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Biomedical subjects

J C Grotta

Publications and source records attributed to J C Grotta.

At least 73 records · Page 4Linked to original sources
PubMed1997

The risks and benefits of carotid endarterectomy in patients with near occlusion of the carotid artery. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

Some believe that carotid endarterectomy (CEA) for carotid near occlusion is a necessary emergency procedure while others call it dangerous. We used the North American Symptomatic Carotid Endarterectomy Trial (NASCET) data to perform an observational study to examine the safety and benefit of CEA for carotid near occlusion. We divided the data of 659 patients into stenosis groups: 70 to 79%, 80 to 89%, 90 to 94%, and near occlusion. The 106 carotid-near-occlusion patients were subdivided into those with a string-like lumen (n = 29) and those without a string-like lumen (n = 77). Of the 48 patients with near occlusion treated with CEA, 3 (6.3%) had perioperative strokes, similar to the 70-94% stenosis group. Only 1 of 58 patients (1.7%) with near occlusion treated medically had a stroke in the first month, suggesting that CEA is not needed on an emergency basis in this circumstance. For medically treated patients, the 1-year risk of stroke increases with escalating degrees of carotid stenosis, where the risk is 35.1% for patients with 90-94% stenosis. For patients with near occlusion, the 1-year stroke risk diminishes to 11.1%, which approximates the risk for patients with 70-89% stenosis. A comparison of treatment differences indicates that surgery reduces the risk of stroke at 1 year by approximately one-half (p < 0.001), regardless of the degree of stenosis or the subcategory of carotid near occlusion (p = 0.89). Our data suggest that CEA is beneficial for near occlusion and not more dangerous than in patients with 70-94% stenosis, provided that the procedure is performed by an experienced surgeon with a low complication rate.

Arterial Occlusive Diseases↗
PubMed1996

Ca2+/calmodulin-dependent protein kinase II in postsynaptic densities after reversible cerebral ischemia in rats.

Compartmentalization of protein kinases and association of the enzyme with strategic cellular substrates may be important for regulating signal transduction in neurons. Cerebral ischemia produced by transient 20 min occlusion of common carotid and vertebral arteries in rats caused a dramatic (3-fold) increase in Ca2+/Calmodulin-dependent protein kinase II (CaM-KII) in the fraction enriched in postsynaptic density (PSDf), the compartment of the neuron that is involved in signal transduction. This change in compartmentalization was not reversible for up to 24 h after termination of the occlusion and was followed by reduction of CaM-KII to 50% of control content one week after the insult. The observed changes in CaM-KII content did not represent general protein redistribution in PSDf after ischemia since there were no parallel changes in PSDf actin concentration. The redistribution of CaM-KII coincided with gradual (up to 80%) reduction of its activity in PSDf as tested using specific peptide substrate and endogenous CaM-KII substrates. This work provides evidence that ischemia disturbs CaM-KII distribution and activity in PSDf and this may lead to long lasting disruption of signal transduction at the synaptic level.

Animals↗
PubMed1996

Treatment of experimental focal ischemia in rats with lubeluzole.

Lubeluzole is a neuroprotective compound in the final stages of clinical evaluation. We evaluated the effects of intravenous followed by intraperitoneal doses of lubeluzole on histological outcome after reversible tandem middle cerebral/common carotid artery occlusion in Long-Evans rats, with particular emphasis on the time window of efficacy. Lubeluzole, started 15 min after the onset of ischemia, had no adverse physiological or behavioral effects and reduce maximal infarct volume produced by 120 min or more of arterial occlusion by approximately 50%, from 143.2 +/- 11.8 mm3 (p < 0.05). Lubeluzole did not prolong the duration of middle cerebral artery occlusion which could be tolerated before histological damage occurred. Lubeluzole was still effective if started 30 min after the onset of ischemia (34% reduction of maximal infarct volume; p < 0.05), but not after delays of 60 or 120 min. we conclude that lubeluzole has promise as a neuroprotective drug, particularly for more severe strokes, but must be started very rapidly after the onset of ischemia to be effective.

