Ischemic Stroke Syndrome Research Articles

Bone Marrow-Derived Progenitor Cells in the Early Phase of Ischemic Stroke: Relation with Stroke Severity and Discharge Outcome

A limited number of studies suggested that in ischemic stroke patients, the number of bone marrow circulating progenitor cells (CPCs), either endothelial progenitor cells (EPCs) or CPCs, was negatively correlated with the number of infarcts as well as with the outcome. The aim of this study was to simultaneously measure CPCs and EPCs in the acute phase of ischemic stroke, and to establish whether a relationship exists with stroke severity and discharge outcome. In 67 (40 M; 27 F) ischemic stroke patients with a median age of 73 (21 to 91) years, the number of CPCs and EPCs was measured by flow cytometry and analyzed in relation to baseline NIH Stroke Scale score, ischemic stroke syndromes, and discharge outcome. Patients with partial anterior circulation syndrome showed a higher CPCs' number with respect to patients with total anterior circulation syndrome. Moreover, a negative relationship between National Institutes of Health Stroke Scale score at the admission and CPCs number was observed. When the outcome was considered, patients discharged to home had a higher number of CPCs, but not of EPCs, compared with those moved to a rehabilitation unit. We report an association between the number of CPCs measured in the early phase after stroke presentation, neurologic severity, and discharge outcome.

Applications of molecular imaging in vulnerable atherosclerotic plaque

Atherosclerosis plaque is the underline cause of ischemic stroke and acute coronary syndrome. In this article, the applications of molecular imaging in vulnerable plaque are reviewed.

CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury

High levels of circulating soluble CD40 ligand (sCD40L) are frequently found in patients with hypercholesterolemia, diabetes, ischemic stroke, or acute coronary syndromes, predicting an increased rate of atherosclerotic plaque rupture and restenosis after coronary/carotid interventions. Clinical restenosis is characterized in part by exaggerated neointima formation, but the underlying mechanism remains incompletely understood. This study investigated the role of elevated sCD40L in neointima formation in response to vascular injury in an atherogenic animal model and explored the molecular mechanisms involved. apoE(-/-) mice fed a Western diet developed severe hypercholesterolemia, significant hyperglycemia, and high levels of plasma sCD40L. Neointima formation after carotid denudation injury was exaggerated in the apoE(-/-) mice. In vivo, blocking CD40L with anti-CD40L monoclonal antibody attenuated the early accumulation of Ly-6G(+) neutrophils and Gr-1(+) monocytes (at 3 days) and the late accumulation of Mac-2(+) macrophages (at 28 days) in the denudated arteries; it also reduced the exaggerated neointima formation at 28 days. In vitro, recombinant CD40L stimulated platelet P-selectin and neutrophil Mac-1 expression and platelet-neutrophil co-aggregation and adhesive interaction. These effects were abrogated by anti-CD40L or anti-Mac-1 monoclonal antibody. Moreover, recombinant CD40L stimulated neutrophil oxidative burst and release of matrix metalloproteinase-9 in vitro. We conclude that elevated sCD40L promotes platelet-leukocyte activation and recruitment and neointima formation after arterial injury, potentially through enhancement of platelet P-selectin and leukocyte Mac-1 expression and oxidative activity.

Venous and arterial thromboembolism in severe sepsis

The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.

"Mechanism of multiple infarcts in multiple cerebral circulations on diffusion weighted imaging" by Cho et al.

