperthermia in stroke. We conducted a case-control study including patients with IS (n = 100) and ICH (n = 100) within the first 12 hours from symptom onset. Specifically, IS and ICH patients were consecutively included into 2 subgroups, according to the highest body temperature within the first 24 hours: Tmax <37.5°C and Tmax ≥37.5°C, up to reach 50 patients per subgroup of temperature for both IS and ICH patients. Body temperature was determined at admission and every 4 hours during the first 48 hours. Main outcome variable was poor functional outcome (modified Rankin scale score >2) at 3 months. Serum levels of glutamate and active MMP-9 were measured at admission. Our results showed that Tmax ≥37.5°C within the first 24 hours was independently associated with poor outcome in both IS (OR, 12.43; 95% CI, 3.73–41.48; p<0.0001) and ICH (OR, 4.29; 95% CI, 1.32–13.91; p = 0.015) after adjusting for variables with a proven biological relevance for outcome. However, when molecular markers levels were included in the logistic regression model, we observed that glutamate (OR, 1.01; 95% CI, 1.00–1.02; p = 0.001) and infarct volume (OR, 1.06; 95% CI, 1.01–1.10; p = 0.015) were the only variables independently associated to poor outcome in IS, and active MMP-9 (OR, 1.04; 95% CI, 1.00–1.08; p = 0.002) and National Institute of Health Stroke Scale (NIHSS) at admission (OR, 1.29; 95% CI, 1.13–1.49; p<0.0001) in ICH. In conclusion, these results suggest that although the outcome associated to hyperthermia is similar in human IS and ICH, the underlying mechanisms may be different.     

Early Depression Screening Is Feasible in Hospitalized Stroke Patients

Background and Purpose

Post-stroke depression (PSD) is common but is not routinely assessed for in hospitalized patients. As a Comprehensive Stroke Center, we screen all stroke inpatients for depression, though the feasibility of early screening has not been established. We assessed the hypothesis that early depression screening in stroke patients is feasible. We also explored patient level factors associated with being screened for PSD and the presence of early PSD.

Methods

The medical records of all patients admitted with ischemic stroke (IS) or intracerebral hemorrhage (ICH) between 01/02/13 and 15/04/13 were reviewed. A depression screen, modified from the Patient Health Questionnaire-9, was administered (maximum score 27, higher scores indicating worse depression). Patients were eligible if they did not have a medical condition precluding screening. Feasibility was defined as screening 75% of all eligible patients.

Results

Of 303 IS and ICH inpatients, 70% (211) were eligible for screening, and 75% (158) of all eligible patients were screened. More than one-third of all patients screened positive for depression (score > 4). Women (OR 2.06, 95% CI 1.06–4.01) and younger patients (OR 0.97, 95% CI 0.96–0.99) were more likely to screen positive. Screening positive was not associated with poor discharge/day 7 outcome (mRS > 3; OR 1.45, 95% CI 0.74–2.83).

Conclusions

Screening stroke inpatients for depression is feasible and early depression after stroke is common. Women and younger patients are more likely to experience early PSD. Our results provide preliminary evidence supporting continued screening for depression in hospitalized stroke patients.     

GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases

We studied whether the serum levels of glial fibrillary acidic protein (GFAP) and of antibodies against the N‐methyl‐d ‐aspartate receptor subunit NR2 (NR2 R_NMDA) can discriminate between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) in stroke patients. We prospectively recruited patients with suspected stroke (72 confirmed) and 52 healthy controls. The type of brain lesion (ICH or IS) was established using brain imaging. The levels of GFAP and of antibodies against NR2 R_NMDA were measured in blood samples obtained within 12 hrs after stroke onset and 24, 48 and 72 hrs and 1 and 2 weeks later using ELISA immunoassay. Improvement in diagnostic performance was assessed in logistic regression models designed to predict the diagnosis and the type of stroke. GFAP peaks early during haemorrhagic brain lesions (at significantly higher levels), and late in ischaemic events, whereas antibodies against NR2 R_NMDA have significantly higher levels during IS at all time‐points. Neither of the two biomarkers used on its own could sufficiently discriminate patients, but when they are used in combination they can differentiate at 12 hrs after stroke, between ischaemic and haemorrhagic stroke with a sensitivity and specificity of 94% and 91%, respectively.     

