Patient safety in trials of therapy for acute ischemic stroke.
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Brain Ischemia↗
Biomedical subjects
Larry B Goldstein
Publications and source records attributed to Larry B Goldstein.
Utility of noninvasive studies in the evaluation of patients with carotid artery disease.
Endarterectomy reduces the risk of stroke in selected patients with carotid artery stenosis, and the benefit is related to the degree of stenosis. Although the randomized trials demonstrating this benefit measured the degree of stenosis with conventional catheter angiography, many physicians are relying on noninvasive tests to select patients for surgery. Technologic advancement in this area is outpacing the availability of quality data supporting the clinical utility of the newer noninvasive tests.
Carotid Artery Diseases↗
Uranyl acetate-induced sensorimotor deficit and increased nitric oxide generation in the central nervous system in rats.
We investigated the effects of uranyl acetate on sensorimotor behavior, generation of nitric oxide and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with intramuscular injection of 0.1 and 1 mg/kg uranyl acetate in water, daily for 7 days. Control animals received equivalent amount of water. The treatment was stopped after the seventh injection because the animals in the 1-mg/kg group appeared lethargic. The animals were maintained for an additional observation period of 30 days. The study was initiated as a dose-finding study that covered doses of 10 and 100 mg/kg, as well. However, all the animals in the 100-mg/kg treatment group died after the third and fourth injections, and all animals given 10 mg/kg died after the fifth and sixth injections. On Day 30 following the cessation of treatment, the sensorimotor functions of the animals in the 0.1- and 1-mg/kg treatment groups were evaluated using a battery of tests that included measurements of postural reflexes, limb placing, orientation to vibrissae touch, grip time, beam walking and inclined plane performance. The animals were sacrificed the same day and the cerebral cortex, brainstem, cerebellum and midbrain were dissected. The levels of nitric oxide as marker for increased oxidative stress, and the integrity of the cholinergic system as reflected in acetylcholinesterase (AChE) activity and m2 muscarinic acetylcholine receptors ligand binding, were determined. The data from behavioral observations show that there was a dose-related deficit at the 0.1- and 1-mg/kg treatment groups for inclined plane performance. Both doses reduced grip time, but there was no significant difference between the two doses. Similarly, both beam-walk score and beam-walk time were impaired at both doses as compared with the controls. A significant increase in nitric oxide was seen at 0.1 mg/kg dose in cortex and midbrain, whereas brainstem and cerebellum showed an insignificant decrease at both the doses. Similarly, there was no significant change in nitric oxide levels in kidneys and liver of the treated animals as compared with the controls. There was a significant increase in AChE activity in the cortex of the animals treated with 1 mg/kg uranyl acetate, but not in other brain regions. Ligand binding densities for the m2 muscarinic receptor did not show any change. These results show that low-dose, multiple exposure to uranyl acetate caused prolonged neurobehavioral deficits after the initial exposure has ceased.
Acetylcholinesterase↗
Sensorimotor deficit and cholinergic changes following coexposure with pyridostigmine bromide and sarin in rats.
A myriad of neurological symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty in concentration have been reported by Persian Gulf War (PGW) veterans. A large number of these veterans were prophylactically treated with pyridostigmine bromide (PB) and possibly exposed to sarin. In the present study we investigated the effects of PB and sarin, alone and in combination, on sensorimotor performance and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with PB (1.3 mg/kg, 15 daily doses, oral) and sarin (50, 75, 90, and 100 microg/kg, single im dose on day 15), alone and in combination. The animals were evaluated for postural reflexes, limb placing, orienting to vibrissae touch, incline plane performance, beam-walk time, and forepaw grip time 7 and 15 days following treatment with sarin. Treatment with either PB or sarin alone resulted in significant sensorimotor impairments. Coexposure to sarin and PB resulted in significant sensorimotor deficits that worsened over time. By 15 days following sarin treatment, plasma butyrylcholinesterase (BChE) activity returned to normal levels in the animals treated with sarin alone, whereas in the animals exposed to PB or PB plus sarin, there was an increase in the enzyme activity. Cortical acetylcholinesterase (AChE) activity remained inhibited in the animals treated with sarin alone and in combination with PB. Muscarinic acetylcholine receptor (m2 mAChR) ligand binding with [(3)H]AFDX-384 in cortex and brain stem showed significant increases (approximately 120-130% of control) following coexposure to PB and sarin at higher doses. To evaluate the potential of PB for augmentation or inhibition of the toxicity induced by acute sarin exposure, the animals were exposed to either 10 or 100 microg/kg sarin (single im injection) with or without pretreatment with PB, and sacrificed 3 h after treatment with sarin. Pretreatment with PB offered slight protection in the plasma as well as brain regional enzyme activities. Pretreatment with PB did not have any effect on sarin-inhibited brain regional AChE activity following treatment with 100 microg/kg sarin. These results show that prophylactic treatment with PB offers some degree of protection in peripheral cholinesterase. Furthermore, these results show that treatment with either sarin or PB alone resulted in sensorimotor impairments, while coexposure to high doses of sarin with PB caused an exacerbated deficit.
Acetylcholinesterase↗
Physician knowledge and practices in the evaluation of coagulopathies in stroke patients.
BACKGROUND AND PURPOSE: Coagulopathies are a rare cause of ischemic stroke. Prior studies demonstrate that current physician test-ordering practices for the evaluation of these conditions in patients with ischemic stroke is not optimal. We sought to determine neurologists' views regarding their use of specialized coagulation testing to better understand the possible reasons for these practices. METHODS: A survey with multiple-choice and open-ended questions regarding knowledge of and approaches to the evaluation of coagulopathies was sent to a convenience sample of 79 neurologists (26 academic neurology faculty, 24 residents/fellows, and 29 community-based practitioners). RESULTS: Fifty-nine (75%) surveys were completed (response rates: faculty 73%, residents/fellows 88%, and community-based practice 66%). Specialized coagulation tests were reported to infrequently influence stroke patient management (<25% of the time or never for 95% of respondents). Factors reported to increase test-ordering included young patient age (76%), history of thrombosis (46%), history of miscarriages (36%), and having few traditional stroke risk factors (35%). Most (88%) indicated they would order specialized coagulation tests for a hypothetical young patient with no known stroke risk factors. In contrast, only 14% would obtain the tests for a patient having traditional stroke risk factors, and none would order the tests for a stroke patient with atrial fibrillation. CONCLUSIONS: Physician-reported practices for obtaining specialized coagulation tests differ from those found in observational studies in which more indiscriminate test ordering was observed. Closing knowledge gaps and improving application of physician's current knowledge to their test-ordering practices could help to optimize diagnostic testing for coagulopathies in patients with ischemic stroke.
Academic Medical Centers↗
Contrast-enhanced magnetic resonance angiography of carotid arteries: utility in routine clinical practice.
BACKGROUND AND PURPOSE: Contrast-enhanced magnetic resonance angiography (CEMRA) is among the newer noninvasive tests used for the evaluation of patients with carotid artery disease. Evidence supporting its utility in routine clinical practice is lacking. METHODS: The results of CEMRA were compared with those of catheter angiography in 50 consecutive patients being evaluated for carotid endarterectomy (CEA) at a community hospital. Using indications for CEA based on published guidelines, we determined the rate of misclassification for surgery, sensitivity, specificity, and positive and negative predictive values. In addition, the interrater agreement (kappa score) of CEMRA was compared with that of catheter angiography in the studied population and with interpretations provided by 2 blinded radiologists. RESULTS: Compared with catheter angiography, 24% (95% CI, 12% to 36%) of patients would have been misclassified for CEA on the basis of CEMRA results alone. CEMRA was associated with sensitivity of 92%, specificity of 62%, positive predictive value of 78%, and negative predictive value of 89%. When both CEMRA and duplex Doppler ultrasound were performed and the results were concordant, the misclassification rate decreased to 17% (95% CI, 2% to 32%). kappa scores were similar for CEMRA and catheter angiography (0.72 and 0.75, respectively). CONCLUSIONS: CEMRA was found to be highly sensitive for detection of surgically amenable carotid stenosis. kappa scores for the interpretation of CEMRA and catheter angiography were similar. However, clinicians should be cautious when using CEMRA alone for surgical decision making in CEA candidates because a significant number of patients may be misclassified. The rate of misclassification is reduced when the results of CEMRA and duplex Doppler ultrasound are concordant.
Adult↗
Differential effects of haloperidol and clozapine on motor recovery after sensorimotor cortex injury in rats.
BACKGROUND: A variety of drugs impair motor recovery after sensorimotor cortex (SMCTX) injury in laboratory animals and may have similar effects in humans. METHODS: Rats (n = 142) underwent unilateral suction-ablation of the hindlimb SMCTX or sham lesion. After 24 hours, rats were given a single dose of placebo, haloperidol (0.1, 1.0, or 10.0 mg/kg, intraperitoneal), or clozapine (0.1, 0.5, 1.0, or 10.0 mg/kg, intraperitoneal), and motor recovery was measured. RESULTS: Neither haloperidol (analysis of variance [ANOVA] F[3, 12], P = 0.43) nor clozapine (ANOVA F[4, 19], P = 1.00) affected motor performance in controls. Haloperidol impaired motor recovery (ANOVA F[3, 42], P = 0.002) at each tested dose, with no differences between the doses. The effect persisted after 2 weeks. In contrast, although rats given a single dose of clozapine of 1.0 or 10.0 mg/kg had poorer recoveries (ANOVA F[4, 51], P = 0.014), only those given the highest dose differed from controls. The effect was no longer apparent after 2 weeks. CONCLUSION: Consistent with previous reports, haloperidol retards motor recovery after SMCTX injury in rats. In contrast, there was no detrimental effect of clozapine when given at low doses. The use of low doses of atypical antipsychotics such as clozapine may provide a safer alternative to haloperidol in the treatment of agitated stroke patients.
Analysis of Variance↗