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Objective: The EUROSTAR (European Collaborators on Stent/graft techniques for aortic aneurysm repair) Registry was established in 1996 to collect data on the outcome of treatment of patients with infrarenal aortic aneurysms with endovascular repair. To date, 88 European centers of vascular surgery have contributed. The purpose of the study was to evaluate the results of this treatment in the medium term (up to 4 years) according to the analysis of "hard" or primary end points of rupture, late conversion, and death., Patients and Methods: Patients with aortic aneurysms suitable for endovascular aneurysm repair were notified to the EUROSTAR Data Registry Centre before treatment to eliminate bias due to selective reporting. The following information was collected on all patients: (1) demographic details and the anatomic characteristics of their aneurysms, (2) details of the endovascular device used, (3) complications encountered during the procedure and the immediate outcome, (4) results of contrast enhanced computed tomographic imaging at 3, 6, 12, and 18 months after operation and at yearly intervals thereafter, and (5) all adverse events. Life table analysis was performed to determine the cumulative rates of (1) death from all causes, (2) rupture, and (3) late conversion to open repair. Risk factors for rupture and late conversion were identified through regression analysis., Results: By March 2000, 2464 patients had been registered, and their mean duration of follow-up was 12.19 months (SD, 12.3 months). There were 14 patients with confirmed rupture of their aneurysms. The cumulative rate (risk) of rupture was approximately 1% per year. Emergency surgery was undertaken in 12 (86%) patients, of whom five (41.6%) survived. Two patients who were not treated surgically also died, which resulted in an overall death rate of 64.5% (9/14) of the patients. Significant risk factors for rupture were proximal type I endoleak (P =.001), midgraft (type III) endoleak (P =.001), graft migration (P =.001), and postoperative kinking of the endograft (P =.001). Forty-one patients underwent late conversion to open repair with a perioperative mortality rate of 24.4% (10/41). The cumulative rate (risk) of late conversion was approximately 2.1% per year. Risk factors (indications) for late conversion were proximal type I endoleak (P =. 001), midgraft (type III) endoleak (P =.001), type II endoleak (P =. 003), graft migration (P =.001), graft kinking (P =.001), and distal type I endoleak (P =.001)., Conclusions: Endovascular repair of infrarenal aortic aneurysms with the first- and second-generation devices that predominated in this study was associated with a risk of late failure, according to an analysis of observed hard end points of 3% per year. Action taken to address the risk factors identified by the study may improve results in the future.

Background: Carotid endarterectomy (CEA) is the most common surgical procedure performed for the treatment of symptomatic carotid stenosis greater than 70%. Among the recognised complications, such as stroke and myocardial infarction, is injury to cranial nerves., Methods: We report the incidence and follow-up of cranial nerve injury in 269 patients who underwent carotid endarterectomy between January 1994 and December 1997 at the Royal Liverpool University Hospital., Results: Fifteen cranial nerve injuries were documented (5.6%). Seven patients (2.6%) had unilateral vocal cord paralysis, nine (3.3%) hypoglossal palsy, two (0.7%) glossopharyngeal nerve injury and one (0.4%) facial nerve palsy (marginal mandibular nerve). All patients showed improvement within a few weeks and none had residual disability at the last follow-up (two weeks to 14 months)., Conclusions: Patients manifesting symptoms of cranial nerve dysfunction should undergo a thorough otolaryngological evaluation and long-term follow-up. Most cranial nerve injuries are transient and result from trauma during dissection, retraction or carotid clamping. Knowledge of cranial nerve anatomy is essential if the surgeon is to avoid such injuries.

Purpose: To investigate the incidence, significance, and mechanism of stent-graft distortion after endovascular repair (EVR) of abdominal aortic aneurysm., Methods: EVR of abdominal aortic aneurysm was performed in 51 cases (49 modular, bifurcated; 2 tube). Thirty-two patients were followed for 6 or more months and had equivalent baseline and follow-up images which could be used to determine changes in graft configuration. Sac dimensions were measured using computed tomographic (CT) images and graft-related complications were recorded., Results: Amongst 32 patients evaluated on follow-up, there was graft distortion in 24. Distorted grafts were significantly (p = 0.002) associated with sac diameter reduction (mean 5 mm) and sac length reduction (mean 8.1 mm). All graft-related complications occurred in the limbs of eight distorted grafts, with a mean reduction of sac length in this group of 7.8 mm on reformatted CT images., Conclusion: There was a highly significant association between graft distortion and limb complications, and reduced sac dimensions.

There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.