Post-Stroke Epilepsy in Young Adults: A Long-Term Follow-Up Study

Background

Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH).

Methods and Findings

We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18–50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03–1.11 and 1.08, 95% CI 1.02–1.14).

Conclusions

Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.     

Sex differences in the effects of the moon on ischemic stroke incidence: new findings from Beijing,China

ABSTRACT

Stroke is a major cause of death and disability in China, and no therapies have proven effective to prevent it. Popular belief holds that the lunar cycle affects human physiology, behavior, and health. The aim of our study is to determine whether the lunar cycle impacts the incidence of stroke subtypes [intracerebral hemorrhage (ICH), transient ischemic attack (TIA) and ischemic stroke (IS)]. We retrospectively extracted the discharge registry data of all patients with first-ever acute stroke hospitalized in the affiliated hospital of Beijing University of Traditional Chinese Medicine during 2002–2015. The onset times of stroke were assigned to four primary lunar phases based on NASA definitions. Chi-square tests and multiple logistic regression analyses were used to estimate the association between the lunar cycle and stroke incidence with adjustment for age, sex and season. A total of 5,965 patients with stroke (4,909 admissions for ischemic stroke IS, 754 admissions for ICH, and 302 admissions for TIA) were evaluated in our study. Subgroup analysis indicated that the admission rates of different sexes for IS tended to have opposite variation during the four moon phases. More female patients were admitted during the new moon than in the first and third quarters, while fewer male patients were admitted during the new moon than in the first and third quarters (χ2 = 15.589, P = .001). Multiple logistic regression analyses revealed that men were more likely to be admitted for IS in the first quarter than during the new moon (odds ratio [OR] = 1.252, 95% confidence interval [CI] = 1.076–1.456) (P = .004), and a corresponding trend was also identified for the third quarter (OR = 1.235, 95% CI = 1.062–1.437) (P = .006). No significant gender differences were shown in ICH or TIA. No sex difference is obvious during the full moon. Moon phases seem to affect both genders, but in very different ways. It seems that the new moon is a protective factor for male ischemic stroke patients and a risk factor for female ones. Woman tends to be more vulnerable than ever at the new moon, so deserves more attention and care. The mechanisms underlying this observation are worth studying further.     

The prognostic value of biomarkers in stroke

Background

Ischemic injury triggers inflammatory cascades and changes in the protein synthesis, neurotransmitters and neuro-hormones in the brain parenchyma that may further amplify the tissue damage. The “Triage® Stroke Panel”, a biochemical multimarker assay, detects Brain Natriuretic Peptide (BNP), D-Dimers (DD), Matrix-Metalloproteinase-9 (MMP-9), and S100β protein generating a Multimarker index of these values (MMX). The aims of this prospective study in consecutive patients with ischemic or hemorrhagic stroke were to assess: 1) the rate of an increase of biomarkers (BNP, D-dimer, MMP-9 and S-100β) tested with the Triage Stroke Panel; 2) the correlation between the increase of these biomarkers and functional outcome at 4 months; 3) the risk factors for the increase of biomarkers.

Methods

The outcome of the study was 120-day mortality and it was compared in patients with Stroke Panel >4 and ≤4. Multiple logistic regression analyses were performed to identify independent predictors for death and for the increase of biomarkers.

Results

244 consecutive patients (mean age 73.02 years; 53.7 % males) were included in the study; 210 ischemic strokes and 34 hemorrhagic strokes. 161/244 (66.0 %) had an increase of biomarkers. At 120 days, 85 patients had died (34.8 %). Death was seen in 68/161 patients with an increase of biomarkers (42.2 %) compared with 17/83 patients without (20.5 %). Regression logistic analysis found that a Stroke Panel >4 (OR 3.1; 95 % CI 1.5–6.2, p?=?0.002) was associated with mortality. The increase of biomarkers was independently predicted by an increase of PCR on admission (OR 2.9, 95 CI 1.4–6.0, p?=?0.003).

