From A to E: Uniting vitamins against stroke risk-A systematic review and network meta-analysis.

BACKGROUND AND AIM: Stroke represents a significant public health challenge, necessitating the exploration of preventive measures. This network meta-analysis aimed to assess the efficacy of different vitamin treatments compared to a placebo in preventing stroke. METHODS: A systematic electronic search in databases including PubMed, EmBASE, Web of Science, clinicaltrials.gov, and Google Scholar until 31 May 2023 was conducted, to identify published studies investigating the association between vitamin intake and the risk of stroke. Pooled risk ratio (RR) with 95% confidence intervals (CIs) was calculated using a frequentist network meta-analysis. Furthermore, we ranked vitamins based on p-scores, facilitating a comparative assessment of their effectiveness in preventing stroke. RESULTS: A total of 56 studies, including 17 randomized controlled trials (RCTs) and 39 cohort studies were analyzed. Direct estimates obtained from network meta-analysis, we found that vitamin A (RR: .81 [.72-.91]), vitamin B-complex (RR: .85 [.74-.97]), vitamin B6 (RR: 79 [.68-.92]), folate (RR: .86 [.75-.97]), vitamin C (RR: .77 [.70-.85]) and vitamin D (RR: .73 [.64-.83]) were significantly associated with a decreased stroke risk. However, no significant association was observed for vitamin B2, vitamin B12, and vitamin E. Subsequent to network meta-analysis, vitamins were ranked in decreasing order of their efficacy in stroke prevention based on p-score, with vitamin D (p-score = .91), vitamin C (p-score = .79), vitamin B6 (p-score = .70), vitamin A (p-score = .65), vitamin B-complex (p-score = .53), folate (p-score = .49), vitamin B2 (p-score = .39), vitamin E (p-score = .28), vitamin B12 (.13) and placebo (.10). CONCLUSION: Our study has established noteworthy connections between vitamin A, vitamin B-complex, vitamin B6, folate, vitamin C, and vitamin D in the realm of stroke prevention. These findings add substantial weight to the accumulating evidence supporting the potential advantages of vitamin interventions in mitigating the risk of stroke. However, to solidify and validate these observations, additional research is imperative. Well-designed clinical trials or cohort studies are needed to further explore these associations and formulate clear guidelines for incorporating vitamin supplementation into effective stroke prevention strategies.

Correlation Between Optical Coherence Tomography Angiography Findings at 3 to 6 Weeks and Functional Outcome at 3 Months Following Acute Ischaemic Stroke Due to Extracranial Carotid Artery Atherosclerotic Disease.

We wanted to evaluate if optical coherence tomography angiography OCTA findings could predict the functional outcome in extracranial carotid artery atherosclerotic disease (ECAD) associated stroke. This exploratory study was performed on adults with acute ischaemic stroke due to ECAD at 3-6 weeks following stroke onset with risk factor matched controls without carotid artery stenosis. Twenty-three stroke patients (cases) and 23 controls were enrolled. There was significant difference between cases and controls in deep vessel density at the macula (p = .0007) and in radial peripapillary capillary perfusion density (RPCPD) at the optic nerve head (ONH) (p = .0007). Statistically significant difference was noted in the total superficial vessel density (SVD) at the macula (SVD within 1 standard deviation [SD] versus SVD beyond 1 SD of control data) in the ipsilateral eye and functional outcome at 3 months (poor versus very good outcome, modified Rankin scale [mRS] 0-1 versus mRS 2-6, respectively; p = .0361). There was statistically insignificant correlation between the RPCPD at the ONH and the National Institutes of Health Stroke Scale score at admission, mRS at discharge, and mRS at 3 months following stroke onset (r = .33, r = .35, r = .39; p = .11, p = .09, p = .06, respectively). The findings of this exploratory study suggested that OCTA findings may predict 3 month outcomes in cases of ECAD-related stroke and could be useful in decision making in future intervention studies as to whether intervene or not in patients having critical or non-critical ECAD for preventing stroke.

Decompressive surgery in cerebral venous thrombosis: A systematic review and meta-analysis.

