Biomedical subjects

Peter J Pappas

Publications and source records attributed to Peter J Pappas.

At least 19 recordsLinked to original sources

PubMed2006

Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo.

Nitric oxide (NO) is an important regulator of blood flow, but its role in permeability is still challenged. We tested in vivo the hypotheses that: (a) endothelial nitric oxide synthase (eNOS) is not essential for regulation of baseline permeability; (b) eNOS is essential for hyperpermeability responses in inflammation; and (c) molecular inhibition of eNOS with caveolin-1 scaffolding domain (AP-Cav) reduces eNOS-regulated hyperpermeability. We used eNOS-deficient (eNOS-/-) mice and their wild-type control as experimental animals, platelet-activating factor (PAF) at 10(-7) m as the test pro-inflammatory agent, and integrated optical intensity (IOI) as an index of microvascular permeability. PAF increased permeability in wild-type cremaster muscle from a baseline of 2.4 +/- 2.2 to a peak net value of 84.4 +/- 2.7 units, while the corresponding values in cremaster muscle of eNOS-/- mice were 1.0 +/- 0.3 and 15.6 +/- 7.7 units (P < 0.05). Similarly, PAF increased IOI in the mesentery of wild-type mice but much less in the mesentery of eNOS-/- mice. PAF increased IOI to comparable values in the mesenteries of wild-type mice and those lacking the gene for inducible NOS (iNOS). Administration of AP-Cav blocked the microvascular hyperpermeability responses to 10(-7) m PAF. We conclude that: (1) baseline permeability does not depend on eNOS; (2) eNOS and NO are integral elements of the signalling pathway for the hyperpermeability response to PAF; (3) iNOS does not affect either baseline permeability or hyperpermeability responses to PAF; and (4) caveolin-1 inhibits eNOS regulation of microvascular permeability in vivo. Our results establish eNOS as an important regulator of microvascular permeability in inflammation.

Animals↗

PubMed2006

Noninvasive identification of the unstable carotid plaque.

Intraplaque hemorrhage, enlarging lipid cores, and their proximity to the flow lumen are important determinants of carotid plaque rupture and neurological complications. We developed an image-analysis method for B-mode ultrasound, pixel distribution analysis (PDA), for preprocedural identification of these high-risk features in carotid plaques. This technique may improve selection of patients for carotid endarterectomy and carotid artery stenting. Forty-two patients with high-grade carotid stenosis in 45 arteries, 18 symptomatic and 27 asymptomatic, underwent preoperative ultrasound. Intraplaque hemorrhage, lipid, fibromuscular tissue, calcium, lipid core area, and distance from the flow lumen were quantified using pixel intensities of tissues in control subjects. These findings were contrasted between symptomatic and asymptomatic plaques and correlated with histology. Inter- and intraobserver variabilities were determined for this technique. Pixel intensities of control tissues were discrete and significantly different from each other (median: blood 0, lipid 27, muscle 45.5, fibrous tissue 204, and calcium 245). There was more intraplaque hemorrhage (p<0.001) and lipid (p=0.002) but less calcium (p<0.001) within symptomatic plaques. Lipid cores were larger (p=0.005) and their distance from the flow lumen was lower (p=0.01) in symptomatic plaques. Intraplaque hemorrhage, lipid, fibromuscular tissue, calcium, lipid core size, and distance from flow lumen measured by PDA correlated with histology. No significant inter- or intraobserver variabilities were observed in these measurements. PDA accurately identified more intraplaque hemorrhage and lipid, less calcium, and larger lipid cores located closer to the flow lumen in symptomatic patients with carotid stenosis. These data indicate that PDA may be used to identify high-risk carotid atherosclerotic plaques and thereby improve the selection of patients requiring treatment.

Aged↗

PubMed2006

Current management of venous ulceration.

It has been estimated that chronic venous insufficiency affects 10 to 35 percent of the entire U.S. population and that 4 percent of people older than 65 have active venous ulcers. The high prevalence of the disease results in an annual expenditure of more than 1 billion dollars a year to the U.S. health care system. To have a rational approach toward patients with venous ulcers, it is important to understand the pathophysiology and clinical characteristics of the disease process, in order to initiate appropriate treatment and prevent venous ulcer recurrence.