Objective: Interposition of a vein cuff between a prosthetic infrainguinal bypass graft and a recipient infrageniculate artery can improve graft patency. There is evidence that the improved performance may be explained by a redistribution of myointimal hyperplasia (MIH) away from the critical areas at the heel and toe of the cuff-artery anastomosis. It is widely accepted that there is an association between hemodynamic forces, more specifically, low wall shear stress (WSS), and the development of MIH. The aim of this study was to determine whether the reported redistribution of MIH in the interposition vein cuff (IVC) may be explained by differences in magnitude and distribution of WSS. Design of Study and Method: Detailed flow velocity measurements were made in life-size models of conventional end-to-side (ETS) and IVC anastomoses using a two-component laser Doppler anemometer under pulsatile flow conditions. Velocity vectors were determined in the plane of symmetry of the anastomosis, and the variation of WSS was estimated from near-wall velocity measurements on the floor and upper wall of the artery., Results: The main flow features in the ETS anastomosis were flow separation at the graft hood, strong radial velocity at the heel, and a stagnation point on the floor of the artery that moved slightly during the flow cycle. In the IVC anastomosis, a coherent vortex that occupied most of the cuff volume was present from the systolic deceleration phase to end diastole. A stagnation point on the anastomosis floor was found to oscillate by about 4 mm. Critical regions of low mean WSS (ie, below 0.5 N/m(2)) were identified. In the ETS anastomosis, they were found at the heel and along the floor. In the IVC anastomosis, low mean WSS was found only on the floor, and it was generally less extensive than in the ETS anastomosis., Conclusion: The vein cuff anastomosis alters the mean WSS distribution within the recipient artery and removes the area of low WSS at the heel. This may explain the redistribution of MIH away from important sites in the recipient artery.

Instruction encouraging imagery improves logical reasoning with counterfactual premises by normal preschool children. In contrast, children with autism have been reported to reason accurately with counterfactual premises in the absence of such instruction (F. J. Scott, S. Baron-Cohen, & A. M. Leslie, 1999). To investigate this pattern of findings, we compared the performance of children with autism, children with learning disabilities, and normally developing 4-year-olds, who were given reasoning problems both with and without instruction in two separate testing sessions 2 to 3 weeks apart. Overall, instruction to use imagery led to persistent logical performance. However, children with autism displayed a distinctive pattern of responding, performing around chance levels, showing a simple response bias, and rarely justifying their responses by elaborating on the premises. We propose that instruction boosts logical performance by clarifying the experimenter's intention that a false proposition be accepted as a basis for reasoning and that children with autism have difficulty grasping this intention., (Copyright 2000 Academic Press.)

Objective: To determine whether freedom from endoleak after endovascular repair of abdominal aortic aneurysm (EVAR) is a reliable guide to freedom from persistent or recurrent pressurisation of the aneurysm sac (endotension) and therefore freedom from risk of rupture., Patients and Methods: The records of 55 patients followed for more than 3 months after EVAR were reviewed to correlate the presence or absence of endoleak on contrast-enhanced CT and/or angiography with changes in maximum aneurysm diameter (DMAX)., Results: in 22 (40%) patients there was no significant change in DMAX during follow-up. In 21 of these no endoleak was observed on CT or angiography. One patient developed a secondary side-branch endoleak which remains under observation. In 18 (33%) patients, DMAX decreased during follow-up. Thirteen of these remained free of endoleak. Four patients developed secondary endoleaks which were treated by secondary intervention. One patient with persistent primary endoleak suffered fatal aneurysm rupture three days before planned intervention. DMAX increased in 15 (27%) patients. In only five of these could an endoleak be identified on CT and/or angiography. One primary side-branch endoleak persists following failed embolisation. Four secondary endoleaks have been corrected by secondary intervention. Four of the remaining 10 patients died suddenly from unknown cause. All had DMAX greater than 65 mm at last follow-up. One patient underwent late conversion, which suggested continued pressurisation through thrombus at the site of a "sealed" primary proximal endoleak. Two patients are scheduled to undergo embolisation of patent side-branches revealed only by Levovist enhanced Duplex scanning and three patients remain under observation., Conclusion: Freedom from endoleak on conventional imaging incorrectly suggested freedom from endotension in 10 (18%) of our patients. Follow-up after endovascular repair must include regular measurement of DMAX and/or aneurysm sac volume to identify those patients who remain at risk of rupture., (Copyright 1999 Harcourt Publishers Ltd.)

Purpose: To examine the structure and healing characteristics of chronically implanted Stentor endografts that were explanted due to migration, endoleak, thrombosis, or aneurysm expansion., Methods: The devices were harvested following reoperation (n = 5) or autopsy (n = 1) with implantation times ranging from 13 to 53 months. Structural modifications to the metal components were examined using radiography, endoscopy, and magnetic resonance imaging (MRI). Specimens taken from components of the modular stent-grafts were examined histologically and with scanning electron microscopy (SEM) to assess healing behavior. Physical and chemical stability of the nitinol wires and woven polyester graft material was evaluated using SEM and electron spectroscopy for chemical analysis., Results: Although the endografts were retrieved for a variety of reasons, they exhibited similar healing and structural modifications. The woven polyester sleeve showed evidence of yarn shifting and distortion, yarn damage, and filament breakage leading to the formation of openings in the fabric. The luminal surface endografts showed incomplete healing characterized by a poorly organized, nonadherent thrombotic matrix of variable thickness. Radiographic and endoscopic observations indicated that structural failure of the grafts, particularly in the main aortic component, was related to severe compaction and dislocation of the metallic frame due to suture breaks. Corrosion marks were observed on some nitinol wires in all devices. Chemical analysis and ion bombardment of the nitinol wires revealed that the surface concentrations of titanium and nickel were not homogenous. The first layer was composed of carbon or organic elements, followed by a stratum of highly oxidized titanium with a low nickel concentration; the titanium-nickel alloy lay beneath these layers., Conclusions: Although the materials selected for construction of endovascular grafts appears judicious, the assembly of these biomaterials into various interrelated structures within the device requires further improvement.

Research on text comprehension shows that readers construct a model of the situation described in a narrative. A major factor in constructing a situational model is the perspective from which the action of the narrative is imagined. J. B. Black, T. J. Turner, and G. H. Bower (1979) found that adults recall a deictic verb of motion more accurately if it is spatially consistent with the point of view of the main protagonist. Recall is more accurate for the verbs come and bring if they describe a movement toward the protagonist; recall is more accurate for go and take if they describe a movement away from the protagonist. Thus, adults interpret movements in a narrative from the perspective of the protagonist. This study indicates that 3- and 4-year-old children show the same pattern of recall. They accurately recall verbs of motion that are consistent with the protagonist's perspective but make substitution errors on verbs inconsistent with that perspective.

The competence of vascular surgeons defined as the level of skill, knowledge and experience necessary to safely perform vascular surgical procedures is determined to a high degree by the quality of the preceding training. In Europe, quality assurance of vascular surgical training, unlike in the USA, is not uniform and is not the responsibility of a centralized European authority, but is a matter in which the different countries have autonomous regulations. Consequently, different targets for duration, contents and general principles for training in vascular surgery have been set. Although in the past this may not have been a problem, the unification of countries in the European Community (EC), at present known as the European Union (EU), has changed this perspective because there is increasing impetus towards a mutual recognition of trade and education between member states. In 1975, EC directive 75/362 was adopted, which insured 'freedom of migration' for medical doctors along with many other professional trades (Publications of the European Communities no. L167, 30-6-1975, p. 1). This directive implicated that certificates, diplomas and other documents issued by the national competent authorities proving medical qualification allowed physicians to practice in any EU country. In order to make this law practical it seems essential that specialist training programmes throughout the EU should conform to certain agreed basic standards. The objective of this article is to present an overview on the current pattern of vascular surgical training in Europe. In addition, the structures that were established during the recent years to promote uniformly high standards of training in vascular surgery throughout the EU will be discussed.

Multiple lines of evidence indicate that oxidative stress is an integral component of the pathogenesis of Alzheimer disease (AD). The precipitating cause of such oxidative stress may be misregulated iron homeostasis because there are profound alterations in heme oxygenase-1 (HO-1), redox-active iron, and iron regulatory proteins. In this regard, HasA, a recently characterized bacterial protein involved in heme acquisition and iron metabolism, may also be important in the generation of reactive oxygen species (ROS) given its ability to bind heme and render iron available for free radical generation through the Fenton reaction. To study further the role of heme binding and iron metabolism in AD, we show an abnormal localization of anti-HasA to the neurofibrillary pathology of AD, but not in normal-appearing neurons in the brains of cases of AD or in age-matched controls. These results suggest the increased presence in AD of a HasA homologue or protein sharing a common epitope with HasA, which we term HasAh. We conclude that heme binding of HasAh is a potential source of free soluble iron and therefore toxic free radicals in AD and in aging. This furthers the evidence that redox-active iron and subsequent Fenton reaction generating reactive oxygen are critical factors in the pathogenesis of AD.

Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease., (Copyright 2000 Wiley-Liss, Inc.)

Refinement in anaesthetic and surgical techniques for repair of abdominal aortic aneurysms has significantly reduced the mortality associated with treating this condition. Endovascular techniques have further pushed back the frontiers for the treatment of aortic aneurysms, and higher risk patients are now being treated under local or regional anaesthesia. The question of when not to offer intervention is becoming more and more difficult. Age is not a bar to aneurysm surgery in a patient who is physically fit; but the risk and benefit of intervention must be carefully evaluated for each patient on an individual basis, and risk calculation must be evidence based. Contraindications to aneurysm surgery are relative and few and include: small aneurysms (<5.5 cm), a co-morbidity that increases surgical risk by >10% and a life expectancy of <1 year. Endovascular graft technology is rapidly advancing, but until the long term results of endovascular repair of aortic aneurysms are proven, the indications for intervention should be the same as for open repair.

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.

Recent studies have shown how children develop an understanding of emotion: pre-school children identify and talk accurately about the basic emotions and increasingly appreciate the way that desires and beliefs give rise to those emotions. However, children also display stable individual differences in their understanding. Two different interpretations of such individual differences are discussed. Caregivers show more or less sensitivity to their children's emotions. One interpretation, therefore, is that early variation in caregiver sensitivity is responsible for individual differences in children's attachment status; in turn, children's attachment status leads to enduring differences in their understanding of emotion. A second interpretation focuses on the fact that children grow up in families that vary in the manner and extent to which feelings are put into words. Accordingly, early differences in family discourse about emotion, especially on the part of the primary caregiver, may lead to variation among children in their understanding of emotion. Evidence supporting or undermining these two different interpretations is reviewed.

