Biomedical subjects
A J Fox
Publications and source records attributed to A J Fox.
Stimulation of guinea-pig tracheal afferent fibres by non-isosmotic and low-chloride stimuli and the effect of frusemide.
1. Inhalation of low-chloride or non-isosmotic solutions evokes cough or reflex bronchoconstriction in humans that is inhibited by frusemide (furosemide), whilst capsaicin-evoked cough is unaffected. Here we have examined the responses of single vagal afferent fibres innervating the isolated guinea-pig trachea to these stimuli, and tested the effect of frusemide on fibre responses. 2. Both distilled water and hypertonic saline applied for 30 s onto identified receptive fields produced marked excitation of all A delta and C fibres tested. Isotonic glucose, a low-chloride solution, was a less potent stimulant and caused excitation in 37% of A delta fibres and 69% of C fibres. There was no difference in the distribution of low-chloride sensitive and insensitive receptive fields. 3. In the presence of frusemide, responses of A delta fibres to isotonic glucose were significantly inhibited to 34.2 +/- 6.2% of the pre-drug control level. However, frusemide was without effect either on responses of A delta fibres to distilled water or hypertonic saline, or on responses of C fibres to capsaicin. 4. These data support a role for tracheo-bronchial A delta and C fibres in airway reflexes evoked by hypotonic, hypertonic and low-chloride stimuli. The protective effect of frusemide against airway responses to low-chloride but not to non-isosmotic solutions may reflect an action on sensory nerve endings.
Lack of relationship between leukoaraiosis and carotid artery disease. The North American Symptomatic Carotid Endarterectomy Trial.
OBJECTIVE: Leukoaraiosis (LA) (white matter changes) is frequently observed on computed tomographic scans of the brain of elderly patients at risk of stroke. A localized vascular-ischemic cause has been suggested for its underlying mechanism. Our aim was to assess whether high-grade carotid stenosis is associated with LA. DESIGN/SETTING: Patients enrolled in the North American Symptomatic Carotid Endareterectomy Trial (also known as NASCET) were evaluated for LA using a recently proposed grading scale. Ordinal regression analysis was used to assess the association between the severity of carotid artery stenosis and the extent of LA observed on computed tomographic scans. The patients' brain hemisphere was selected as the unit of analysis. RESULTS: Of the 2394 brain hemispheres contributed to the analyses, 352 (14.7%) had signs of LA. After controlling for known stroke risk factors in the ordinal regression analysis, only the history of stroke and increasing age were significantly related to LA. Severity of stenosis was observed to be unrelated (odds ratio [severe vs mild stenosis] = 1.08; 95% confidence interval, 0.73-1.62; P = .952) as were a history of hypertension and a history of myocardial infarction. CONCLUSION: Leukoaraiosis is not associated with severe carotid artery stenosis.
Therapeutic embolization in the treatment of intractable epistaxis.
OBJECTIVE: To determine the effectiveness of therapeutic embolization in the treatment of intractable epistaxis. DESIGN: Cohort. SETTING: Tertiary care hospital. PATIENTS: Consecutive referred sample of 57 patients with intractable epistaxis. INTERVENTION: Percutaneous transfemoral catheterization and angiography of the internal maxillary arteries. Embolization of the most distal branches with 0.1- to 0.9- cm3 medium-sized polyvinyl alcohol particles on the suspected side of bleeding. OUTCOME: Outcome was successful if no further interventional treatment was required for epistaxis. RESULTS: Anatomical abnormalities precluded embolization in three patients. Three of the remaining 54 patients required supplementry embolization. Including these three patients, 52 (96%) of 54 patients had successful control epistaxis. The major neurologic complication rate was 6% (three of 54 patients), with no permanent deficits. CONCLUSIONS: Therapeutic embolization is an effective and safe technique and should be considered as the primary treatment modality in severe epistaxis.
Quantitative and qualitative changes in AMPA receptor expression during spinal cord development.