Sirs: Modern concepts of the pathophysiology of cerebral ischemic syndromes have been strongly influenced by modern brain imaging. The high contrast of the acute ischemic lesion on diffusion-weighted MRI (DWI) against the dark background facilitates the detection of acute lesions even when they are of minute size. For large stroke lesions, it has been repeatedly shown that acute lesions on DWI, the area of severe hypoperfusion on perfusion-weighted MRI (PWI), and the vessel status on MR angiographic images, all provide important information with regard to the underlying pathophysiology. Consequently the socalled mismatch concept between the acute DWI and PWI lesion is nowadays frequently used in clinical trials, and within institutional protocols, to estimate the potential benefit from thrombolytic treatment. Although the diagnostic information obtained in large strokes is important, the value of demonstrating acute, small DWI lesions is also very considerable. In particular, conventional T2weighted MRI and (even more so) CT may not be able to differentiate the acute from chronic lesions (or to detect a small lesion at all on CT). Because of this lack of sensitivity, a negative conventional MRI or CT often generates diagnostic uncertainty. It is not surprising that very small DWI lesions may not directly cause clinical manifestations. However, the information conveyed by the presence and morphological appearance of acute lesions may be clinically useful. The mechanism of acute stroke is often of relevance for the assignment of the stroke etiology and for an early estimation of the individual prognosis. Such new information has already led to a reassessment of the concepts of transient ischemic attacks and subcortical stroke syndromes [1, 2]. From the multiplicity of lesions and their anatomical pattern and distribution, several papers have already demonstrated that the aetiology can be inferred, e.g. hemodynamic stroke patterns versus stroke patterns in endocarditis with a proximal embolic source or cerebral vasospasm [3, 4]. In this issue of the Journal of Neurology, Cho and co-authors report their experience with the analysis of multiple cerebral infarcts in acute stroke patients. The authors investigated 67 patients with multiple acute lesions, who underwent DWI within 48 hours after symptom onset. DW images and ADC maps were used for lesion classification. Furthermore, blood markers were also analysed. In 29% of the patients there were indications of possible cardioembolism. Large artery atherosclerosis, or small vessel occlusion in multiple territories, or both in combination, were identified in 34.3%. It is a very interesting but also demanding task to investigate the origin of multiple lesions in more detail. This is particularly so when an embolic source is suspected as the cause of stroke in patients with multiple lesions. In future studies, serial MRI may ascertain the timing of events: whether repeat embolic events have occurred and are responsible for the multiplicity of the lesions or whether a single event and break up of a large embolus is responsible. In this context, transcranial ultrasound can be helpful to confirm the presence of embolic material within the blood flow to the hemispheres. It is a common procedure to use the TOAST criteria for stroke classification. However, for such a detailed analysis with very specific questions this classification may not be ideal. The demonstration of thrombus or a patent foramen ovale on trans-oesophageal echocardiography appears to provide more direct evidence. A most interesting finding in this study was that the CRP was increased in many of the patients with multiple infarcts. This should provide motivation for further investigation of this group of patients, including follow-up MRI and in depth analysis of the potential causes of a CRP elevation, in order to generate new insights into the mechanisms of stroke.

Clopidogrel

Clopidogrel (Plavix), Iscover) selectively and irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Long-term administration of clopidogrel was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with established cardiovascular disease in the CAPRIE trial. In other large well designed multicentre trials, such as CURE, COMMIT and CLARITY-TIMI 28, the addition of clopidogrel to aspirin therapy improved outcomes in patients with acute coronary syndromes. However, some issues regarding the use of clopidogrel remain unresolved, such as the optimal loading dose in patients undergoing percutaneous coronary interventions (PCI) and the optimal treatment duration following drug-eluting intracoronary stent placement. Results of several large randomised trials, therefore, have established clopidogrel as an effective and well tolerated antiplatelet agent for the secondary prevention of ischaemic events in patients with various cardiovascular conditions, including those with ischaemic stroke or acute coronary syndromes. In addition, treatment guidelines from the US and Europe acknowledge the importance of clopidogrel in contemporary cardiovascular medicine.

Characteristics and six-month outcomes in a cohort of 8288 diabetic and non-diabetic patients with previous history of acute coronary syndrome or stroke: the French PREVENIR 3 survey

