Intracellular calcium transients are necessary for platelet-derived growth factor but not extracellular matrix protein–induced vascular smooth muscle cell migration

AbstractPurposeVascular smooth muscle cell (SMC) migration is a critical component of the hyperplastic response that leads to recurrent stenosis after interventions to treat arterial occlusive disease. We investigated the relationship between intracellular calcium ([Ca2+]i) and migration of vascular SMCs in response to platelet-derived growth factor (PDGF) and extracellular matrix (ECM) proteins.MethodsHuman saphenous vein SMCs were used for all experiments. SMC migration in response to agonists was measured with a microchemotaxis assay. A standard fluorimetric assay was used to assess changes in [Ca2+]i in response to the various combinations of growth factors and ECM proteins.ResultsThe calcium ionophore A23187 produced a rapid rise in [Ca2+]i and a corresponding 60% increase in SMC migration, whereas chelation of [Ca2+]i with BAPTA (1,2-bis [aminophenoxy] ethane-N,N,N′,N′-tetraacetic acid) produced a fivefold decrease in PDGF-induced chemotaxis, suggesting that [Ca2+]i is both sufficient and necessary for SMC migration. Stimulation of SMCs with PDGF produced an early peak followed by a late plateau in [Ca2+]i. To establish a relationship between temporal fluctuations in [Ca2+]i and SMC migration, SMCs were pretreated with caffeine and ryanadine, which eliminated the initial peak but not the late plateau in [Ca2+]i, and had no effect on chemotaxis in response to PDGF. Incubation of SMCs with nickel chloride eliminated the late plateau, but had no effect on the initial peak in [Ca2+]i, and reduced PDGF-stimulated migration by fivefold. We then evaluated the role of calcium in SMC migration induced by ECM proteins such as laminin, fibronectin, and collagen types I and IV. All four matrix proteins stimulated SMC migration, but none produced an elevation in [Ca2+]i. Moreover, preincubation of SMCs with caffeine and ryanadine or nickel chloride had no effect on ECM protein-induced chemotaxis.Conclusion[Ca2+]i transients are necessary for PDGF but not ECM protein-induced SMC chemotaxis. Moreover, the ability of PDGF to stimulate vascular SMC migration appears dependent on influx of extracellular calcium through membrane channels.AbstractClinical relevanceRecurrent stenosis after angioplasty or surgical bypass remains a significant challenge in treating vascular occlusive disease. In addition to growth factors, extracellular matrix (ECM) proteins may be potent agonists of this process. In this study we show that the influx of extracellular calcium is an important mechanism for platelet-derived growth factor–induced smooth muscle cell migration but not ECM-induced migration. Of note, in clinical trials calcium channel blockers failed to inhibit recurrent stenosis. Our data provide mechanistic insight to help explain this negative outcome in that therapies designed to inhibit restenosis depend on the effects of both growth factors and ECM proteins

Endovascular repair of bleeding aortoenteric fistulas: A 5-year experience

AbstractPurpose: Aortoenteric fistula (AEF) is an uncommon but catastrophic complication that can occur either primarily or after aortic reconstruction. Untreated, it is uniformly fatal. Conventional surgical management is associated with a perioperative mortality rate of 25% to 90% and frequent major complications. We reviewed our experience with the endovascular treatment of both primary and secondary AEFs in an effort to determine whether endovascular repair is a less morbid alternative to traditional surgical treatment in select patients. Methods: In a 5-year period, seven high-risk patients who had bleeding and an AEF documented by means of radiology or endoscopy (2 primary, 5 secondary) were treated with coil embolization (1) or placement of an endovascular aortic stent graft (3 aortouniiliac, 2 tube, 1 bifurcated). One patient underwent computed tomography (CT)-guided percutaneous catheter drainage of an infected perigraft collection. The average follow-up period was 27 months (range, 11-66 months), and follow-up consisted of physical examination, complete blood count, and contrast-enhanced helical CT scanning at 3, 6, and 12 months and yearly thereafter. All patients were treated with intravenous antibiotics perioperatively and were prescribed life-long oral antibiotics on discharge. Results: There was one perioperative death (14%) caused by fungal sepsis. Persistent sepsis after stent-graft placement necessitated laparotomy and bowel resection in one patient. One patient had three bouts of recurrent sepsis that were successfully treated with a change of antibiotic. There were three late deaths (43%) unrelated to the procedure or AEF. Three patients (43%) were alive and well an average of 36 months (range, 23-67 months) after the procedure, with no clinical or radiologic evidence of recurrent bleeding or infection. Conclusion: Endovascular management of AEFs is technically feasible and may be the preferred treatment in select patients with bleeding and no signs of sepsis. In the setting of gross infection, it may also be considered in high-risk patients as a bridge to more definitive treatment after hemodynamic stabilization and optimization. (J Vasc Surg 2001;34:1055-9.