Conclusions

An increase of biochemical markers such as BNP, D-Dimers, MMP-9, and S100β tested with a Triage Stroke Panel (>4) was correlated with mortality at 120 days from stroke onset.

     

Neuroprotection or increased brain damage mediated by temperature in stroke is time dependent

The control of temperature during the acute phase of stroke may be a new therapeutic target that can be applied in all stroke patients, however therapeutic window or timecourse of the temperature effect is not well established. Our aim is to study the association between changes in body temperature in the first 72 hours and outcome in patients with ischemic (IS) and hemorrhagic (ICH) stroke. We prospectively studied 2931 consecutive patients (2468 with IS and 463 with ICH). Temperature was obtained at admission, and at 24, 48 and 72 hours after admission. Temperature was categorized as low (<36°C), normal (36–37°C) and high (>37°C). As the main variable, we studied functional outcome at 3 months determined by modified Rankin Scale.Temperature in stroke patients is higher than in controls, and increases gradually in the first 72 hours after stroke. A positive correlation between temperature and stroke severity determined by NIHSS was found at 24 and 48 hours, but not at admission or 72 hours. In a logistic regression model, high temperature was associated with poor outcome at 24 hours (OR 2.05, 95% CI 1.59–2.64, p<0.0001) and 48 hours (OR 1.93, 95% CI 1.08–2.34, p = 0.007), but not at admission or 72 hours.Temperature increases in patients with stroke in the first 72 hours, with the harmful effect of high temperature occurring in the first 48 hours. The neuroprotective effect of low temperature occurs within the first 24 hours from stroke onset.     

Comparing Risk Factor Profiles between Intracerebral Hemorrhage and Ischemic Stroke in Chinese and White Populations: Systematic Review and Meta-Analysis

Background

Chinese populations have a higher proportion of intracerebral hemorrhage (ICH) in total strokes. However, the reasons are not fully understood.

Methods

To assess the differences in frequency of major risk factors between ICH and ischemic stroke (IS) in Chinese versus white populations of European descent, we systematically sought studies conducted since 1990 that compared frequency of risk factors between ICH and IS in Chinese or white populations. For each risk factor, in Chinese and Whites separately, we calculated study-specific and random effects pooled prevalence and odds ratios (ORs) for ICH versus IS.

Results

Six studies among 36190 Chinese, and seven among 52100 white stroke patients studied hypertension, diabetes, atrial fibrillation (AF), ischemic heart disease (IHD), hypercholesterolemia, smoking and alcohol. Pooled prevalence of AF was significantly lower in Chinese. Pooled ORs for ICH versus IS were mostly similar in Chinese and Whites. However, in Chinese–but not Whites–mean age was lower (62 versus 69 years), while hypertension and alcohol were significantly more frequent in ICH than IS (ORs 1.38, 95% CI 1.18–1.62, and 1.46, 1.12–1.91). Hypercholesterolemia and smoking were significantly less frequent in ICH in Whites, but not Chinese, while IHD, AF and diabetes were less frequent in ICH in both.

Conclusions

Different risk factor distributions in ICH and IS raise interesting possibilities about variation in mechanisms underlying the different distributions of pathological types of stroke between Chinese and Whites. Further analyses in large, prospective studies, including adjustment for potential confounders, are needed to consolidate and extend these findings.     

Relationship between C - Reactive Protein and Stroke: A Large Prospective Community Based Study

Objective

Previous studies have suggested that C-reactive protein (CRP) was associated with risk of stroke. There were few studies in Asian population, or on stroke subtypes other than ischemic stroke. We thus investigated the relationship between CRP and the risks of all stroke and its subtypes in a Chinese adult population.