Adult↗

PubMed2005

Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction.

Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM d-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM d-glucose (control) exhibited log-phase growth on days 7-10. d-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM d-glucose. d-Glucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM d-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM d-glucose. We conclude that d-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.

Cell Division↗

PubMed2005

When is a more proximal amputation needed?

Amputation may be the most appropriate therapy for an ischemic or infected limb, but the level at which to amputate is often difficult to determine. Selecting the appropriate level is crucial when performing an amputation. The goals of surgery are to maintain maximal limb length and ensure successful healing. When more of the foot and limb can be preserved, the chances for rehabilitation are improved. This article reviews how to determine the most appropriate level of amputation.

Amputation, Surgical↗

PubMed2005

Causes of severe chronic venous insufficiency.

A large number of adults in this country have some form of chronic venous insufficiency and a significant percentage of these have venous ulcers. The past decade has refined understanding of leukocyte-mediated injury and has elucidated the role of inflammatory processes in the dermal pathology of chronic venous insufficiency. Understanding of these pathologic cellular functions and molecular regulation of these processes is increasing.

Chronic Disease↗

PubMed2004

Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation.

Vascular endothelial growth factor (VEGF) induces mild vasodilation and strong increases in microvascular permeability. Using intravital microscopy and digital integrated optical intensity image analysis, we tested, in the hamster cheek pouch microcirculation, the hypothesis that differential signaling pathways in arterioles and venules represent an in vivo regulatory mechanism in the control of vascular diameter and permeability. The experimental design involved blocking specific signaling molecules and simultaneously assessing VEGF-induced changes in arteriolar diameter and microvascular transport of FITC-Dextran 150. Inhibition of Akt [indirectly via phosphatidylinositol 3-kinase with LY-294002 or wortmannin] or PKC (with bisindolylmaleimide) reduced VEGF-induced hyperpermeability. However, phosphatidylinositol 3-kinase/Akt inhibition enhanced the early phase and attenuated the late phase of VEGF-induced vasodilation, whereas blocking PKC had no effect. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 (with PD-98059 or AG-126) also reduced VEGF-induced hyperpermeability but did not block VEGF-induced vasodilation. Blockade of endothelial nitric oxide synthase (with N(omega)-monomethyl-l-arginine) inhibited VEGF-induced changes in both permeability and diameter. Furthermore, immunofluorescence studies with human umbilical vein endothelial cells revealed that bisindolylmaleimide, PD-98059, and l-NMMA attenuate VEGF-induced reorganization of vascular endothelial cadherin. Our data demonstrate that 1) endothelial nitric oxide synthase is a common convergence pathway for VEGF-induced changes in arteriolar diameter and microvascular permeability; 2) PKC and ERK-1/2 do not play a major role in VEGF-induced vasodilation in the hamster cheek pouch microcirculation; and 3) Akt, PKC, and ERK-1/2 are elements of the signaling cascade that regulates VEGF-stimulated microvascular hyperpermeability. Our data provide evidence for differential signaling as a regulatory step in VEGF-stimulated microvascular dynamics.

Animals↗

PubMed2004

Observer variability of iliac artery measurements in endovascular repair of abdominal aortic aneurysms.

