GRM7 polymorphisms are not associated with ischemic stroke in Iranian population

Abstract

Objectives: Ischemic stroke is the main neurological cause of acquired incapability in adults and a prominent cause of mortality. Several association studies have been conducted to explore the role of candidate genes in this neurological condition.

Methods: In the present study, we aimed at identification of association between Glutamate Metabotropic Receptor 7 (GRM7) and risk of ischemic stroke in Iranian population. Two intronic variants within this gene (rs6782011 and rs779867) were genotyped in 318 sporadic ischemic stroke cases and 300 unrelated, healthy controls individuals.

Results: No significant difference was found in allele, genotype or haplotype frequencies of these SNPs between cases and controls after correction for multiple comparisons.

Conclusion: Consequently, the assessed GRM7 variants are not implicated in risk of ischemic stroke in Iranian population.     

Identifying the brain regions associated with acute spasticity in patients diagnosed with an ischemic stroke

Spasticity is a common impairment found in patients that have been diagnosed with a stroke. Little is known about the pathophysiology of spasticity at the level of the brain. This retrospective study was performed to identify an association between the area of the brain affected by an ischemic stroke and the presence of acute spasticity. Physical and occupational therapy assessments from all patients (n?=?441) that had suffered a stroke and were admitted into a local hospital over a 4-year period were screened for inclusion in this study. Subjects that fit the inclusion criteria were grouped according to the presence (n?=?42) or absence (n?=?129) of acute spasticity by the Modified Ashworth Scale score given during the hospital admission assessment. Magnetic resonance images from 20 subjects in the spasticity group and 52 from the control group were then compared using lesion density plots and voxel-based lesion–symptom mapping. An association of acute spasticity with the gray matter regions of the insula, basal ganglia, and thalamus was found in this study. White matter tracts including the pontine crossing tract, corticospinal tract, internal capsule, corona radiata, external capsule, and the superior fronto-occipital fasciculus were also found to be significantly associated with acute spasticity. This is the first study to describe an association between a region of the brain affected by an infarct and the presence of acute spasticity. Understanding the regions associated with acute spasticity will aid in understanding the pathophysiology of this musculoskeletal impairment at the level of the brain.     

Cerebral vascular changes associated with hemorrhagic stroke in hypertension.

There are a number of alterations that protect the cerebrovasculature from hemorrhagic stroke development during hypertension. The upper limit of cerebral blood flow autoregulation is shifted to higher blood pressure levels; this allows a constant blood flow to be maintained during hypertension. Studies we have performed have indicated that the middle cerebral arteries (MCA) of Wistar-Kyoto stroke-prone spontaneously hypertensive rats (spSHR) lose their ability to constrict in response to elevations in transmural pressure. The decline in such function precedes stroke development and totally disappears at an age where there is a 100% mortality from stroke. Prior to stroke development, spSHR also develop uremic conditions and signs of renal failure. The induction of uremia in stroke-resistant SHR (srSHR) via nephrectomy induces these animals to develop stroke. Like prestroke spSHR, prestroke uremic srSHR also have MCA with attenuated pressure-dependent myogenic function. It is hypothesized that the inability to increase vascular resistance in response to elevations in pressure might promote overperfusion of the more distal vasculature leading to cerebral hemorrhage formation. Since uremia promotes bleeding tendencies, such alterations along with the loss of cerebrovascular myogenic function could initiate or aggravate hemorrhage formation.     

Plasma melatonin concentrations in hypertensive patients with the dipping and non-dipping blood pressure profile

Some patients with hypertension exhibit disturbed circadian organization in the cardiovascular system. Hormone melatonin can synchronize circadian rhythms and its repeated administration can improve synchronization of rhythmicity in blood pressure (BP). In our study we measured endogenous melatonin production in patients with essential hypertension exhibiting a dipping and non-dipping BP profile. Blood pressure was monitored for at least 24-hr with an automatic ambulatory BP monitor and patients with no decline in BP were classified as non-dippers. Plasma melatonin was measured in the middle of the daytime and night-time by radioimmunoassay. As expected night-time systolic (P <0.05), diastolic (P <0.001) and mean arterial (P <0.001) BP was higher in non-dippers than in dippers. No significant difference was found between both groups in BP during the day. Mean melatonin concentrations were higher during the night than during the day in both dippers and non-dippers. When patients were divided into dippers and non-dippers on the basis of mean arterial or diastolic BP a lower ratio of night/day concentration was determined in non-dippers than in dippers. Our study showed a blunted night/day difference in plasma melatonin concentrations in hypertensive patients with the non-dipping profile in diastolic BP indicating disturbances in the circadian system of these patients.     

Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China

Background

Atrial fibrillation (AF) is reported to be a less frequent cause of ischemic stroke in China than in Europe and North America, but it is not clear whether this is due to underestimation. Our aim was to define the true frequency of AF-associated stroke, to determine the yield of 6-day Holter ECG to detect AF in Chinese stroke patients, and to elucidate predictors of newly detected AF.

Methods

Patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled in a prospective, multicenter cohort study of 6-day Holter monitoring within 7 days after stroke onset at 20 sites in China between 2013 and 2015. Independent predictors of newly-detected AF were determined by multivariate analysis.

Results

Among 1511 patients with ischemic stroke and TIA (mean age 63 years, 33.1% women), 305 (20.2%) had either previously known (196, 13.0%) or AF newly-detected by electrocardiography (53, 3.5%) or by 6-day Holter monitoring (56/1262, 4.4%). A history of heart failure (OR?=?4.70, 95%CI, 1.64–13.5), advanced age (OR?=?1.06, 95%CI, 1.04–1.09), NIHSS at admission (OR?=?1.06, 95%CI, 1.02–1.10), blood high density lipoprotein (HDL) (OR?=?1.52, 95%CI, 1.09–2.13), together with blood triglycerides (OR?=?0.64, 95%CI, 0.45–0.91) were independently associated with newly-detected AF.

Conclusions

Contrary to previous reports, AF-associated stroke is frequent (20%) in China if systemically sought. Prolonged noninvasive cardiac rhythm monitoring importantly increases AF detection in patients with recent ischemic stroke and TIA in China. Advanced age, history of heart failure, and higher admission NIHSS and higher level of HDL were independent indicators of newly-detected AF.

Trial registration

NCT02156765 (June 5, 2014).

     

Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients

Background

The Mannose-binding lectin (MBL) pathway of complement plays a pivotal role in the pathogenesis of ischemia/reperfusion (I/R) injury after experimental ischemic stroke. As comparable data in human ischemic stroke are limited, we investigated in more detail the association of MBL deficiency with infarction volume and functional outcome in a large cohort of patients receiving intravenous thrombolysis or conservative treatment.

Methodology/Principal Findings

In a post hoc analysis of a prospective cohort study, admission MBL concentrations were determined in 353 consecutive patients with an acute ischemic stroke of whom 287 and 66 patients received conservative and thrombolytic treatment, respectively. Stroke severity, infarction volume, and functional outcome were studied in relation to MBL concentrations at presentation to the emergency department. MBL levels on admission were not influenced by the time from symptom onset to presentation (p = 0.53). In the conservative treatment group patients with mild strokes at presentation, small infarction volumes or favorable outcomes after three months demonstrated 1.5 to 2.6-fold lower median MBL levels (p = 0.025, p = 0.0027 and p = 0.046, respectively) compared to patients with more severe strokes. Moreover, MBL deficient patients (<100 ng/ml) were subject to a considerably decreased risk of an unfavorable outcome three months after ischemic stroke (adjusted odds ratio 0.38, p<0.05) and showed smaller lesion volumes (mean size 0.6 vs. 18.4 ml, p = 0.0025). In contrast, no association of MBL concentration with infarction volume or functional outcome was found in the thrombolysis group. However, the small sample size limits the significance of this observation.

Conclusions

MBL deficiency is associated with smaller cerebral infarcts and favorable outcome in patients receiving conservative treatment. Our data suggest an important role of the lectin pathway in the pathophysiology of cerebral I/R injury and might pave the way for new therapeutic interventions.     