OBJECTIVE: The efficacy of decompressive surgery (DS) in cerebral venous thrombosis (CVT) patients has been reported in several case reports and case series. We aimed at determining the association of DS compared with medical management and timing of surgery with functional outcome and mortality. We also aimed at determining the prevalence of DS in CVT patients. METHODS: The literature search was conducted till 7 November 2022 in PubMed, Google Scholar, EMBASE and Cochrane Library databases. Risk of bias was examined using Joanna Briggs Institute scale for case series and case reports. Association of DS compared with medical management and timing of surgery with functional outcome and mortality was determined using odds ratio (OR) and 95% confidence interval (CI). Pooled prevalence of DS in CVT patients with 95%CI was calculated. Heterogeneity was explored using outlier, meta-regression, sensitivity and subgroup analyses. RESULTS: Fifty-one studies consisting of 483 CVT cases with DS were included. The OR of poor outcome with surgery was 0.03; (95%CI: 0.00-0.22) and of mortality with surgery was 0.25; (95%CI: 0.02-2.60) versus that with medical management. Surgery done ≤48 h of admission was significantly associated with less mortality (OR: 0.26; 95%CI: 0.10-0.69). Pooled prevalence of DS in CVT was 12% (95%CI: 8%-17%; I2  = 91%). Revised pooled prevalence after removing outliers was 10% (95%CI: 7%-13%; I2  = 73%). CONCLUSIONS: Surgery ≤48 h of admission might decrease mortality in CVT patients and may result in improved functional outcome. Further prospective studies with appropriate control arms are required to confirm its efficacy over medical management.

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Association of modifiable risk factors with ischaemic stroke subtypes in Asian versus Caucasian populations: A systematic review and meta-analysis.

BACKGROUND: Ischaemic stroke (IS) is associated with various modifiable risk factors but the association of these risk factors based on TOAST classification, which characterises IS into five subtypes: large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolic disease (CE), other determined aetiology (ODE) and undetermined aetiology (UDE), is unknown. We aimed to summarise the published evidence for the association of modifiable risk factors with IS subtypes based on TOAST classification, specifically focussing on the Asian versus Caucasian population. METHOD: A comprehensive search for all the published articles was performed in electronic databases including PubMed, EMBASE, Cochrane Library, and Google Scholar from 01st January 1950 to 10th April 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratio (OR) with 95% confidence interval (CIs) along with random-effect models was used to calculate summary estimates. RESULTS: In our meta-analysis, 32 studies with a total of 23,404 IS (14,364 in Asian vs. 9040 in Caucasian population), 7121 LAA (5219 in Asian vs. 1902 in Caucasian), 5532 SVO (3604 in Asian vs. 1928 in Caucasian), 3498 CE (1634 in Asian vs. 1864 in Caucasian), 1131 ODE (546 in Asian vs. 585 in Caucasian) and 4519 UDE (2076 in Asian vs. 2443 in Caucasian) were included. Our findings suggest a significant association between LAA and hypertension (OR = 1.07, 95% CI = 1.02-1.12), smoking (OR = 1.11, 95% CI = 1.04-1.17), dyslipidemia (OR = 1.13, 95% CI = 1.06-1.21), diabetes mellitus (OR = 1.18, 95% CI = 1.11-1.25) and atrial fibrillation (OR = 0.55, 95% CI = 0.40-0.75). Significantly strong association of hypertension, smoking, dyslipidemia, diabetes mellitus and atrial fibrillation was observed with SVO and CE stroke subtypes. Subgroup analysis based on ethnicity revealed a significant association for dyslipidemia, diabetes mellitus and atrial fibrillation in LAA for both Asians and Caucasians. Hypertension was significantly associated with SVO and ODE subtypes in both Asians and Caucasians; however, only Asian population showed significant association of hypertension in LAA and CE subtypes. The other risk factors did not show any statistical difference between the ethnic groups for the different stroke subtypes. The majority of the risk factors depicted positive association with LAA and SVO, negative with CE and neutral with ODE and UDE. CONCLUSION: Our findings suggest strong association of smoking, dyslipidemia and diabetes mellitus with LAA and SVO subtypes in the Caucasian population. However, only diabetes mellitus showed significant association with both LAA and SVO subtypes in Asian population as well. Thus, a majority of the traditional modifiable risk factors had a positive association in LAA and SVO, while a negative protective association was observed in CE subtype, among both the Asian and the Caucasian subgroups.

Carotid intima-media thickness and risk of mild cognitive impairment: A systematic review and meta-analysis.