To evaluate the cardiovascular prognosis of 1845 Diabetic Patients (DP) and 6443 Non-Diabetic Patients (NDP) in secondary prevention. Patients were recruited prospectively if they had had a previous history of ischemic stroke or acute coronary syndrome (ACS) i.e. Myocardial Infarction (MI) or Unstable Angina (UA) within a period of five years preceding inclusion. For each patient, the number of hospitalizations and vital status were recorded each month over a 6-month period (mean follow-up: 4.8 months). 306 patients (9.5/100--person years; 95% CI, 8.5 to 10.6) had undergone at least one subsequent event (hospitalization for ACS, ischemic stroke, or cardiovascular death). A majority of these events were non-fatal ACS (n=248). The cumulative incidence rate of subsequent events was higher in DP: 12.6/100- person years (10.0 to 15.2) than in NDP: 8.6/100--person years (7.5 to 9.8). DP were significantly at higher risk of subsequent cardiovascular events (OR: 1.34; P=0.025) after adjustment for confounding factors. 93% of coronary DP and NDP underwent a recurrent event affecting the same location. When the index episode was a stroke, 71% of DP had a subsequent stroke vs. 47% of NDP. in secondary prevention, the risk of mortality and subsequent vascular events is independently higher in French DP than in NDP. The locations affected by each type of subsequent cardiovascular event seemed correlated to the baseline diagnosis, whatever the diabetic status, even when the frequency of subsequent strokes increased (not significantly) in DP when compared to NDP.

Anticoagulation Strategies for Treatment of Ischemic Stroke and Antiphospholipid Syndrome: Case Report and Review of the Literature

A 49-year-old Caucasian man with antiphospholipid syndrome who experienced an ischemic stroke required multidisciplinary decisions regarding acute and long-term care. The patient first received warfarin and unfractionated heparin, followed by low-molecular-weight heparin. However, he developed complications from these drugs (warfarin-induced necrosis and heparin-induced thrombocytopenia), resulting in thigh necrosis and multiple additional cerebral and peripheral infarcts. His condition improved after warfarin and the heparins were discontinued, and a direct thrombin inhibitor, argatroban, was given intravenously for acute treatment. Argatroban is the only anticoagulant known to be safe in patients who experience an acute ischemic stroke in the setting of heparin-induced thrombocytopenia. For long-term anticoagulation, fondaparinux, an indirect, selective factor Xa inhibitor, was given subcutaneously. The patient received intravenous dexamethasone, later changed to azathioprine, for immunomodulatory treatment. He had significant improvement in his neurologic deficits without recurrent events over the next 18 months. Management of anticoagulation therapy in patients with antiphospholipid syndrome is complex and challenging, and therapeutic strategies need to be evaluated further.

Genomic profiles for human peripheral blood T cells, B cells, natural killer cells, monocytes, and polymorphonuclear cells: Comparisons to ischemic stroke, migraine, and Tourette syndrome

Blood genomic profiling has been applied to disorders of the blood and various organ systems including brain to elucidate disease mechanisms and identify surrogate disease markers. Since most studies have not examined specific cell types, we performed a preliminary genomic survey of major blood cell types from normal individuals using microarrays. CD4 + T cells, CD8 + T cells, CD19 + B cells, CD56 + natural killer cells, and CD14 + monocytes were negatively selected using the RosetteSep antibody cocktail, while polymorphonuclear leukocytes were separated with density gradient media. Genes differentially expressed by each cell type were identified. To demonstrate the potential use of such cell subtype-specific genomic expression data, a number of the major genes previously reported to be regulated in ischemic stroke, migraine, and Tourette syndrome are shown to be associated with distinct cell populations in blood. These specific gene expression, cell-type-related profiles will need to be confirmed in larger data sets and could be used to study these and many other neurological diseases.

Protein Z levels and prognosis in patients with acute coronary syndromes

Protein Z, a vitamin K-dependent glycoprotein, serves as a cofactor for the inhibition of activated coagulation factor X. During recent years, a role for low levels of protein Z in prothrombotic disorders such as ischemic stroke and acute coronary syndromes (ACS) has been reported. The aims of this study were to test changes in protein Z and their association with outcome at 1-year follow-up in 193 (150 male, 43 female) patients with ACS. Protein Z plasma levels were significantly lower (p<0.0001) after 1 year [1,600 (28-3,736) ng/mL] compared to the baseline [1,695 (294-4,068) ng/mL]. Regression analysis showed a significant association between baseline protein Z below the 5th percentile of our control group and subsequent adverse cardiac events at follow-up (odds ratio 3.3; 95% CI 1.04-10.7; p=0.04). Moreover, Cox regression analysis showed that low protein Z levels at admission were significant predictors of major adverse cardiac events (cardiac death, non-fatal recurrent myocardial infarction, and need for target lesion revascularization) after 1 year (hazard risk 2.5; 95% CI 1.02-6.5, p=0.04). Our results show that in patients with ACS: 1) protein Z decreases moving from the acute to the convalescent phase; and 2) low levels of baseline protein Z are significantly associated with adverse outcome at 1-year follow-up.

