Reprinted article "Realistic expectations for patients with stent-graft treatment of abdominal aortic aneurysms. Results of a European multicentre registry".

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.

Ready-to-fenestrate stent grafts in the treatment of juxtarenal aortic aneurysms: proposal for an off-the-shelf device.

OBJECTIVE: A prototype ready-to-fenestrate stent graft (RFSG) was designed with a fixed scallop, and eight potential fenestrations allowing for variation in the position of each renal artery (RA) relative to the superior mesenteric artery (SMA). We aimed to determine the proportion of juxtarenal aneurysms treatable using this potentially 'off-the-shelf' device. METHODS: A total of 439 consecutive orders for custom-made devices were analysed, and positions for potential fenestrations in the RFSG were determined, based on the most frequent anatomical target vessel variations: a fixed SMA scallop 12 mm deep at 12:00, RA fenestrations at 9:15, 10:15 (target within the range 8:45-10:45), 2:15 and 3:15 (target within the range 1:45-3:45), each either 19 or 28 mm from the graft edge (GE); (within the range 15-32 mm), and 6 x 8 mm in diameter. Proximal diameters of 24, 26, 28, 30, 32 and 36 mm were chosen. RESULTS: Of the 439 plans, 372 standard juxtarenal (SJR) cases, defined by the inclusion of a scallop and 0, 1 or 2 small fenestrations (12%, 13% and 75% of the cases, respectively) were identified and used to test the applicability of the model. Mean CP (clock position) for right RA was 9:30, for the left RA 3:00, being a mean of 21 +/- 5 and 22 +/- 5 mm, respectively from the GE. RA CP was within the RFSG range in 86% (right) and 88% (left) of the cases, with 96% and 98%, respectively, within the allowable distance from the GE. A total of 81% of all SJR cases were potentially treatable using the RFSG model. CONCLUSIONS: An RFSG device would allow for the treatment of the majority of juxtarenal aortic aneurysms, which currently require custom-made devices.

Wholly endovascular repair of thoracoabdominal aneurysm.

BACKGROUND: The aim was to evaluate a wholly endovascular approach to the repair of thoracoabdominal aortic aneurysm (TAAA). METHODS: Six patients (median age 71 years) underwent wholly endovascular repair of TAAA (maximum diameter 56-85 mm) employing individually customized endografts. Procedures were performed under general anaesthesia, with spinal drainage in five patients. Patients were followed by serial computed tomography, plain radiography and duplex imaging for a median of 17 (range 8-44) months. RESULTS: All grafts were deployed as intended, with preservation of all target vessels. There were no postoperative deaths, strokes or paraplegia. One patient suffered a silent myocardial infarction. In two patients a persistent paraostial endoleak was treated by further balloon dilatation of the stent within the endograft fenestration. Imaging before discharge confirmed aneurysm exclusion in all patients. Two patients required late secondary intervention to abolish endoleaks due to side-branch disconnection. One patient suffered late occlusion of the coeliac axis without clinical sequelae, and late occlusion of a solitary renal artery in another resulted in dependence on dialysis. There have been no late deaths and all aneurysms remain excluded. CONCLUSION: Wholly endovascular TAAA repair is relatively safe, but long-term follow-up is required to establish its durability.

Fenestrated endovascular repair for juxtarenal aortic aneurysm.

BACKGROUND: The outcome of fenestrated endovascular aneurysm repair (F-EVAR) was evaluated. METHODS: Between February 2003 and December 2006, 45 patients (median age 73 (range 53-85) years) underwent primary (41) or secondary (four) F-EVAR for an abdominal aortic aneurysm with infrarenal neck anatomy unsuitable for a standard stent-graft. Median aneurysm diameter was 68 (range 55-100) mm and median infrarenal aortic neck length was 6 (range 0-13) mm. Customized fenestrated Zenith stent-grafts were employed in all procedures, incorporating fenestrations to preserve flow into renal (80), superior mesenteric (35) and coeliac (two) arteries. Eighty-two target vessels were stented (61 bare metal, 21 covered). RESULTS: All aneurysms were isolated successfully, with preservation of the target vessels. One accessory renal artery was lost. One patient died after 5 days from myocardial infarction, and another at 3 months from multiorgan failure secondary to atheroembolism. At median follow-up of 24 (range 1-48) months, all aneurysms were stable or shrinking, with no late ruptures or graft-related endoleaks. Six patients required a secondary intervention. The primary vessel patency rate was 96.6 per cent. There were four late deaths, unrelated to the aneurysm. CONCLUSION: F-EVAR enabled successful treatment of juxtarenal aortic aneurysm with a low complication rate.

Swirling flow pattern in a non-planar model of an interposition vein cuff anastomosis.

One of the main causes of long-term failure of ePTFE grafts is the development of anastomotic intimal hyperplasia which leads to graft thrombosis. Experimental studies with bypass grafts have shown an inverse relationship between mean wall shear stress and intimal hyperplasia. The geometry of the anastomosis has a strong influence on the flow pattern and wall shear stress distribution. The aim of this in vitro study was to investigate the influence of non-planarity in a model of a distal anastomosis with interposition vein cuff, an anastomosis configuration that is increasingly being used because of improved clinical results. Laser Doppler anemometer measurements were carried out in silicone rubber models of interposition vein cuff anastomoses with planar and non-planar inflow. The pulsatile flow waveforms were typical of those found in femoro-infrapopliteal bypass. Axial and radial velocities were measured in the proximal and distal outflow segments. As expected a symmetrical helical flow pattern (Dean flow) was evident in the planar model. The model with non-planar inflow, however, gave rise to swirling flow in both the distal and proximal artery outflow segments for during the systolic phase. In patients, the anastomosis is usually non-planar. Since the configuration depends in part upon the tunnelling of the graft, this may be altered to some extent. Non-planar anastomotic configurations induce a swirling flow pattern, which may normalise wall shear stress, thereby potentially reducing intimal hyperplasia.

Mitochondrial abnormalities in Alzheimer's disease.

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes.

Neurons of adults apparently lack the components necessary to complete the cell division process. Therefore, in Alzheimer disease, the increased expression of cell cycle-related proteins in degenerating neurons likely leads to an interrupted mitotic process associated with cytoskeletal abnormalities and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer disease, we undertook a study of polo-like kinase (Plk), a protein that plays a crucial role in the cell cycle. Our results show disease-related increases in Plk in susceptible hippocampal and cortical neurons in comparison to young or age-matched controls. An increase in neuronal Plk further implicates aberrations in cell cycle control in the pathogenesis of Alzheimer disease and provides a novel mechanistic basis for therapeutic intervention.

Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?

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.

Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine.

Advanced glycation end products are a diverse class of posttranslational modifications, stemming from reactive aldehyde reactions, that have been implicated in the pathogenesis of a number of degenerative diseases. Because advanced glycation end products are accelerated by, and result in formation of, oxygen-derived free radicals, they represent an important component of the oxidative stress hypothesis of Alzheimer disease (AD). In this study, we used in situ techniques to assess N(epsilon)-(Carboxymethyl)lysine (CML), the predominant advanced glycation end product that accumulates in vivo, along with its glycation-specific precursor hexitol-lysine, in patients with AD as well as in young and aged-matched control cases. Both CML and hexitol-lysine were increased in neurons, especially those containing intracellular neurofibrillary pathology in cases of AD. The increase in hexitol-lysine and CML in AD suggests that glycation is an early event in disease pathogenesis. In addition, because CML can result from either lipid peroxidation or advanced glycation, while hexitol-lysine is solely a product of glycation, this study, together with studies demonstrating the presence of 4-hydroxy-2-nonenal adducts and pentosidine, provides evidence of two distinct oxidative processes acting in concert in AD neuropathology. Our findings support the notion that aldehyde-mediated modifications, together with oxyradical-mediated modifications, are critical pathogenic factors in AD.

Evidence for a novel heme-binding protein, HasAh, in Alzheimer disease.

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.

Protein disulfide isomerase in Alzheimer disease.

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.

Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine.

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.

Children's use of counterfactual thinking in causal reasoning.

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.

Melatonin acts as antioxidant and pro-oxidant in an organotypic slice culture model of Alzheimer's disease.

