Development of the Halifax Visual Scanning Test: A New Measure of Visual-Spatial Neglect for Personal, Peripersonal, and Extrapersonal Space.

OBJECTIVES: Visual-spatial neglect is a common attentional disorder after right-hemisphere stroke and is associated with poor rehabilitation outcomes. The presence of neglect symptoms has been reported to vary across personal, peripersonal, and extrapersonal space. Currently, no measure is available to assess neglect severity equally across these spatial regions and may be missing subsets of symptoms or patients with neglect entirely. We sought to provide initial construct validity for a novel assessment tool that measures neglect symptoms equally for these spatial regions: the Halifax Visual Scanning Test (HVST). METHODS: In Study I, the HVST was compared to conventional measures of neglect and functional outcome scores (wheelchair navigation) in 15 stroke inpatients and 14 healthy controls. In Study II, 19 additional controls were combined with the control data from Study I to establish cutoffs for impairment. Patterns of neglect in the stroke group were examined. RESULTS: In Study I, performance on all HVST subtests were correlated with the majority of conventional subtests and wheelchair navigation outcomes. In Study II, neglect-related deficits in visual scanning showed dissociations across spatial regions. Four inpatients exhibited symptoms of neglect on the HVST that were not detected on conventional measures, one of which showed symptoms in personal and extrapersonal space exclusively. CONCLUSIONS: The HVST appears a useful measure of neglect symptoms in different spatial regions that may not be detected with conventional measures and that correlates with functional wheelchair performance. Preliminary control data are presented and further research to add to this normative database appears warranted.

Principal-component analysis for assessment of population stratification in mitochondrial medical genetics.

Although inherited mitochondrial genetic variation can cause human disease, no validated methods exist for control of confounding due to mitochondrial population stratification (PS). We sought to identify a reliable method for PS assessment in mitochondrial medical genetics. We analyzed mitochondrial SNP data from 1513 European American individuals concomitantly genotyped with the use of a previously validated panel of 144 mitochondrial markers as well as the Affymetrix 6.0 (n = 432), Illumina 610-Quad (n = 458), or Illumina 660 (n = 623) platforms. Additional analyses were performed in 938 participants in the Human Genome Diversity Panel (HGDP) (Illumina 650). We compared the following methods for controlling for PS: haplogroup-stratified analyses, mitochondrial principal-component analysis (PCA), and combined autosomal-mitochondrial PCA. We computed mitochondrial genomic inflation factors (mtGIFs) and test statistics for simulated case-control and continuous phenotypes (10,000 simulations each) with varying degrees of correlation with mitochondrial ancestry. Results were then compared across adjustment methods. We also calculated power for discovery of true associations under each method, using a simulation approach. Mitochondrial PCA recapitulated haplogroup information, but haplogroup-stratified analyses were inferior to mitochondrial PCA in controlling for PS. Correlation between nuclear and mitochondrial principal components (PCs) was very limited. Adjustment for nuclear PCs had no effect on mitochondrial analysis of simulated phenotypes. Mitochondrial PCA performed with the use of data from commercially available genome-wide arrays correlated strongly with PCA performed with the use of an exhaustive mitochondrial marker panel. Finally, we demonstrate, through simulation, no loss in power for detection of true associations with the use of mitochondrial PCA.

Common mitochondrial sequence variants in ischemic stroke.

OBJECTIVE: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV). METHODS: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke. RESULTS: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037). INTERPRETATION: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.

Independent susceptibility markers for atrial fibrillation on chromosome 4q25.

BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

Melatonin treatment following stroke induction modulates L-arginine metabolism.

The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.

Hyperlipidemia and reduced white matter hyperintensity volume in patients with ischemic stroke.

