Abdullah Nassief

Effects of Lipopolysaccharide Priming on Acute Ischemic Brain Injury

BACKGROUND AND PURPOSE Infection has been implicated as a stroke risk factor. Activation and infiltration of polymorphonuclear neutrophils (PMNs) after cerebral ischemia may contribute to ischemic brain injury. This study was conducted to investigate how enhanced postischemic PMN infiltration by lipopolysaccharide (LPS) altered the acute ischemic outcomes. METHODS LPS (0.05 mg/kg SC) or vehicle was given to Long-Evans male rats 24 hours before ischemia. Focal cerebral ischemia was induced by temporary ligation of the right middle cerebral artery and both common carotid arteries for 45 minutes. Animals were killed 6 and 24 hours after reperfusion to determine the extent of PMN infiltration (myeloperoxidase assay), brain edema (wet-dry weight method), and vascular injury (fluorescein isothiocyanate-conjugated dextran extravasation). The infarct volumes were measured on the basis of TTC stain 24 hours after ischemia. RESULTS LPS had little effect on body temperature or peripheral white count but substantially enhanced PMN infiltration into the ischemic right middle cerebral artery cortex on the basis of myeloperoxidase activity (6 hours: control, 0 U/g; LPS, 0.186+/-0. 025 U/g; 24 hours: control, 0.185+/-0.025 U/g; LPS, 0.290+/-0.040 U/g; P<0.001) and morphological studies. The extent of vascular injury defined by the extravasation of fluorescein isothiocyanate-conjugated dextran into the ischemic tissue (6 hours: control, 3.11+/-0.41 microliter/mg protein; LPS, 0.48+/-0.16 microliter/mg protein; 24 hours: control, 1.77+/-0.23 microliter/mg protein; LPS, 0. 90+/-0.19 microliter/mg protein; P<0.001) and brain edema determined by the brain water content (6 hours: control, 84.77+/-1.63%; LPS, 82. 09+/-1.25%; 24 hours: control, 89.40+/-0.43%; LPS, 87.88+/-0.58%; P<0.01) were paradoxically reduced by LPS priming. LPS-primed rats also had smaller infarct volumes (control, 135+/-5 mm(3); LPS, 108+/-12 mm(3); P<0.05). CONCLUSIONS Enhanced postischemic PMN infiltration is anticipated to facilitate ischemic brain injury. Contrary to this expectation, results from the present study suggest that an increase in postischemic PMN infiltration after LPS priming was not detrimental. These findings challenge the notion that postischemic PMN infiltration is uniformly deleterious.

Statin Therapy for Stroke Prevention

Background and Purpose— Statins are widely used to reduce the risk of stroke in patients with coronary artery disease (CAD), but less so in patients without CAD. We reviewed recent trials for new evidence for the reduction in risk of stroke. Summary of Review— In patients with CAD, moderate-intensity statin treatment has been associated with reductions in risk of stroke, with no increase in hemorrhagic stroke. Additionally, in the TNT trial, intensive lipid lowering provided further stroke risk reduction compared with moderate lipid lowering in patients with stable CAD. Evidence is now available that statin therapy also reduces stroke risk in patients without CAD but at high cardiovascular risk, or with diabetes mellitus. The SPARCL trial showed that intensive statin therapy started within 6 months after a cerebrovascular event significantly reduced stroke risk and stroke severity. Low cholesterol levels have been associated with increased risk of hemorrhagic stroke, but although an increased risk of hemorrhagic stroke was observed in patients with prior hemorrhagic stroke in SPARCL, this was not related to low-density lipoprotein cholesterol levels. Clinical trials have recruited few patients with both coronary and cerebrovascular disease, but these patients are also expected to experience significant cardiovascular benefit with statin therapy. Conclusions— Trial data show that statins reduce the risk of stroke, in addition to providing cardiovascular benefits. Consequently, physicians should consider statin therapy in all patients at high risk of stroke.

