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Biomedical subjects

W M Clark

Publications and source records attributed to W M Clark.

At least 37 records · Page 2Linked to original sources
PubMed1999

Neuroprotection in acute ischaemic stroke. Current status and future potential.

Acute ischaemic strokes can potentially be treated by 2 different mechanisms: lysing the thrombus to enhance brain perfusion or salvaging brain tissue directly. Neuroprotective agents are designed to try to salvage brain tissue. They work either during acute ischaemia or during reperfusion, when additional brain injury may occur. Despite the completion of a number of clinical trials investigating neuroprotective agents that have various mechanisms of action, as yet no effective agent has been identified. Some drugs, such as N-methyl-D-aspartate (NMDA) receptor antagonists and anti-leucocyte adhesion agents, have been limited by adverse effects and drug reactions. However, the development of other agents in these classes that have better risk to benefit ratios may lead to an effective neuroprotective drug. Other drugs, including citicoline, clomethiazole and nalmefene, have more efficacy in certain patient subgroups than in the stroke population as a whole. Therefore, targeting these agents toward the groups in which they are most likely to work, such as patients with a certain size of stroke, may uncover efficacy. Encouragingly, a number of drugs that are in the early stages of development, such as YM 872, Bay X 3702 and BMS 204352, appear to offer new hope for neuroprotection.

Acute Disease↗
PubMed1999

Clinical assessment and outcome scales in acute stroke.

This article reviews both the commonly used functional outcome scales and the detailed neurologic deficit scales that are currently employed in stroke therapeutic efficacy trials. Both types of scales have their apparent advantages, with the neurologic scales being able to detect smaller changes in the patient's neurologic function, whereas the functional outcome scales appear to have more relevance to the patient's ability to function independently. Clearly, both types of scales also possess weaknesses, and to date there is no agreement on a single gold standard for measuring a drug's therapeutic efficacy after a stroke.

Activities of Daily Living↗
PubMed1998

The role of angioplasty in the treatment of cerebrovascular disease.

Percutaneous transluminal angioplasty (PTA), an established treatment of arterial stenosis in coronary, renal, and other peripheral sites, is being applied to the cerebrovascular territory with greater frequency. Early results suggest that PTA may be safe and efficacious in the treatment of extracranial arterial stenosis secondary to atherosclerosis and fibromuscular dysplasia. PTA is also being used with promising results in treating symptomatic intracranial arterial stenosis from atherosclerosis. This review examines PTA in the treatment of cerebrovascular disease, current indications, and results.

Angioplasty↗
PubMed1998

Persistent inflammatory response in stroke survivors.

OBJECTIVE: Goals were to determine how long acute-phase markers remain elevated after ischemic stroke and how marker levels relate to stroke risk factors, stroke mechanism, and subsequent vascular events. METHODS: Fibrinogen (FIB), C-reactive protein (CRP), leukocytes (WBC), neutrophils (PMN), interleukin-6, and interleukin-1 receptor antagonist were measured at stroke onset and at 6 weeks, 6 months, and 1 year after enrollment, or until a vascular event occurred in 136 acute ischemic stroke patients, 76 patients with comparable risk factors for stroke, and 48 age-balanced healthy subjects. RESULTS: Multivariate logistic analysis showed that prior stroke and FIB level predicted new events in stroke patients (p < 0.04 for both), whereas congestive heart failure (p < 0.02) and creatinine level (p < 0.006) were predictive in at-risk patients. After controlling for infection, FIB, CRP, and PMN levels at baseline were higher in at-risk but not in stroke patients with recurrent events (p < 0.05 for all). At 1 year, FIB levels remained elevated in event-free stroke survivors compared with levels in the risk and control groups (p < 0.001 for both). FIB also remained higher in stroke survivors who had atheroembolism (AE) compared with non-AE stroke survivors (381+/-72 versus 342+/-78 mg/dL, p < 0.02). Peripheral vascular disease was an independent predictor (p < 0.0001) of longitudinal FIB in stroke survivors. Of note, both WBC and PMN levels were chronically elevated in patients with stroke risk factors and in stroke survivors (p < 0.0001 for both) compared with healthy elderly subjects. CONCLUSIONS: Most acute-phase markers decline gradually after stroke, but FIB remains significantly elevated and is associated with increased risk for recurrent vascular events.

