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Biomedical subjects

W M Clark

Publications and source records attributed to W M Clark.

At least 55 records · Page 3Linked to original sources
PubMed1995

Time course of ICAM-1 expression and leukocyte subset infiltration in rat forebrain ischemia.

The time course of ICAM-1 expression and leukocyte subset infiltration was studied in a model of CNS reperfusion injury in adult rats. Leukocyte adhesion and infiltration, mediated in part by intercellular adhesion molecule-1 (ICAM-1), appears to potentiate CNS reperfusion injury. The timing and relationship between ICAM-1 staining and leukocyte infiltration postglobal CNS ischemia is unknown. Reversible forebrain ischemia was produced in 32 adult Sprague-Dawley rats using the two-vessel occlusion model with histologic analysis performed at specific intervals postischemia: 1, 3, 6, 12, and 24 h, 4 and 7 d, or sham-operated controls (n = 4 each group). Monoclonal antibodies against ICAM-1 (1A29 and TM8), a specific granulocyte (PMN) (HIS48), and a specific monocyte/macrophage (M phi) (ED1) were used. No specific leukocyte and only rare ICAM-1 vessel immunoreactivity was observed in sham controls. ICAM-1: Significant expression in microvessels beginning at 1 h with additional diffuse CA1 pyramidal layer staining beginning at 4 d. Leukocytes: No PMN cells and rare M phi identified at 6 and 12 h. By 24 h: moderate infiltrate in areas of ICAM-1 expression of PMN and M phi. At 4 and 7 d: only M phi accumulation, cellular morphology now similar to microglia. The results of this study indicate that early and persistent ICAM-1 expression occurs following CNS ischemia with associated leukocyte infiltration.

Animals↗
PubMed1995

Safety and efficacy of percutaneous transluminal angioplasty for intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE: Percutaneous transluminal angioplasty (PCTA) is increasingly used to treat extracerebral arterial stenosis. The present study evaluates the safety and efficacy of PCTA treatment of symptomatic intracranial atherosclerotic stenosis. METHODS: A series of 22 vessels in 17 patients were treated with PCTA. All patients had recurrent neurological symptoms referable to the stenotic vessel despite optimal medical therapy. Critical (> 70%) arterial stenosis was confirmed by angiogram, and angioplasty was performed with a 3.0- to 3.5-mm Stealth balloon. RESULTS: The average preangioplasty stenosis (North American Symptomatic Carotid Endarterectomy Trial criteria) was 72 +/- 8% (mean +/- SD), with a significant improvement seen after angioplasty; the best angiographic stenosis (after healing of intimal injury, if any) was 43 +/- 24% (P < .001). Overall PCTA was successful in 82% of the vessels. There were two strokes during angioplasty for a 30-day morbidity rate of 9.1% per treated vessel and 11.7% per case. The other 15 patients were clinically evaluated at 3 and 6 months; all cases were without further events. Restenosis was evaluated in 8 patients (12 vessels) with an angiogram at 6 months showing further improvement compared with the initial post-PCTA stenosis (51 +/- 10% versus 37 +/- 21% [P = .05]). CONCLUSIONS: PCTA may be a beneficial therapy in selected cases of symptomatic intracranial atherosclerotic stenosis. Further study using a randomized trial is needed.

Aged↗
PubMed1995

Spontaneous early improvement following ischemic stroke.

BACKGROUND AND PURPOSE: Recognizing that early spontaneous neurological improvement not uncommonly follows acute ischemic stroke, we conducted this study to determine the incidence of such improvement and its potential relation to stroke etiology. METHODS: We prospectively evaluated 68 patients who presented within 12 hours after ischemic stroke, exhibited moderate or severe new functional neurological deficit acutely, and received either no stroke-specific therapy or only antiplatelet therapy over the ensuring week. We reexamined all patients 1 week after stroke onset. RESULTS: Sixteen (24%) of the 68 patients improved to the point of having no or mild functional neurological deficit at 1 week. Patients with lacunar stroke were more likely to enjoy early spontaneous improvement (8/22 = 36% versus 8/46 = 17%), but this difference did not reach statistical significance (P = .15). CONCLUSIONS: Early spontaneous improvement after ischemic stroke may occur in a substantial proportion of patients and more commonly after lacunar stroke. Even so, the majority of patients with acutely disabling stroke will remain significantly impaired 1 week after stroke onset.