Animals↗
PubMed1996

Citicoline for treatment of experimental focal ischemia: histologic and behavioral outcome.

We evaluated the effect of chronic administration of CDP-choline, an intermediate of phospholipid synthesis, on outcome from middle cerebral artery occlusion, ranging from 30 to 120 min in duration in spontaneously hypertensive rats. Rats were randomly assigned to either CDP-choline 500 mg kg-1 or saline. CDP-choline treatment was initiated by intraperitoneal injection 15 min after the onset of ischemia and continued once a day for 14 days. Morphologic damage and behavioral dysfunction (motor and sensorimotor performance) were evaluated, and the maximal morphologic damage (Volmax), maximal behavioral dysfunction (BDmax) as well as the duration of ischemia producing half-maximal morphologic damage (T50) or behavioral dysfunction (BD50) were calculated using a curve-fitting program (ALLFIT). Ischemia in control animals produced a Volmax of 103.3 +/- 13.6 mm3. CDP-choline did not affect this value (Volmax of 101.6 +/- 11.4 mm3). However, CDP-choline significantly extended the T50 from 38.3 +/- 5.9 to 60.5 +/- 4.3 min (p < 0.05). Similar to the morphologic outcome, CDP-choline had no effect on BDmax but significantly extended BD50 from 41.9 +/- 4.6 to 72.9 +/- 24.5 min (p < 0.05). Our results suggest that the effectiveness of CDP-choline is greater in animals demonstrating submaximal ischemic injury which in this model is produced by 30-75 min of ischemia (effect on T50 and BD50), than in animals suffering maximal ischemic injury produced by ischemia longer than 75 min (no effect on Volmax and BDmax). These results may reflect a threshold of biological membrane damage within which CDP-choline is able to restore phospholipid content/arrangement and retain membrane integrity.

Animals↗
PubMed1996

Ischemia-induced neuronal damage: a role for calcium/calmodulin-dependent protein kinase II.

Calcium/calmodulin-dependent protein kinase II (CaM-kinase) is a central enzyme in regulating neuronal processes. Imbalances in the activity and distribution of this enzyme have been reported following in vivo ischemia, and sustained decreases in activity correlate with subsequent neuronal death. In this report, mice that had been rendered deficient in the alpha subunit of CaM-kinase using gene knock-out technology were utilized to determine whether this enzyme is causally related to ischemic damage. Using a focal model of cerebral ischemia, we showed that homozygous knock-out mice lacking the alpha subunit exhibited an infarct volume almost twice that of wild-type litter mates. Heterozygous mice exhibited slightly less damage following ischemia than did homozygous mice, but infarct volumes remained significantly larger than those of wild-type litter mates. We conclude that reduced amounts of the alpha subunit of CaM-kinase predisposes neurons to increased damage following ischemia and that any perturbation that decreases the amount or activity of the enzyme will produce enhanced susceptibility to neuronal damage.

Actins↗
PubMed1996

An alternative method for the quantitation of neuronal damage after experimental middle cerebral artery occlusion in rats: analysis of behavioral deficit.

We tested the hypothesis that increasing durations of focal ischemia that have been shown to result in enlargement of cortical infarct will be associated with progression of behavioral dysfunction that can be measured by a battery of tests sufficiently sensitive and reproducible to detect a positive effect of pharmacotherapy. Untreated or N-methyl-D-aspartate receptor antagonist (CNS-1102)-treated spontaneously hypertensive rats underwent 45, 60, 90, or 120 min of tandem middle cerebral and common carotid artery occlusion followed by reperfusion. We then evaluated the extent of damage and its recovery for up to 21 days using nine behavioral tests aimed at analyzing strength, coordination, and bilateral asymmetry. Also using a graded bioassay that employs a curve-fitting computer program (ALLFIT) to correlate duration of ischemia with degree of behavioral dysfunction, we calculated the average of maximal behavioral dysfunction and duration of ischemia required to produce half-maximal behavioral dysfunction and compared these values in untreated controls with analogous values obtained from animals treated with CNS-1102. Three behavioral tests, forearm flex, tape (somatosensory neutralization), and foot-fault placing, were each separately and combined able to distinguish between the degrees of damage produced by increasing durations of ischemia. The behavioral abnormalities assessed using the tape test were reversible within a week, whereas those using forearm flex or foot-fault tests persisted for at least 21 days. CNS-1102 significantly reduced behavioral dysfunction measured by all three tests. This analysis of behavioral dysfunction represents a useful experimental model to grade efficacy of therapies aimed at protecting the brain from damage produced by acute stroke and might also be used to assess recovery from preexisting ischemic damage.

Animals↗
PubMed1996

Combined neuroprotection and reperfusion therapy for stroke. Effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia.

BACKGROUND AND PURPOSE: In search of a better treatment for acute ischemic stroke, we evaluated the use of lubeluzole and hemodilution with diaspirin cross-linked hemoglobin (DCLHb) therapy to test whether treatment with two complementary acting compounds provides more potent protection than either treatment alone. METHODS: We used unilateral reversible middle cerebral artery (MCA) and common carotid artery (CCA) occlusion of various durations in Long-Evans rats to produce ischemic cortical lesions. We calculated the average maximal lesion volume (Volmax) and the time required to produce half maximal lesion size (T50) in control animals (n = 31) and evaluated the effects on cerebral perfusion and infarct size of treatment with lubeluzole (n = 23), hemodilution (to 30% hematocrit) with albumin (n = 17) or DCLHb (n = 23), and combined lubeluzole + DCLHb therapy initiated 15 minutes after MCA/CCA occlusion. RESULTS: The Volmax produced by MCA/CCA occlusion in control animals was 138.5 +/- 7.7 mm3, and T50 was 98.5 +/- 10.2 minutes. Lubeluzole alone reduced Volmax by 53% with no significant effect on T50. In contrast to lubeluzole, DCLHb hemodilution prolonged T50 by 68% with no significant effect on Volmax. Prolongation of T50 by DCLHb was not due to hemodilution itself, since a similar degree of hemodilution with albumin had no effect. Finally, combined lubeluzole+DCLHb rescued 72% of the tissue and augmented the effect of lubeluzole alone by 40% (Volmax, 66.3 +/- 13.0 versus 39.4 +/- 12.2 mm3) while prolonging T50 by 31%. CONCLUSIONS: Combination therapy for acute stroke using compounds with complementary action can result in more complete attenuation of neuronal damage and demonstrates the possible clinical utility of combined neuroprotective and reperfusion therapies.

Animals↗
PubMed1996

Anterior choroidal artery aneurysm and stroke.

We report the unique combination of a mid anterior choroidal artery (AChA) aneurysm and ischemic stroke presenting as a movement disorder in a young man. The mechanism for stroke in the AChA territory may either reflect a cause or an effect of aneurysm formation. We provide evidence for both arguments and speculate on the anatomic basis for the initial presentation of hemibody spasm.

Adult↗
PubMed1995

Current emergency department management of stroke in Houston, Texas.

BACKGROUND AND PURPOSE: This study describes emergency department (ED) management of stroke in Houston, Tex, in 1992 to identify delays and deficiencies in recognition and management of stroke patients in various hospital subtypes and to quantitate the impact of a rapid response stroke team. METHODS: ED logs of eight hospitals were retrospectively screened, and 112 patients with suspected acute stroke onset within 6 hours were identified. EDs were divided into four groups based on hospital size (175 to 979 beds), acuity, number of stroke admissions (50/y to 210/y), and availability of neurological consultations. The intervals from stroke onset to triage, examination by a physician, neurological evaluation, computed tomography (CT) and other tests, vital signs, and treatments were recorded. RESULTS: The average time from stroke to ED arrival was 115 minutes, and times from ED arrival to examination by a physician and CT scan were 28 and 100 minutes, respectively, with little variability among hospital groups except that the public hospital was slower. Neurological examinations were poorly documented in community and public hospitals. The presence of a stroke team shortened the time to examination by a physician and to CT by 13 and 63 minutes, respectively, and increased the number of patients admitted to the intensive care unit. Blood pressure was excessively lowered in 31% of hypertensive patients, and hypotonic dextrose intravenous fluids were given to 69% of all patients. CONCLUSIONS: Transport, initial evaluation, and ED care of acute stroke patients are currently slow and often inexpert in all types of hospitals. A stroke team can speed initial ED management.