Mild cognitive impairment (MCI) is an early phase of cognitive decline signalling the beginning of severe neurological diseases. Carotid intima-media thickness (cIMT) has shown some correlation with MCI development. This study was conducted to investigate the impact of elevated cIMT on the risk of MCI in adults. A literature search was conducted in PubMed, EMBASE, Cochrane Library, Scopus, Google Scholar and CINAHL databases till 30 July 2021, with keywords: ('Carotid Intima-Media Thickness' OR 'cIMT' OR 'IMT' AND 'Cognitive Impairment' OR 'Cognition' OR 'Cognitive Decline' AND 'Mild Cognitive Impairment' OR 'MCI'). Pooled standardized mean difference (SMD)/odds ratio (OR) and 95% confidence interval (CI) were determined for factor-disease association using either fixed (when I2 <50%) or random effect (when I2 >50%) models. Eight studies involving 1,585 MCI cases and 6,700 normal subjects were included in our meta-analysis which showed no significant association of increased cIMT with the risk of MCI [SMD 1.17, 95% CI -0.09 to 2.42]. However, sensitivity analysis revealed an outlier study significantly affecting the effect size. On omitting the outlier study, the re-evaluated meta-analysis revealed a significant association of cIMT with the risk of MCI [SMD 0.52, 95% CI 0.26 to 0.78]. This significant association was also observed during subgroup analysis in Caucasian population [SMD 0.65, 95% CI 0.13 to 1.18] but not in Asian population [SMD 0.39, 95% CI -0.01 to 0.79]. Elevated cIMT poses a potential risk for MCI. However, more population-based studies are required to corroborate these findings.

Epigenetics Mechanisms in Ischemic Stroke: A Promising Avenue?

Stroke has emerged as the second most common cause of mortality worldwide and is a major public health problem. It is a multi-factorial disease and genetics plays an important role in its pathophysiology, however, mechanisms of genome involvement in the disease remain unclear. Both genetic and epigenetic mechanisms could play a role in the development of stroke disease. Although epigenetic characteristics may also be heritable, they can be modified during the lifetime under different environmental exposure in response to lifestyle. Recent studies provide clear evidence that epigenetic factors play an important role in the pathological mechanisms leading to an elevated risk of cardiovascular diseases and stroke. Epigenetic changes are reversible therefore; studying epigenetic factors may serve as a marker for disease progression, biomarker for disease diagnosis, and development of novel targets for therapeutic intervention. Identifying the factors which predispose the risk of stroke provides information for the mechanism of stroke and the design of new drug targets where epigenetic modifications play a significant role. Epigenetic modifications play an essential role in a large variety of multifactorial diseases. This review will focus on the evidence that epigenetic mechanisms play a crucial role in the pathophysiology of ischemic stroke.

Efficacy of various treatment modalities for nCOV-2019: A systematic review and meta-analysis.

BACKGROUND: Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and meta-analysis to assess the efficacy of various treatment modalities in nCOV-2019 patients. METHODS: A literature search was conducted before 29 June 2020 in PubMed, Google Scholar and Cochrane library databases. A fixed-effect model was applied if I2  < 50%, else results were combined using random-effect model. Risk ratio (RR) or standardized mean difference (SMD) along with 95% confidence interval (95% CI) was used to pool the results. Between-study heterogeneity was explored using influence and sensitivity analyses, and publication bias was assessed using funnel plots. Entire statistical analysis was conducted in R version 3.6.2. RESULTS: Fifty studies involving 15 in vitro and 35 clinical studies including 9170 nCOV-2019 patients were included. Lopinavir-ritonavir was significantly associated with shorter mean time to clinical recovery (SMD -0.32; 95% CI -0.57 to -0.06), remdesivir was significantly associated with better overall clinical recovery (RR 1.17; 95% CI 1.07 to 1.29), and tocilizumab was associated with less all-cause mortality (RR 0.38; 95% CI 0.16 to 0.93). Hydroxychloroquine was associated with longer time to clinical recovery and less overall clinical recovery. It additionally had higher all-cause mortality and more total adverse events. CONCLUSION: Our meta-analysis suggests that except in vitro studies, no treatment has shown overall favourable outcomes in nCOV-2019 patients. Lopinavir-ritonavir, remdesivir and tocilizumab may have some benefits, while hydroxychloroquine administration may cause harm in nCOV-2019 patients. Results from upcoming large clinical trials may further clarify role of these drugs.