Acute-Phase Proteins↗
PubMed1997

Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat.

Agents that inhibit leukocyte adhesion including intercellular adhesion molecule-1 antibodies (anti-ICAM-1) have shown beneficial effects in experimental central nervous system (CNS) ischemia. Doxycycline inhibits leukocyte function in vitro by binding divalent cations and reduces spinal cord reperfusion injury. The authors used a clinically relevant model of focal CNS reperfusion injury to test whether treatment with doxycycline would reduce cerebral ischemic damage and improve functional outcome. Reversible middle cerebral artery occlusion was produced in adult Sprague-Dawley rats by advancing a filament into the internal carotid artery for 2 h. Animals received either i.p. doxycycline (10 mg/kg) (N = 13) or saline (N = 11) 30 min before ischemia, followed by 10 mg/kg every 8 h x 6. Both functional assessment (5 point neurologic scale) and infarct volume was evaluated at 48 h. Functional efficacy: doxycycline 0.5 +/- 0.2 (mean +/- SE) vs control 1.3 +/- 0.3 (p = 0.03). Infarct volume: doxycycline 56 +/- 18 mm3 vs control 158 +/- 44 mm3 (p = 0.03); This protective effect supports the role of doxycycline in reducing CNS reperfusion injury.

Animals↗
PubMed1997

Monofilament intraluminal middle cerebral artery occlusion in the mouse.

The rat middle cerebral artery (MCA) occlusion model with an intraluminal filament is well characterized with a two hour period of occlusion in widespread use. The recent availability of transgenic animals has led to an interest in adapting the MCA model in the mouse. To date the model has not been well characterized in the mouse. We performed the present study to compare different durations of MCA occlusion and to validate new functional assessments in this model. The MCA occlusion model (5-0 filament) was used. Swiss-Webster mice, 24-44 g, were randomly assigned to four groups: one hour of occlusion; two hours of occlusion; three hours of occlusion; or permanent occlusion. At 48 hours post-ischemia, the animals were rated on three neurologic function scales, and then the brains were removed for lesion size determination. Overall, there was a significant difference in lesion volume (p < 0.001) between the groups. In the permanent group of mice, the average lesion volume was 78.41 +/- 17.47 mm (n = 12); two and three hours of ischemia produced 51.29 +/- 29.82 mm3 (n = 11) and 54.85 mm3 (n = 13), respectively, significantly different than the one hour group 14.84 +/- 31.34 mm3 (n = 11). All three functional scoring systems found significant overall differences between the four groups with our detailed General and Focal scores producing more robust between group treatment differences and showing correlation coefficients of r = 0.766 and r = 0.788, respectively to infarct volume. The MCA filament occlusion model can be successfully adapted in the mouse with either two or three hour occlusions producing reliable infarcts. New functional scoring systems unique to the mouse appear to add additional information.

Analysis of Variance↗
PubMed1997

Rotational vertebral artery occlusion: a mechanism of vertebrobasilar insufficiency.