Platelets and atherothrombosis: An essential role for inflammation in vascular disease — A review

Atherothrombosis is the common link between clinical manifestations of arterial vascular disease including ischemic stroke and acute coronary syndromes, such as unstable angina and acute myocardial infarction. Our understanding of the common pathologic mechanisms underlying these conditions has significantly increased during the past ten years, yet atherothrombosis as the “root cause” of a large proportion of cardiovascular and cerebrovascular diseases is largely underappreciated. Although the classical risk factors of dyslipidemia, smoking, diabetes, hypertension, obesity, and sedentary lifestyle are widely recognized as being associated with a heightened risk of vascular disease, inflammation of the vascular system during the past decade has become increasingly regarded as the principal underlying mechanism in the development of clinical atherothrombotic disease. In addition, platelet-derived inflammatory mediators play an essential role in the pathogenesis of cardiovascular disease, being involved at all stages of plaque development until their eventual rupture and subsequent formation of a platelet-rich thrombus. Mounting evidence supports the role of both localized and systemic inflammation in these events. Platelets are central to vascular inflammatory processes. Thus, inflammation can stimulate local thrombosis and thrombosis can amplify inflammation. Consequently, antiplatelet therapy for the prevention of serious vascular events may provide a double benefit via an anti-inflammatory action of the antiplatelet agent in modifying plaque formation and stability and antiplatelet activity that inhibits platelet aggregation and thrombus formation from occurring following plaque rupture.

Leg Ulcers in Sickle Cell Anemia Are Associated with Laboratory Markers of Hemolysis and SNPs in KL and Genes of the TGF-β/BMP Pathway.

Sickle cell disease patients have a high risk of developing leg ulcers. In the CSSCD database we found 378 patients with a confirmed history of leg ulcers and chose 920 patients without ulcers to serve as controls. α Thalassemia reduces hemolysis in sickle cell anemia which is consistent with our finding using an age-adjusted comparison, that sickle cell anemia-α thalassemia was more frequent among controls than cases (OR: 0.7, 95% CI: 0.5–0.9). This suggests that sickle cell anemia-α thalassemia patients are significantly less likely to have leg ulcers. Also, leg ulcer patients had lower hemoglobin levels, higher LDH, bilirubin, AST, reticulocyte and white blood cell count than controls. These differences were highly statistically significant (p < 0.001, except for AST, whose p was <0.005) and support the impression that cases have a higher rate of hemolysis than controls. Fetal hemoglobin was higher in controls compared with cases (p=0.002). The haplotype of the β-like globin gene cluster, creatinine and ALT were not associated with leg ulcers. Leg ulcers were associated with other clinical manifestations of sickle cell disease like ischemic stroke (OR:1.4, 95% CI: 0.9–2.0) and acute chest syndrome (OR:1.5, 95% CI:1.1–1.9). When analysis of laboratory data was restricted to the 759 patients (243 cases vs. 516 controls) that were also genotyped for SNPs in candidate genes, the results were similar. We studied 132 SNPs in 47 candidate genes for their association with leg ulcers. SNPs were studied by mass spectrometry in a screening phase and by using haplotype tagging (ht) SNPs and the ABI SNPlex for follow-up. Candidate genes included: mediators of inflammation; oxidant injury; NO biology; vasoregulation; cell-cell interaction; blood coagulation; hemostasis; growth factors; cytokines and receptors. The candidate genes having multiple SNPs associated with leg ulcers were KL (rs685417 and rs516306; p values <0.02), TEK (rs603085 and rs671084; p values <0.025), SMAD1 (rs1899784, rs10519733 and rs2068991; p values <0.05), and SARA1 (rs2271690 and rs870801; p values <0.04). KL directly or indirectly promotes endothelial NO production. The TEK receptor tyrosine kinase (TIE2) is expressed almost exclusively in endothelial cells, is involved in angiogenesis and is the ligand for angiopoietin-1 (ANG1). SMAD1 and SARA1 are members of the TGF-β/BMP pathway. The TGF-β receptor signals through the SMAD family of transcriptional regulators that are anchored to the cell membrane by factors like SARA (SMAD Anchor for Receptor Activation). This pathway modulates immunosuppression, cell migration, wound healing and angiogenesis, among its other functions. Hemolysis is likely to be an antecedent of certain vascular complications of sickle cell disease, like pulmonary hypertension This, and the current studies, suggest that there is a hemolysis-driven phenotype in sickle cell disease that now includes leg ulcers. While candidate genes that might modulate the rate of hemolysis have not yet been studied, we find that SNPs in genes that may be pathogenetically important in sickle vasculopathy are associated with the disease subphenotype of leg ulcer. Linking gene polymorphisms with disease subphenotypes, may eventually provide useful means of foretelling the likelihood of complications and allow better individualized treatment.