Cerebrovascular Disorders↗
PubMed1995

Lazaroids. CNS pharmacology and current research.

The 21-aminosteroids (lazaroids) are inhibitors of lipid membrane peroxidation and appear to function as oxygen free radical scavengers. The therapeutic potential of the lazaroid tirilazad mesylate has been extensively studied in several CNS disorders. Tirilazad and related compounds have been found to be highly beneficial in spinal cord trauma. Spinal cord injury studies utilising tirilazad are currently underway to determine the optimal combination of medications. Tirilazad has also been found to be beneficial in experimental head injury models, however current clinical studies have failed to confirm this efficacy, due in part to difficulties in obtaining therapeutic drug concentrations. Clinical studies using tirilazad in subarachnoid haemorrhage have been more promising. It has been shown to be beneficial in terms of reducing vasospasm and cerebral infarction associated with subarachnoid haemorrhage, and has now been approved in several European countries in this indication. Results from US studies are expected shortly. Finally, tirilazad has also been extensively tested in a variety of stroke models. Although it appears to be highly beneficial in experimental models, the clinical studies to date have failed to confirm this efficacy. Again, this failure appears to be due largely to inadequate drug concentrations having so far been tested.

Antioxidants↗
PubMed1994

Therapeutic efficacy of tirilazad in experimental multiple cerebral emboli: a randomized, controlled trial.

OBJECTIVE: A significant proportion of patients who undergo cardiac surgery or carotid endarterectomy appear to develop subtle cognitive deficits, with the occurrence of multiple cerebral microemboli documented by Doppler ultrasound during these procedures. We used an experimental multiple cerebral embolism model to test whether treatment with tirilazad (U74006F), a putative inhibitor of lipid peroxidation, would improve functional outcome after multiple brain emboli. DESIGN: Randomized, controlled trial. SETTING: Animal care facility procedure room. SUBJECTS: A total of 44 New Zealand White rabbits weighing 2 to 3.0 kg. INTERVENTIONS: Variable quantities of 125I-labeled 50-microns microspheres were injected via a carotid catheter to produce multifocal brain ischemia. Rabbits randomly received either: tirilazad (3 mg/kg i.v.) 5 mins before embolization (pretreatment), or 30 mins after embolization (posttreatment) followed by 1.5 mg/kg every 5 hrs x 3 doses. A third group received vehicle only (control) 5 mins before, followed by three doses every 5 hrs. MEASUREMENTS AND MAIN RESULTS: The animals were rated by a blinded observer at 18 hrs after ischemia and scored as either grossly abnormal/dead or normal. The animals were killed and the amount of microspheres in the brain that were required to produce abnormal function at 18 hrs was calculated for each group. To determine if tirilazad also modified leukocyte function during ischemia, neutrophil adhesion to laminin was determined at baseline and 18 hrs after ischemia using a myeloperoxidase assay. In this study, pretreatment, but not posttreatment with tirilazad produced a significant reduction in neurologic deficits. Tirilazad also attenuated postischemic increases in neutrophil adhesion. CONCLUSIONS: Tirilazad pretreatment reduces neurologic deficits from multiple cerebral emboli. This significant protective effect suggests that pretreatment with tirilazad may play a role in clinical situations where the risk of cerebral emboli is high, with changes in leukocyte adherence as a potential mechanism.

Animals↗
PubMed1994

Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment.