LIPG promoter polymorphism is associated with ischemic stroke in Korean population

Endothelial lipase (LIPG) is a member of the triglyceride lipase family which includes hepatic lipase and lipoprotein lipase. Its activity is related to clinically important parameters like blood lipid levels, hypertension, and obesity. In this work, we investigated the association of a LIPG promoter polymorphism, rs9958947C>T, with susceptibility to ischemic stroke in a Korean population. A total of 1,144 subjects (656 cerebral infarction patients and 488 controls) were enrolled on a voluntary basis. The rs9958947C>T polymorphism was genotyped using the single-base extension method. The association of rs9958947C>T with disease status was evaluated by statistical analyses. The frequencies of the rs9958947 C and T alleles were significantly different between the stroke patient group and control group (OR [95% CI], 1.300 [1.000?C1.691], P=0.0449). A significantly higher frequency of the CT+TT genotype was observed in the patient group compared to the control group (CC/CT+TT, OR [95% CI], 1.632 [1.094?C2.435], P=0.0164). The results suggest that the T allele of the LIPG promoter polymorphism rs9958947C>T should be considered as a genetic risk factor for ischemic stroke. Further association studies in other ethnic populations would help to generalize this hypothesis.     

Predictors of thrombolysis in the telestroke and non telestroke settings for hypertensive acute ischemic stroke patients

Background

In acute ischemic stroke patients, telestroke technology provides sustainable approaches to improve the use of thrombolysis therapy. How this is achieved as it relates to inclusion or exclusion of clinical risk factors for thrombolysis is not fully understood. We investigated this in a population of hypertensive stroke patients.

Methods

Structured data from a regional stroke registry that contained telestroke and non telestroke patients with a primary diagnosis of acute ischemic stroke with history of hypertension were collected between January 2014 and June 2016. Clinical risk factors associated with inclusion or exclusion for recombinant tissue plasminogen activator (rtPA) in the telestroke and non telestroke were identified using multiple regression analysis. Associations between variables and rtPA in the regression models were determined using variance inflation factors while the fitness of each model was determined using the ROC curve to predict the power of each logistic regression model.

Results

The non telestroke admitted more patients (62% vs 38%), when compared with the telestroke. Although the telestroke admitted fewer patients, it excluded 11% and administered thrombolysis therapy to 89% of stroke patients with hypertension. In the non telestroke group, adjusted odd ratios showed significant associations of NIH stroke scale score (OR?=?1.059, 95% CI, 1.025–1.093, P <?0.001) and coronary artery disease (OR?=?2.003, 95% CI, 1.16–3.457, P?=?0.013) with inclusion, while increasing age (OR?=?0.979, 95% CI, 0.961–0.996, P?=?0.017), higher INR (OR?=?0.146, 95% CI, 0.032–0.665, P?=?0.013), history of previous stroke (OR?=?0.39, 95% CI, 0.223–0.68, P?=?0.001), and renal insufficiency (OR?=?0.153, 95% CI, 0.046–0.508, P?=?0.002) were associated with rtPA exclusion. In the telestroke, only direct admission to the telestroke was associated with rtPA administration, (OR?=?4.083, 95% CI, 1.322–12.611, P?=?0.014).

Conclusion

The direct admission of hypertensive stroke patients to the telestroke network was the only factor associated with inclusion for thrombolysis therapy even after adjustment for baseline variables. The telestroke technology provides less restrictive criteria for clinical risk factors associated with the inclusion of hypertensive stroke patients for thrombolysis.