Accurate measurement of iliac arteries is essential for successful delivery of aortic endografts without iliac limb endoleak. Although intravascular ultrasound measurements may be reliable, they require an invasive procedure. Therefore, helical computed tomography (hCT) has become the most commonly used modality for obtaining preprocedure arterial diameter measurements. The accuracy of hCT remains ill-defined, however, because an anatomic gold standard with which to compare the measurements is not available. We therefore assessed inter- and intraobserver variability of hCT measurements. We also applied accepted cutoff measurements to determine the clinical impact of observer variability in predicting the need for adjunctive iliac access and iliac limb seal procedures. hCT scans were analyzed in 30 patients who had undergone successful placement of a bifurcated endograft (26 Ancure, 4 Aneurex). Mean age of patients was 75 years, the male/female ratio was 27:3. Three blinded observers measured transverse diameters (maximal aortic aneurysm [Amax], narrowest infrarenal aortic neck [Amin], maximal common iliac [Imax], and narrowest iliac artery [Imin]). Inter- and intraobserver variability was calculated as standard deviation of mean pair differences according to the method of Bland and Altman. The true incidence of adjunctive procedures to facilitate delivery of the device into the aorta and ensure iliac limb seal was compared with that predicted by the observers to obtain sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for the measurements. Interobserver variability of iliac measurements was higher than intraobserver variability (p < 0.05). Interobserver variability of Amax ranged from 4.37 to 10.73% of the mean Amax. Conversely, variability of Amin was 8.91-18.89%, that of Imax was 12.11-22.23%, and that of Imin was 10.51-18.73% (p < 0.05 vs. Amax). Therefore, interobserver variability influenced aortic neck and iliac diameter twice as much as it did aneurysm measurements. To successfully place 30 endografts we performed 8 adjunctive access procedures (4 angioplasties, 4 common iliac artery conduits) and 17 adjunctive procedures in 60 limbs to ensure limb seal (9 unilateral IIA coil embolizations, 8 stents). We used 8.5 (Ancure) and 8.0 (Aneurex) mm as lower limits of acceptability for uncomplicated access, and 13.4 (Ancure) and 16 (Aneurex) mm as the upper limits of acceptability for uncomplicated iliac limb seal. These limits were applied to measurements from the three observers to predict need for adjunctive access or iliac seal procedures in this cohort. Sensitivity, specificity, PPV, and NPV of these observer measurements for a need to perform additional access procedures were 0.67, 0.80, 0.55, and 0.87; the same values for a need to perform additional seal procedures were 0.71, 0.74, 0.52, and 0.86, respectively. Interobserver variability was approximately 20% of measured iliac diameter. This explains why helical CT measurements were noted to have low PPV in predicting the need for an adjunctive access or limb seal procedure. These data establish PPV and NPV for hCT and provide objective evidence for the need to improve iliac artery imaging. Until more accurate imaging becomes available, we recommend oversizing of iliac limbs by 10-20% in patients with wide landing zones and that surgeons be prepared to resolve unexpected iliac artery access or seal problems intraoperatively.

Aortic Aneurysm, Abdominal↗

PubMed2004

Inferior vena cava filters prevent pulmonary emboli in patients with metastatic pathologic fractures of the lower extremity.

The records of 47 consecutive patients with metastatic pathologic fractures of the lower extremity were analyzed with respect to thromboembolic complications. All patients were unable to receive pharmacologic deep venous thrombosis prophylaxis, and were stratified into two groups, based on use of an inferior vena cava filter. Group I (n = 24) consisted of patients who had an inferior vena cava filter plus mechanical deep venous thrombosis prophylaxis (compression stockings and sequential compression boots); Group II (n = 23) consisted of a group of patients receiving only mechanical deep venous thrombosis prophylaxis. All patients had routine lower extremity venous duplex imaging preoperatively, postoperatively, and before hospital discharge. At final followup, patients were examined for deep venous thrombosis and reviewed for thromboembolic events. At a mean followup of 11.5 months, Group I had two detectable deep venous thromboses and no pulmonary emboli; Group II had one detectable deep venous thrombosis and five pulmonary embolisms. In Group II, 40% (two of five) of pulmonary embolisms were fatal, yielding an 8.7% (two of 23) group mortality rate. Overall, the entire group had an approximately 17% deep venous thrombosis rate. Only 6.4% (three of 47) of deep venous thromboses were detectable by standard duplex imaging. The majority of deep venous thromboses (five of eight, 62.5%) were nondetectable by duplex imaging. Overall, a 4.3% (two of 47) death rate was attributable to pulmonary embolism. In contrast, an 8.6% (four of 47) mortality rate occurred in Group II alone. All pulmonary embolisms occurred in patients who did not receive an inferior vena cava filter. The majority of venous thromboses (62.5%) were not detectable on duplex scanning, therefore were thought to arise from the pelvic venous system. Complications related to inferior vena cava filter insertion were minimal. For patients with metastatic pathologic fractures of the lower extremities who are unable to receive pharmacologic deep venous thrombosis prophylaxis, the use of inferior vena cava filters, in conjunction with standard mechanical deep venous thrombosis prophylaxis, is a procedure that has a low risk and is useful adjunct to prevent fatal pulmonary embolisms.