BACKGROUND AND PURPOSE: Activated leukocytes appear to potentiate central nervous system reperfusion injury, and agents that block leukocyte adhesion have shown neuroprotective efficacy in experimental models. Doxycycline, a tetracycline antibiotic, inhibits leukocyte function in vitro, presumably through divalent cation binding. We used a model of focal central nervous system reperfusion injury to determine the efficacy of doxycycline treatment in preserving neurological function. METHODS: Rabbits randomly received 10 mg/kg i.v. doxycycline 30 minutes before ischemia (pretreatment group) or 45 minutes after ischemia (posttreatment group) or received phosphate-buffered saline vehicle (control group) followed by 10 mg/kg q 8 hours times two. The average length of reversible spinal cord ischemia required to produce paraplegia (P50) at 18 hours was calculated for each group. RESULTS: For the control group (n = 13), the P50 was 22.8 +/- 2.2 minutes; for the pretreatment group (n = 14), 35.5 +/- 2.4 minutes (P < .01; t = 3.8); and for the posttreatment group (n = 13), 31.4 +/- 4.2 minutes (not significant; t = 1.6). Doxycycline also attenuated postischemic decreases in vivo leukocyte counts and inhibited in vitro leukocyte adhesion. Therapeutic doxycycline levels at 24 hours were confirmed in the plasma and spinal cord. CONCLUSIONS: This significant protective effect suggests that doxycycline, a safe and readily available agent, may play a role in reducing clinical central nervous system reperfusion injury.

Animals↗
PubMed1994

Spontaneous echo contrast and hemorheologic abnormalities in cerebrovascular disease.

BACKGROUND AND PURPOSE: Spontaneous echo contrast (SEC) is thought to represent a risk factor for cardioembolic stroke. In vitro studies suggest that SEC results from interaction between red cells and fibrinogen. To better understand the relation between SEC and stroke and to investigate the in vivo genesis of SEC, we examined the relation between SEC, the constituents of the blood, and plasma and serum viscosity in patients with acute stroke or chronic cerebrovascular disease. METHODS: Fifty patients with acute stroke or chronic cerebrovascular disease referred for transesophageal echocardiogram (TEE) were studied by transthoracic echocardiography and TEE. Complete blood count, fibrinogen, albumin, gamma-globulin, and plasma and serum viscosity determinations were made. Left atrial SEC was graded as absent, mild, or marked by means of TEE. RESULTS: SEC was absent in 31 patients, mild in 10 patients, and marked in 9 patients. Higher grade of SEC was associated with a significantly greater percentage of patients with atrial fibrillation and larger left atrial dimension. Atrial fibrillation was present in 23% of the patients in the SEC absent group, 50% of the patients in the mild SEC group, and 78% of the patients in the marked SEC group (P < .01). Left atrial diameter averaged 3.8 +/- 0.6 cm in the SEC absent group, 4.3 +/- 1.1 in the mild SEC group, and 4.9 +/- 0.7 in the marked SEC group (P < .001). Hematocrit, white blood cell count, and platelet count did not differ among the three groups. Fibrinogen, gamma-globulin, plasma viscosity, and serum viscosity values were all significantly higher in the presence of SEC (P < .05). Fibrinogen values were 361 +/- 97 mg/dL in the SEC absent group and 427 +/- 135 mg/dL in the marked SEC group. gamma-Globulin levels were 0.75 +/- 0.23 g/dL in the SEC absent group and 1.06 +/- 0.48 g/dL in the marked SEC group. Both plasma viscosity (1.97 cp) and serum viscosity (1.64 cp) were higher in the marked SEC group than in the SEC absent group (1.77 and 1.50 cp, respectively). CONCLUSIONS: In patients with acute stroke or chronic cerebrovascular disease, the severity of SEC was not related to albumin, hematocrit, white cell count, or platelet count but rather to elevated fibrinogen levels and concomitant increases in both plasma and serum viscosity. Moreover, increasing grade of SEC was associated with significantly increased left atrial diameter and a higher percentage of patients in atrial fibrillation.

Aged↗
PubMed1994

Safety and efficacy of delayed intraarterial urokinase therapy with mechanical clot disruption for thromboembolic stroke.