Synaptic activity in early postnatal life is important for the acquisition of mature structural and functional properties of neurons. Previous studies indicate that the mature molecular features of spinal motor neurons emerge during a period of activity-dependent development in early postnatal life. Since glutamatergic synaptic transmission provides the major excitatory drive into motor neurons, glutamate receptors are likely to play a central role in motor neuron activity-dependent development. To gain insight into this process, we have used receptor autoradiography, immunoblotting and immunohistochemistry to determine the distribution, temporal expression and potential subunit composition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype glutamate receptors in the developing rat spinal cord. Using two different ligands, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and [3H]-6-cyano-7-nitroquinoxaline-2,3-dione, we find that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites in the adult are largely restricted to the substantia gelatinosa. In marked contrast, during early postnatal life, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites are transiently expressed at high levels in the ventral horn. This parallels previous findings on the developmental regulation of N-methyl-D-aspartate receptor expression. Using alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit-specific antibodies we show by immunoblot analysis and immunohistology that, to varying degrees, the expression patterns of glutamate receptor subunit 1 and glutamate receptor subunits 2/3 are significantly developmentally regulated. The most conspicuous change is the downregulation of glutamate receptor 1 expression within motor neurons over the first three weeks of postnatal life. The qualitative and quantitative changes we observe in glutamate receptor expression in early postnatal life are likely to have a major impact on the electrophysiological properties of young motor neurons and thus may contribute to their activity-dependent development.
Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig.
We have examined the effects of low pH and the selectivity of the capsaicin antagonist capsazepine on single sensory fibres innervating the guinea-pig trachea in vitro, and on the whole isolated vagus nerve. Application of a pH 5 solution for 1 min to the exposed receptive fields of single fibres caused excitation of all C-fibres tested but had no effect on A delta-fibres. Capsazepine (1 microM) perfused onto the receptive field for 5 min produced a reversible inhibition of both low pH- and capsaicin (60 nM)-evoked firing of C-fibres. In contrast, capsazepine had no effect on responses of C-fibres to bradykinin (0.1 microM) or of A delta-fibres to hypertonic saline. Perfusion of tissues with zero-calcium Krebs' solution containing trypsin produced denudation of the epithelium. In these tissues responses to low pH and capsaicin were unchanged and, moreover, the inhibitory effect of capsazepine against low pH and capsaicin was maintained. C- and A delta-fibre responses to bradykinin and hypertonic saline were similarly unaffected by epithelium removal. Perfusion of the whole guinea-pig vagus nerve with capsaicin (0.3 microM) or pH 5 buffer caused depolarization. However, in this preparation prior perfusion with capsazepine (1 microM) abolished responses to capsaicin whilst low pH-evoked depolarization was unchanged. These data show that capsazepine is a specific antagonist of proton- and capsaicin-evoked activation of the peripheral endings of sensory nerves in the guinea-pig airways, and suggest the release by protons of an endogenous ligand for the capsaicin receptor that does not originate from the epithelium.
Accuracy and prognostic consequences of ultrasonography in identifying severe carotid artery stenosis. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.
BACKGROUND AND PURPOSE: The accuracy of routine ultrasonography in detecting severe carotid artery stenosis was evaluated in comparison with cerebral angiography. The precision of ultrasonographic criteria in predicting the risk of stroke was also assessed. METHODS: A total of 1011 symptomatic carotid bifurcations were studied in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Given that all patients were considered for entry into the trial, the chance of a verification bias affecting the analyses was minimized. The ultrasonographic data consisted of peak systolic velocities and frequency changes from both the internal and common carotid arteries. Angiographic stenosis was calculated as in NASCET. Receiver operating characteristic (ROC) curves were constructed from the ultrasonographic data for the detection of 70% or greater stenosis on the basis of an angiographic assessment. Kaplan-Meier stroke-free survival curves were used to predict the risk of stroke. RESULTS: The areas under the ROC curves ranged from 0.74 to 0.75 (95% confidence interval [CI], 0.69 to 0.79). The sensitivities and specificities ranged from 0.65 to 0.71. The risk of stroke at 18 months declined sharply as the degree of angiographically defined stenosis declined from 99% to 70%. No pattern of decline was apparent on the basis of the ultrasonographic data. CONCLUSIONS: The results indicate that the accuracy of ultrasonography is moderate when flow parameters are used to assess the degree of stenosis. Ultrasonography should be used as a screening tool to exclude patients with no carotid artery disease from further testing. Conventional angiography remains an essential investigation before assigning the risk of stroke and deciding appropriate treatment for extracranial carotid artery disease.