Purpose: To investigate the use of contrast-enhanced ultrasound in the detection of endoleak after endovascular repair of abdominal aortic aneurysm., Materials and Methods: Eighteen patients underwent follow-up on 20 occasions after endovascular aortic aneurysm repair by arterial-phase contrast-enhanced spiral computed tomography (CT). All patients had unenhanced color Doppler ultrasound and Levovist-enhanced ultrasound on the same day. The ultrasound examinations were reported in a manner that was blind to the CT results. CT was regarded as the gold standard for the purposes of the study., Results: There were three endoleaks shown by CT. Unenhanced ultrasound detected only one endoleak (sensitivity, 33%). Levovist-enhanced ultrasound detected all three endoleaks (sensitivity, 100%). Levovist-enhanced ultrasound indicated an additional six endoleaks that were not confirmed by CT (specificity, 67%; positive predictive value, 33%). In one of these six cases, the aneurysm increased in size, which indicates a likelihood of endoleak. Two of the remaining false-positive results occurred in patients known to have a distal implantation leak at completion angiography., Conclusion: In this small group of patients, contrast-enhanced ultrasound appears to be a reliable screening test for endoleak. The false-positive results with enhanced ultrasound may be due to the failure of CT to detect slow flow collateral pathways. Although the number of patients in this study is small, enhanced ultrasound may be more reliable than CT in detecting endoleak.

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Which objects and animals are children willing to accept as referents for words they know? To answer this question, the authors assessed early word comprehension using the preferential looking task. Children were shown 2 stimuli side by side (a target and a distractor) and heard the target stimulus named. The target stimulus was either a typical or an atypical exemplar of the named category. It was predicted that children first connect typical examples with the target name and broaden the extension of the name as they get older to include less typical examples. Experiment 1 shows that when targets are named, 12-month-olds display an increase in target looking for typical but not atypical targets whereas 24-month-olds display an increase for both. Experiment 2 shows that 18-month-olds display a pattern similar to that of 24-month-olds. Implications for the early development of word comprehension are discussed.

One of the most striking features of Alzheimer disease (AD) is an accumulation of iron in neurofibrillary tangles and senile plaques. Intriguingly, this iron is found as both iron (II) and iron (III) and is redox-active. To address the issue of whether such iron participates in redox cycling, it was essential to investigate how iron (II) accumulates, since oxidation of iron (II) can lead to the generation of reactive oxygen species. To begin to address this issue, here we investigated ceruloplasmin, a key protein involved in the regulation of the redox state of iron by converting iron (II) to iron (III). Cases of AD and age-matched controls, obtained at autopsy with similar postmortem intervals, display similar levels of ceruloplasmin immunoreactivity that is mainly confined to neurons. However, in marked contrast, cases of AD show a significant increase in ceruloplasmin within the neuropil determined by immunoblot analysis of tissue homogenates as well as a generalized increased neuropil staining. Together, these findings suggest that neuronal induction of ceruloplasmin is feeble in AD, even while there is an increase in tissue ceruloplasmin. Therefore, a failure of neuronal ceruloplasmin to respond to iron may be an important factor that then leads to an accumulation of redox-active iron in neurons in AD.

Objective: the outcomes for patients after endovascular treatment of abdominal aortic aneurysm (AAA) are determined primarily by the endpoints of death and endoleaks, the latter representing continued risk of rupture. The data of a multicentre registry were analysed with regard to the early outcome of stent-graft procedures for AAA and the complications associated with this treatment. In addition, the results during follow-up were analysed by determining mortality and endoleak development as separate endpoints and as a combined endpoint defined as endoleak-free survival., Setting: 38 European institutions of Vascular Surgery collaborating in a multicentre registry project., Patients and Methods: 899 patients with AAA underwent between May 1994 and March 1998 elective endovascular repair (818 men and 81 women; mean age 69 years). 80 (8.9%) of the patients had medical conditions that excluded them from open repair. 818 (91%) of patients had a bifurcated device, 63 (7%) had a straight tube graft, and only 18 (2%) had an aorto-uni-iliac device. Clinical examination and contrast-enhanced computed tomography was performed at fixed follow-up intervals to assess increase or decrease of the maximum transverse diameter (MTD). Endoleaks observed at follow-up were discriminated into persistent endoleak and temporary endoleak. The latter is defined as single time observed endoleaks or with two or more negative imaging studies between observed endoleaks. Life-table analyses were used to calculate the rates of freedom-from-endoleak (no endoleak at any time), freedom-from-persistent endoleak (no persistent endoleak), patient survival, and persistent-endoleak-free-survival., Results: the median follow-up of this patient series was 6.2 months. The ratio between observed and expected follow-up data was 82% for the overall follow-up period. However, at 18 months of follow-up this rate was only 45%. The number of patients followed during this period was sufficient to allow statistically meaningful assessment. The MTD in patients with temporary endoleaks demonstrated a significant decrease at 6 to 12 months compared to preoperative values (mean 57 and 53 respectively, p =0.004). In patients with persistent endoleaks there was no change between the preoperative and 6-month MTD (mean 57 and 60 mm respectively). At 6 and 18 months freedom-from-endoleak was 83% and 74% and freedom-from-persistent endoleak was 93% and 90%, respectively. The 18-month cumulative patient survival was 88% and the main outcome measure, the persistent endoleak-free-survival was 79%., Conclusions: the MTD decreases in patients with temporary endoleak, but not in patients with persistent endoleak. Therefore, the use of the rate of freedom-from-persistent endoleak, reflecting absence of persisting endoleaks to estimate the prognosis with regard to the AAA, is justified. Determining persistent endoleak-free survival appears a rational approach to provide a realistic outlook for patients with stent-grafted AAA. The observed 18-month endoleak-free survival reflects a satisfactory mid-term result., (Copyright 1999 W.B. Saunders Company Ltd.)

BACKGROUND: An audit of endovascular aneurysm repair (EVAR) was undertaken in order to assess the efficacy of this new approach in the treatment of abdominal aortic aneurysm. METHODS: An international register of EVAR was started in 1996, with emphasis on close follow-up. RESULTS: Data have now been accumulated for 895 cases. The 30-day mortality rate is low at 3 per cent; patients who died generally had major co-morbidity. At discharge 14 per cent were identified as having an endoleak (persistent blood flow outside the lumen of the endoluminal graft but within the aneurysm sac) and another 18 per cent developed new endoleaks during the first year of follow-up. Continued expansion of the aneurysm was observed in 22 per cent. This occurred in 53 per cent of patients with an identified endoleak compared with 11 per cent of those in whom no endoleak was demonstrated (P < 0.01). Aneurysm rupture after EVAR occurred in six patients, three of whom died. CONCLUSION: That EVAR is technically feasible is beyond doubt. Close follow-up has identified problems specific to the minimally invasive approach. The significance of endoleaks in particular remains unclear, but the strong association with continued aneurysm expansion is of concern. The primary purpose of EVAR, however, is to prolong life and in this study the cumulative 2-year survival rate (including operative deaths) was 85 per cent. In patients without any complications the benefits of the minimally invasive approach are readily apparent. Thus, while there is no place for unrealistic optimism, there certainly appears to be a role for EVAR. To prevent inappropriate widespread application of this new approach, or indeed unwarranted condemnation, randomized controlled trials comparing EVAR with conventional management are essential.

The Eurostar Registry was established in 1996 to collate information, from centres across Europe, on the outcome from endovascular grafting of aortic aneurysms. At the end of the first year of the project, data on 430 patients had been entered onto the database. In 420 patients (97.7%), the endografts were deployed without major complications. The 30-day mortality rate was low at 3.4% and deaths were confined mostly to 'high risk' patients with major co-morbidity. Endoleaks, which were present on discharge from hospital in 15.7% of patients, were associated with a significantly increased incidence of continued expansion of the aneurysm sac postoperatively (P < 0.01). Thus the early results confirmed the feasibility and low complication rate of endovascular repair of aneurysms, but a higher than expected incidence of endoleaks. At 2 years, 895 patients had been registered. The rate of early endoleaks remained significantly unchanged but another 18% of patients had developed new endoleaks during the first year of follow-up. Six delayed ruptures had been reported, 3 fatal. There were indications that 'self sealed' endoleaks continued to pressurise the aneurysm sac. Severe distortion of the grafts with kinking and other structural changes associated with postoperative longitudinal shrinking of the aneurysm sac was observed in 69% of patients at 1 year. Clinical complications associated with these changes included late endoleak and graft limb occlusion. Early unrealistic optimism about endovascular aneurysm repair has been replaced with a more realistic understanding of its benefits and limitations as a result of the Eurostar project and other registries. Randomised studies are now required to establish the most appropriate role for this approach, alongside established therapies.

A paradigm devised by M. Lewis, C. Stanger, and M. W. Sullivan (1989) was adapted to study deception and false-belief understanding. In Study 1, 3- and 5-year-olds were asked not to touch a toy in the experimenter's absence. Just over half of the children touched the toy, and of those children, the majority denied having done so. Of control children who were given permission to touch the toy, all touched it and admitted having done so. In Study 2, 3- and 5-year-olds were asked not to look in a box to identify its contents. Almost all children looked, most denied having looked, and a minority consistently feigned ignorance of the contents. False-belief understanding was linked to denial of looking but not to feigning ignorance. Of control children who were given permission to look, all acknowledged looking, and they almost always revealed their knowledge of the contents. The studies confirm that preschoolers deceive in the context of a minor misdemeanor but are less effective at feigning ignorance.

Objectives: To compare graft patency and limb salvage rate following femoro-infrapopliteal bypass using ePTFE grafts with and without the addition of adjuvant arterio-venous fistula., Design: A prospectively randomised controlled trial., Materials: Patients referred to two teaching hospital vascular surgery units in the U.K. for the treatment of critical limb ischaemia., Methods: Eighty-seven patients (M:F; 2.3:1) undergoing 89 femoro-intrapopliteal bypass operations with ePTFE grafts for critical limb ischaemia were randomly allocated to have AVF included in the operative procedure (n = 48) or to a control group without AVF (n = 41). An interposition vein-cuff was incorporated at the distal anastomosis in all patients., Results: The cumulative rates of primary patency and limb salvage at 1-year after operation for patients with AVF were 55.2% and 54.1% compared to 53.4% and 43.2%, respectively, for the control group. The differences between the AVF and control groups did not reach statistical significance, in terms of either graft patency or limb salvage, at any stage after operation (Log-Rank test)., Conclusions: AVF confers no additional significant clinical advantage over interposition vein cuff in patients having femoro-infrapopliteal bypass with ePTFE grants for critical limb ischaemia.

One of the main causes of failure of expanded polytetrafluoroethylene (PTFE) bypass grafts used in the lower limbs is the development of myointimal hyperplasia (MIH). Clinical studies show that higher patency rates can be obtained with the use of an autologous vein cuff (the Miller cuff) interposed between the graft and artery. The reasons for the improved performance are still unclear, but preliminary studies suggest that the change in local haemodynamics due to the cuff geometry may be the significant factor rather than the presence of autologous material. If this is the case, then PTFE grafts can be produced with an integral cuff, i.e. a precuffed graft, with similar haemodynamic patterns to that of the Miller cuff. In this paper, two different types of precuffed graft are presented and their flow patterns are compared with those recorded in the Miller cuff and the conventional end-to-side anastomosis. The haemodynamic studies were carried out using optically clear silicone rubber models under simulated in vivo pulsatile flow conditions. Flow structures similar to those observed in the Miller cuff were seen in the precuffed grafts.

The design and development of a simulator for endovascular repair of abdominal aortic aneurysm (AAA) is described. The simulator consists of an interchangeable model of a human AAA based on computed tomography data and is produced by means of computer-aided design and manufacture (CAD/CAM) techniques. The model has renal, iliac, and femoral arteries, and is perfused with a temperature controlled blood-analog fluid under simulated physiological flow conditions. "Fluoroscopic imaging" is simulated by a computerized imaging system that uses visible light. A movable video camera relays images in the antero-posterior and lateral planes of the AAA to a monitor. The imaging system allows "arteriography" and "road-mapping" to be performed so as to facilitate accurate deployment of endovascular stent-grafts. The system has been used for teaching and demonstrating endovascular techniques to clinicians, as well as the evaluation of new stent-graft devices. Its successful incorporation into endovascular workshops has demonstrated its role in the training of clinicians in endovascular repair of AAA.

Formation of carbonyls derived from lipids, proteins, carbohydrates, and nucleic acids is common during oxidative stress. For example, metal-catalyzed, "site-specific" oxidation of several amino acid side-chains produces aldehydes or ketones, and peroxidation of lipids generates reactive aldehydes such as malondialdehyde and hydroxynonenal. Here, using in situ 2,4-dinitrophenylhydrazine labeling linked to an antibody system, we describe a highly sensitive and specific cytochemical technique to specifically localize biomacromolecule-bound carbonyl reactivity. When this technique was applied to tissues from cases of Alzheimer disease, in which oxidative events including lipoperoxidative, glycoxidative, and other oxidative protein modifications have been reported, we detected free carbonyls not only in the disease-related intraneuronal lesions but also in other neurons. In marked contrast, free carbonyls were not found in neurons or glia in age-matched control cases. Importantly, this assay was highly specific for detecting disease-related oxidative damage because the site of oxidative damage can be assessed in the midst of concurrent age-related increases in free carbonyls in vascular basement membrane that would contaminate biochemical samples subjected to bulk analysis. These findings demonstrate that oxidative imbalance and stress are key elements in the pathogenesis of Alzheimer disease.

Increased awareness for a role of oxidative stress in the pathogenesis of Alzheimer's disease has highlighted the issue of whether oxidative damage is a fundamental step in the pathogenesis or instead results from disease-associated pathology. In vitro experiments support both possibilities: Oxidative stress increases amyloid-beta production, and, conversely, amyloid-beta increases oxidative damage. To address the relationship between amyloid-beta and oxidative stress in vivo, we examined, using an array of oxidative markers, transgenic mice that overexpress amyloid-beta precursor protein and, as in Alzheimer's disease, develop characteristic amyloid-beta deposits within the brain parenchyma. Transgenic animals show the same type of oxidative damage that is found in Alzheimer's disease, and it is important that this damage directly correlates with the presence of amyloid-beta deposits. The significance of these studies is twofold. First, they provide evidence that amyloid-beta and oxidative damage are inextricably linked in vivo. Second, they support the use of transgenic animals for the development of antioxidant therapeutic strategies.

A role for altered iron metabolism in the pathogenesis of Alzheimer's disease has been suggested by several reports associating the cardinal neuropathologic lesions with markers of free radical-induced damage and redox-active iron. We hypothesized that the abnormal distribution of iron in Alzheimer brain might result from alterations in iron regulatory proteins (IRP) such as IRP-1 and IRP-2, the main control elements of cellular iron homeostasis. Here, we report that while IRP-1 is present at similar levels in both Alzheimer and control brain tissue, IRP-2 shows striking differences and is associated with intraneuronal lesions, including neurofibrillary tangles, senile plaque neurites and neuropil threads. Since IRP-2 colocalizes with redox-active iron, our results suggest that alterations in IRP-2 might be directly linked to impaired iron homeostasis in Alzheimer's disease., (Copyright 1998 Elsevier Science B.V.)