PURPOSE: To evaluate safety and efficacy of delayed intraarterial urokinase therapy with mechanical disruption of clot to treat thromboembolic stroke. METHODS: Thirteen patients with cerebral thrombolic disease (10 carotid territory, 3 basilar territory) were treated with catheter-directed intraarterial urokinase therapy with mechanical disruption of the clots. All patients were excluded from a 6-hour multicenter thrombolytic trial by either time, recent surgery, age, seizure, or myocardial infarction. Time elapsed before treatment ranged from 3.5 to 48 hours (12 +/- 13 hours), with 200,000 to 900,000 U of urokinase used. RESULTS: Ten patients had successful vessel recanalization, confirmed by repeat angiography. Cases with distal branch vessel occlusions were less likely to recanalize. Asymptomatic hemorrhagic conversion occurred in 2 patients on repeat scans. Both acute neurologic and functional outcomes were assessed with significant improvement occurring in 9 (69%) of 13 patients at 48 hours (greater than four-point change on the National Institutes of Health scale) and in 100% of 3-month survivors. All patients who improved had normal initial CT scans. CONCLUSIONS: Intraarterial cerebral thrombolysis with mechanical disruption of clot seems to be a useful therapy in selected stroke cases even after 6 hours.

Adolescent↗
PubMed1993

Neutrophil adhesion in central nervous system ischemia in rabbits.

Activated neutrophils appear to be directly involved in potentiating central nervous system ischemic injury. After initial endothelial adherence, neutrophils can potentiate ischemia by causing capillary plugging and infiltrating ischemic tissue to release toxic metabolites. We used an endothelial component adherence assay to characterize neutrophil adhesion following reversible central nervous system ischemia. Rabbit spinal cord ischemia was produced by 40 min of reversible arterial occlusion. Neutrophils were isolated using density gradient centrifugation and adherence to laminin or fibronectin was determined using a myeloperoxidase assay. The baseline (N = 26) percentage of adherent neutrophils was 3.8 +/- 0.3/5.6 +/- 0.6 (laminin/fibronectin), sham-operated controls (2 h post) (N = 6) 3.3 +/- 0.5/3.9 +/- 0.4, 30 min post ischemia (N = 6) 2.5 +/- 1.1/4.1 +/-1.9, 2 h (N = 6) 7.6 +/- 1.4/9.9 +/- 2.6 (p < .05 to baseline and sham), 18 h (N = 8) 4.9 +/- 1.5/7.1 +/- 3.1, and 42 h (N = 6) 3.4 +/- 0.4/6.6 +/- 2.1. Concurrent serum fibrinogen values were baseline 142 +/- 12, sham (18 h) 141 +/- 14, 2 h 166 +/- 21, 18 h 512 +/- 43 (p < .01), and 42 h 580 +/- 86 (p < .01). These results suggest that neutrophil adherence is increased after acute central nervous system ischemia. There appears to be a limited period of increased adherence that occurs earlier than other acute phase reactants.

Acute Disease↗
PubMed1993

Circulating intercellular adhesion molecule-1 levels and neutrophil adhesion in stroke.

To examine whether changes in leukocyte adhesion properties occur during stroke, we measured circulating serum intercellular adhesion molecule 1 (cICAM-1) levels and neutrophil adhesion in acute stroke, patients at high risk of stroke, and in matched controls. Levels of cICAM-1 were significantly lower in the stroke group (186.2 +/- 15.6 ng ml-1) compared to controls (257.7 +/- 24.8) and risks (257.7 +/- 16.5). Neutrophil adhesion was significantly higher in the stroke group (23.6 +/- 4.3%; n = 14) compared to controls (9.7 +/- 2.3%; n = 12) and risks (12.7 +/- 2.5%; n = 13). These data suggest that changes in leukocyte adhesion dynamics are occurring in acute stroke.

Cell Adhesion↗
PubMed1993

Abnormalities of hemostasis in ischemic stroke.

