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ABSTRACT: The burden of stroke is disproportionately high in the South Asian subcontinent with South Asian ethnicity conferring a greater risk of ischemic stroke than European ancestry regardless of country inhabited. While genes associated with stroke in European populations have been investigated, they remain largely unknown in South Asians. We conducted a comprehensive meta-analysis of known genetic polymorphisms associated with South Asian ischemic stroke, and compared effect size of the MTHFR C677T-stroke association with effect sizes predicted from homocysteine-stroke association. Electronic databases were searched up to August 2012 for published case control studies investigating genetic polymorphisms associated with ischemic stroke in South Asians. Pooled odds ratios (OR) for each gene-disease association were calculated using a random-effects model. We identified 26 studies (approximately 2529 stroke cases and 2881 controls) interrogating 33 independent genetic polymorphisms in 22 genes. Ten studies described MTHFR C677T (108 with TT genotype and 2018 with CC genotype) -homocysteine relationship and six studies (735 stroke cases and 713 controls) described homocysteine-ischemic stroke relationship. Risk association ORs were calculated for ACE I/D (OR 5.00; 95% CI, 1.17-21.37; p = 0.03), PDE4D SNP 83 (OR 2.20; 95% CI 1.21-3.99; p = 0.01), PDE4D SNP 32 (OR 1.57; 95% CI 1.01-2.45, p = 0.045) and IL10 G1082A (OR 1.44; 95% CI, 1.09-1.91, p = 0.01). Significant association was observed between elevated plasma homocysteine levels and MTHFR/677 TT genotypes in healthy South Asians (Mean difference (ΔX) 5.18 µmol/L; 95% CI 2.03-8.34: p = 0.001). Our results demonstrate that the genetic etiology of ischemic stroke in South Asians is broadly similar to the risk conferred in Europeans, although the dataset is considerably smaller and warrants the same clinical considerations for risk profiling.
PLoS ONE 01/2013; 8(3):e57305. · 4.09 Impact Factor
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ABSTRACT: Identification of biomarkers for stroke will aid our understanding of its aetiology, provide diagnostic and prognostic indicators for patient selection and stratification, and play a significant role in developing personalized medicine. We undertook the largest systematic review conducted to date in an attempt to characterize diagnostic and prognostic biomarkers in acute ischaemic and haemorrhagic stroke and those likely to predict complications following thrombolysis.
A comprehensive literature search was carried out to identify diagnostic and prognostic stroke blood biomarkers. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for each biomarker.
We identified a total of 141 relevant studies, interrogating 136 different biomarkers. Three biomarkers (C-reactive protein, P-selectin and homocysteine) significantly differentiated between ischaemic stroke and healthy control subjects. Furthermore, glial fibrillary acidic protein levels were significantly different between haemorrhagic stroke and ischaemic stroke patients (MD 224.58 ng l⁻¹; 95% CI 25.84, 423.32; P= 0.03), high levels of admission glucose were a strong predictor of poor prognosis after ischaemic stroke and symptomatic intracerebral haemorrhage post-thrombolysis, glutamate was found to be an indicator of progressive (unstable) stroke (MD 172.65 µmol l⁻¹, 95% CI 130.54, 214.75; P= 0.00001), D-dimer predicted in-hospital death (MD 0.67 µg ml⁻¹, 95% CI 0.35, 1.00; P= 0.0001), and high fibrinogen levels were associated with poor outcome at 3 months (MD 47.90 mg l⁻¹, 95% CI 14.88, 80.93; P= 0.004) following ischaemic stroke.
Few biomarkers currently investigated have meaningful clinical value. Admission glucose may be a strong marker of poor prognosis following acute thrombolytic treatment. However, molecules released in the bloodstream before, during or after stroke may have potential to be translated into sensitive blood-based tests.
British Journal of Clinical Pharmacology 02/2012; 74(2):230-40. · 2.96 Impact Factor
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ABSTRACT: We report the first family of Indian origin known to be affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Seventeen members of the family spanning 3 generations had neurologic syndromes compatible with CADASIL, of whom 5 were genetically confirmed carriers of the Notch3 gene R141C mutation in exon 4 (421(C→T) and 141(Cys→Arg)). Our report highlights that CADASIL not only occurs sporadically in South Asians, but also may account for stroke in South Asians with a strong family history. Furthermore, the similarity of clinical presentations described here to those typical for Caucasian case series suggests that the CADASIL phenotype is preserved across racial groups.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 07/2011;
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ABSTRACT: Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing 'effort'-associated activations in prefrontal regions; and deactivation of a 'resting-state network' in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an 'inverted-U shaped' pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications.