Aged↗

PubMed2003

Methicillin-resistant Staphylococcus aureus infection does not adversely affect clinical outcome of lower extremity amputations.

Methicillin-resistant Staphylococcus aureus was first identified in isolation in Europe during the 1960's. Now widespread throughout the world, infection with this organism has emerged as a major problem in surgical practice. However, it remains debatable whether MRSA is more virulent than methicillin-susceptible strains. We have reviewed our most recent 4-year experience of lower extremity amputations to examine the influence of MRSA and non-MRSA infection on clinical outcome. During the past 4 years, 165 patients underwent lower extremity amputation for SVS/ISCVS category III acute limb ischemia and grades II and III chronic limb ischemia. Forty-five had documented MRSA infection, while 57 patients had documented infection with other flora. All patients were treated with appropriate sensitivity-specific antibiotics and aggressive wound care. No significant differences were noted in the level of primary amputation required by the two groups. Similarly, no significant differences were noted in either number of revisions or revision to higher-level amputation, time to heal, hospital length of stay, or 30-day morbidity and mortality rates. Our results demonstrate that MRSA infection does not adversely affect clinical outcome in patients undergoing lower extremity amputations. Appropriate treatment of infections with sensitivity-specific antibiotics, thorough wound debridement, and aggressive wound monitoring should be routine in all patients, regardless of bacterial flora.

Aged↗

PubMed2003

Durability and cumulative functional patency of transposed and nontransposed arteriovenous fistulas.

OBJECTIVES: Preoperative duplex scanning of arm and forearm veins has increased the creation of autogenous arteriovenous (AV) fistulas. However, the cumulative functional patency and durability of transposed AV fistulas (TAVF) compared with nontransposed AV fistulas (AVF) and prosthetic bridging grafts (AVG) remains ill-defined. METHODS: From January 1998 to December 2002, 245 dialysis access procedures were performed at University Hospital and the Veteran Affairs Medical Center in New Jersey. Follow-up data were available for 125 procedures (TAVF, n = 42; AVF, n = 30; AVG, n = 53) performed in 97 patients. All access procedures were planned on the basis of preoperative duplex scans of arm and forearm veins. Functional patency was defined as ability to cannulate and hemodialyze patients successfully. Primary and secondary cumulative functional patency of TAVFs, AVFs, and AVGs was determined with life table analysis, and differences were analyzed with the log-rank test. Differences in revision rates, including thrombolysis, thrombectomies, and operative revisions, were determined with the Fisher exact t test. RESULTS: Mean follow-up was 18 months (range, 4-24 months). For TAVFs, AVFs, and AVGs, primary functional patency rate at 1 year was 76.2%, 53.3%, and 47.2%, respectively, and at 2 years was 67.7%, 34.4%, and 25.5%, respectively. Similarly, secondary functional patency rate at 1 year was 83.2%, 66.7%, and 58.5%, respectively, and at 2 years was 74.6%, 56.2%, and 40.2%, respectively. Primary and secondary functional patency rates for TAVFs were superior to those for AVGs at 1 and 2 years (P <.001). AVFs had superior secondary functional patency rate at 2 years, compared with AVGs (P <.05), and TAVFs had superior primary and secondary patency rates at 2 years, compared with AVFs (P <.05). AVGs required significantly more revisions than did TAVFs (28.5% vs 54.7%; P <.001) or AVFs (36.7% vs 54.7%; P <.05). CONCLUSIONS: Preoperative duplex scanning of upper arm and forearm veins facilitated successful creation of all types of autogenous fistulas at our institution. TAVF cumulative functional patency rates were superior compared with AVGs and AVFs. Furthermore, TAVFs and AVFs were more durable and required fewer revisions than did AVGs. When preoperative duplex criteria indicate that TAVFs can be performed, they should be the initial access of choice, because of their superior long-term patency and durability.

Adult↗

PubMed2003

In-stent recurrent stenosis after carotid artery stenting: life table analysis and clinical relevance.

OBJECTIVES: Carotid artery stenting has been proposed as an alternative to carotid endarterectomy in cerebral revascularization. Although early results from several centers have been encouraging, concerns remain regarding long-term durability of carotid artery stenting. We report the incidence, characteristics, and management of in-stent recurrent stenosis after long-term follow-up of carotid artery stenting. METHODS: Carotid artery stenting (n = 122) was performed in 118 patients between September 1996 and March 2003. Indications included recurrent stenosis after previous carotid endarterectomy (66%), primary lesions in patients at high-risk (29%), and previous ipsilateral cervical radiation therapy (5%). Fifty-five percent of patients had asymptomatic stenosis; 45% had symptomatic lesions. Each patient was followed up with serial duplex ultrasound scanning. Selective angiography and repeat intervention were performed when duplex ultrasound scans demonstrated 80% or greater in-stent recurrent stenosis. Data were prospectively recorded, and were statistically analyzed with the Kaplan-Meier method and log-rank test. RESULTS: Carotid artery stenting was performed successfully in all cases, with the WallStent or Acculink carotid stent. Thirty-day stroke and death rate was 3.3%, attributable to retinal infarction (n = 1), hemispheric stroke (n = 1), and death (n = 2). Over follow-up of 1 to 74 months (mean, 18.8 months), 22 patients had in-stent recurrent stenosis (40%-59%, n = 11; 60%-79%, n = 6; > or =80%, n = 5), which occurred within 18 months of carotid artery stenting in 13 patients (60%). None of the patients with in-stent recurrent stenosis exhibited neurologic symptoms. Life table analysis and Kaplan-Meier curves predicted cumulative in-stent recurrent stenosis 80% or greater in 6.4% of patients at 60 months. Three of five in-stent recurrent stenoses occurred within 15 months of carotid artery stenting, and one each occurred at 20 and 47 months, respectively. Repeat angioplasty was performed once in 3 patients and three times in 1 patient, and repeat stenting in 1 patient, without complications. One of these patients demonstrated asymptomatic internal carotid artery occlusion 1 year after repeat intervention. CONCLUSIONS: Carotid artery stenting can be performed with a low incidence of periprocedural complications. The cumulative incidence of clinically significant in-stent recurrent stenosis (> or =80%) over 5 years is low (6.4%). In-stent restenosis was not associated with neurologic symptoms in the 5 patients noted in this cohort. Most instances of in-stent recurrent stenosis occur early after carotid artery stenting, and can be managed successfully with endovascular techniques.

Aged↗

PubMed2003

Altered proliferative responses of dermal fibroblasts to TGF-beta1 may contribute to chronic venous stasis ulcer.