Methods

In the current study, we included 90,517 Chinese adults free of stroke and myocardial infarction at baseline (June 2006 to October 2007) in analyses. Strokes were classified as ischemic stroke (IS), intracranial heamorrhage (ICH) and subarachnoid heamorrhage (SAH). High-sensitivity CRP (hs-CRP) were categorized into three groups: <1 mg/L, 1 to 3 mg/L, and >3 mg/L. Cox proportional hazards regression was used to calculate the association between hs-CRP concentrations and all stroke, as well as its subtypes.

Results

During a median follow-up time of 49 months, we documented 1,472 incident stroke cases. Of which 1,049 (71.3%) were IS, 383 (26.0%) were ICH, and 40 (2.7%) were SAH. After multivariate adjustment, hs-CRP concentrations ≥1 mg/L were associated with increased risks of all stroke (hs-CRP 1–3 mg/L: hazard ratio (HR) 1.17, 95% confidential interval (CI) 1.03–1.33; hs-CRP>3 mg/L: HR 1.25, 95% CI 1.07–1.46) and IS (hs-CRP 1–3 mg/L: HR 1.17, 95% CI 1.01–1.36; hs-CRP>3 mg/L: HR 1.33, 95% CI 1.11–1.60), but not with ICH and SAH. Subgroup analyses showed that higher hs-CRP concentration was more prone to be a risk factor for all stroke and IS in non-fatal stroke, male and hypertensive participants.

Conclusion

We found that higher hs-CRP concentrations were associated with a higher risk of IS, particularly for non-fatal stroke, male and hypertensive subjects. In contrast, we did not observe significant associations between hs-CRP and ICH/SAH.     

Hyperacute Detection of Neurofilament Heavy Chain in Serum Following Stroke: A Transient Sign

Serological biomarkers which enable quick and reliable diagnosis or measurement of the extent of irreversible brain injury early in the course of stroke are eagerly awaited. Neurofilaments (Nf) are a group of proteins integrated into the scaffolding of the neuronal and axonal cytoskeleton and an established biomarker of neuro-axonal damage. The Nf heavy chain (NfH^SMI35) was assessed together with brain-specific astroglial proteins GFAP and S100B in hyperacute stroke (6 and 24 h from symptom onset) and daily for up to 6 days. Twenty-two patients with suspected stroke (median NIHSS 8) were recruited in a prospective observational study. Evidence for an ischaemic or haemorrhagic lesion on neuroimaging was found in 18 (ischaemia n = 16, intracerebral haemorrhage n = 2). Serum NfH^SMI35 levels became detectable within 24 h post-stroke (P < 0.0001) and elevated levels persisted over the study course. While GFAP was not detectable during the entire course, S100B levels peaked at the end of the observation period. The data indicate that significant in vivo information on the pathophysiology of stroke may be obtained by the determination of NfH^SMI35. Further studies are required to evaluate whether NfH^SMI35 in hyperacute stroke reflects the extent of focal ischaemic injury seen on neuroimaging or is a consequence of more diffuse neuro-axonal damage.     

Circulating S100A12 Levels Are Associated with Progression of Abdominal Aortic Calcification in Hemodialysis Patients

Vascular calcification is an important factor associated with mortality in dialysis patients. Recently, soluble receptor for advanced glycation end product (sRAGE) and extracellular RAGE binding protein S100A12 (EN-RAGE) have been reported to be involved in the process of vascular calcification. Therefore, we investigated whether sRAGE and S100A12 are useful indicators of progression of abdominal aortic calcification in hemodialysis (HD) patients. We analyzed annual changes in vascular calcification score (VCS) for up to 4 years, compared to clinical and biological parameters in 149 HD patients. VCS was assessed annually using plain X-ray images of the lateral lumbar spine. The progression group was defined as patients with an increase in VCS more than 1 point each year on average during the observation period. Time-averaged concentrations were also evaluated to examine the association between biological parameters and changes in VCS. The patients had a mean age of 58.59 ± 12.93 years; 53.7% were male, and 45% were diabetic. The VCS increased in 55 patients; the mean increase was 1.60 ± 2.91 points. In a stepwise multivariate logistic analysis, we found that higher levels of S100A12 were significantly associated with progression of VCS (odds ratio [OR], 2.622; 95% confidence interval [CI], 1.371–5.016; P = 0.004). The relationship between sRAGE and VCS was not statistically significant (OR, 0.644; 95% CI, 0.302–1.374; P = 0.255). Our findings suggest that serum levels of S100A12 are associated with progression of abdominal aortic calcification in HD patients, independent of sRAGE level.     