Progress in Neurobiology 06/2011; 94(4):360-88. · 8.87 Impact Factor
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ABSTRACT: The potential effectiveness of cell therapies is dependent upon homing of transplanted cells to relevant target organs. In this study we firstly characterise the range of methods employed in all human therapeutic-cell studies published to date investigated with cell-tracking. Secondly, we determine factors that predict target-organ cell uptake efficiency by meta-regression. Following a comprehensive literature search, we identified 19 relevant trials, representing 145 patients over the following 7 diseases: myocardial infarction; Chagasic cardiomyopathy; ischemic stroke; traumatic injury of brain or spinal cord; diabetes and cirrhosis. Cell-labelling strategies employed were: 18-fluorodeoxyglucose-PET, 111-indium-SPECT; 99-technetium-SPECT, and iron oxide-MRI. The following methodological parameters were extracted: label type; label dose; labelling efficiency; stability; cell dose; percentage labelled cells; disease type and chronicity; cell purity; cell type; and cell uptake efficiency. Meta-regression techniques were used to identify predictors of cell-labelling efficiency; viability and cell uptake efficiency. These analyses found that labelling efficiency is proportionate to cell dose, while cell viability is lowest with indium and long label incubation times. Uptake efficiency of cells is predicted by stem cell purity (positive association) and cell infusion number (negative association), although these two variables are themselves strongly negatively correlated between studies. In summary the methodological factors associated with enhanced therapeutic-cell homing from both our own analysis, and within-trial comparisons, are: acute (versus chronic) disease, selective stem cells (versus unselected cells), and intra-arterial (versus intravenous) delivery. However, future trials need to keep cell doses and imaging times constant so as to enable meaningful comparisons in uptake efficiency.
Stem cell reviews 04/2011; 7(4):1031-40. · 5.08 Impact Factor
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Sunaina Yadav,
Renata Schanz,
Ankita Maheshwari,
Muhammad Saleem Khan,
Julia Slark,
Ranil de Silva, Paul Bentley,
Philippe Froguel,
Jaspal Kooner,
Padma Shrivastav,
Kameshwar Prasad,
Pankaj Sharma
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ABSTRACT: Stroke is one of the commonest causes of mortality in the world and anticipated to be an increasing burden to the developing world. Stroke has a genetic basis and identifying those genes may not only help us define the mechanisms that cause stroke but also identify novel therapeutic targets. However, large scale highly phenotyped DNA repositories are required in order for this to be achieved.
The proposed Bio-Repository of DNA in Stroke (BRAINS) will recruit all subtypes of stroke as well as controls from two different continents, Europe and Asia. Subjects recruited from the UK will include stroke patients of European ancestry as well as British South Asians. Stroke subjects from South Asia will be recruited from India and Sri Lanka. South Asian cases will also have control subjects recruited.
We describe a study protocol to establish a large and highly characterized stroke biobank in those of European and South Asian descent. With different ethnic populations being recruited, BRAINS has the ability to compare and contrast genetic risk factors between those of differing ancestral descent as well as those who migrate into different environments.
BMC Medical Genetics 03/2011; 12:34. · 2.33 Impact Factor
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ABSTRACT: Quantitative predictions of the risk of cerebral venous thrombosis (CVT) conferred by certain genotypes have yet to be reliably established. We conducted a comprehensive meta-analysis of all candidate genes studied to assess their genetic contribution to the etiology of CVT. We compared our findings against equivalent analyses for pediatric CVT and adult ischemic stroke.
Databases were searched to August 2010 for all genes investigated in adult CVT, and odds ratios (ORs) for each gene-disease association were calculated. A mendelian randomization strategy was also undertaken to determine whether a causal relation to one gene could be ascertained.
We identified 26 case-control studies investigating 6 polymorphisms in 6 genes and included 1183 CVT cases and 5189 controls. Statistically significant associations with CVT were found for factor V Leiden/G1691A (OR=2.40; 95% CI, 1.75 to 3.30; P<0.00001) and prothrombin/G20210A (OR=5.48; 95% CI, 3.88 to 7.74; P<0.00001). After iterative analysis controlling for interstudy heterogeneity, methylene tetrahydrofolate reductase/C677T was also found to be significantly associated (OR=2.30; 95% CI, 1.20 to 4.42; P=0.02). Variants in the remaining 3 genes (Janus kinase-2, plasminogen activator inhibitor-1, and protein Z) were not significantly associated. Pooled ORs for CVT risk in adults for factor V Leiden and prothrombin were significantly greater when compared against childhood CVT and adult arterial ischemic stroke. A causal relation with methylene tetrahydrofolate reductase may exist.
CVT has a genetic basis. Genes involved in the clotting cascade provide a greater level of thrombosis risk in the cerebral venous circulation compared with its arterial circulation, and a greater level of risk exists for adults compared with children.
Stroke 02/2011; 42(4):913-8. · 5.73 Impact Factor
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ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cause of cerebral small-vessel disease associated with one of many recognised mutations of the NOTCH3 gene. Spinal cord involvement is not a recognised feature. The authors describe a unique CADASIL pedigree that manifested a stereotypical pattern of cord lesions, in association with a novel and atypical NOTCH3 mutation.
Clinical, radiological, laboratory and genetic characterisation of three affected family members. The associated NOTCH3 mutation was further evaluated by site-directed mutagenesis, immunohistochemistry, CBF1-transcription reporter assay, and screened for in 100 unrelated pathologically confirmed multiple sclerosis (MS) patients.
Three members of a family presented with CADASIL caused by a novel NOTCH3 missense mutation, C212Y. Two daughters of the proband also manifested a distinctive pattern of cord lesions confined to the posterocentral zone, cerebral lesions showing both a demyelinating and a typical CADASIL topography, positive antinuclear antibodies and intrathecally derived oligoclonal bands. The mutation occurred in exon 4--that is, outside the Notch3 ligand-binding domain--yet unusually for this location impaired Notch function as assessed by Jagged1 signal transduction. The C212Y mutation did not occur in 100 separate MS cases.
This is the first description of an inherited pattern of cord lesions in association with CADASIL. The fact that certain features of dysregulated immunity also occurred, in association with a novel and atypical loss-of-function NOTCH3 mutation, supports evidence for functional interactions of Notch3 with the immune system, in addition to its vascular support role.
Journal of neurology, neurosurgery, and psychiatry 01/2011; 82(8):855-60. · 4.87 Impact Factor
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ABSTRACT: Effective treatments exist for the acute management and prevention of stroke, but their uptake depends upon public awareness of stroke symptoms and cardiovascular risk factors. We evaluated the extent of both types of knowledge amongst high-risk individuals. Furthermore, we determined whether knowledge of risk factors, and appreciation of personal risk, influences risk avoidance behaviour.
A validated comprehensive questionnaire assessing knowledge of stroke symptoms and personal risk factors was completed by stroke survivors across the United Kingdom.
Questionnaires were completed by 622 stroke survivors (age range, 18-91 yrs; mean, 55.4 yrs). Recall of all 3 cardinal stroke symptoms (face, arm or leg, and speech disturbance) was made by only 14% of respondents, with 34% citing none of these symptoms. Knowledge of any established stroke risk factor was cited by 55% of respondents, with the remainder believing that stroke occurs because of chance. Similarly, 45% did not acknowledge that having had a previous stroke predisposed to future cardiovascular disease. Respondents recognising their own personal future risk were more likely to consume less alcohol (P < .0001) and salt (P < .005) and to eat more fruits and vegetables (P < .02).
Knowledge of stroke symptoms and cardiovascular risk factors is poor amongst high-risk stroke patients. However, an awareness of personal risk of future stroke increased the likelihood of adopting secondary prevention behaviours after stroke. Our results have important implications for the prevention of secondary vascular disease in stroke patients and the effects of public health campaigns on high-risk stroke groups.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 11/2010; 21(5):358-62.
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Circulation Research 04/2010; 106(6):1019-21. · 9.49 Impact Factor
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ABSTRACT: Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 - 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes--glycoprotein IIIa, PAI-1 and angiotensinogen--show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.
PLoS ONE 01/2010; 5(2):e9136. · 4.09 Impact Factor
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ABSTRACT: Healthcare inequalities within the UK based on patients' ethnicity have been found over the last five years in a large number of medical specialties. One possible explanation for this lies in ignorance of ethnic minority healthcare needs among professionals. Cultural diversity programmes have been shown to improve patient outcomes including compliance, yet these are not as yet requirements for any UK healthcare professionals with the exception of psychiatrists. This paper documents the frequency, regional variation, characteristics and motivations for cultural diversity training through a questionnaire survey of the educational leads of every UK medical school, postgraduate deanery and schools of nursing, physiotherapy, occupational therapy, speech and language therapy, and pharmacy. The results showed a wide variation in teaching practices between healthcare professions and geographical regions. This study provides evidence for the need for national guidelines to incorporate cultural competency training by all UK healthcare professional training bodies.