OBJECTIVE: Symptomatic dynamic changes in blood flow secondary to vertebral artery compression with rotational head motion are evaluated in a series of patients as a cause for posterior circulation transient ischemic attacks. These cases are classic examples of rotational vertebral artery occlusion and allow for the discussion of the anatomic basis, angiographic features, and treatment options. ILLUSTRATIVE CASES: In our series, symptoms of vertebrobasilar insufficiency were reproducible with rotational head movement. Compression of the vertebral artery was demonstrated angiographically. The correct site of occlusion of the vertebral artery was apparent only by dynamic angiography with progressive head rotation. All of the patients presented in the illustrative cases had occlusion at the C2 level; however, one patient had been previously misdiagnosed and another had an additional site of occlusion. The anatomic course of the vertebral artery is described in addition to the sites of rotational occlusion. CONCLUSION: Rotational vertebral occlusion is an important cause of vertebrobasilar symptoms, which may lead to permanent neurological deficit if left undiagnosed. Dynamic angiography is the established method of diagnosis. Great care must be taken to avoid misdiagnosing the site of occlusion or missing a second occlusive site. For this reason, it is crucial to have a thorough understanding of the anatomic course of the vertebral artery and the muscular and tendinous insertions, which may cause rotational occlusion. The decision for treatment must be based on the site of occlusion as well as the assessment of the patient as a surgical candidate. A review of the literature reveals that surgical treatment is effective and must be considered to avoid further morbidity.

Adult↗
PubMed1997

Twenty years and still in the dark? Content analysis of articles pertaining to gay, lesbian, and bisexual issues in marriage and family therapy journals.

To what extent do marriage and family therapy journals address gay, lesbian, and bisexual issues and how does this coverage compare to allied fields? To answer these questions, a content analysis was conducted on articles published in the marriage and family therapy literature from 1975 to 1995. Of the 13,217 articles examined in 17 journals, only 77 (.006%) focused on gay, lesbian, and/or bisexual issues or used sexual orientation as a variable. Findings support the contention that gay, lesbian, and bisexual issues are ignored by marriage and family therapy researchers and scholars.

Bisexuality↗
PubMed1997

A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group.

Citicoline (CDP-choline) is a key intermediary in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. It has been shown to produce beneficial effects in both animal models and non-US clinical stroke trials. This study comprised a randomized (3 doses of citicoline to 1 placebo), vehicle-controlled, double-blind trial at 21 US centers. Treatment was to be started within 24 hours of stroke onset and was continued orally for 6 weeks. Final outcome assessments were at 12 weeks. Two hundred fifty-nine patients were enrolled, with approximately 65 in each of the four groups. Mean time from stroke onset to treatment was 14.5 hours, and there were no significant differences in baseline characteristics between the four groups except for patient weight. A significant difference between the groups, favoring citicoline treatment, was seen in terms of functional outcome as measured by the Barthel Index and Rankin scale, neurologic evaluation as measured by the National Institutes of Health (NIH) stroke scale, and cognitive function as measured by the Mini Mental Status Examination. When the baseline NIH stroke scale was used as a covariate, both the 500-mg citicoline group and the 2,000-mg citicoline group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. This study suggests that oral citicoline can be used safely with minimal side effects in acute stroke treatment. Citicoline appears to improve functional outcome and reduce neurologic deficit with 500 mg of citicoline appearing to be the optimal dose.

Acute Disease↗
PubMed1997

The therapeutic potential of anti-cytokine strategies in central nervous system ischaemia.

Central nervous system (CNS) ischaemia is associated with an acute inflammatory response which appears to potentiate CNS injury, especially following reperfusion. This response includes the release of inflammatory mediators, including the cytokines interleukin-1 (IL-1) and TNF-alpha. These trigger the production of additional cytokines, including IL-6, and activate leukocytes which infiltrate the CNS. IL-6 appears to play a central role in modulating this response, exhibiting both pro-inflammatory and anti-inflammatory activities. Preliminary clinical studies suggest that plasma levels of IL-6 are correlated with stroke size and functional recovery. Conversely, brain levels of cytokines have been demonstrated to increase following experimental ischaemia. Although there are at present no clinical ;anti-cytokine' treatment studies, experimental studies modulating cytokines have shown neuroprotection.

Journal Article↗
PubMed1996

Endovascular treatment for acute and chronic brain ischemia.

Recent advances in intracranial vascular catheterization along with new microballoon technology have led to increasing interest in the use of interventional techniques to treat cerebrovascular disease. We review several areas in which interventional neuroradiology is emerging as an important component of a brain ischemia treatment program.

Angioplasty↗
PubMed1996

Intracranial intraarterial thrombolysis facilitated by microcatheter navigation through an occluded cervical internal carotid artery.

This report covers a series of four patients with acute cervical carotid occlusion and profound neurological deficits who were treated with intracranial intraarterial thrombolysis. All of the patients presented with arm plegia with variable leg involvement and two of them had global aphasia. Angiography identified occlusion of the proximal internal carotid artery (ICA) in each case and intracranial thromboembolus of the supraclinoid ICA and/or its branches. Catheter navigation through the occluded ICA segment was straightforward in three patients and somewhat difficult in one patient with an 80% ICA stenosis. Intraarterial urokinase infusion along with mechanical clot disruption was performed at the clot site in the middle cerebral artery, supraclinoid ICA, and/or anterior cerebral artery. All patients had recanalization of the treated artery after urokinase infusion. Antegrade flow through the ICA was reestablished in two patients, and good collateral filling across the anterior communicating artery was established in the other two. All patients had major pretreatment deficits (mean National Institutes of Health (NIH) Stroke Score 24 +/-4) with significant improvement noted at 3 months posttreatment (NIH Stroke Score 7 +/-6;p=0.03). Two patients made a dramatic early recovery. Postprocedure computerized tomography revealed no abnormality in one and asymptomatic basal ganglia high density from repeated local contrast injections in two patients. On the basis of their findings in this small study group the authors suggest that catheter navigation through a presumably occluded carotid artery is feasible and possibly effective in thrombolytic therapy of intracranial thrombolysis. Further study with clinical trials is necessary to determine the safety and efficacy of this technique.

Adult↗
PubMed1995

Interleukin-6 and interleukin-1 receptor antagonist in acute stroke.

Elevated plasma levels of interleukin-6 (IL-6), a key regulator of the acute phase response that includes increased fibrinogen synthesis, have recently been detected in patients with acute stroke. Nevertheless, the role of the acute phase response in stroke has been controversial, with some studies suggesting that preexisting infection accounts for most of the acute phase response. Increased IL-6 could signal the involvement of antiinflammatory activity, since IL-6 stimulates the production of endogenous antiinflammatory mediators such as interleukin-1 receptor antagonist (IL-1RA). To better understand the interaction of pro- and antiinflammatory acute phase processes in brain infarction, plasma levels of IL-1RA, IL-6, and acute phase proteins including fibrinogen and c-reactive protein (CRP) were measured within 4 +/- 2 days of onset in 50 patients with acute ischemic stroke and in 20 age-matched healthy controls. After excluding patients with evidence of infection, both IL-1RA and IL-6 were significantly elevated in stoke patients compared with controls (p < 0.0001). IL-1RA and IL-6 were both significantly correlated with levels of CRP, p < 0.05 and p < 0.001, respectively, but not with each other. Levels of IL-6 and IL-1RA, together with fibrinogen and CRP were higher in patients with infarcts of greater than 3 cm and lowest in patients with lacunar syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

The influence of antiadhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats.

Although treatment with agents that block leukocyte function, including anti-ICAM-1 and doxycycline, reduces experimental central nervous system (CNS) ischemic injury, it is not known how leukocyte subset accumulation is affected by these agents. Using the rat two-vessel occlusion model and immunohistochemistry, we investigated granulocyte (PMN) and monocyte/macrophage (M phi) accumulation at 1 and 4 d postischemia. A total of 24 animals were randomized to sham surgery, or to ischemia with saline, anti-ICAM-1, or doxycycline treatments. No leukocytes were observed in sham animals. At 24 h postischemia, there was a moderate infiltration of PMN and M phi in untreated animals that was significantly decreased with either treatment. At 4 d after ischemia no PMN were identified, with extensive M phi accumulation occurring in untreated animals that was only partially reduced with doxycycline treatment. These results confirm that both anti-ICAM-1 and doxycycline treatments reduce PMN and M phi infiltration at 24 h. Delayed M phi accumulation occurs despite treatment, suggesting that some of these cells represent transformed resident microglia.

Animals↗