Metabolic Syndrome as a Predictor of Ischemic Stroke in Elderly Persons

To estimate the prevalence and risk of ischemic stroke associated with metabolic syndrome. In 197 stroke patients (80 cases of atherothrombotic infarction, 97 lacunar infarction, 16 cardioembolic infarction, 4 others) and 356 age- and sex-matched control subjects aged 65 years and older in Seiyo Municipal Nomura Hospital, we investigated the association between metabolic syndrome and risk factor-dependent augmentation of ischemic stroke in subjects with several risk factors for atherosclerosis. The diagnosis of cerebral infarction in each patient was confirmed by CT findings of the brain and metabolic syndrome was defined as at least 3 of the 5 following conditions: visceral obesity, hypertension (HT), hypertriglyceridemia, low HDL-cholesterol and diabetes mellitus (DM). After adjustment for sex, age, and smoking, metabolic syndrome was significantly related to atherothrombotic infarction (odds ratio, 3.08; 95% confidence interval, 1.69-5.61). Of the individual components, visceral obesity, HT and DM were independent risk factors for atherothrombotic infarction. Increased risk for atherothrombotic infarction was also associated with increases in the 5 component conditions of the metabolic syndrome. The clustering of cardiovascular risk factors called metabolic syndrome increases the risk of cardiovascular morbidity, and its identification may thus be important in risk assessment and treatment of patients.

Intra-arterial Thrombolysis for Acute Ischemic Stroke: Preliminary Experience with Platelet Glycoprotein IIb/IIIa Inhibitors as Adjunctive Therapy

To evaluate the safety profile of platelet glycoprotein IIb/IIIa inhibitors administered as adjunctive therapy to patients with large-vessel occlusion and acute ischemic stroke refractory to pharmacological thrombolysis with recombinant tissue plasminogen activator (rtPA) and mechanical disruption, balloon angioplasty, or both. Twenty-one patients (mean age, 62 yr; range, 29-88 yr) met the following criteria: 1) large-vessel occlusion and acute ischemic stroke syndrome at presentation, 2) failure to recanalize after administration of rtPA (intra-arterial and/or intravenous) with or without mechanical thrombolysis, and 3) subsequent treatment with IIb/IIIa inhibitors (intra-arterial or intravenous). Eleven patients had ischemia in the dominant hemisphere, 8 in the vertebrobasilar system, and 2 in the nondominant hemisphere. Twelve patients received intravenous rtPA without significant improvement; 9 patients were not candidates for intravenous rtPA. All patients received intra-arterial rtPA. The IIb/IIIa inhibitors were administered intravenously in 3 patients, intra-arterially in 16, and both intravenously and intra-arterially in 2. Balloon angioplasty was performed in 18 patients. Complete or partial recanalization was achieved in 17 of the 21 patients. After thrombolysis, 15 improved clinically. Three patients (14%) sustained an asymptomatic intracerebral hemorrhage after thrombolytic therapy. No patient was clinically worse after intervention. At last follow-up (mean, 8.5 mo), 13 patients were functionally independent (modified Rankin score, 0-3) and 8 were disabled or dead. IIb/IIIa inhibitors are an alternative for achieving recanalization. The risk of hemorrhage may be low. As part of an escalating protocol that includes pharmacological and mechanical thrombolysis, IIb/IIIa inhibitors may improve clinical outcomes.

Potential role of platelet FcγRIIA in collagen-mediated platelet activation associated with atherothrombosis

Collagen-mediated platelet activation contributes significantly to coronary and cerebrovascular thrombus formation associated with atherosclerotic plaque destabilization. Recent clinical and laboratory observations support a potential role for the platelet Fc receptor (FcγRIIA) in this process. The purpose of this study was to elucidate any association between platelet Fc receptor (FcR) expression levels and both atherosclerosis risk factors (ARFs) along with collagen-dependent platelet activation. Age and gender-independent variation has been described in the expression of this receptor that is stable over time. Platelet Fc surface expression was compared between patients experiencing an acute coronary or cerebrovascular event, healthy patients with two or more ARFs, and healthy patients with fewer than two ARFs. Platelet FcR expression was significantly and stably (6–52 weeks, mean 20 weeks) increased in 101 patients with acute myocardial infarction, unstable angina, or ischemic stroke syndrome ( P<0.001) and 38 healthy patients with two or more ARFs ( P=0.027) compared with 109 healthy patients with fewer than two ARFs. Patients with diabetes mellitus from all groups had significantly increased platelet FcR expression over those without diabetes ( P<0.0001). Platelet aggregation studies suggested a correlation between number of ARFs per patient, platelet Fc expression levels, and relative sensitivity to collagen stimulation. Platelet FcR surface expression is increased in patients with an acute coronary or cerebrovascular event, non-acutely ill patients with two or more ARFs, and in patients with diabetes mellitus. Increased platelet FcR expression may therefore contribute towards risk for atherothrombotic events.

Association between seropositivity to Chlamydia pneumoniae and acute ischaemic stroke.

Recent studies suggest an association between Chlamydia pneumoniae infection with atherosclerosis, including cerebrovascular disease. We investigated the prevalence of Chlamydial seropositivity in patients with acute ischaemic stroke syndrome compared with age- and sex-matched control subjects. Specific antibodies (IgA) to C. pneumoniae were measured by microimmunofluorescence in both the clinical group (n=91) and the control group (n=112). Forty patients (43.9%) and 34 controls (30.3%) had positive IgA titres (P < 0.05). The pooled data from this and previous series yielded 45% of seropositivity in cerebrovascular patients vs. 19% in control subjects (P < 0.001). In conclusion, we suggest an association between chronic infection by C. pneumoniae and acute ischaemic stroke.

Apoptosis: mechanisms and clinical implications.

The balance between cell survival and death is under tight genetic control. A multiplicity of extracellular signals and intracellular mediators is involved in maintaining this balance. When the cell is exposed to physical, biochemical or biological injury, or deprived of necessary substances, it activates a series of stress-response genes. With minimal insults, the cell may recover. With greater insults, single cell death, or apoptosis, results; the cell dies and is recycled to its neighbours. If the insult overwhelms a large number of cells then necrosis ensues, with an accompanying inflammatory response. Dysregulation of the controlling mechanisms of this system results in disease. Deficient apoptosis is associated with cancer, auto-immunity and viral infections. Excessive apoptosis is associated with ischaemic heart disease, stroke, neurodegenerative disease, sepsis and multiple organ dysfunction syndrome. There are myriad therapeutic options unfolding as understanding is gained of apoptosis and its control.

Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease.

Intracranial large-artery occlusive disease is the predominant vascular lesion found in stroke patients of Asian, African, and Hispanic ancestry, making it numerically perhaps the most common vascular cause of stroke in the world. Relatively little is known about the clinical significance of finding such lesions. We investigate whether the presence and the extent of these vascular lesions help predict outcome after stroke. On the basis of transcranial Doppler of the intracranial arteries with supplementary duplex ultrasound of the carotid arteries, we determined the number of occlusive arteries in the craniocervical circulation of consecutive patients who were hospitalized for acute cerebral ischemia. Patients were followed for 6 months for further vascular events (including transient ischemic attack, stroke, and acute coronary syndrome) or death. Among 705 consecutive Chinese patients studied, occlusive arteries were found in 345 patients (49%): 258 patients (37%) had intracranial lesions only, 71 (10%) had both extracranial and intracranial lesions, and 16 (2.3%) had extracranial lesions only. Sixty-three (18%) of the 345 patients with occlusive arteries and 35 (9.7%) of the 360 patients without occlusive arteries had further vascular event or death within 6 months. The risk of vascular events or death increased rapidly with rising numbers of occlusive arteries, after adjustment for vascular risk factors and stroke severity (adjusted odds ratio [OR] 1.25 per occlusive artery, 95% CI 1.12 to 1.39). Other independent risk factors included age (OR 1.03 per year of age, 95% CI 1.01 to 1.05) and atrial fibrillation (OR 3.00, 95% CI 1.40 to 6.69). In patients with predominantly intracranial large-artery occlusive disease, the presence and the total number of occlusive arteries in the craniocervical circulation predict further vascular events or death within 6 months after stroke. Transcranial Doppler ultrasound is an important investigation for the evaluation of patients with stroke in populations at risk of intracranial atherosclerotic disease.

Prediction of infarct topography using the Oxfordshire Community Stroke Project classification of stroke subtypes

The Oxfordshire Community Stroke Project clinical classification of ischemic stroke syndromes has been shown to be predictive of important clinical outcomes. In this study, we examined the correlation between this classification system and infarct topography on computed tomography (CT) of the brain. A cohort of consecutive cases of acute ischemic stroke admitted to an acute stroke service during the 3-year period ending December 31, 1996 were identified from a prospective stroke registry. Brain scans were reviewed by a single neuroradiologist without knowledge of the clinical features. There were 418 patients with acute ischemic stroke who met the study admission criteria. Forty patients were excluded, 20 (5%) did not have a CT scan during the admission, and 20 scans were not available for review. In 239 of 378 patients (63%), the brain scan revealed the lesion responsible for the clinical syndrome. In patients with positive scans, the positive predictive values of the clinical subtypes were: 86% (95% confidence interval, 78-94) for the total anterior territory stroke syndrome, 96% (92-100) for the partial anterior territory stroke syndrome, 99% (97-100) for the lacunar stroke syndrome, and 100% for the posterior circulation stroke syndrome. The Oxfordshire Community Stroke Project classification of ischemic stroke syndromes usefully predicts infarct topography on CT scan.

The evolution of surgery for the treatment and prevention of stroke. The Willis Lecture.

Thomas Willis, the man for whom this lecture is named, was an Englishman and a leading neuroanatomist of the 17th century. Born in 1621, he attended Oxford University, graduating from Christ Church College in 1639. While still at Oxford, he became Sedleian Professor of Natural History in 1660. He did much experimental work with his associate Richard Lower. He performed injection experiments on cadavers and noted that if he injected the carotid artery on one side, the dye solution would come forth from the carotid on the opposite side. In 1664 Willis published his monumental work Cerebri Anatome , the most complete and accurate account of the nervous system that had hitherto appeared. In it he contributed the term “neurology” to medicine, a word derived from the Greek, meaning “sinew,” “tendon,” or “bowstring.” The word was translated and introduced into the English language in 1681 in Samuel Pordage's translation of Willis' work. Cerebri Anatome contains a classification of the cerebral nerves, the first description of the eleventh nerve, and a description of the hexagonal network of arteries at the base of the brain that we know as the circle of Willis. Although others had described the circle before Willis, he was the first to grasp its physiological and pathological significance. He records the clinical histories of two patients in whom he suggests that the anatomic configuration of the arteries at the base of the brain could prevent apoplexy. The book was illustrated by Christopher Wren, an associate of Willis at Oxford, later to become England's leading architect and designer of St Paul's Cathedral, numerous other English churches, and many historic secular buildings. Willis moved to London in 1666 and acquired the largest fashionable practice of his day. He continued his careful clinical observations and made a number of other important …