Primary immunoblastic B-cell lymphoma of the sternum

AbstractJ Thorac Cardiovasc Surg 1997;114:684-

Reduced primary patency rate in diabetic patients after percutaneous intervention results from more frequent presentation with limb-threatening ischemia

ObjectiveAlthough patients with diabetes are at increased risk of amputation from peripheral vascular disease, excellent limb-salvage rates have been achieved with aggressive surgical revascularization. It is less clear whether patients with diabetes will fare as well as nondiabetics after undergoing percutaneous lower extremity revascularization, a modality which is becoming increasingly utilized for this disease process. This study aimed to assess differential outcomes in between diabetics and nondiabetics in lower extremity percutaneous interventions.MethodsWe retrospectively studied 291 patients with respect to patient variables, complications, and outcomes for percutaneous interventions performed for peripheral occlusive disease between 2002 and 2005. Tibial vessel run-off was assessed by angiography. Patency (assessed arterial duplex) was expressed by Kaplan-Meier method and log-rank analysis. Mean follow-up was 11.6 months (range 1 to 56 months).ResultsA total of 385 interventions for peripheral occlusive disease with claudication (52.2%), rest pain (16.4%), or tissue loss (31.4%) were analyzed, including 336 primary interventions and 49 reinterventions (mean patient age 73.9 years, 50.8% male). Comorbidities included diabetes mellitus (57.2%), chronic renal insufficiency (18.4%), hemodialysis (3.8%), hypertension (81.9%), hypercholesterolemia (57%), coronary artery disease (58%), tobacco use (63.2%). Diabetics were significantly more likely to be female (55.3% vs 40.8%), and suffer from CRI (23.5% vs 12.0%), a history of myocardial infarction (36.5% vs 18.0%), and <three-vessel tibial outflow (83.5% vs 71.8%), compared with nondiabetics, although all other comorbidities and lesion characteristics were equivalent between these groups. Overall primary patency (± SE) at 6, 12, and 18 months was 85 ± 2%, 63 ± 3% and 56 ± 4%, respectively. Patients with diabetes suffered reduced primary patency at 1 year compared with nondiabetics. For nondiabetics, primary patency was 88 ± 2%, 71 ± 4%, and 58 ± 4% at 6, 12, and 18 months, while for diabetics it was 82 ± 2%, 53 ± 4%, and 49 ± 4%, respectively (P = .05). Overall secondary patency at 6, 12, and 18 months was 88 ± 2%, 76 ± 3%, and 69 ± 3%, and did not vary by diabetes status. One-year limb salvage rate was 88.3% for patients with limb-threatening ischemia, which was also similar between diabetics and nondiabetics. While univariate analysis revealed that female gender, <three-vessel tibial outflow, and a history of tobacco use were all predictive of reduced primary patency (P < .05), none of these factors significantly impacted secondary patency or limb-salvage rate. Furthermore, only limb-threatening ischemia remained a significant predictor of outcome on multivariate analysis, suggesting that the poorer primary patency in diabetics is related primarily to their propensity to present with limb-threatening disease compared with nondiabetics.ConclusionPatients with diabetes demonstrate reduced primary patency rates after percutaneous treatment of lower extremity occlusive disease, most likely due to their advanced stage of disease at presentation. However, despite a higher reintervention rate, diabetics and others with risk factors predictive of reduced primary patency can attain equivalent short-term secondary patency and limb-salvage rates. Therefore, these patient characteristics should not be considered contraindications to endovascular therapy

Evaluation of pressure transmission and intra-aneurysmal contents after endovascular repair using the Trivascular Enovus expanded polytetrafluoroethylene stent graft in a canine model of abdominal aortic aneurysm