BACKGROUND AND PURPOSE: White matter hyperintensity (WMH), or leukoaraiosis, is a radiologic finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relation to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small-vessel disease such as intracerebral hemorrhage are associated with low levels of cholesterol. We sought to determine the relation between hyperlipidemia and WMH severity in patients with acute ischemic stroke (AIS). METHODS: We analyzed 2 independent, hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semiautomated volumetric image analysis and a semiquantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relation between WMH severity and study variables. RESULTS: A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (P<0.001) in both cohorts. In the multivariable analysis, after controlling for age, sex, and significant risk factors in the univariate and age-adjusted analyses, patients with a history of hyperlipidemia had less severe WMH in both cohorts (P<0.01). CONCLUSIONS: Results from 2 independent cohorts demonstrate that AIS patients with a history of hyperlipidemia have less severe WMH at the time of stroke. These data support the hypothesis that hyperlipidemia may play a relatively protective role in cerebral small-vessel disease.

Determinants of white matter hyperintensity volume in patients with acute ischemic stroke.

BACKGROUND: White matter hyperintensity (WMH) is a common radiographic finding in the aging population and a potent risk factor for symptomatic cerebrovascular disease. It is unclear whether WMH represents a single or multiple biological processes. We sought to investigate the extent and determinants of WMH in patients with acute ischemic stroke (AIS). METHODS: We retrospectively analyzed a prospectively enrolled hospital-based cohort of patients with AIS. WMH volume (WMHV) was measured using a previously published method with high interrater reliability based on a semiautomated image analysis program. RESULTS: WMHV was measured in 523 consecutive patients with stroke (mean age 65.2 years, median WMHV 8.2 cm(3)). In univariate linear regression analyses, individuals who were older, had elevated homocysteine (HCY) level or systolic blood pressure, or history of hypertension (all P < .0001), decreased glomerular filtration rate (P < .0002), atrial fibrillation (P < .0008), or coronary artery disease (P < .03) had significantly greater WMHV. After multivariable adjustment, only age (P < .0001) and HCY levels greater than 9 mumol/L (P < .003) remained independently associated with WMHV. CONCLUSIONS: In patients with AIS, risk factors for WMH severity do not appear to overlap with those previously reported for population-based cohorts. Only age and higher HCY levels were independently associated with more severe WMH in patients with stroke. This suggests that some of the processes underlying WMH burden accumulation in patients with stroke may differ from those in the general population and are not simply mediated by traditional vascular risk factors.

Expression of Cathepsins B, D, and G in WHO Grade I Meningioma.

Aim: We have recently demonstrated the presence of putative tumor stem cells (TSCs) in World Health Organization (WHO) grade I meningioma (MG) localized to the microvessels, which expresses components of the renin-angiotensin system (RAS). The RAS is known to be dysregulated and promotes tumorigenesis in many cancer types, including glioblastoma. Cathepsins B, D, and G are isoenzymes that catalyze the production of angiotensin peptides, hence providing bypass loops for the RAS. This study investigated the expression of cathepsins B, D, and G in WHO grade I MG in relation to the putative TSC population we have previously demonstrated. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining with antibodies for cathepsins B, D, and G was performed on WHO grade I MG tissue samples from 10 patients. Three of the MG samples subjected to DAB IHC staining underwent immunofluorescence (IF) IHC staining to investigate co-expression of each of these cathepsins using combinations of smooth muscle actin (SMA) and embryonic stem cell marker OCT4. NanoString mRNA expression (n = 6) and Western blotting (WB; n = 5) analyses, and enzyme activity assays (EAAs; n = 3), were performed on snap-frozen WHO grade I MG tissue samples to confirm transcriptional activation, protein expression, and functional activity of these proteins, respectively. Results: DAB IHC staining demonstrated expression of cathepsins B, D, and G in all 10 MG samples. NanoString mRNA expression and WB analyses showed transcriptional activation and protein expression of all three cathepsins, although cathepsin G was expressed at low levels. EAAs demonstrated that cathepsin B and cathepsin D were functionally active. IF IHC staining illustrated localization of cathepsin B and cathepsin D to the endothelium and SMA+ pericyte layer of the microvessels, while cathepsin G was localized to cells scattered within the interstitium, away from the microvessels. Conclusion: Cathepsin B and cathepsin D, and to a lesser extent cathepsin G, are expressed in WHO grade I MG. Cathepsin B and cathepsin D are enzymatically active and are localized to the putative TSC population on the microvessels, whereas cathepsin G was localized to cells scattered within the interstitium, These results suggest the presence of bypass loops for the RAS, within WHO grade I MG.