Relationship between Interleukin-10 ?1082A/G Polymorphism and Risk of Ischemic Stroke: A Meta-Analysis

Objective

To analyze the association between −1082A/G polymorphism in interleukin-10 (IL-10) gene and ischemic stroke (IS) risk by meta-analysis.

Methods

We carried out a systematic electronic search in PubMed, BIOSIS Previews, Science Direct, Chinese National Knowledge Infrastructure, Chinese Biomedical Database, Weipu database and WANGFANG Database. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated to assess the strength of the association.

Results

7 studies were included. There was no significant association between IL-10 −1082A/G polymorphism and IS risk under all genetic models in overall estimates (A vs. G: OR = 1.23,95%CI = 0.85–1.79;AA vs. GG: OR = 1.01,95%CI = 0.47–2.19; AG vs. GG: OR = 0.76, 95%CI = 0.38–1.55; AA+AG vs. GG: OR = 0.89,95%CI = 0.46–1.73; AA vs. AG+GG: OR = 1.39, 95%CI = 0.91–2.13). Similarly, no associations were found in subgroup analysis based on ethnicity and source of controls. However, removing the study deviating from Hardy–Weinberg equilibrium (HWE) produced statistically significant associations for overall estimates under recessive model(AA VS. AG+GG OR 1.58, 95% CI 1.04–2.42) and among Asians in all genetic models (A VS.G OR 1.64, 95% CI 1.07–2.53; AA vs. GG OR1.91, 95% CI 1.31–2.80; AG vs. GG OR1.44, 95% CI 1.09–1.91; AA+AG vs. GG OR 1.54, 95% CI 1.18–2.01;AA VS. AG+GG OR 1.79, 95% CI 1.07–3.00). Even after Bonferroni correction, the associations were observed still significantly in Asians under the two models (AA vs. GG OR1.91, 95% CI 1.31–2.80, P = 0.0008; AA+AG vs. GG OR 1.54, 95% CI 1.18–2.01, P = 0.001).

Conclusion

This meta-analysis indicates that IL10 −1082 A/G polymorphism is associated with IS susceptibility in Asians and the −1082 A allele may increase risk of IS in Asians. Considering the sample size is small and between-study heterogeneity is remarkable, more studies with subtle design are warranted in future.     

A Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population

To investigate whether single nucleotide polymorphisms (SNPs) of eicosanoid biosynthesis genes are associated with intracerebral hemorrhage (ICH) and ischemic stroke (IS), seven SNPs in the coding or promoter regions were selected: ALOX12 (rs434473, Asn322Ser), ALOX5 (rs2228064, Thr90Thr), ALOX5AP (rs17222919, -1316T/G), PTGES (rs7872802, -404A/G), PTGIS (rs5628, Leu256Leu), PTGS1 (rs3842788, Gln41Gln) and PTGS2 (rs5275, 3'UTR). A total of 398 control subjects and 196 stroke patients (79 ICH and 117 IS) were genotyped by direct sequencing. The rs17222919 SNP was associated with ICH in codominant 1 (P=0.008), dominant (P=0.003) and log-additive (P=0.004) models. Allele frequencies of rs17222919 were different between ICH and controls (P=0.007). However, the seven tested SNPs were not associated with clinical phenotypes (NIHSS, MBI and CRPS) in ICH and IS. These results suggest that the promoter SNP rs17222919 of ALOX5AP may be associated with the development of ICH in Korean population.     