ObjectiveEndotension has been defined as persistently increased pressure within the excluded sac of an abdominal aortic aneurysm (AAA) resulting in increasing aneurysm size after endovascular repair in the absence of endoleak. Devices that use expanded polytetrafluoroethylene (ePTFE) have been associated with the development of endotension and continued AAA enlargement. In this study, intra-aneurysmal pressure and aneurysm content were evaluated after endovascular repair with the Enovus ePTFE stent graft in a canine model.MethodsProsthetic ePTFE aneurysms, each containing a solid-state, strain-gauge pressure transducer, were implanted in the infrarenal aorta of 13 mongrel dogs (25-35 kg). A second pressure transducer was inserted into the native aorta for systemic arterial pressure measurement. The stent graft was then deployed to exclude the aneurysm via distal aortic access. Comparison was made among three distinct stent grafts: the Trivascular Enovus (nonporous ePTFE; four animals), the original Gore Excluder (porous ePTFE; five animals), and the Medtronic AneuRx (Dacron; four animals). Daily systemic and intra-AAA pressures were measured for 4 weeks. Intra-aneurysmal pressures were indexed to simultaneously measured systemic pressures. After 4 weeks, the aorta, the prosthetic aneurysm, and its contents were harvested, photographed, and processed for histologic investigation with hematoxylin and eosin and Masson trichrome staining.ResultsWithin 24 hours after exclusion, the mean arterial pressure and pulse pressure within the AAA sac tapered to less than 20% of systemic pressure for all three stent graft types. Throughout the postoperative period, significantly lower indexed intra-aneurysmal pressures were present in the Enovus- and AneuRx-treated aneurysms as compared with those treated with the original Excluder stent graft (0.05 ± 0.04, 0.16 ± 0.06, and 0.06 ± 0.03 for the Enovus, Excluder, and AneuRx, respectively). Histologic analysis of the Enovus-treated aneurysms demonstrated intraluminal content characterized almost entirely by erythrocytes and infrequent white blood cells without the fibrin organization—characteristics of acute or chronic thrombus. This contrasted with the content of the Excluder-treated aneurysms, which contained poorly organized fibrin deposition suggestive of acute thrombus, and of the AneuRx-treated aneurysms, which demonstrated mature, well-organized collagenous connective tissue.ConclusionsExclusion of the AAA with the Enovus stent graft resulted in nearly complete elimination of intra-aneurysmal pressure in this model. Histologic analysis of the aneurysm content further suggested complete exclusion, including elimination of circulating clotting factors and fibroblasts responsible for thrombus formation and reorganization. Ultimately, clinical evaluation will be necessary to demonstrate the effectiveness of this stent graft in preventing the development of endotension.Clinical RelevanceEndovascular aneurysm repair is an effective method for the treatment of abdominal aortic aneurysm (AAA) subjected to the unique complications of endoleak and endotension, the indirect pressurization of a sac in the absence of endoleak. In our model, AAA exclusion with the Enovus stent graft results in inhibition of fluid and serum transudation into the AAA sac, a corresponding prompt pressure decay profile, and near-complete elimination of intra-aneurysmal pressure. With the advent of implantable wireless pressure transducers, this research can be readily translated to the clinical setting. Future intraoperative and postoperative studies may help elucidate the clinical significance of pressure decay profiles in identifying successful AAA exclusion and monitoring for the development of endotension and its clinical sequelae

Inner speech deficits in people with aphasia

Despite the ubiquity of inner speech in our mental lives, methods for objectively assessing inner speech capacities remain underdeveloped. The most common means of assessing inner speech is to present participants with tasks requiring them to silently judge whether two words rhyme. We developed a version of this task to assess the inner speech of a population of patients with aphasia and corresponding language production deficits. Patients’ performance on the silent rhyming task was severely impaired relative to controls. Patients’ performance on this task did not, however, correlate with their performance on a variety of other standard tests of overt language and rhyming abilities. In particular, patients who were generally unimpaired in their abilities to overtly name objects during confrontation naming tasks, and who could reliably judge when two words spoken to them rhymed, were still severely impaired (relative to controls) at completing the silent rhyme task. A variety of explanations for these results are considered, as a means to critically reflecting on the relation between inner speech and silent rhyme judgments more generally

Predicting iliac limb occlusions after bifurcated aortic stent grafting: Anatomic and device-related causes