Prognosis for patients following a transient ischemic attack with and without a cerebral infarction on brain CT. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.
BACKGROUND: Although cerebral infarctions are commonly observed on brain CTs of patients with TIAs, their prognostic importance is unknown. METHOD: The association between appropriately sited brain infarctions (ie, lesions located in the anterior circulation of the brain and ipsilateral to the symptomatic stenosed carotid artery) visualized on CT and the risk of subsequent stroke was assessed by Cox proportional hazards regression in 164 patients presenting with TIA (and no history of previous stroke) and severe angiographically defined carotid stenosis (70 to 99%) from the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: Patients with a TIA and CT-verified brain lesions were older and were more likely to have higher degrees of carotid stenosis and carotid plaque ulceration, a longer duration of symptoms, and a history of hypertension. With regard to prognosis, after adjusting for all known risk factors (patient characteristics) in a regression analysis, the presence of ischemic lesions observed on CT was not associated with an increased risk of ipsilateral stroke at 2 years (adjusted hazard ratio = 1.00; 95% CI: 0.39 to 2.58; p value = 0.99). CONCLUSION: Considered in combination with other patient characteristics, the mere presence of an appropriately sited cerebral infarction on CT does not alter the prognosis (risk of ipsilateral strokes) of severely stenosed patients with TIA. Therefore, there is no clinical rationale in differentiating patients with TIA on the basis of CT findings alone.
Magnetic resonance imaging of brain death.
OBJECTIVE: To demonstrate the magnetic resonance imaging (MRI) appearance of the brain in patients with clinical brain death. PATIENTS AND METHODS: High-field (1.5-T) MRI was performed on five patients who were subsequently proven clinically brain dead. Conventional T1-weighted and T2-weighted imaging was performed. RESULTS: MRI exhibited similar features for all of the patients: loss of the subarachnoid spaces of the brain; slow flow in the intracavernous and cervical internal carotid arteries; and loss of flow void in the small and large intracranial arteries, as well as in the major intracranial venous sinuses. The differentiation between grey and white matter in the brain was preserved, although the brain had a "supernormal" appearance due to the absence of cerebrospinal fluid and arterial pulsations. These findings have not been observed in MRI of comatose patients who were not clinically brain dead. CONCLUSION: With the advent of MRI-compatible ventilators and noninvasive monitoring, which facilitate imaging of patients under intensive care, MRI may offer another method of confirming the clinical diagnosis of brain death.
Symptomatic pulmonary complications from liquid acrylate embolization of brain arteriovenous malformations.
PURPOSE: To describe symptomatic pulmonary emboli from brain arteriovenous malformation embolization with liquid acrylates and to analyze the reasons for these complications and describe preventive techniques. METHODS: The clinical records of 182 patients embolized with acrylate glue since 1978 for treatment of brain AVMs were searched for evidence of symptomatic pulmonary complications. Originally iso-butyl-2-cyanoacrylate and more recently n-butyl-2-cyanoacrylate were used in all patients. Arteriovenous malformation morphology, amounts and techniques of glue injection, and clinical and radiologic investigations in the symptomatic patients were recorded. RESULTS: Three patients had pulmonary symptoms within 48 hours of glue injection. One patient with a left frontal arteriovenous malformation had embolization with an isobutyl-2-cyanoacrylate/pantopaque/acetic acid mixture; severe pleuritic chest pain developed 2 days later. One patient with a left temporal and one with a left cerebellar arteriovenous malformation had embolization with n-butyl-2-cyanoacrylate/lipiodol mixtures; a cough, pleuritic chest pain, and bloody sputum developed in both within 24 hours. Two patients experienced a significant drop in PO2. No flow-arrest techniques were used for any of the injections in these three patients. All patients demonstrated significant changes on chest x-ray and CT chest examinations. All were treated conservatively and recovered spontaneously. CONCLUSIONS: Symptomatic pulmonary complications can occur after acrylate glue injection, particularly when delivery systems without flow arrest are used in high-flow vascular brain lesions. Techniques using acetic acid to delay polymerization time and "sandwich" techniques in which glue is pushed with dextrose are also more susceptible to this complication.
Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.
1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.
Further comments on the measurement of carotid stenosis from angiograms. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.
BACKGROUND AND PURPOSE: Three different methods for estimating the percentage of reduction in the diameter of the internal carotid artery (ie, stenosis) have been proposed in the literature. Further comparisons of the methods were carried out with the intent of recommending a current standard for determining the percentage of stenosis from angiograms. METHODS: Angiograms from 112 patients were obtained. For each angiogram, stenosis was estimated in the manner of the European Carotid Surgery Trial (ECST method), the North American Symptomatic Carotid Endarterectomy Trial (NASCET method), and by a method using the common carotid artery lumen diameter (CC method). RESULTS: Although there is much discrepancy among the estimates of stenosis arising from the three different methods for any particular patient, it is possible to predict (on average) the percentage of stenosis from one method to another. The relationship between the NASCET and CC methods is linear, with a mean ratio of distal internal carotid artery to common carotid diameter of 0.62 (SD of 0.11). The variability in the diameter of the common carotid artery lumen stabilizes only beyond 2.5 common carotid diameter units (approximately 20 to 30 mm by conventional angiography) proximal to the bifurcation. Unexpectedly, the relationships between both the ECST and NASCET methods and ECST and CC methods were parabolic (P < .001). The reasons underlying these departures from linearity are uncertain. CONCLUSIONS: The comparability of our results with those reported in the literature regarding the CC and NASCET methods provides further evidence of the reproducibility of methods measuring anatomic features that can be visualized on an angiogram. Disease of the internal carotid artery is one of the important causes of ischemic symptoms. Measuring the narrowest portion of the internal artery relative to the normal portion of the same artery, well beyond the bulb, is a logical method. Moreover, benefits of carotid endarterectomy for patients with 70% to 99% stenosis as determined by the NASCET method have been well established in a clinical trial. Converting from the NASCET method to the CC method, given that the CC method is neither superior nor easier to calculate, is not recommended.
Bilateral occipital infarctions associated with carotid stenosis in a patient with persistent trigeminal artery. The Collaborators of the North American Carotid Endarterectomy Trial (NASCET).
BACKGROUND: Embolization via a persistent trigeminal artery, one of the embryonic vascular connections that may persist between the carotid and basilar arteries, is an unusual occurrence. CASE DESCRIPTION: We describe a 76-year-old man with bilateral occipital infarctions presumably related to an ulcerated left carotid stenosis. Clinically, a left inferior homonymous quadrantanopia was present. CONCLUSIONS: Anomalous connections between the carotid and the usual posterior circulation territory should be considered in evaluating patients with vertebrobasilar stroke. When they are identified, patients with symptoms attributable to the pontine vertebrobasilar territory supplied by the anomaly may be considered for carotid endarterectomy in the presence of concomitant severe carotid stenosis detected angiographically. Proper identification and treatment of such cases would be expected to prevent recurrence of disabling strokes in the vertebrobasilar circulation. These anomalies will likely be overlooked by ultrasound techniques and depend on good intracranial arteriographic images.
Demonstration of lipooligosaccharide immunotype and capsule as virulence factors for Neisseria meningitidis using an infant mouse intranasal infection model.
Using an infant mouse intranasal infection model, we have compared the virulence of 17 epidemiologically related isolates of Neisseria meningitidis associated with an outbreak of meningococcal disease in Gloucestershire, UK, and one German isolate. The isolates were all of serotype 15 subtype P1:7, 16 and were identical by restriction fragment length polymorphism analysis, but differed in either (i) whether they were isolated from a case or a carrier, (ii) the presence or absence of group B capsule, or (iii) their lipooligosaccharide (LOS) immunotype. The results indicate that capsule is a major virulence determinant and is required for colonization and hence for invasion. In addition, the LOS L3,7,9 immunotype, when compared to the L1,8,10 immunotype, is a secondary virulence factor which enhances colonization of nasal passages and invasion of the blood stream by both case and carrier isolates. Two case isolates which were unusual in possessing the L1,8,10 immunotype, established invasive infection, but this was associated with a switch to the L3,7,9 immunotype. The results confirm that LOS is a virulence factor for N. meningitidis and that immunotype L3,7,9 is associated with invasive disease.