Despite important new diagnostic laboratory and imaging technologies, the cause of brain infarction remains unexplained in 20% to 40% of subjects. Most stroke patients do not require extensive evaluations of coagulation, but hypercoagulability may account for a significant proportion of unexplained strokes. Hemostatic abnormalities associated with stroke may be broadly classified as familial or acquired. Principal among the familial thrombotic coagulopathies are deficiencies in concentration or function in protein-C, protein-S, and antithrombin III, but other hereditary abnormalities include sickle cell disease, homocystinuria, and dysfibrinogenemia. The acquired disorders of hemostasis associated with stroke probably constitute a larger proportion of the important stroke-related coagulopathies. In particular, the aPL antibody syndrome is now strongly associated with thrombotic events including stroke, although neither the mechanism of thrombosis nor effective therapies for this syndrome have been clearly elucidated. Many of the acquired hemostatic abnormalities exist within a special clinical setting such as with malignancy or with myeloproliferative diseases, nephrotic syndrome, and liver disease. Presumably many of these share common pathways of coagulation activation or dysfunction with the inherited disorders. Most of the hemostatic disorders in stroke are associated with dysfunction of vascular endothelium and abnormalities of or interference with the natural anticoagulant proteins: protein-C, protein-S, and antithrombin III. Improved understanding of these relationships should lead to better diagnosis and treatment for people at risk of stroke.

Antithrombin III Deficiency↗
PubMed1993

Delayed therapy of experimental ischemia with competitive N-methyl-D-aspartate antagonists in rabbits.

BACKGROUND AND PURPOSE: N-methyl-D-aspartate antagonists are effective in limiting ischemic damage to the brain and spinal cord if treatment is begun at time of ischemic injury. More clinically relevant delayed therapy has not been adequately investigated. We report the temporal profile of efficacy for two competitive N-methyl-D-aspartate antagonists in therapy of central nervous system ischemia. METHODS: CGS-19755 (30 mg/kg) or LY233053 (100 mg/kg) was administered 5, 30, or 60 minutes after reversible spinal cord ischemia in rabbits, induced by temporary occlusion of the infrarenal aorta. Duration of occlusion for individual animals was varied to provide a range of ischemia for each experimental group. The P50 represents the duration (in minutes) associated with a 50% probability of resultant permanent paraplegia. Neuroprotection is demonstrated if a drug prolongs the P50. RESULTS: CGS-19755 significantly prolonged the P50 (t test, P = .003) when given 5 minutes after ischemia, but not if delayed by 30 or 60 minutes (P50: control, 24.1; 5 minutes, 31.4; 30 minutes, 30.1; 60 minutes, 26.6). LY233053 was efficacious at 5 (P = .0008) and 30 (P = .002) minutes, but not at 60 minutes (P50: control, 26.8; 5 minutes, 39.4; 30 minutes, 36.0; 60 minutes, 25.6). CONCLUSIONS: These competitive N-methyl-D-aspartate antagonists are effective in limiting ischemic damage, but protection is lost if therapy is not initiated within 60 minutes of injury.

Animals↗
PubMed1992

Tissue plasminogen activator cerebrovascular thrombolysis in rabbits is dependent on the rate and route of administration.

BACKGROUND AND PURPOSE: The main aim of our study was to assess the cerebrovascular thrombolytic efficacy of different tissue plasminogen activator treatment protocols with Doppler ultrasound. METHODS: We occluded one internal carotid artery in 48 New Zealand White rabbits with whole blood emboli. Five minutes later the rabbits were assigned to receive one of the following tissue plasminogen activator protocols: 1) intravenous square-wave infusion in a total dose of 10 mg/kg, 2) intravenous constant infusion in a total dose of 10 mg/kg, 3) intravenous square-wave infusion in a total dose of 3 mg/kg, or 4) regional intra-arterial square-wave infusion in a total dose of 3 mg/kg. Blood flow velocities in the internal carotid arteries were continuously monitored during the study with Doppler ultrasound. RESULTS: In all 12 animals treated with a 10-mg/kg square-wave intravenous tissue plasminogen infusion, internal carotid artery blood flow was reestablished within 2 hours (57.9 +/- 33.3 minutes) after the initiation of treatment, whereas this was the case for only six (50%) of the 12 animals treated with a constant 10-mg/kg intravenous tissue plasminogen activator infusion (p less than 0.05, Fisher's exact test). Internal carotid artery blood flow was restored within 2 hours (33.5 +/- 40.4 minutes) in all animals treated with a regional intra-arterial tissue plasminogen infusion in a total dose of 3 mg/kg and in only three (50%) of the six animals treated with the same dosage intravenously (p less than 0.05, signed rank test). CONCLUSIONS: The thrombolytic efficacy of tissue plasminogen activator in the rabbit cerebral vasculature was superior when the same intravenous dose was given as a square-wave rather than a constant infusion and when the drug was given as a regional intra-arterial infusion rather than intravenously.