Adult↗
PubMed1995

Shear-induced platelet aggregation in normal subjects and stroke patients.

Elevated levels of shear stress that occur in stenotic arteries may induce platelet aggregation and initiate thrombosis. Shear-induced platelet aggregation (SIPA) was studied in groups of ischemic stroke patients and normal subjects using a viscometric-flow cytometric technique. Twenty-three patients who sustained an ischemic stroke that was not of cardiac origin were included in this study, and were classified either as atherosclerotic (n = 15) or as lacunar (n = 8) stroke patients. The results show that shear stresses at the levels which occur in arteries partially occluded by atherosclerosis or vascular spasm strongly activate and aggregate platelets, and this response is much more pronounced in non-lacunar stroke patients who had documented atherosclerotic disease of their cerebral vessels. SIPA is not affected by the time of blood drawing after the onset of stroke suggesting that these platelet abnormalities are not transient but chronic. Furthermore, the extent of platelet activation detected by an anti-P-selectin monoclonal antibody and the proportion of neutrophil-platelet aggregates circulating in vivo are significantly higher in the atherosclerotic stroke patients studied at least one month after the onset of stroke. The results indicate that the enhanced platelet responses observed in atherosclerotic stroke patients are not consequences of ischemia, and therefore both platelet activation and elevated SIPA may be considered as important risk factors for stroke. The methodology developed in this work may be useful for characterization of platelet reactivity, and may contribute to our understanding of thrombotic mechanisms.

Aged↗
PubMed1994

Motor performance, histologic damage, and calcium influx in rats treated with NBQX after focal ischemia.

2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, has been reported to provide neuronal protection after global ischemia. The objectives of this study were to evaluate the neuroprotective effects of NBQX initiated after focal cortical ischemia and to validate a method for measuring functional outcome in this model. Male spontaneously hypertensive rats (SHRs) were exposed to various durations of transient or permanent tandem middle cerebral artery (MCA) occlusion. Studies compared motor performance using balance beam and prehensile-traction tests, calcium-calmodulin (Ca-CaM) binding by immunohistochemistry, and infarct volume between NBQX-treated animals [intravenous (i.v.) 5 mg/kg/h x 6 h or intraperitoneal (i.p.) 30 mg/kg q 30 min x 3 begun postischemia] and controls. All ischemic groups performed less well than sham-operated controls on the motor performance tasks in proportion to the severity of ischemia. No significant improvement in motor performance was noted in the NBQX-treated versus the control animals after 1 h or permanent MCA/CCA occlusion. Treatment with NBQX (i.v. or i.p. dosing) did not reduce Ca-CaM binding after 1 h of occlusion with 1 h of reperfusion or after 2 h of occlusion. Similarly, there was no reduction in infarct size between NBQX-treated and control animals after 24 h of permanent MCA/CCA occlusion (74.6 +/- 7.1 vs. 80.1 +/- 6.0 ml; ns) or after 1 h of occlusion with 23 h of reperfusion (55.1 +/- 4.4 vs. 47.4 +/- 6.2 ml; ns).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Graded bioassay for demonstration of brain rescue from experimental acute ischemia in rats.