The serum resistance of gonococci in the majority of urethral exudates is due to sialylated lipopolysaccharide seen as a surface coat.
Examined before subculture, gonococci in 18 urethral exudates collected from different patients were serum-resistant. For 15 exudates, the resistance was drastically reduced by treatment with neuraminidase and by one subculture on laboratory media. It was restored by incubation with cytidine 5'-monophospho-N-acetyl neuraminic acid (CMP-NANA). Electron microscopic examination of gonococci in eight exudates showed a surface structure stained by Ruthenium red which disappeared in most samples when they were treated with neuraminidase. These results were identical with those of previous studies on in vitro grown gonococci which had shown that serum resistance is due to sialylation of a 4.5-kDa conserved component of gonococcal lipopolysaccharide (LPS) by host CMP-NANA, which masks the target site for bactericidal IgM and renders surface LPS stainable by Ruthenium red. The serum resistance of gonococci in the remaining three exudates was not reduced by neuraminidase nor by subculture. The mechanism of this stable resistance is unknown.
The lipooligosaccharide immunotype as a virulence determinant in Neisseria meningitidis.
We have studied the antigenic (immunotype) and physical characteristics of the lipooligosaccharide (LOS) of epidemiologically related Neisseria meningitidis case (36) and carrier (76) isolates associated with a virulent clone of meningococci (ET-5 complex). LOS immunotypes were determined by dot blotting using immunotype specific monoclonal antibodies and physical characteristics were determined from silver stained SDS-PAGE following proteinase K digestion. The genetic similarity of the different isolates was confirmed by analysis of the restriction fragment length polymorphisms. An association between LOS immunotype expression and invasive disease was found; 97% of case isolates expressed the L3,7,9 immunotype, of which 13% additionally expressed the L1,8,10 determinant. The LOS immunotypes of carrier strains were much more heterogeneous. The predominant immunotype was L1,8,10 (70%) and only 24% expressed L3,7,9 alone. Genotypically related case isolates from Norway (6) and Austria (18) expressed the L3,7,9 immunotype with similar frequency to the U.K. isolates. The combination of LOS immunotype and capsule expression appears to be related to the virulence of these meningococcal strains.
The cloning, sequencing and expression of a major antigenic region from the feline calicivirus capsid protein.
RNA purified from the feline calicivirus (FCV) F9 vaccine strain was used to prepare a cDNA library in the expression vector lambda gt11. The library was screened for expression of FCV antigen using a rabbit antiserum prepared against purified FCV. A 330 bp cDNA clone was identified and used as a probe to obtain a larger overlapping clone of 1369 bp. Comparative sequence analysis with the CFI and F4 strains showed that the clones were derived from the 3' open reading frame encoding the capsid protein. The region encoded by the 330 bp clone was shown to be variable in the three strains compared, and therefore the probable location of major antigenic variation. This clone was expressed in a bacterial system and antiserum to the recombinant protein was used in immunoblots to confirm that this clone was derived from the gene encoding the capsid protein. From these immunoblots, several other capsid-related polypeptides were identified. Comparison with immunoblots using post-vaccination cat sera showed the antibody response in the cat was directed mainly against the capsid protein. Antiserum to the recombinant protein was shown to be effective in neutralizing the infectivity of FCV, indicating that at least one major neutralizing epitope had been cloned.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
BACKGROUND: Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis. METHODS: We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up. RESULTS: Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients--an absolute risk reduction (+/- SE) 17 +/- 3.5 percent (P less than 0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent--an absolute risk reduction of 10.6 +/- 2.6 percent (P less than 0.001). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P less than 0.001). CONCLUSIONS: Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery.