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Michael E Sughrue

Publications and source records attributed to Michael E Sughrue.

13 recordsLinked to original sources
PubMed2006

Complement component C3 mediates inflammatory injury following focal cerebral ischemia.

The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3-/- mice were protected, as demonstrated by 34% reductions in both infarct volume (P<0.01) and neurological deficit score (P<0.05). C3-deficient mice also manifested decreased granulocyte infiltration (P<0.02) and reduced oxidative stress (P<0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction (P<0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism.

Animals↗
PubMed2006

An improved test of neurological dysfunction following transient focal cerebral ischemia in rats.

The Adhesive Removal (sticky-tape) test is a commonly used test of somatosensory dysfunction following cerebral ischemia in rats. This test requires several days of pre-training prior to surgery, which can be time consuming. We present our results with an improved version of the sticky-tape test. Male Wistar rats were subjected to either sham surgery (n = 4) or right middle cerebral artery occlusion (rMCAo) using an intraluminal filament (n = 9), followed by a 10-day survival period. On post-operative days (POD) 1, 3, 7, and 10 animals underwent both the conventional sticky-tape test (CST) with measurement of the time to remove the stimulus (trs), as well as a modified sticky-tape test (MST), in which a non-removable tape sleeve was placed around the animal's paw. Time spent attending to this stimulus (tas) was recorded. Despite 3 days of pre-training, animals undergoing baseline CST still exhibited marked variability in pre-operative baseline test performance (trs range 1-60s). In contrast, animals undergoing MST for the first time demonstrated nearly uniformly excellent performance (% tas range 91.5-98.5% of the 30s testing period). Although, affected (left) limb performance on both CST (6.8-fold increase in trs on POD 1 compared to baseline) and MST (100% decrease in tas on POD 1 compared to baseline) was markedly altered by rMCAo, CST performance declined bilaterally, and no significant differences in the ratio of affected (left) and unaffected (right) limb performance between sham-operated and rMCAo animals were observed at any time point. In contrast, the ratio of left to right performance on the MST was significantly different at all time points (P<0.01). In conclusion, we present a simple modification of the widely used Adhesive Removal test and provide evidence that this test can accurately assess neurological dysfunction in rodents, not only with minimal pre-training, but also with improved localization of the side of injury.

Animals↗
PubMed2006

Temporal pattern of C1q deposition after transient focal cerebral ischemia.

Recent studies have focused on elucidating the contribution of individual complement proteins to post-ischemic cellular injury. As the timing of complement activation and deposition after cerebral ischemia is not well understood, our study investigates the temporal pattern of C1q accumulation after experimental murine stroke. Brains were harvested from mice subjected to transient focal cerebral ischemia at 3, 6, 12, and 24 hr post reperfusion. Western blotting and light microscopy were employed to determine the temporal course of C1q protein accumulation and correlate this sequence with infarct evolution observed with TTC staining. Confocal microscopy was utilized to further characterize the cellular localization and characteristics of C1q deposition. Western Blot analysis showed that C1q protein begins to accumulate in the ischemic hemisphere between 3 and 6 hr post-ischemia. Light microscopy confirmed these findings, showing concurrent C1q protein staining of neurons. Confocal microscopy demonstrated co-localization of C1q protein with neuronal cell bodies as well as necrotic cellular debris. These experiments demonstrate the accumulation of C1q protein on neurons during the period of greatest infarct evolution. This data provides information regarding the optimal time window during which a potentially neuroprotective anti-C1q strategy is most likely to achieve therapeutic success.

Animals↗
PubMed2006

Alterations in plasma complement levels after human ischemic stroke.

OBJECTIVE: Stroke is a leading cause of morbidity and mortality in the United States. Recent animal studies have implicated the complement system in cerebral ischemia/reperfusion injury and suggest that complement inhibition may improve stroke outcomes. To assess the applicability of these findings to humans, we evaluated the characteristics and time course of human complement activation after stroke. METHODS: We compared peripheral blood levels of complement factor 3a (C3a), 5a (C5a), and sC5b-9 drawn from 15 patients on poststroke Days 1, 2, 3, 7, 14, 21, and 28 to age-, race/ethnicity-, and sex-matched controls from the same population. Statistical analysis was performed using unpaired Mann-Whitney nonparametric tests with Bonferroni correction. All data is presented as the mean +/- standard deviation. RESULTS: Mean C3a concentrations showed significant early elevations in stroke patients relative to matched controls (controls: 1080 +/- 189 ng/ml; Day 1: 1609 +/- 422 ng/ml, P = 0.0008; Day 3: 1520 +/- 317 ng/ml, P = 0.0005; Day 7: 1526 +/- 386 ng/ml, P = 0.001). C3a was also significantly elevated on Day 28 (1448 +/- 386 ng/ml, P = 0.004). Before poststroke Day 7, mean C5a levels did not differ significantly from controls. However, beginning on Day 7 and continuing through Day 14, there were significant elevations in C5a (controls: 3.33 +/- 2.1 ng/ml; day 7: 6.86 +/- 3.5 ng/ml, P = 0.005; Day 14: 7.65 +/- 4.6 ng/ml, P = 0.004). Mean sC5b-9 concentrations showed early depressions that reached significance on Days 1 and 2 (controls: 275.6 +/- 107 ng/ml; Day 1: 167.0 +/- 108 ng/ml, P = 0.006; Day 2: 156.3 +/- 80.0 ng/ml, P = 0.005) and did not differ significantly from controls at any other time point. CONCLUSION: C3a is acutely elevated after human ischemic stroke, C5a shows delayed elevations 7 to 14 days after cerebral ischemia, and sC5b-9 is acutely depressed after stroke. Together, these data confirm complement activation after stroke and suggest that this activation is a heterogeneous process, with varying responses for different components.

Aged↗
PubMed2006

Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke.

OBJECT: Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke. METHODS: A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts. CONCLUSIONS: A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.

Animals↗
PubMed2005

C1q-deficiency is neuroprotective against hypoxic-ischemic brain injury in neonatal mice.

BACKGROUND AND PURPOSE: This study was undertaken to determine whether the initial component of the classical complement (C) activation pathway contributes to hypoxic-ischemic brain injury in neonatal mice. METHODS: Hypoxia-ischemia (HI) was produced in C1q(-/-) and wild-type (WT) neonatal mice. At 24 hours after HI, neonatal mouse reflex performance and cerebral infarct volume were assessed. Long-term outcomes were measured by water-maze performance and degree of cerebral atrophy at 7 to 8 weeks after HI. Activation of circulating neutrophils, and C1q, C3, and neutrophil deposition in brains were examined. RESULTS: C1q(-/-) mice were significantly protected against HI (mean+/-SE infarct volume in C1q(-/-) mice=17.3+/-5.5% versus 53.6+/-6.8% in WT mice; P<0.0001) and exhibited significantly less neurofunctional deficit compared with WT mice. Immunostaining revealed significantly greater deposition of C3 (and C1q) as well as granulocytes in the infarcted brains in WT mice compared with C1q(-/-) animals. Activation of circulating leukocytes was significantly decreased in C1q(-/-) mice compared with WT mice, which correlated strongly (r=0.7) with cerebral infarct volumes. CONCLUSIONS: Cerebral deposition of C1q and C3 after hypoxic-ischemic insult is associated with significantly greater neurologic damage in WT mice compared with C1q(-/-) mice, providing strong evidence that the classical C pathway contributes to the hypoxic-ischemic brain injury. Significantly decreased activation of circulating neutrophils associated with diminished local accumulation and attenuation of brain injury in C1q(-/-) mice suggests a potential cellular mechanism by which C1q mediates neurodegeneration in HI.

Animals↗
PubMed2005

Toward objective quantification of perfusion-weighted computed tomography in subarachnoid hemorrhage: quantification of symmetry and automated delineation of vascular territories.

RATIONALE AND OBJECTIVES: Perfusion-weighted computed tomography (CTP) is a relatively recent innovation that estimates a value for cerebral blood flow (CBF) using a series of axial head CT images tracking the time course of a signal from an intravenous contrast bolus. MATERIALS AND METHODS: CTP images were obtained using a standard imaging protocol and were analyzed using commercially available software. A novel computer-based method was used for objective quantification of side-to-side asymmetries of CBF values calculated from CTP images. RESULTS: Our method corrects for the inherent variability of the CTP methodology seen in the subarachnoid hemorrhage (SAH) patient population to potentially aid in the diagnosis of cerebral vasospasm (CVS). This method analyzes and quantifies side-to-side asymmetry of CBF and presents relative differences in a construct termed a Relative Difference Map (RDM). To further automate this process, we have developed a unique methodology that enables a computer to delineate vascular territories within a brain image, regardless of the size and shape of the brain. CONCLUSIONS: While both the quantification of image symmetry using RDMs and the automated assignment of vascular territories were initially designed for the analysis of CTP images, it is likely that they will be useful in a variety of applications.

Adult↗
PubMed2005

Decompressive hemicraniectomy for poor-grade aneurysmal subarachnoid hemorrhage patients with associated intracerebral hemorrhage: clinical outcome and quality of life assessment.

OBJECTIVE: Decompressive hemicraniectomy has been proposed as a potential treatment strategy in patients with poor-grade aneurysmal subarachnoid hemorrhage presenting with focal intracerebral hemorrhage causing significant mass effect. Although hemicraniectomy improves overall survival rates, the long-term quality of life (QoL) for survivors in this patient population has not been reported. METHODS: Using adjudicated outcome assessments, we compare long-term clinical outcomes and QoL between a group of patients with poor-grade aneurysmal subarachnoid hemorrhage receiving decompressive hemicraniectomy (n=12) and a control group of similar patients managed more conservatively (n=10). RESULTS: Patients receiving decompressive hemicraniectomy experienced a statistically insignificant decrease in short-term mortality compared with controls (25 versus 42%); however, long-term QoL in hemicraniectomy survivors was generally poor. Furthermore, hemicraniectomy patients did not experience an increase in mean quality-adjusted life years over control patients (2.31 versus 2.22 yr). CONCLUSION: Decompressive hemicraniectomy prolongs short-term survival in patients with poor-grade aneurysmal subarachnoid hemorrhage with associated intracerebral hemorrhage; however, this trend is not statistically significant, and the overall QoL experienced by survivors is poor. Decompressive hemicraniectomy may be indicated if performed early in a select subset of patients. On the basis of our preliminary data, large prospective studies to investigate this issue further may not be warranted.

Adult↗
PubMed2004

Pilomyxoid astrocytoma: a review.

Pilomyxoid astrocytoma (PMA) is a recently described type of brain tumor. PMA shares similar features with pilocytic astrocytoma (PA), the most common central nervous system (CNS) tumor in the pediatric population, yet displays subtle histologic differences. Previous studies have shown PMA to behave more aggressively than PA, with shorter progression-free and overall survival as well as a higher rate of recurrence and CNS dissemination. These findings suggest that PMA may be a unique and distinct neoplasm. This review summarizes the histologic, clinical, and radiographic characteristics of PMA. In addition, the current treatment options and research endeavors involving this disease are described. Increased recognition of PMA within the medical community has the potential to affect the treatment and prognosis of pediatric low-grade astrocytomas.

Astrocytoma↗