BACKGROUND AND PURPOSE: This study explored the correlation between duration of focal ischemia and infarct volume in spontaneously hypertensive rats as a measure of outcome after neuroprotective intervention. METHODS: We used 2,3,5-triphenyltetrazolium chloride staining to discriminate infarcted tissue and calculate infarct volume 24 hours after temporary tandem common carotid/middle cerebral artery occlusion lasting 5 to 150 minutes. We used a graded bioassay described by logistic function and executed by computer program (ALLFIT) to evaluate changes in infarct volume after increasing durations of ischemia. The method allowed us to calculate the maximal infarct volume (Volmax) and the duration of ischemia before reperfusion producing half-maximal infarct size (T50). Hypothermia and the N-methyl-D-aspartate antagonist CNS-1102 begun after the onset of ischemia were tested for their ability to reduce Volmax and prolong T50 as analyzed by ALLFIT. RESULTS: Volmax was 180.6 +/- 22.4 mm3 and T50 was 45.9 +/- 5.8 minutes in control rats. Hypothermia (30 degrees C) applied during ischemia reduced Volmax by 66 mm3 and extended T50 by 50% (P < .05 for each comparison). CNS-1102, like hypothermia, extended T50 by 44% but did not have an effect on Volmax. CONCLUSIONS: Analysis of the changes of infarct size after increasing durations of ischemia indicates that although both were protective, the two treatments tested may exhibit different profiles of efficacy. This method of analyzing ischemia-induced damage may be very sensitive for studying the efficacy and possible clinical use of neuronal protective therapies for hyperacute stroke.

Acute Disease↗
PubMed1994

Calcium/calmodulin-dependent protein kinase II activity in focal ischemia with reperfusion in rats.

BACKGROUND AND PURPOSE: Evidence linking changes in calcium/calmodulin-dependent protein kinase II activity with ischemic cell death has been reported in animal models of global ischemia. The purpose of this study was to delineate the course of these changes after focal ischemia and to clarify the relation of changes in activity of calcium/calmodulin-dependent protein kinase II to the process of ischemic cell death. METHODS: Change in calcium/calmodulin-dependent protein kinase II activity was evaluated in a rat model of focal ischemia after 5 minutes, 30 minutes, and 1 hour of tandem middle cerebral artery and common carotid artery occlusion both with and without reperfusion. RESULTS: Calcium/calmodulin-dependent protein kinase II activity was significantly decreased after all three durations of ischemia followed by immediate decapitation compared with sham-operated animals, in both ischemic core and border-zone regions (P < .05 for all groups). Depression of activity occurred in a regionally graded fashion, with the most severe decrease in infarct core and progressively smaller decreases in samples moving out from the center, corresponding to the severity of histological injury later detected in infarct core and border-zone regions. There were only minor differences between the three durations of ischemia in the degree of enzyme depression noted in the more peripheral regions, indicating that the initial decrease in calcium/calmodulin-dependent protein kinase II activity is an early, sensitive marker for an ischemic insult. After reperfusion, the differences between the 5-minute group and longer periods of ischemia widened because of an increase toward baseline in the 5-minute group and a trend toward further decrease in the 30- and 60-minute groups. CONCLUSIONS: The extreme sensitivity of calcium/calmodulin-dependent protein kinase II to focal ischemia and the parallel temporal and regional changes in its activity to those of more delayed cell injury point to a potential role for this enzyme in the process of excitotoxic injury.

Amino Acid Sequence↗
PubMed1994

Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation.

Criteria for selecting patients for possible surgery in the management of intracerebral hemorrhage (ICH) are needed to plan a prospective therapeutic evaluation of surgical intervention. This study specifically addressed patients seen in the emergency room within a few hours of the ictus, many of whom were still awake, to identify and subsequently exclude from surgical procedure those expected to recover completely and those expected to die regardless of treatment. We retrospectively studied 75 patients evaluated at a mean time of 3 hours and 37 minutes after hemispheric ICH to determine factors that would predict both good and poor outcomes at the time of discharge. Eighty percent of our patients presented within 6 hours of symptom onset. These patients were younger and had more severe lesions than did those presenting later, yet most were still awake (mean admission Glasgow Coma Scale [GCS] score = 11.0). Using multivariate regression, we created two models. The first model predicts independent outcome, ie, Rankin 0 to 2, of all patients with a GCS score greater than 9 on admission who do not undergo surgery. The significant factors in this model were hemorrhage diameter, intraventricular extension, and age. The second model predicts poor outcome, ie, Rankin 5 and death, of all patients. GCS score, hemorrhage volume, age, and gender were the important factors in this model. We conclude that ICH patients presenting early to the emergency room have more severe lesions radiologically, although their initial clinical status may not be different from those seen late. Our models should identify and thus exclude those with very good and very poor prognoses from future randomized surgical trials.

Adult↗