Preexisting cognitive impairment in women before cardiac surgery and its relationship with C-reactive protein concentrations

Preoperative cognitive state is seldom considered when investigating the effects of cardiac surgery on cognition. In this study we sought to determine the prevalence of cognitive impairment in women scheduled for cardiac surgery using nonhospitalized volunteers as a reference group and to examine the relationship between C-reactive protein levels and cognitive impairment. Psychometric testing was performed in 108 postmenopausal women scheduled for cardiac surgery and in 58 nonhospitalized control women. High sensitivity C-reactive protein levels were measured in the surgical patients. Preoperative cognitive impairment was defined as >2 sd lower scores on ≥2 tests compared with the controls. Cognitive impairment was present in 49 of 108 (45%) patients. C-reactive protein levels were higher for patients with compared with those without cognitive impairment (median, 8.1 mg/L versus 4.7 mg/L; P = 0.04). Based on multivariate logistic regression analysis, patient age, lower attained level of education, type 2 diabetes mellitus, and prior myocardial infarction identified risk for cognitive impairment (P < 0.05) but C-reactive protein levels did not (P = 0.09). In conclusion, cognitive impairment is prevalent in women before cardiac surgery. C-reactive protein levels are increased in women with this condition but the relationship between this inflammatory marker and preexisting cognitive impairment is likely secondary to the acute phase reactant serving as a marker for other predisposing conditions.

Validation of a Dysphagia Screening Tool in Acute Stroke Patients

BACKGROUND Although many dysphagia screening tools exist, none has high sensitivity and reliability or can be administered quickly with minimal training. OBJECTIVE To design and validate a swallowing screening tool to be used by health care professionals who are not speech language pathologists to identify dysphagia and aspiration risk in acute stroke patients. METHODS In a prospective study of 300 patients admitted to the stroke service at an urban tertiary care hospital, interrater and test-retest reliabilities of a new tool (the Acute Stroke Dysphagia Screen) were established. The tool was administered by nursing staff when patients were admitted to the stroke unit. A speech language pathologist blinded to the results with the new tool administered the Mann Assessment of Swallowing Ability, a clinical bedside evaluation, with dysphagia operationally defined by a score less than 178. RESULTS The mean time from admission to screening with the new tool was 8 hours. The mean time between administration of the new tool and the clinical bedside evaluation was 32 hours. For the new tool, interrater reliability was 93.6% and test-retest reliability was 92.5%. The new tool had a sensitivity of 91% and a specificity of 74% for detecting dysphagia and a sensitivity of 95% and a specificity of 68% for detecting aspiration risk. CONCLUSIONS The Acute Stroke Dysphagia Screen is an easily administered and reliable tool that has sufficient sensitivity to detect both dysphagia and aspiration risk in acute stroke patients.

Combination therapy for ischemic stroke: Potential of neuroprotectants plus thrombolytics

Thrombolysis improves clinical outcome in patients with acute ischemic stroke. However, only a small fraction of patients receive thrombolytic therapy due to the narrow therapeutic time window available for the treatment in patients with ischemic stroke. A better understanding of the mechanisms underlying ischemic injury may lead to the development of novel therapeutic strategies to reduce brain damage after stroke. Cerebral ischemia triggers a number of pathophysiological and biochemical changes in the brain that present potential targets for therapeutic intervention. Candidate pathways include those regulating cellular calcium influx, excitatory neurotransmitter uptake, and generation of reactive oxygen species, as well as activation of enzymes including kinases, proteases, and lipases. The end result of these pathophysiological pathways may be apoptosis (programmed cell death) or necrosis. The activation of inflammatory cascades following ischemia also contributes to brain injury. Several neuroprotective agents which block cell death pathways have been proposed to have therapeutic potential in patients with stroke including calcium channel antagonists, glutamate receptor antagonists, free radical scavengers, anti-inflammatory strategies, inhibitors for nitric oxide synthase, and growth factors. Although results from clinical trials to date have been disappointing, there is reason to believe that combination therapy involving both thrombolytics and neuroprotectants holds promise for stroke treatment and warrants further investigation.