Tissue microstructural changes are independently associated with cognitive impairment in cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive impairment and is associated with white matter hyperintensities and cerebral microbleeds. MRI diffusion tensor imaging detects microstructural tissue damage in advanced CAA even in areas that appear normal on conventional MRI. We hypothesized that higher global mean apparent diffusion coefficient (mean ADC), reflecting a higher amount of chronic tissue disruption caused by CAA, would be independently associated with CAA-related cognitive impairment. METHODS: Preintracerebral hemorrhage cognitive impairment was systematically assessed using a standardized questionnaire (IQCODE) in 49 patients. Volume of white matter hyperintensities, number of microbleeds, and mean ADC were determined from MRIs obtained within 14.0+/-22.5 days of intracerebral hemorrhage cognitive impairment. White matter hyperintensities and mean ADC were measured in the hemisphere uninvolved by intracerebral hemorrhage to avoid confounding. RESULTS: Preintracerebral hemorrhage cognitive impairment was identified in 10 of 49 subjects. Mean ADC was the only variable associated with preintracerebral hemorrhage cognitive impairment and was elevated in those with preintracerebral hemorrhage cognitive impairment compared with those without (12.4x10(-4) versus 11.7x10(-4) mm(2)/s; P=0.03). Mean ADC positively correlated with age but not white matter hyperintensities or number of microbleeds. In logistic regression controlling for age and visible cerebral atrophy, mean ADC was independently associated with preintracerebral hemorrhage cognitive impairment (OR per 1x10(-4) mm(2)/s increase=2.45, 95% CI 1.11 to 5.40, P=0.04). CONCLUSIONS: Mean ADC is independently associated with preintracerebral hemorrhage cognitive impairment in CAA. The lack of correlation with other MRI markers of CAA suggests that mean ADC may be sensitive to distinct aspects of CAA pathology and its tissue consequences. These results suggest that global MRI diffusion changes are sensitive to clinically relevant microstructural alterations and may be useful markers of CAA-related tissue damage.

Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain.

Until recently the cannabinoid CB2 receptor was believed to be absent from the central nervous system. In this study we have identified CB2 expressing cells that appear in the rat brain following stroke and hypoxic-ischemia. At 3 days following surgery CB2-positive macrophages, deriving from resident microglia and/or invading monocytes appear on the lesioned side of the brain. By day 7, a mixed population of CB2-positive cells is present. Microglia-derived macrophages are the key cells in the first stages of brain inflammation, and a pivotal step in the neurodegeneration that follows the acute stage of injury. Thus, CB2 may be important in the brain during injury, and in inflammatory neurodegenerative disorders. The presence of CB2-positive cells in the brain following stroke may provide a novel strategy for cannabinoid-mediated intervention into stroke induced neurodegeneration without the psychoactive effects of CB1 receptor stimulation.

Clomethiazole: mechanisms underlying lasting neuroprotection following hypoxia-ischemia.

Damage after hypoxia-ischemia (HI) is observed in both cortical and subcortical regions. In this study, we employed a "Levine" rat model of HI (left carotid ligation + 1 h global hypoxia on PND-26) and used histological and electrophysiological paradigms to assess the long-term neuroprotective properties of clomethiazole (CMZ; a GABA(A) receptor modulator). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess potential CMZ mechanisms not involving GABA-R activation. Assessments were carried out 3 and 90 days post-HI. Extensive CNS lesions were evident after HI ipsilaterally at both short- and long-term intervals. CMZ significantly decreased the lesion size at 3 and 90 days (P<0.01; P<0.05). Evoked field potential analyses were used to assess hippocampal CA1 neuronal activity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function after HI relative to short- and long-term controls (P<0.001, 3 and 14 days; P<0.01, 90 days), with CMZ treatment providing near complete protection (P<0.001 at 3 and 14 days; P<0.01 at 90 days). Both NOS and arginase activities were significantly increased at 3 days (P<0.01), with arginase remaining elevated at 90 days post-HI (P<0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P<0.001; P<0.05). These data provide evidence of long-term functional neuroprotection by CMZ in a model of HI. We further conclude that under conditions of HI, functional deficits are not restricted to the ipsilateral hemisphere and are due, at least in part, to changes in the activity of NOS and arginase.