Clinical medicine (London, England) 11/2008; 8(5):493-7. · 1.15 Impact Factor
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ABSTRACT: Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate that physostigmine can improve both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions in AD, while perturbing the normal pattern of responses in many of the same regions in healthy controls.
Brain 03/2008; 131(Pt 2):409-24. · 9.46 Impact Factor
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Archives of Neurology 01/2008; 64(12):1788-9. · 7.58 Impact Factor
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ABSTRACT: Current pharmacological strategies for acute ischemic stroke largely mirror those employed in acute coronary syndromes. However, important differences in the effectiveness and versatility of the principal agents have emerged between these 2 clinical settings. In general, the level of success achieved with drugs in acute coronary syndromes has not carried over to the same extent when the same drug types are used in stroke. The principal reason is that reperfusion or anticoagulant therapies in the setting of brain infarction run a significant risk of hemorrhagic transformation that has no direct equivalent in myocardial infarction. Consequently, a significant challenge in acute stroke therapeutics is the ability to select patients for drugs where only a narrow therapeutic margin exists and to identify methods that can minimize hemorrhage risk. Other brain-specific vascular factors also pertain in explaining differences in outcome of drugs generally regarded as having a broad cardiovascular remit. The relatively limited efficacy of antiplatelets in stroke might relate to the composition and heterogeneity of the cerebrovascular lesion, while the poor outcome associated with acute anti-hypertensive use is partly due to loss of cerebrovascular autoregulation. Finally, downstream consequences of arterial occlusion within the brain such as excitotoxicity and plasticity are organ specific and, as such, deserve their own pharmacological approaches. In this review, we describe the general mechanism of each drug class used in ischemic stroke and then report on the clinical experience and application for each.
Pharmacology [?] Therapeutics 01/2006; 108(3):334-52. · 8.56 Impact Factor
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ABSTRACT: Neocortical cholinergic afferents are proposed to influence both selective attention and emotional processing. In a study of healthy adults we used event-related fMRI while orthogonally manipulating attention and emotionality to examine regions showing effects of cholinergic modulation by the anticholinesterase physostigmine. Either face or house pictures appeared at task-relevant locations, with the alternative picture type at irrelevant locations. Faces had either neutral or fearful expressions. Physostigmine increased relative activity within the anterior fusiform gyrus for faces at attended, versus unattended, locations, but decreased relative activity within the posterolateral occipital cortex for houses in attended, versus unattended, locations. A similar pattern of regional differences in the effect of physostigmine on cue-evoked responses was also present in the absence of stimuli. Cholinergic enhancement augmented the relative neuronal response within the middle fusiform gyrus to fearful faces, whether at attended or unattended locations. By contrast, physostigmine influenced responses in the orbitofrontal, intraparietal and cingulate cortices to fearful faces when faces occupied task-irrelevant locations. These findings suggest that acetylcholine may modulate both selective attention and emotional processes through independent, region-specific effects within the extrastriate cortex. Furthermore, cholinergic inputs to the frontoparietal cortex may influence the allocation of attention to emotional information.
NeuroImage 10/2003; 20(1):58-70. · 5.89 Impact Factor
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ABSTRACT: We examined whether behavioral and neural effects of repeating faces are modulated by independent factors of selective attention, emotion, and cholinergic enhancement, during functional MRI. Face repetition occurred either between task-relevant (spatially attended) or task-irrelevant (unattended) stimuli; faces could be fearful or neutral; subjects received either placebo or physostigmine. Under placebo, a reaction time advantage occurred with repetition (i.e., priming) that did not differ between levels of attention, but was attenuated with emotion. Inferior temporo-occipital cortex demonstrated repetition decreases to both attended and unattended faces, and showed either equivalent or greater repetition decreases with emotional compared with neutral faces. By contrast, repetition decreases were attenuated for emotional relative to neutral faces in lateral orbitofrontal cortex. These results distinguish automatic repetition effects in sensory cortical regions from repetition effects modulated by emotion in orbitofrontal cortex, which parallel behavioral effects. Under physostigmine, unlike placebo, behavioral repetition effects were seen selectively for attended faces only, whereas emotional faces no longer impaired priming. Physostigmine enhanced repetition decreases in inferior occipital cortex selectively for attended faces, and reversed the emotional interaction with repetition in lateral orbitofrontal cortex. Thus we show that cholinergic enhancement both augments a neural signature of priming and modulates the effects of attention and emotion on behavioral and neural consequences of repetition.
Journal of Neurophysiology 09/2003; 90(2):1171-81. · 3.32 Impact Factor
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The Lancet 365(9459):552-3. · 38.28 Impact Factor