Gender influence on cognitive function after cardiac operation

BACKGROUND Women are at higher risk than men for stroke after cardiac operation. The purpose of this study was to evaluate for gender influences on the more common postoperative neurologic complication, cognitive dysfunction. METHODS A standard battery of neuropsychological tests was administered to 117 patients (79 men and 38 women) the day before and again 4 to 6 weeks after cardiac operation. The battery assessed a broad array of cognitive domains, including attention, memory, executive function, and psychomotor processing speed. Analysis was performed only on patients with data from both testing sessions. Data were analyzed to assess for a dichotomous definition of postoperative cognitive impairment and to evaluate for factors influencing test results for specific cognitive domains. RESULTS The frequency of one standard deviation decline on two or more cognitive tests compared with preoperative results (women, 10.7 % versus men, 9.9 %; p = 0.527), no decline, or one standard deviation improvement on each test postoperatively was no different between genders. After adjusting for age, gender, preexisting medical conditions, level of attained education, preoperative cognitive tests results, type of operation, and duration of cardiopulmonary bypass, female gender was independently associated with poorer performance postoperatively on visuospatial tasks. Other variables significantly related to postoperative cognitive function varied among the specific cognitive domains. CONCLUSIONS These data suggest that, although the frequency of cognitive dysfunction after cardiac operation is similar for women and men, women appear more likely to suffer injury to brain areas subserving visuospatial processing. Risk factors for postoperative cognitive impairment vary depending on cognitive domain, suggesting multiple etiologies for this form of perioperative neurologic injury.

Pravastatin Attenuates Ceramide-Induced Cytotoxicity in Mouse Cerebral Endothelial Cells with HIF-1 Activation and VEGF Upregulation

Abstract: Ceramide is a pro‐apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF‐α/cycloheximide, lipopolysaccharide, oxidized LDL, IL‐1, and amyloid peptide. Exposure of CECs to C2 ceramide for 12 h caused cell death in a concentration‐dependent manner, with a LC50 of 30 μM. Statins are inhibitors of 3‐hydroxyl‐3‐methyl coenzyme A reductase which is the rate‐limiting enzyme for cholesterol biosynthesis. Pretreatment with pravastatin at 20 μM for 16 h substantially attenuated ceramide cytotoxicity in mouse CECs. Increases in vascular endothelial growth factor (VEGF) expression were detected within 1‐3 h after pravastatin treatment. This pravastatin action was accompanied by the activation of hypoxia‐inducible factor‐1 (HIF‐1), a transcription factor known to activate VEGF expression. These results raise the possibility that pravastatin may protect CECs against ceramide‐induced death via the HIF‐VEGF cascade.

Resident-Based Acute Stroke Protocol Is Expeditious and Safe

Background and Purpose— The decision to administer tPA to acute stroke patients is frequently made by stroke attendings or fellows, but placing residents in this position may make tPA delivery more efficient. Methods— Beginning in 2004, we instituted a resident-based acute stroke protocol placing neurology residents in decision-making roles. Time-intervals, symptomatic hemorrhage rate, and discharge locations were prospectively collected and compared between two epochs, before and after 2004. Results— 59 acute ischemic stroke patients were treated with tPA before protocol initiation (1998 to 2002), while 113 patients were treated after protocol initiation (2004 to 2007). The average door-to-needle and onset-to-needle times were significantly shorter after initiation of the resident-based protocol (81 versus 60 minutes [P<0.001] and 138 versus 126 minutes [P<0.05]), respectively. Symptomatic hemorrhage rate (5.1% versus 3.5%) and favorable discharge location (68% versus 76%) did not differ between the two time periods. Conclusion— A resident-driven tPA protocol, with formal training and quality control, is safe and efficient.