Mechanisms of action of green tea catechins, with a focus on ischemia-induced neurodegeneration.

Catechins are dietary polyphenolic compounds associated with a wide variety of beneficial health effects in vitro, in vivo and clinically. These therapeutic properties have long been attributed to the catechins' antioxidant and free radical scavenging effects. Emerging evidence has shown that catechins and their metabolites have many additional mechanisms of action by affecting numerous sites, potentiating endogenous antioxidants and eliciting dual actions during oxidative stress, ischemia and inflammation. Catechins have proven to modulate apoptosis at various points in the sequence, including altering expression of anti- and proapoptotic genes. Their anti-inflammatory effects are activated through a variety of different mechanisms, including modulation of nitric oxide synthase isoforms. Catechins' actions of attenuating oxidative stress and the inflammatory response may, in part, account for their confirmed neuroprotective capabilities following cerebral ischemia. The versatility of the mechanisms of action of catechins increases their therapeutic potential as interventions for numerous clinical disorders. However, more epidemiological and clinical studies need to be undertaken for their efficacy to be fully elucidated.

(-)-Epigallocatechin gallate as an intervention for the acute treatment of cerebral ischemia.

This study examined the neuroprotective effects and possible hepatotoxicity of (-)-epigallocatechin gallate (EGCG) in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats (265-295 g) were treated with either 50 mg kg(-1) of EGCG or saline, i.p., immediately post-ischemia and every day thereafter, in a middle cerebral artery occlusion model of stroke. Sacrifice occurred 72 h post-ischemia and 2,3,5-triphenyltetrazolium chloride staining was used to quantify neuronal infarction. Hepatotoxicity was determined by taking blood samples for plasma alanine aminotransferase (ALT) activity. Spleen, kidney, liver and testes wet weights were also recorded. Total infarct volume was significantly (P<0.05) reduced in the EGCG-treated group as compared to controls. Analysis of the mean infarct area showed a significant (P<0.05) decrease in slices 6 and 7 in the EGCG-treated group. No significant differences were found in organ weights or ALT levels between treatment groups. Our findings, in part, validate and extend previous observations illustrating that 50 mg kg(-1), i.p. EGCG is non-toxic and neuroprotective. However, we also found that EGCG treatment appreciably increased (>50%) the number of animals that developed an intracerebral hemorrhage. We therefore conclude that 50 mg kg(-1) EGCG is not a viable intervention for the acute treatment of cerebral ischemia, as it is likely to increase the risk of intracerebral hemorrhaging.

Inflammation and autoimmunity as a central theme in neurodegenerative disorders: fact or fiction?

Irrespective of the initiating stimuli, neurodegenerative disorders including multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease and stroke share many characteristics of inflammation and autoimmunity. This review summarizes and correlates the information relating to the role of cytokines and chemokines in initiating and propagating the inflammatory/immune response in these pathologies. For example, in MS there is a continuous realignment in the inflammatory and immune response. However, due to the redundancy in the cytokine/chemokine response, it is extremely unlikely that any one therapy will be successful in treating neurodegenerative diseases. This review attempts to highlight specific targets for therapeutic intervention.

Packed red blood cell transfusion and decreased mortality in intracerebral hemorrhage.