PURPOSE: Venous ulcer fibroblasts demonstrate decreased proliferative responses to growth factor stimulation, suggesting cellular senescence. However, the role of chronic venous insufficiency (CVI) disease progression and extracellular matrix (ECM) proteins in agonist-induced cellular proliferation is ill-defined. We hypothesize that CVI-induced fibroblast proliferative resistance to growth factors worsens with disease progression and is regulated by the composition of ECM. METHODS: Fibroblast explants were isolated from biopsy specimens from two patients without CVI and 16 patients with CVI of the lower calf (LC) and lower thigh (LT) and stratified according to CEAP disease severity: non-CVI (NC; n = 2), class 2-3 (n = 5), class 4 (n = 5), class 5 (n = 3), and class 6 (n = 3). Proliferation experiments were standardized with a neonatal foreskin fibroblast cell line (HS68). A 10-day course and dose response experiment with 0, 0.5, 1.0, 2.5, 5, 10, and 20 ng/mL of transforming growth factor-beta(1) (TGF-beta(1)) demonstrated maximal cell proliferation at 5 ng/mL of TGF-beta(1) on day 4. Under these conditions, CVI dermal fibroblasts were challenged with and without TGF-beta(1) and evaluated for proliferative responses on plates coated with polystyrene, collagen, and fibronectin. RESULTS: No differences in unstimulated proliferation were observed in LT and LC fibroblasts from patients with class 2-3 disease and LT fibroblasts from patients with class 4 and 5 disease, compared with NC and HS68 cells. LC fibroblasts from patients with class 4 disease (P <.05) and class 5 disease (P <.001), and LC (P <.001), and LT fibroblasts from patients with class 6 disease (P <.001) proliferated to a lesser degree than did NC and HS68 cells. The diminished proliferation observed in class 4 LC cells was reversible with TGF-beta(1) stimulation (P <.004); however, class 5 and class 6 LC and LT fibroblasts did not respond to stimulation with TGF-beta(1). Collagen increased proliferation of HS68 cells with (P <.05) and without (P <.01) TGF-beta(1), compared with cells grown on polystyrene, but did not increase proliferative responses in NC or CVI fibroblasts with and without TGF-beta(1). Similarly, fibronectin increased proliferation of HS68 cells (P <.05) compared with cells grown on polystyrene, but did not alter proliferation in CVI fibroblasts. Fibronectin did seem to inhibit TGF-beta(1)-induced proliferation observed in class 4 LC cells. CONCLUSION: These data indicate that clinical disease progression correlates with cellular dysfunction. Fibroblasts from patients with class 2-3 disease retain their unstimulated and agonist- induced proliferative capacity, compared with NC and HS68 cells. The onset of inflammatory skin changes (class 4 and class 5 disease) diminishes agonist-induced proliferation, and ulcer formation (class 6 disease) severely inhibits it. In addition, the composition of ECM does not affect TGF-beta(1)-induced proliferation of fibroblasts in CVI.

Cell Movement↗

PubMed2003

Carotid artery stenting: analysis of data for 105 patients at high risk.

OBJECTIVES: Carotid artery stenting (CAS) has been recommended as an alternative to carotid endarterectomy (CEA) by some clinicians. However, recently published clinical trials have reported 30-day stroke and death rates of 10% to 12%. This prompted review of our experience with CAS in patients at high risk, to document our results and guide further use of CAS. METHODS: From September 1996 to the present, we performed 114 consecutive CAS procedures in 105 patients. Sixty-three patients were men (60%) and 42 patients were women (40%), with mean age of 70 years (range, 45-93 years). Indications for CAS included recurrent stenosis after previous CEA in 74 patients (65%), primary lesions in 32 patients at high risk (28%), and carotid stenosis with previous ipsilateral radiation therapy in 8 patients (7%). Asymptomatic stenosis (>80%) was managed in 70 patients (61%), and symptomatic lesions (>50%) were treated in 44 patients (39%). RESULTS: CAS was technically successful in all patients. Mean severity of stenosis before CAS was 87% +/- 6%, compared with 9% +/- 4% after CAS. Two patients (1.9%) died, 1 of reperfusion-intracerebral hemorrhage and 1 of myocardial infarction 10 days after discharge; and 1 patient (0.95%) had a stroke (retinal infarction), for a 30-day stroke and death rate of 2.85%. Two patients (1.9%) had transient neurologic events. No cranial nerve deficits were noted. No neurologic complications have been noted in the last 27 patients (26%). CONCLUSIONS: A 30-day stroke and death rate of 2.85% in our experience demonstrates acceptability of CAS as an alternative to repeat operation or primary CEA in patients at high risk or in patients with radiation-induced stenosis. We recommend further clinical investigation of CAS and participation in clinical trials by vascular surgeons.

Aged↗

PubMed2003

Does severe venous insufficiency have a different etiology in the morbidly obese? Is it venous?