     

Oxidative stress markers are associated to vascular recurrence in non-cardioembolic stroke patients non-treated with statins

ABSTRACT: BACKGROUND: Since atherogenesis is related to oxidative stress, our objective was to study the association of oxidative stress markers with the vascular recurrence in non-cardioembolic stroke. For this purpose, atherosclerotic and oxidative stress markers (ox-LDL, Cu/Zn SOD and 8-OHDG) were evaluated in 477 non-cardioembolic stroke patients on admission (136 were being treated with statins) and patients were followed at 6 and 12 months. RESULTS: Patients who suffered vascular recurrence or vascular-origin death had higher levels of 8-OHDG (40.06+/-24.70vs33.11+/-15.18;p=0.003). We also found associations between vascular recurrence or vascular origin death and Cu/ZnSOD (OR,1.02; 95%CI,1.00-1.03;p=0.0001) and 8-OHDG (OR,1.12;95%CI,1.08-1.16;p<0.0001) in a subgroup of 333 patients that were not in treatment with statins on admission. We also found associations between 8-OHDG and intima media thickness (IMT) (OR,1.13;95%CI,1.09-1.16;p<0.0001), presence of ipsilatieral stenosis[greater than or equal to]50% (OR,1.03;95%CI1.00-1.05;p=0.007) and other atherosclerotic plaque characteristics. CONCLUSIONS: Specific oxidative stress markers were found to be markers of atherosclerosis plaque types and vascular recurrence in non-statins treated patients at admission.     

Fatty Acid binding protein 4 is associated with carotid atherosclerosis and outcome in patients with acute ischemic stroke

Background and Purpose

Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke.

Methods

We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages.

Results

FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics.

Conclusions

FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke.     

Expression of signaling molecules associated with apoptosis in human ischemic stroke tissue

There is growing evidence that, because of the highly significant differences in gene activation/protein expression between animal models of stroke and stroke patients, the current treatment strategies based on animal stroke models have been unsuccessful. Therefore, it is imperative that the pathobiology of human stroke be studied. As a first step here, Western blotting and immunohistochemistry were employed to examine expression and tissue localization of key apoptotic proteins in infarct and peri-infarcted (penumbra) from grey and white matter in human postmortem tissue of 18 patients who died between 2 and 37 d after stroke caused by large vessel disease. The contralateral hemisphere was used as a control. JNK1, JNK2, and p53 were upregulated in the majority of samples, whereas Bcl-2, caspase-3, active caspase-3, phosphorylated p53 (p-p53), phosphorylated JNk1 (p-JNK1), and phosphorylated JNK2 (p-JNK2) were upregulated in approximately half of the samples. JNK1 expression was positively correlated with JNK2 expression in grey and white matter infarct and penumbra, whereas active caspase-3 levels were positively correlated with p-JNK2 levels in grey and white matter infarct. Using indirect immunoperoxidase staining of paraffin-embedded sections, active caspase-3 was found in infarcted neurons that co-localized with TUNEL-positive cells. p-JNK localization in the nuclei of TUNEL-positive cells with the morphological appearance of neurons from infarct and penumbra was also demonstrated. The use of Kaplan Meier survival data demonstrated that the presence of Bcl-2 in penumbra of grey matter correlated significantly with shorter survival (p=0.006). In conclusion, the present study has identified significantly altered expression of apoptotic proteins in human stroke tissue and shown that the presence of Bcl-2 in penumbra of grey matter has prognostic value. It is tempting to suggest that further studies of apoptotic proteins in human stroke may lead to identification of novel targets for drug discovery.     

Lack of nocturnal blood pressure fall in elderly bedridden hypertensive patients with cerebrovascular disease

To prevent recurrence of cerebrovascular disease (CVD), adequate control of blood pressure (BP) is extremely important for the treatment of hypertensive CVD patients. As absence of the nocturnal fall of BP by the expected 10-20% from daytime levels is reported to exaggerate target organ injury, 24-h ambulatory blood pressure monitoring (ABPM) was conducted, especially to obtain data during nighttime sleep. Forty-eight elderly bedridden chronic phase CVD hypertensive patients (assessed 1-3 mo after CVD accident) participated. As a group, nocturnal BP was higher than diurnal BP, whereas nocturnal pulse rate was lower than diurnal pulse rate. The nocturnal BP fall was blunted in most (～90%) of the patients. These results suggest that to perform a rational drug treatment, it is essential to do 24-h ABPM before initiation of antihypertensive therapy in elderly bedridden hypertensive CVD patients.     

Prognostic significance of plasma visfatin levels in patients with ischemic stroke

Plasma visfatin concentration has been enhanced in ischemic stroke. The aim of the current investigation was to test whether determination of visfatin in plasma is associated with 6-month clinical outcomes including mortality and unfavorable outcome (modified Rankin Scale score > 2) in the patients with ischemic stroke. Between July 2009 and January 2012, plasma visfatin concentrations of 186 patients and 100 healthy individuals were quantified by enzyme-linked immunosorbent assay. Plasma visfatin concentrations were higher in patients than in healthy individuals (108.5 ± 41.1 ng/mL vs. 13.8 ± 3.9 ng/mL, P < 0.001). A logistic regression analysis selected plasma visfatin concentration as an independent predictor for 6-month clinical outcomes (both P < 0.01). Using receiver operating characteristic curve analysis, plasma visfatin concentration was found to predict 6-month clinical outcomes with the high predictive performance. The predictive value of visfatin was in the range of National Institutes of Health Stroke Scale score (both P > 0.05). Combined use of visfatin and National Institutes of Health Stroke Scale score did not improve the predictive significance (both P > 0.05). Thus, visfatin may help in the prediction of long-term clinical outcomes in patients with ischemic stroke.     

Conserved aquaporin 4 levels associated with reduction of brain edema are mediated by estrogen in the ischemic brain after experimental stroke

Aquaporin 4 (AQP4), the most abundant water channel protein in the brain, is involved in brain edema induced by ischemic insults. To evaluate whether the neuroprotective effects of estrogen are associated with AQP4 expression and edema formation, changes in AQP levels and ischemic edema were examined in the brains of male and female mice subjected to transient middle cerebral artery occlusion. Infarct volume and edema formation were markedly less in females than in males. AQP4 expression in the ischemic cortex of females was relatively well preserved, whereas it was significantly decreased in males. These effects disappeared in ovariectomized females but were reversed by estrogen replacement. Furthermore, AQP4 expression was decreased with increased brain edema in females treated with ICI182,780, an estrogen receptor antagonist. These findings suggest that the estrogen effect on the reduction of ischemic brain edema is associated with the preserved level of AQP4 that is partly mediated by estrogen receptors.     

Cerebral glucose transporter: The possible therapeutic target for ischemic stroke

Hyperglycemia is considered to be associated with poor outcomes of ischemic stroke. However, it is controversial about the blood glucose-lowering therapy in patients with stroke. According to the current reports, hyperglycemia is an indicator of severe stroke and cannot increase cerebral glucose content but promotes further ischemia in brain. Consequently, cerebral glucose control is significant to maintain the energy homeostasis. Compared with blood glucose level, the cerebral glucose content, controlled by glucose transporters (GLUTs), is more directly and important to maintain the energy supply in brain, especially to the patients with ischemic stroke. Some active materials, such as Glucagon-like peptide-1, progesterone, tPA and N-acetylcysteine, have been found to ameliorate ischemic stroke by regulating GLUTs expression. Therefore, this review discusses the significance of cerebral glucose level and GLUTs. Additionally, cerebral GLUTs and their actions in ischemic stroke are detailed in order to promote research on GLUTs as a possible therapeutic target for ischemic stroke.     

Serum metabolomic patterns in young patients with ischemic stroke: a case study

Metabolomics - Maternal metabolism changes substantially during pregnancy. However, few studies have used metabolomics technologies to characterize changes across gestation. We applied liquid...     

Serum levels of heat shock protein 27 in patients with acute ischemic stroke

Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.     

Rheological properties of blood in patients with ischemic stroke in selected clinical groups]

Hemorheological parameters have been analysed in 34 patients with the acute ischemic stroke. The patients have been divided into two clinical subgroups: with accompanying arterial hypertension (group HA), and free of other diseases (group NHA). Comparative studies have not revealed the significant differences between both groups. However, blood viscosity has been significantly higher in the hypertensive patients. It was related to the decrease in the erythrocyte ability to elastic deformation Group NHA has been characterized by the high fibrinogen levels and by the decrease of the cerebral blood flow.