CIMT as a risk factor for stroke subtype: A systematic review.

INTRODUCTION: An increase in the common carotid artery intima-media thickness (CCA-IMT) is generally considered an early marker of atherosclerosis and is a well-established predictor of cardiovascular disease (CVD). An association between changes in CCA-IMT and risk of stroke has been reported but has conflicting findings. OBJECTIVE: The present meta-analysis was aimed to clarify the association between CCA-IMT with the risk of stroke and its subtype by estimating pooled analysis of published literature. METHODS: Comprehensive search for all published articles was performed in electronic databases including PubMed, Embase, Cochrane Library, Trip Databases, Worldwide Science, CINAHL and Google Scholar from 01 January 1950 to 30 April 2020. RESULTS: In our meta-analysis, a total of 19 studies, of which sixteen studies involving 3475 ischaemic stroke (IS) cases and 11 826 controls; six studies with 902 large vessel disease (LVD) and 548 small vessel disease (SVD) of IS subtypes; five studies with 228 intracerebral haemorrhage (ICH) and 1032 IS cases, were included. Our findings suggest a strong association between increased CCA-IMT with risk of IS as compared to control subjects [SMD = 1.46, 95% CI = 0.90-2.02]. However, there is an increased risk of LVD as compared to the SVD subtype of IS [SMD = 0.36, 95% CI = 0.19-0.52] and more chance of occurrence of IS rather than ICH [SMD = 0.71, 95% CI = 0.28-1.41]. CONCLUSIONS: Carotid intima thickness measurements are found to be associated with the risk of stroke along with its subtypes and may be used as a diagnostic marker for predicting the risk of stroke events.

Cystatin C and Risk of Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

INTRODUCTION: Cystatin C (Cys C) has been found as a novel biomarker of neurodegenerative diseases, such as dementia and Alzheimer's disease. Published studies on the role of Cys C as a biomarker of mild cognitive impairment (MCI) have not been reviewed systematically. OBJECTIVE: Present meta-analysis was performed to elucidate the association between Cys C and risk of MCI. METHODS: A comprehensive search was performed in PubMed, EMBASE, Cochrane Library, Trip databases, Worldwide Science, and Google Scholar from January 1, 1950, to April 30, 2020. Standardized mean difference (SMD) with 95% confidence interval (CI) using fixed or random effect models were used to calculate summary estimates. Quality of evidence was also assessed using the Diagnostic Accuracy Quality Scale (DAQS) and grading quality of evidence and strength of recommendations approach. RESULTS: In our meta-analysis, 12 studies with a total of 2,433 MCI patients and 1,034 controls were included. Our findings suggest a strong association between increased levels of Cys C and risk of MCI as compared to control subjects (SMD = 2.39, 95% CI = 0.22-4.57). Subgroup analysis based on ethnicity, a significant association for the high level of Cys C with the risk of MCI was observed in the Asian population (SMD = 1.63, 95% CI = 0.44-2.82) but not in the Caucasian population (SMD = 2.80, 95% CI = [-0.66]-6.26). CONCLUSION: Cys C was associated with MCI, and it could be considered as a predictor for the risk of cognitive impairment.

Role of glial fibrillary acidic protein as a biomarker in differentiating intracerebral haemorrhage from ischaemic stroke and stroke mimics: a meta-analysis.

Background: Studies have suggested promising evidence that glial fibrillary acidic protein (GFAP) could be used as a blood biomarker to distinguish between ischaemic stroke (IS) and intracerebral haemorrhage (ICH) in acute stage.Objective: To determine the available evidence for GFAP as a blood biomarker for differentiating ICH from IS and stroke mimics using a meta-analysis approach.Methods: Search terms were used for literature search: ("STROKE" [Mesh] OR "BIOMARKER" [Title/Abstract] OR "GFAP" [Title/Abstract])] OR "SPECIFICITY" OR "SENSTIVITY" at various search engines like PubMed, Google scholar, Trip database, clinicaltrial.gov for articles from 1990 to April 2019 using filter 'human subjects'. Data were analysed using software STATA version 13.Results: A pooled analysis including 12 studies suggested that GFAP if used as a biomarker to differentiate between different types of strokes (ICH from IS and mimics) had a sensitivity of 78% (95% CI: 67-86%) and a specificity of 95% (95% CI: 88-98%). Positive likelihood ratio (LR) was 14.4 and negative LR was 0.23. SROC with prediction and confidence contours suggests promising area under the curve 0.93, 95% CI ranges from 0.90 to 0.95. Diagnostic odds ratio with 95% CI was observed 63 (31-125).Conclusion: Our meta-analysis suggests that GFAP has a promising diagnostic accuracy for the differentiation of ICH from IS and mimics. Further, phase II and phase III diagnostic test studies are required to validate the findings before using GFAP as a blood based biomarker for clinical use. Trial Registration: This study was registered in OSF registries 10.17605/OSF.IO/B9JP4.