BACKGROUND: Accumulating data suggest that anemia worsens outcomes in critically ill patients, including those with subarachnoid and intracerebral hemorrhage (ICH). Although packed red blood cell (PRBC) transfusion appears to increase brain tissue oxygen, it is unknown whether such transfusions, which are commonly administered in patients with intracranial hemorrhage, alter outcome. OBJECTIVE: Following up on our observation that anemia is associated with poor outcome in patients with ICH, we investigated whether PRBC transfusion was associated with any benefit. METHODS: Five hundred forty-six consecutive subjects were identified from an ongoing single-center, prospective cohort study of nontraumatic ICH over a 6-year period. Clinical and radiographic characteristics, laboratory values including admission and daily mean hemoglobin values, and all instances of PRBC transfusion were recorded. Aggressiveness of care was assessed by whether the patient had a "do not resuscitate" order activated during hospitalization. The primary endpoint was 30-day survival. RESULTS: Anemia was present in 144 of 546 patients (26%) on admission and developed subsequently in an additional 250, leaving just 152 of 546 patients (28%) who never developed anemia. PRBC transfusion was administered to 100 patients (18%) during their hospital stay, 98% of whom were anemic. In multivariable analysis, PRBC transfusion was associated with improved survival at 30 days (odds ratio: 2.76; 95% confidence interval: 1.45-5.26; P = .002). CONCLUSION: Anemia develops in the majority of patients with ICH at some point during their hospitalization. PRBC transfusion was associated with improved outcome in these patients.

Lack of replication in polymorphisms reported to be associated with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia and has a substantial heritable component. Numerous associations between single nucleotide polymorphisms (SNPs) and AF have been described, but few have been replicated. OBJECTIVE: We sought to systematically replicate SNPs that are reported to be associated with AF in two large study samples of European descent. METHODS: We searched PubMed for studies reporting associations between SNPs and AF published before July 1, 2007. SNPs were genotyped in two independent case-control samples from Germany and the United States. Associations between SNPs and AF were assessed using logistic regression models adjusting for age, sex, and hypertension. A meta-analysis of the results from the two studies was performed. RESULTS: We identified 21 SNPs and the angiotensin-converting enzyme insertion/deletion polymorphism that were reported to be associated with AF in the literature. Nine of these genetic variants were not represented on common genome-wide SNP arrays. We successfully genotyped 21 of these 22 variants in 2,145 cases with AF from the German Competence Network for Atrial Fibrillation and 4,073 controls from the KORA S4 study and 16 variants in 790 cases and 1,330 controls from the Massachusetts General Hospital. None of the SNPs replicated in independent populations with AF. CONCLUSION: Our results suggest that previously reported associations to AF were likely false positives and highlight the need for systematic replication of genetic associations in large, independent cohorts to accurately detect variants associated with disease.

Cerebral heme oxygenase 1 and 2 spatial distribution is modulated following injury from hypoxia-ischemia and middle cerebral artery occlusion in rats.

The regional and cellular distribution of heme oxygenase (HO)-1 and -2 following cerebral ischemia has not been ascertained. Employing the transient middle cerebral artery occlusion (MCAO) and hypoxia-ischemia (HI) models of unilateral brain injury, the aim was to elucidate immunolocalization of HO-1 and HO-2. Animals were sacrificed 3 days post-ischemia and immunohistochemistry and Western blotting were utilized to determine HO-1 and HO-2 expression. In the ipsilateral hemisphere following HI, HO-1 immunoreactivity was significantly upregulated in many neuronal and glial populations (including the cortex, hippocampus and thalamus). HO-1 was also detected in macrophages/microglia within the infarct. In addition to widespread neuronal HO-2 labelling, HO-2 was also expressed in vascular endothelial cells. Inflammatory cells within the infarct of MCAO and HI animals were surprisingly immunoreactive for HO-2, but only HI animals had significantly elevated HO-2 protein expression in the ipsilateral hemisphere. This may be due to the presence of global hypoxia in the HI model which can upregulate vascular endothelial growth factor and subsequent proliferation of endothelial cells. This report of HO-2 protein expression upregulation following HI coupled with an increase in HO-1 immunoreactivity suggests that this response may be implicated in reducing cell death or repairing damage induced by cerebral ischemia.