An organotypic mouse brain slice culture system of Alzheimer's disease (AD) under low oxygen partial pressures was developed to determine the antioxidant properties of the pineal hormone melatonin in vitro. Assays for biochemical markers of oxidative stress including redox active iron assay, heme-oxygenase-1 and 8-hydroxyguanosine inmunoreactivity were performed along with morphological analysis for stressed tissue following amyloid-beta (A beta) 1-40 insult. Melatonin (100 microM) significantly reduced the appearance of condensed chromatin, redox active iron, heme-oxygenase-1 induction and 8-hydroxyguanosine immunoreactivity caused by 50 microM A beta. Melatonin also prevented A beta-induced morphological signs of oxidative stress in tissue ultrastructure, including edema and dark degenerating profiles as visualized under electron microscope. At elevated concentrations (1 mM), melatonin induced redox active iron and heme-oxgenase-1 immunoreactivity. Thus, while melatonin may be a potential therapeutic agent in the prevention of oxidative stress associated with A beta and AD, it can also induce markers of oxidative stress at millimolar concentrations.

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation.

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.

Abnormal localization of iron regulatory protein in Alzheimer's disease.

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.

Advanced lipid peroxidation end-products in Alexander's disease.

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.

Advanced glycation modification of Rosenthal fibers in patients with Alexander disease.

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.

Outflow distribution at the distal anastomosis of infrainguinal bypass grafts.

Outflow distribution at the distal anastomosis of infrainguinal bypass grafts remains unquantified in vivo, but is likely to influence flow patterns and haemodynamics, thereby impacting upon graft patency. This study measured the ratio of distal to proximal outflow in 30 patients undergoing infrainguinal bypass for lower limb ischaemia, using a flow probe and a transit-time ultrasonic flow meter. The mean outflow distribution was approximately 75% distal to 25% proximal, with above knee anastomoses having a greater proportion of distal flow (84%) compared to below knee grafts (73%). These in vivo flow characteristics differ significantly from those used in theoretical models studying flow phenomena (50:50 and/or 100:0), and should be incorporated into future research.

Lessons learnt from the EUROSTAR registry on endovascular repair of abdominal aortic aneurysm repair.

OBJECTIVE: The EUROSTAR project is a multicentred database of the outcome of endovascular repair of infra-renal aortic aneurysms. To date 92 European centres of vascular surgery have contributed. The purpose of the article here is to review the medium term (up to 4 years) results of endovascular aneurysm repair as reported to Eurostar. PATIENTS AND METHODS: Patients intended for endovascular aneurysm repair were notified to the EUROSTAR Data Registry Centre before treatment in order to eliminate bias due to selective reporting. The following data was collected on all patients: (1) their demographic details and the anatomical characteristics of their aneurysms, (2) details of the endovascular device used, (3) procedural complications and the immediate outcome, (4) results of contrast enhanced CT imaging at 3, 6, 12 and 18 months after operation and at yearly intervals thereafter, (5) all adverse events. Life table analysis was performed to determine the cumulative rates of: (1) death from all causes, (2) secondary intervention. Risk factors for rupture and late conversion were identified by regression analysis. RESULTS: By July 2000, 2862 patients had been registered and their median duration of follow-up was 12 mo (range 0-72). Successful deployment was achieved in 2812 patients with a perioperative (30 day) mortality of 2.9%. In 2464 patients enrolled by March 2000 late rupture of the aneurysm occurred in 14 patients for an annual cumulative rate of 1%. The significant factors were proximal type I endoleak (P=0.001), midgraft (type III) endoleak (P=0.001), graft migration (P=0.001) and post-operative kinking of the endograft (P=0.001). Forty-one patients had late conversion to open repair for an annual cumulative rate (risk) of approximately 2.1%. Risk factors (indications) for late conversion were: proximal type I endoleak (P=0.001), midgraft (type III) endoleak (P=0.001), type II endoleak (P=0.003), graft migration (P=0.001), graft kinking (P=0.001) and distal type I endoleak (P=0.001). CONCLUSIONS: Endovascular repair of infra-renal aortic aneurysms using the first and second-generation devices that predominated in this study was associated with a risk of late failure of 3% per year, based upon an analysis of observed primary endpoints of rupture and conversion. Eurostar continues to provide responsible evaluation of the technique for the benefit of both physicians and the industry.