Association between endothelial nitric oxide synthase gene polymorphisms and risk of ischemic stroke: A meta-analysis.

Previously published studies that have examined whether the three polymorphisms, G894T, T786C, and 4b/a in the endothelial nitric oxide synthase (eNOS) gene, are associated with ischemic stroke (IS) have reported conflicting results. Thus, we performed a meta-analysis to examine the potential association between these three single nucleotide polymorphisms (SNPs) of the eNOS gene and IS risk. A literature search was carried out for eligible candidate gene studies published before August 05, 2015 in the PubMed, Embase, and Google Scholar databases. The following combinations of main keywords were used in our study: ('endothelial nitric oxide synthase') or ('eNOS') and ('G894T, 4b/a, and T786C') and ('polymorphism') or ('polymorphisms') and ('Ischemic Stroke' or 'IS') and ('Cerebral Infarction' or 'CI') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using fixed or random effects model. Meta-regression analysis was used to investigate the potential sources of heterogeneity. Begg's funnel plots were used to explore the publication bias, and heterogeneity was assessed by I2 test. Twenty seven case-control studies involving 6733 cases and 7305 controls were analyzed in our meta-analysis. Significant association was observed for G894T (OR = 1.17; 95% CI: 1.08 to 1.28; P< 0.001) and 4b/a (OR = 1.25; 95% CI: 1.13 to 1.39; P < 0.001) whereas a non-significant association was observed for T786C (OR = 1.11; 95% CI: 0.98 to 1.26; P =0.109) eNOS gene polymorphisms and IS. Our meta-analysis establishes that the G894T and 4b/a polymorphisms of eNOS gene are significantly associated with the risk of IS. However, a non-significant association was found between T786C polymorphism of the eNOS gene and IS risk. Further prospective large epidemiological studies need to be done to confirm these findings.

Prediction of upper extremity motor recovery after subacute intracerebral hemorrhage through diffusion tensor imaging: a systematic review and meta-analysis.

INTRODUCTION: Early assessment of the pyramidal tracts is important for intracerebral hemorrhage (ICH) patients in order to decide the optimal treatment or to assess appropriate rehabilitation strategies, and management of patient expectations and goals. The purpose of this study was to systematically review and summarize the current available literature on the value of Fractional Anisotropy (FA) parameter of the diffusion tensor imaging (DTI) in predicting upper extremity (UE) motor recovery after subacute ICH. METHODS: PubMed, EMBASE, MEDLINE, Google Scholar, and Cochrane CENTRAL searches were conducted from 1 January 1950 to 31 March 2016 which were supplemented with relevant articles identified in the references. Pooled estimate using correlation between DTI parameter FA and UE motor recovery was done using comprehensive meta-analysis software. RESULTS: Out of 97 citations, only eight studies met the criteria for inclusion in the systematic review and six studies were included in the meta-analysis. A random effects model revealed that DTI parameter FA is a significant predictor for UE motor recovery after subacute ICH (correlation coefficient = 0.56; 95 % confidence interval 0.44 to 0.65, P value <0.001). However, moderate heterogeneity was observed between the studies (Tau-squared = 0.28, I-squared = 70.3). CONCLUSION: The studies reported so far on correlation between FA parameter of DTI and UE motor recovery in ICH patients are few with small sample sizes. This meta-analysis suggests a strong correlation between DTI parameter FA and UE motor recovery in ICH patients. Further well-designed prospective studies embedded with larger sample size are needed to confirm these findings.

Association of transforming growth factor-ß1 gene C509T, G800A and T869C polymorphisms with intracerebral hemorrhage in North Indian Population: a case-control study.

Transforming growth factor-ß1 (TGF-ß1) is a multifunctional pro-inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-ß1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-ß1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-ß1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-ß1 G800A (OR 9.07; 95% CI 2.3-35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9-13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D' = 0.53, r(2) = 0.23). Our results suggest that TGF-ß1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH.

Association between lymphotoxin alpha (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke in North Indian population: a hospital-based case-control study.

PURPOSE: Lymphotoxin alpha (LTA), a proinflammatory cytokine, plays an important role in promoting atherosclerosis which is an independent risk factor for stroke. Recent genetic studies have suggested that polymorphisms in the LTA gene, which affect its expression and biological function, may contribute to the development of stroke. The aim of this case-control study was to determine the association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke. METHODS: Genotyping was determined by using SNaPshot method for 250 ischemic stroke (IS) patients, 250 age and sex matched IS free controls, 100 intracerebral hemorrhage (ICH) patients and 100 age and sex matched ICH free controls. Conditional logistic regression analysis with adjusting multiple demographic and risk factor variables was used to calculate the strength of association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke. The linkage disequilibrium (LD) was analyzed by using HaploView 4.2 software. RESULTS: The distribution of LTA (-252 A/G and -804 C/A) genotypes was consistent with Hardy-Weinberg equilibrium. Adjusted conditional logistic regression analysis showed no significant association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of both IS and ICH. Based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, a significant association between LTA -252 A/G gene polymorphism and small vessel disease subtype of IS under dominant model (OR, 2.06; 95% CI, 1.03-4.12; p value 0.04) with the risk of IS was observed. No LD was observed for both single nucleotide polymorphisms (SNPs) in north Indian population. CONCLUSION: Neither -252 G/A nor -804 C/A polymorphism of the LTA gene was found to be associated with overall stroke as well as any subtype of IS excluding SVD in North Indian population.

Association between Interleukin-10 -1082G/A Gene Polymorphism and Risk of Stroke in the North Indian Population: A Case-Control Study.

BACKGROUND: Anti-inflammatory interleukin-10 (IL-10) cytokine and its genetic variations may play an important role in the pathogenesis of various human diseases including stroke. OBJECTIVE: The aim of this present case-control study was to determine the association between IL-10 -1082G/A (rs1800896) gene polymorphism and risk of stroke in the North Indian population. METHODS: Genotyping was carried out by using SNaPshot method (Applied Biosystems, Foster City, California, United States) for 250 ischemic stroke (IS) patients, 250 age- and sex-matched IS free controls, 100 intracerebral hemorrhage (ICH) patients, and 100 age- and sex-matched ICH free controls. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis with adjustment for multiple demographic and risk factor variables was used to calculate the strength of association between IL-10 (-1082G/A) polymorphism and risk of stroke. RESULTS: Conditional logistic regression analysis showed an independent association between IL-10 -1082G/A and risk of IS under a dominant model (odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.34-4.27, P = .003) and an allelic model (OR = 2.49, 95% CI 1.71-3.63, P < .001). An independent association between IL-10 -1082G/A, under the dominant model (OR = 6.8, 95% CI 2.2-20.7, P < .001) and the allelic model (OR = 3.4, 95% CI 1.8-6.3, P < .001), and the risk of ICH was also observed. CONCLUSION: Our results suggest that IL-10 -1082G/A gene polymorphism is an independent risk factor for the risk of IS and ICH in the North Indian population. Our findings indicate that IL-10 -1082G/A polymorphism may be used as a genetic marker for identifying individuals at increased risk of developing stroke.

Association between Lymphotoxin Alpha (-252G/A and -804C/A) Gene Polymorphisms and Risk of Ischemic Stroke: A Meta-Analysis.