AbstractObjective: Graft limb occlusion may complicate endovascular abdominal aortic aneurysm repair. The precise etiologic factors that contribute to the development of these graft limb thromboses have not been defined. We evaluated our experience with bifurcated aortic endografts to determine factors that may predict subsequent limb thrombosis. The management of the thrombosed limbs and the results after treatment were also investigated. Methods: During a 4-year period, 351 patients with aortic aneurysms underwent treatment with bifurcated endografts (702 graft limbs at risk). These 351 bifurcated devices included AneuRx (Medtronic, Minneapolis, Minn; n = 35), Ancure (Guidant, Menlo Park, Calif; n = 8), Gore (W.L. Gore & Associates, Sunnyvale, Calif; n = 25), Talent (World Medical, Sunrise, Fla; n = 255), Teramed (Teramed, Minneapolis, Minn; n = 10), and Vanguard (Boston Scientific Vascular, Natick, Mass; n = 18). Details regarding the type of device, mechanism of deployment, and aortoiliac artery anatomy were collected prospectively and analyzed. Graft limbs were analyzed for diameter, use of additional endograft iliac extensions, deployment in the external iliac artery, and endograft to vessel oversizing. Follow-up included physical examination, duplex ultrasonography, and spiral computed tomographic scans at 1 month, 6 months, and 12 months and annually thereafter. The follow-up period ranged from 2 to 54 months, with a mean follow-up period of 20 months. Results: Twenty-six of 702 limbs (3.7%) had an occlusion develop. The risk of limb thrombosis was associated with a smaller limb diameter. Mean graft limb diameter was 14 mm in the occluded population, and patent limbs had a mean diameter of 16 mm. Thrombosis occurred in 16 of 291 limbs (5.5%) that were 14 mm or less and in 10 of 411 limbs (2.4%) that were greater than 14 mm (P = .03). Extension of a graft to the external iliac artery was performed in 96 of the 702 limbs. Eight of these 96 limbs (8.3%) had thrombosis develop as compared with 18 of 606 (3.0%) that extended to the common iliac artery (P = .01). No significant association was present between limb thrombosis and the contralateral or ipsilateral side of a device, the configuration of the iliac graft limb end (closed web, open web, or bare spring), or the degree of iliac graft limb oversizing. AneuRx, Ancure, Vanguard, and Talent grafts each sustained limb occlusions, with no occlusions seen among the Gore and Teramed devices. No significant increased risk of graft limb thrombosis was observed in unsupported grafts (1/16; 6.3%) versus supported grafts (25/686; 3.6%; P = not significant). Thromboses occurred between 1 day and 23 months after surgery. Thirteen of the 26 thromboses (50%) occurred within 30 days of surgery. Presenting symptoms were mild to moderate claudication in eight patients (30.8%), severe claudication in 16 patient (61.5%), and paresthesia and rest pain in two patients (7.7%). Eighteen of 26 patients (69.2%) eventually needed intervention to reestablish flow to the occluded limb, including thrombolysis and stenting in two patients (7.7%), axillary femoral bypass in one patient (3.8%), femoral-femoral bypass in 13 patients (50.0%), and axillary-bifemoral bypass in two patients (7.7%). All patients with mild to moderate symptoms under observation had improvement in symptoms with no further interventions necessary. All revascularizations were successful in relieving symptoms. Conclusion: Graft limb occlusion is a recognized complication of endovascular treatment of abdominal aortic aneurysms that may be associated with smaller graft limb diameter and extension to the external iliac artery. Occlusions usually necessitate additional intervention for resolution of ischemic symptoms. The use of small diameter grafts should be avoided when possible to reduce the risk of graft limb occlusions. (J Vasc Surg 2002;36:679-84.

Assessing abstract thought and its relation to language with a new nonverbal paradigm: Evidence from aphasia

In recent years, language has been shown to play a number of important cognitive roles over and above the communication of thoughts. One hypothesis gaining support is that language facilitates thought about abstract categories, such as democracy or prediction. To test this proposal, a novel set of semantic memory task trials, designed for assessing abstract thought non-linguistically, were normed for levels of abstractness. The trials were rated as more or less abstract to the degree that answering them required the participant to abstract away from both perceptual features and common setting associations corresponding to the target image. The normed materials were then used with a population of people with aphasia to assess the relationship of abstract thought to language. While the language-impaired group with aphasia showed lower overall accuracy and longer response times than controls in general, of special note is that their response times were significantly longer as a function of a trial’s degree of abstractness. Further, the aphasia group’s response times in reporting their degree of confidence (a separate, metacognitive measure) were negatively correlated with their language production abilities, with lower language scores predicting longer metacognitive response times. These results provide some support for the hypothesis that language is an important aid to abstract thought and to metacognition about abstract thought