Rosenthal fibers (RF), intra-astrocytic hyaline inclusions, accumulate in various pathological conditions and are the histological hallmark of Alexander's disease. While the major protein components of RF have been identified, the factors accounting for their pathogenesis, accumulation, and insolubility are largely unknown. In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. In all the cases of Alexander's disease examined, strong immunolabeling of RF by the antibodies to 4-hydroxy-2-nonenal pyrrole adducts were noted. By contrast, age-matched control cases showed no immunoreactivity. These results indicate that modification of protein by lipid peroxidation adducts may play an important role in the formation of RF as well as in the pathogenesis of Alexander's disease. Furthermore, taken together with our previous data indicating advanced Maillard reaction end products in RF, it seems that post-translational modification of RF, initiated by oxidative stress, is critical for both the accumulation and the insolubility of RF, and therefore, by inference, in the pathogenesis of Alexander's disease., (Copyright 1998 Elsevier Science B.V.)

Contemporary findings suggest that the imagination of autistic children is not as limited as was once thought. In contrast, Scott and Baron-Cohen (1996) claim that children with autism are unable to draw pictures of impossible entities. An experiment showed that children with autism, children with moderate learning disabilities, and normal 4-year-olds were equally successful at identifying real and impossible pictures and at completing pictures to make them look either real or impossible. The previously reported inability to draw "impossible" pictures is unlikely to reflect an imaginative deficit and may instead result from a misunderstanding of the task or limitations in the executive abilities required to plan and draw an unusual picture for the first time.

It is often assumed that scientific thinking displaces magical thinking, both historically and ontogenetically, but the tendency to invoke hidden causal powers straddles both modes of thought. The strength of this disposition among children and adults alike stands in need of explanation.

Damage from free radicals has been demonstrated in susceptible neuronal populations in cases of Alzheimer disease. In this study, we investigated whether iron, a potent source of the highly reactive hydroxyl radical that is generated by the Fenton reaction with H2O2, might contribute to the source of radicals in Alzheimer disease. We found, using a modified histochemical technique that relies on the formation of mixed valence iron complexes, that redox-active iron is associated with the senile plaques and neurofibrillary tangles-the pathological hallmark lesions of this disease. This lesion-associated iron is able to participate in in situ oxidation and readily catalyzes an H2O2-dependent oxidation. Furthermore, removal of iron was completely effected using deferoxamine, after which iron could be rebound to the lesions. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together, these findings indicate that iron accumulation could be an important contributor toward the oxidative damage of Alzheimer disease.

Objectives: Interposition vein cuffs improve the patency of below-knee ePTFE arterial grafts, and there is evidence that they do so, at least in part, by modifying the distribution of myointimal hyperplasia (MIH) at the distal anastomosis. Alteration of local haemodynamics is one of the mechanisms which might be involved. The purpose of this study was to characterise the local haemodynamics within an interposition vein cuff., Material and Methods: Flow patterns have been analysed in a laboratory model of cuffed anastomosis and compared with observations made in patients by cine intra-arterial digital subtraction angiography (IA DSA) and dynamic colour duplex scanning., Results: In contrast to non-cuffed anastomoses in which the flow is predominantly laminar, cuffed anastomoses are associated with the formation of a coherent vortex., Conclusion: High frictional forces or shear stress exerted upon the arterial wall by the vortex could explain the beneficial effect of a cuff upon anastomotic MIH, in which case the optimal configuration of small vessel anastomoses would be that which most effectively promotes the formation of this type of vortex.

Two-year-old children were required to use nonliteral words or actions to complete scenarios in which a doll acted as the agent of a series of make-believe events. An experimenter encoded the doll's imaginary intentions either verbally or through pretend actions. No gender differences were observed, but older 2-year-olds performed reliably better than younger 2-year-olds. In addition, episodes that required children to enact the conclusion to events that began with doll-directed actions proved difficult to comprehend. Discussion focuses on the implications of children's understanding of independent agency for joint sociodramatic play and on the problem of intersubjectivity in children's understanding of an adult's nonliteral intentions.

Rosenthal fibers, astrocytic inclusions that accumulate in various neoplastic and non-neoplastic conditions, are a characteristic of Alexander disease, a leukodystrophy of unknown etiology. Given that alphaB crystallin is the major protein component of Rosenthal fibers and that crystallins in the diabetic and aged lens are targets for advanced glycation end product modifications via the Maillard reaction we hypothesized that Rosenthal fibers might contain similar modifications. Using antibodies specific for two products of glycation, pyrraline and pentosidine, we showed labeling of Rosenthal fibers that may account for their insolubility and accumulation. These data suggest that advanced glycation end products may be critical to the pathogenesis of Alexander disease.

In this study, we demonstrate that two important regulators of the cell cycle, cyclin-dependent kinase-4 and its inhibitor p16, are increased in the brains of cases of Alzheimer's disease patients compared with age-matched controls. Both proteins are increased in the pyramidal neurons of the hippocampus, including those neurons containing neurofibrillary tangles and granulovacuolar degeneration. As p16 is not normally found in terminally differentiated neurons, it seems paradoxical that it is increased in Alzheimer's disease unless it is responding to increases in cyclin-dependent kinase-4 or other cell cycle regulators. Induction of the latter, a protein that signals re-entry and progression through the cell cycle, may itself be the consequence of alpha response to a growth stimulus. Re-entry into the cell cycle is likely deleterious in terminally differentiated neurons and may contribute to the biochemical abnormalities, such as oxidative stress and hyperphosphorylated tau protein, as well as the neuronal degeneration characteristic of the pathology of Alzheimer's disease.

Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine-derived pyrrole adducts formed by lipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age-matched control patients. HNE-pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid-beta deposits were unlabeled. Age-matched controls showed only background HNE-pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress-related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.

Increasing evidence suggests that oxidative damage to proteins and other macromolecules is a salient feature of the pathology of Alzheimer's disease. Establishing the source of oxidants is key to understanding what role they play in the pathogenesis of Alzheimer's disease, and one way to examine this issue is to determine which oxidants are involved in damage. In this study, we examine whether peroxynitrite, a powerful oxidant produced from the reaction of superoxide with nitric oxide, is involved in Alzheimer's disease. Peroxynitrite is a source of hydroxyl radical-like reactivity, and it directly oxidizes proteins and other macromolecules with resultant carbonyl formation from side-chain and peptide-bond cleavage. Although carbonyl formation is a major oxidative modification induced by peroxynitrite, nitration of tyrosine residues is an indicator of peroxynitrite involvement. In brain tissue from cases of Alzheimer's disease, we found increased protein nitration in neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was undetectable in the cerebral cortex of age-matched control brains. This distribution is essentially identical to that of free carbonyls. These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer's disease. Moreover, the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs, but instead reflects a generalized oxidative stress that is important in disease pathogenesis.

A prototype simulator for training in endovascular repair of abdominal aortic aneurysms (AAA) has been developed. Employing transparent models of human AAA complete with renal, iliac and femoral arteries, this system allows accurate simulation of aortography, road-mapping, catheter guidewire manipulation and stent-graft deployment while obviating the need for ionising radiation.

EUROSTAR (EUROpean collaborators on Stent-graft Techniques for abdominal aortic Aneurysm Repair) was established for the purpose of combining and studying data on endovascular abdominal aortic aneurysm (AAA) repair, EUROSTAR is independent of any commercial interest and has as its ultimate goal an independent, scientifically reliable assessment of endovascular AAA grafting. A standardized case record form is used for data collection and transmission, and the database is maintained in a central registry office. A comprehensive set of clinical, imaging, technical, and laboratory data obtained at initial admission and follow-up are recorded; these data are analyzed periodically and reports generated on the collated experience. As a first priority, an observational study without controls was initiated in July 1996 to address the issues of procedural safety, device durability, and long-term effect upon the aneurysms. Several ancillary studies have been initiated, including a "Retrieval and Analysis Study" for the evaluation of explanted devices. While a randomized study does not seem feasible at present, this may be organized at the appropriate time when the devices and techniques become more standardized.

Research on children's causal thinking has emphasized the perception of temporal and spatial contiguity between cause and effect. However, our causal judgements often involve a contrast between a perceived sequence (A, then B) and a counterfactual case (in the absence of A, then not B). In three experiments, children's capacity for such counterfactual thinking was assessed. In Experiment I, children aged 3-5 years observed a sequence such as A causing B. Subsequently, they replied quite accurately to a question about a counterfactual sequence, for example: "What if A had not occurred, then B or not B?". In Experiment 2, children were asked about two counterfactual antecedents, one that would not have caused B, and one that (like the actual antecedent) would also have caused B. Children differentiated between the two types of antecedent. Finally, in Experiment 3, children heard stories in which the protagonist chose a course of action that led to a minor mishap (e.g., drawing with a black pen and getting inky fingers), having rejected an option that would have prevented it in experimental stories (e.g., using a pencil) or an option that would have led to an equivalent outcome in control stories (e.g., using a blue pen). Children aged 3 and 4 years often cited the failure to adopt another course of action as the cause of the mishap and, particularly in experimental stories, they focused on the rejection of the alternative option. Children's use of counterfactual thinking is discussed in relation to contemporary accounts of causal reasoning.

It is generally considered that the outcome from critical limb ischaemia (CLI) in people with diabetes is inferior to that in non-diabetic patients. However, excellent results have been reported in diabetic people with the use of bypass surgery to pedal arteries. Data from a prospective national survey on CLI have been analysed to compare surgical practice and outcome from CLI in diabetic and non-diabetic populations. Of 679 limbs included in the survey, 204 (30%) were in diabetic patients. Thirty-seven (18%) of diabetic limbs were treated by primary amputation compared to 43 (9%) in non-diabetics (p = 0.0013). Revascularization was the primary treatment intention in 127 (62.3%) of diabetic limbs compared to 342 (72%) in non-diabetics (p = 0.01). Bypass to pedal arteries was reported in only 2 (1%) diabetic patients. The limb salvage rate in diabetic patients was 60%, compared to 72.5% for non-diabetic patients (p = 0.0013). The mortality rates were 15% and 12% in diabetic and non-diabetic patients, respectively (NS). These results confirm that in the UK and Ireland diabetic patients with CLI fare considerably worse than do people without diabetes. The results may be improved if more pedal artery reconstructions were performed.

The feasibility of minimally invasive treatment of abdominal aortic and other arterial aneurysms by introduction under X-ray control of an endovascular graft via the femoral artery is proven. Until the safety and efficacy of these techniques is established, their introduction into clinical practice needs to be monitored. This paper reports recommendations agreed jointly by the Vascular Surgical Society of Great Britain and Ireland and the British Society of Interventional Radiologists for assessment of endovascular grafting techniques.