PURPOSE: Lymphotoxin-Alpha (LTA) is a mediator of inflammation which may be associated with the risk of ischemic stroke (IS). Polymorphisms (-252A/G and -804C/A) in the LTA gene have been found to be associated with IS with contradictory results. The present meta-analysis aimed to provide a comprehensive account of the association of (-252A/G and -804C/A) gene polymorphisms of LTA gene with susceptibility to IS. METHODS: A literature search for eligible candidate gene studies published before April 20, 2015 was conducted in the PubMed, EMBASE, Trip database and Google Scholar. The following combinations of main keywords were used: ('Lymphotoxin-alpha' or 'LTA' or 'tumour necrosis factor beta' or 'TNF-beta') and ('Ischemic stroke or 'cerebral infarction' or 'IS') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). Fixed or random effects models were used to estimate the strength of association through Odds ratios (ORs) and 95% confidence interval (CI). RESULTS: Four case-control studies for LTA -252A/G gene polymorphism showed no significant association under; dominant (OR, 0.9; 95% CI; 0.8 to 1.0, P value 0.34), recessive (OR, 1.1; 95% CI; 0.9 to 1.3; P value 0.21) models, indicating that GG and AG genotypes may not possibly confer an increased susceptibility to IS as compared to AA genotype. For LTA -804C/A gene polymorphism, three casecontrol studies also showed no significant association under; dominant (OR, 0.5; 95% CI; 0.1 to 2.3; P value 0.44), recessive (OR, 0.8; 95% CI; 0.38 to 2.07, P value 0.79) models with IS risk. CONCLUSION: Based on ethnicity stratification, our meta-analysis suggests that LTA -252A/G gene polymorphism is found to be significantly associated with the risk of IS in Caucasian population, but not in Asian population. However, LTA -804C/A gene polymorphism is not found to be associated with the susceptibility of IS in both Asian as well as in Caucasian population. Further well designed large sample size prospective studies are needed to confirm these findings.

Genetics of ischemic stroke: An Indian scenario.

Stroke, a heterogeneous multifactorial disorder, is known to be a major cause of death and adult disability within both the developed and developing countries. Approximately 85% of stroke cases are ischemic, whereas the remaining 15% are hemorrhagic. It is caused by multiple genetic factors, environmental factors, and interactions among these factors. Several candidate genes have been found to be associated with ischemic stroke. The most extensively studied genes include those involved in hemostasis, inflammation, nitric oxide production, homocysteine and lipid metabolism, and rennin-angiotensin-aldosterone system. Combined linkage/association studies have demonstrated that genes encoding phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) confer risk for stroke. Even though there is substantial evidence for the genetic basis of stroke as provided by the epidemiological data from twin- and family-based studies, the contribution of genetic factors identified till now is either not enough or very less to explain the entire spectrum of encountered phenomena associated with ischemic stroke. Till date, no genome-wide association studies (GWAS) have been carried out in India. We aim to extensively review the studies on candidate genes that may have potential applications in the early diagnosis, prevention, and treatment of ischemic stroke in the Indian population. This article further emphasizes the role of GWAS in ischemic stroke and the need for an extensive GWAS in the Indian population.

Role of neuroimaging in drug development.

The development of new molecular imaging techniques has bridged the gap between preclinical and clinical research. During the last decade, the developments in imaging strategies have taken a great leap by the advancements in new imaging scanners, development of pharmaceutical drugs, diagnostic agents, and new therapeutic regimens that made significant improvements in health care. The knowledge gained from imaging techniques in preclinical research can be applicable to the patients. Similarly, the problems from clinical studies with humans can be tested and studied in preclinical studies. The appropriate application of molecular imaging to drug discovery and development can markedly reduce costs and the time required for new drug development. Some imaging techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI), reveal anatomical images, and single-photon emission computed tomography (SPECT), SPECT/positron emission tomography (PET), and PET show functional images. These developing molecular or neuroimaging methods provide increasingly detailed structural and functional information about the nervous system. The basic principles of each technique are described followed by examples of the current applications to cutting-edge neuroscience research. In summary, it is shown that neuroimaging continues to grow and evolve, embracing new technologies and advancing to address ever more complex and important neuroscience questions.

Advances in drug development for Parkinson's disease: present status.

The major hallmark of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the characteristic motor symptoms of resting tremors, bradykinesia and rigidity. Research in the field of PD therapy has been partly successful in terms of developing symptomatic treatments, but it also experienced several failures with regard to developing disease-modifying therapies. According to the definition of the Committee to Identify Neuroprotective Agents for Parkinson's, neuroprotection would be any intervention that favorably influences the disease process or underlying pathogenesis to produce enduring benefits for patients. A development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages. Novel solutions might be offered by an evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multitarget approaches and network pharmacology. Several promising randomized controlled trials are in progress, and the increased collaboration between pharmaceutical companies and basic and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of PD. The aim of the present review is to give an overview of the neuroprotective agents and their targets currently investigated for the treatment of PD in phase I-III clinical trials.