Polymorphisms in the Promoters of the MMP-2 and TIMP-2 Genes Are Associated with Spontaneous Deep Intracerebral Hemorrhage in the Taiwan Population

Background

Spontaneous intracerebral hemorrhage (ICH) is a devastating stroke subtype. Matrix metalloproteinases (MMPs) function in the degradation of extracellular matrix and the activities of MMPs are modulated by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). This study aimed to discuss relationship of MMP-2 and TIMP-2 to spontaneous deep ICH (SDICH) susceptibility and hematoma size.

Methods

Associations were tested by logistic regression and general linear models (GLM) where appropriate, adjusting with covariables of age, sex, hypertension, diabetes mellitus, smoking, and alcohol consumption. Association analyses were performed first by stratification of genders and then by the age of 65 years old (y/o). Elder population was defined as subjects who were older than 65 y/o.

Results

There were 396 SDICH patients and 376 control subjects in this study. In the elder group, rs7503607 C>A variant in TIMP-2 was associated with SDICH in male and overall patients (OR = 3.49, 95% CI 1.45 to 8.40, P = 0.005 and OR = 2.45, 95% CI 1.37 to 4.38, P = 0.003, respectively) in additive genetic model. In recessive genetic model, rs2285053 TT genotype in MMP-2 was correlated to SDICH in male patients and overall elder group (OR = 7.30, 95% CI 1.3 to 40, P = 0.02 and OR = 2.91, 95% CI 1.02 to 8.31, P = 0.046, respectively), and rs7503726 AA genotype in TIMP-2 was associated with SDICH in female patients (OR = 0.29, 95% CI 0.1 to 0.84, P = 0.02). In younger male and overall younger patients, SDICH patients who had supratentorial hemorrhage had significantly lower frequency of AA genotypes in rs7503726 than those with infratentorial hemorrhage (OR = 0.36, 95% CI 0.17 to 0.75, P = 0.006 and OR = 0.43, 95% CI 0.22 to 0.84, P = 0.014, respectively). Hemorrhage size increased by 9.7 (95% CI 2.1 to 43, P = 0.004) cm³ per minor allele (A) of the rs7503607 variant in the elder female patients and increased by 4.3 (95% CI 1.4 to 12.9, P = 0.009) cm³ per minor allele (A) in all elder patients. In younger patients, the hemorrhage size decreased by 3.3 (95% CI 1.2 to 9.5, P = 0.03) cm³ per minor allele of the s7503726 variant in the female patients.

Conclusions

This study showed a significant association between the variants of MMP-2 and TIMP-2 promoters and SDICH susceptibility with significant age and gender differences. Hemorrhage location and size might be affected by TIMP-2 promoter variants in the SDICH patients.     

“MOONSTROKE”: Lunar patterns of stroke occurrence combined with circadian and seasonal rhythmicity—A hospital based study

Both time of the day and season have been shown to have a significant effect on stroke incidence. In contrast, the role played by the moon has been little studied. We aimed to investigate the potential association of the lunar phase with the incidence of stroke subtypes [intracerebral hemorrhage (ICH), transient ischemic attack (TIA) and ischemic stroke (IS)], adjusted by circadian and seasonal variations. Consecutive stroke admissions to the Royal Melbourne Hospital (RMH) were analyzed from 2004–2011. Of 6252 patients, 4085 (65.3%) had confirmed dates and hour of the day. Of these, 632 (15.5%) had ICH, 658 (16.1%) presented with TIA and 2202 (53.9%) had IS. There were also 593 (14.5%) stroke mimics. We measured the association of stroke incidence with a particular lunar phase using an incidence rate ratio (IRR) with 95% confidence intervals (CI) using Poisson regression model (new moon set as reference). Compared with new moon phase, ICHs occurred significantly more during the first quarter (IRR, 1.55; 95%CI, 1.04 to 2.30; p?=?0.03). More TIAs were observed during the first quarter and full moon than in new moon (IRR, 1.69; 95%CI, 1.16 to 2.46; p?=?0.01; IRR, 1.52; 95%CI, 0.00 to 2.31; p?=?0.05; respectively). Both ICH and TIA occurrence slightly decreased as lunar illumination increased (IRR, 0.99; 95%CI, 0.99 to 1.00; p?=?0.01; IRR, 0.99; 95%CI, 0.99 to 1.00; p?=?0.04; respectively). No association was found between lunar phase or illumination and IS. All stroke subtypes were less likely to happen between 12AM and 6AM than the remaining 18 h of the day. IS occurrence was significantly higher during the spring than summer (IRR, 1.14; 95%CI, 1.02 to 1.28; p?=?0.03). For the patients older than 65 years, incidence of both ICH and IS was higher in spring than in summer (IRR, 1.33; 95%CI, 1.01 to 1.74; p?=?0.04; IRR, 1.22; 95%CI, 1.06 to 1.39; p?=?0.005; respectively). The lunar phase and illumination are associated with both ICH and TIA incidence. These findings should be tested on other stroke databases.     

Neuron Specific Enolase and C-reactive Protein Levels in Stroke and Its Subtypes: Correlation with Degree of Disability

Stroke is an emergency which threatens life and third leading cause of death and long term disability in developed countries. The use of biomarkers in diagnosing stroke and assessing prognosis is an emerging and rapidly evolving field. The study aimed to investigate the predictive value of biochemical marker of brain damage neuron-specific enolase (NSE) and systemic inflammatory marker C-reactive protein (CRP) with respect to degree of disability at the time of admission and short term in stroke patients. We investigated 120 patients with cerebrovascular stroke who were admitted within 72 h of onset of stroke in the Department of Neurology at Sri Aurobindo Institute of Medical Sciences, Indore, India. NSE and CRP were analyzed by solid enzyme linked immunosorbent assay using analyzer and micro plate reader from Biorad 680. In all patients, the neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale on admission and on day 7. Serum NSE and CRP concentration were found significantly increased in acute stroke cases as compared to control in present study (<0.05 and <0.001 respectively). The maximum serum NSE and CRP levels within 72 h of admission were significantly higher in patients with greater degree of disability at the time of admission. Both biomarkers were found significantly correlated with neurological disability and short term outcome. Our study showed that serum biomarkers NSE and CRP have high predictive value for determining severity and early neurobehavioral outcome after acute stroke.     

Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH

Objective

The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) remain poorly understood. The receptor for advanced glycation endproducts (RAGE) and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA), iPAH undergoing lung transplantation (LuTX). The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS) – pressure overload of the left ventricle.

Methods

We enrolled patients with CTEPH(26), iPAH(15), AVS(15) and volunteers(33). Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR).

Results

In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA⁺vimentin⁺CD34⁻), recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001) and CTEPH(p = 0.001) compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042) and significantly reduced in AVS compared to controls(p = 0.001). There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS.

Conclusions

Our data suggest a role for the RAGE pathway in the pathophysiology of CTEPH and iPAH. PEA improves the local control of disease but may not influence the systemic inflammatory mechanisms in CTEPH patients through the RAGE pathway.     

Soluble Forms and Ligands of the Receptor for Advanced Glycation End-Products in Patients with Acute Respiratory Distress Syndrome: An Observational Prospective Study

Background

The main soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated during acute respiratory distress syndrome (ARDS). However other RAGE isoforms and multiple ligands have been poorly reported in the clinical setting, and their respective contribution to RAGE activation during ARDS remains unclear. Our goal was therefore to describe main RAGE isoforms and ligands levels during ARDS.

Methods

30 ARDS patients and 30 mechanically ventilated controls were prospectively included in this monocenter observational study. Arterial, superior vena cava and alveolar fluid levels of sRAGE, endogenous-secretory RAGE (esRAGE), high mobility group box-1 protein (HMGB1), S100A12 and advanced glycation end-products (AGEs) were measured in duplicate ELISA on day 0, day 3 and day 6. In patients with ARDS, baseline lung morphology was assessed with computed tomography.

Results

ARDS patients had higher arterial, central venous and alveolar levels of sRAGE, HMGB1 and S100A12, but lower levels of esRAGE and AGEs, than controls. Baseline arterial sRAGE, HMGB1 and S100A12 were correlated with nonfocal ARDS (AUC 0.79, 0.65 and 0.63, respectively). Baseline arterial sRAGE, esRAGE, S100A12 and AGEs were associated with severity as assessed by PaO₂/FiO₂.

Conclusions

This is the first kinetics study of levels of RAGE main isoforms and ligands during ARDS. Elevated sRAGE, HMGB1 and S100A12, with decreased esRAGE and AGEs, were found to distinguish patients with ARDS from those without. Our findings should prompt future studies aimed at elucidating RAGE/HMGB1/S100A12 axis involvement in ARDS.

Trial Registration

clinicaltrials.gov Identifier: NCT01270295.     

Association between Ischemic Stroke and Iron-Deficiency Anemia: A Population-Based Study

Background

Very little is known about the relationship between non-sickle cell anemia and stroke. The purpose of this study is to evaluate the association of iron-deficiency anemia (IDA) with stroke based on a nationwide coverage database in Taiwan.

Methods

The case-control study subjects were obtained from the Taiwanese Longitudinal Health Insurance Database 2000. We included 51,093 subjects with stroke as cases and randomly selected 153,279 controls (3 controls per case) in this study.Separate conditional logistic regression analyses were used to calculate the odds ratio (OR) for having been previously diagnosed with IDA between cases and controls.We further analyzed the association between stroke and IDA by stroke subtype.

Results

Results showed that 3,685 study subjects (1.81%) had been diagnosed with IDA prior to the index date; of those subjects, 1,268 (2.48%) were cases and 2,417 (1.58%) were controls (p<0.001). Conditional logistic regression shows that the OR of having previously received an IDA diagnosis among cases was 1.49 (95% CI: 1.39~1.60; p < 0.01) that of controls after adjusting for monthly income, geographic region, hypertension, diabetes, coronary heart disease, atrial fibrillation, heart failure, hyperlipidemia, tobacco use disorder, and alcohol abuse/alcohol dependency syndrome. Furthermore, the adjusted OR of prior IDA for cases with ischemic stroke was found to be 1.45 (95% CI: 1.34~1.58) compared to controls. However, we did not find any significant relationship between IDA and subarachnoid/intracerebral hemorrhage even adjusting for other confounding factors (OR=1.17, 95% CI=0.97~1.40).

Conclusion

There is a significant association between prior IDA and ischemic stroke.     

Safety and clinical outcome of thrombolysis in ischaemic stroke using a perfusion CT mismatch between 3 and 6 hours

Objective

It may be possible to thrombolyse ischaemic stroke (IS) patients up to 6 h by using penumbral imaging. We investigated whether a perfusion CT (CTP) mismatch can help to select patients for thrombolysis up to 6 h.

Methods

A cohort of 254 thrombolysed IS patients was studied. 174 (69%) were thrombolysed at 0–3 h by using non-contrast CT (NCCT), and 80 (31%) at 3–6 h (35 at 3–4.5 h and 45 at 4.5–6 h) by using CTP mismatch criteria. Symptomatic intracerebral haemorrhage (SICH), the mortality and the modified Rankin Score (mRS) were assessed at 3 months. Independent determinants of outcome in patients thrombolysed between 3 and 6 h were identified.

Results

The baseline characteristics were comparable in the two groups. There were no differences in SICH (3% v 4%, p = 0.71), any ICH (7% v 9%, p = 0.61), or mortality (16% v 9%, p = 0.15) or mRS 0–2 at 3 months (55% v 54%, p = 0.96) between patients thrombolysed at 0–3 h (NCCT only) or at 3–6 h (CTP mismatch). There were no significant differences in outcome between patients thrombolysed at 3–4.5 h or 4.5–6 h. The NIHSS score was the only independent determinant of a mRS of 0–2 at 3 months (OR 0.89, 95% CI 0.82–0.97, p = 0.007) in patients treated using CTP mismatch criteria beyond 3 h.

Conclusions

The use of a CTP mismatch model may help to guide thrombolysis decisions up to 6 h after IS onset.