Animals↗
PubMed1992

Efficacy of LY233053, a competitive glutamate antagonist, in experimental central nervous system ischemia.

Antagonists of excitatory amino acids appear to serve a neuroprotective role during ischemic conditions in a variety of in vivo and in vitro models. The usefulness of such agents in the clinical setting, however, may be limited by poor central nervous system (CNS) entry and intolerable side effects. The authors report high efficacy in reducing neurological damage and relatively limited side effects of LY233053, a novel competitive glutamate antagonist, in two models of experimental CNS ischemia in the rabbit.

Animals↗
PubMed1991

Effect of protein kinase C modulation on outcome of experimental CNS ischemia.

Protein kinase C (PKC) is an important intracellular regulator, and its activity may play a central role in the modulation of neuronal ischemic damage. Staurosporine and the compound H-7 are potent in vitro inhibitors of PKC, and 1,2-oleoylacetylglycerol (OAG) is an effective activator. We administered these compounds through a spinal subarachnoid catheter and demonstrated in vivo alteration of spinal cord PKC activity. We then tested the effects of altering PKC activity in a well-established rabbit model of reversible spinal cord ischemia. Animals within each experimental group were subjected to a range of spinal cord ischemic durations by temporary occlusion of the infrarenal abdominal aorta. Compared to control, both staurosporine and H-7 significantly shortened the duration of ischemia that the animals could tolerate, without developing permanent paraplegia. OAG resulted in an insignificant lengthening of the ischemic duration that the animals could withstand. The worsening of ischemic outcome by PKC inhibitors suggests that the enzyme is important for maintaining neurologic function under ischemic conditions, possibly secondary to modulation of intracellular calcium levels.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Detection of arterial emboli using Doppler ultrasound in rabbits.

The purpose of this study was to develop an animal model that could be used to test the ability of Doppler ultrasound to detect arterial emboli composed of materials that are often involved in cerebral emboli. Emboli introduced into the rabbit aorta via the left renal artery consisted of clotted whole blood, platelets, atheromatous material, fat, or air. The ultrasound examination was carried out continuously during the studies using a multifrequency transcranial Doppler apparatus with a 2-MHz probe, a sample volume of 15 mm, at a depth of 15 mm. The intensity of the Doppler spectrum was measured and displayed as a 15-shade color scale, each shade representing a 3-dB difference. The diameter of the aorta at the site of the ultrasound examination was similar to the diameter of the middle cerebral artery in humans. All 125 emboli introduced were clearly detected because they caused a Doppler signal at least 15 dB greater than that of the surrounding blood. These results show that the potential for emboli detection using Doppler ultrasound in the clinical situation is now considerable.

Animals↗
PubMed1991

Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits.

We studied the incidence of cerebral hemorrhage in an animal model of embolic stroke to determine the safety of aspirin, heparin, and tissue plasminogen activator therapies. We occluded the middle cerebral arteries of rabbits with labeled blood clots and administered either tissue plasminogen activator, heparin, aspirin, tissue plasminogen activator plus aspirin, tissue plasminogen activator plus heparin, or saline at various times after stroke. Compared to saline controls, both the aspirin-only and the tissue plasminogen activator-plus-aspirin groups had a significantly higher incidence of cerebral hemorrhage, whereas the heparin and tissue plasminogen activator combination groups did not. We conclude that aspirin antiplatelet therapy alone may increase the risk of hemorrhagic infarction, whereas heparin or tissue plasminogen activator therapy appears to be relatively safe.

Animals↗