OBJECTIVE: Chronic venous insufficiency (CVI) is the most common cause of leg ulcers. Patients with morbid obesity are remarkable for particularly recalcitrant ulcers. Because obesity is not specifically incorporated in CEAP or other venous scoring systems, we sought to characterize this group of patients more completely. METHODS: Patients with severe CVI (CEAP clinical class, 4, 5, and 6), and class III obesity (body mass index [BMI], >40) were reviewed. Findings from clinical and duplex ultrasound scan (DU) examinations were compared with the CEAP classification, its adjunctive venous clinical severity score, and sensory thresholds. RESULTS: A review of clinic records identified 20 ambulatory patients with a mean age of 62 years, a mean BMI of 52, and a mean weight of 164 kg (361 lbs); all but one had bilateral symptoms. No evidence of venous insufficiency was detected with DU in 24 of the 39 limbs. Although some valvular incompetence was detected with DU in 15 of 39 limbs, these abnormalities were widely dispersed between 28 sites; eight limbs had findings at only one site. Ulceration (mean area, 29 cm(2)) was present in 25 limbs and necessitated 7 months for healing; 13 (52%) recurred at least once during a mean observation period of 36 months. The mean sensory threshold of 5.21 exceeded current risk thresholds used in diabetic screening programs. The distribution of CEAP clinical class was C4 (n = 14), C5 (n = 14), and C6 (n = 11). Increasing CEAP class correlated with an increased mean BMI of 47, 52, and 56, respectively (P <.01). CEAP also correlated with a rising mean venous clinical severity score of 10, 11, and 15, respectively (P <.05). CONCLUSION: Patients with class III obesity had severe limb symptoms, typical of CVI, but approximately two thirds of the limbs had no anatomic evidence of venous disease. The association of increasing limb symptoms with increasing obesity suggested that the obesity itself contributes to the morbidity.

Aged↗

PubMed2002

VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide.

We tested the hypothesis that VEGF regulates endothelial hyperpermeability to macromolecules by activating the ERK-1/2 MAPK pathway. We also tested whether PKC and nitric oxide (NO) mediate VEGF-induced increases in permeability via the ERK-1/2 pathway. FITC-Dextran 70 flux across human umbilical vein endothelial cell monolayers served as an index of permeability, whereas Western blots assessed the phosphorylation of ERK-1/2. VEGF-induced hyperpermeability was inhibited by antisense DNA oligonucleotides directed against ERK-1/2 and by blockade of MEK and Raf-1 activities (20 microM PD-98059 and 5 microM GW-5074). These blocking agents also reduced ERK-1/2 phosphorylation. The PKC inhibitor bisindolylmaleimide I (10 microM) blocked both VEGF-induced ERK-1/2 activation and hyperpermeability. The NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (200 microM) and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidiazoline-1-oxyl-3-oxide (100 microM) abolished VEGF-induced hyperpermeability but did not block ERK-1/2 phosphorylation. These observations demonstrate VEGF-induced hyperpermeability involves activation of PKC and NOS as well as Raf-1, MEK, and ERK-1/2. Furthermore, our data suggest that ERK-1/2 and NOS are elements of different signaling pathways in VEGF-induced hyperpermeability.

Capillary Permeability↗

PubMed2002

p42/44MAPK regulates baseline permeability and cGMP-induced hyperpermeability in endothelial cells.

We tested the hypothesis that p42/44MAPK and p38MAPK (mitogen-activated protein kinases; MAPK) signaling pathways regulate endothelial cell permeability to macromolecules. Passage 2-4 human umbilical vein endothelial cells (HUVEC) were grown to confluence on fibronectin-coated Snapwell membranes. The flux of fluorescein isothiocyanate-labeled dextran-70 across the HUVEC monolayers served to determine permeability. Application of 1 mM 8-bromo 3' 5'-cyclic guanosine monophosphate (8-Br-cGMP) increased permeability from 7.0 +/- 1.6 x 10(-6) to 12.5 +/- 2.8 x 10(-6) cm/s (P < 0.05). Pretreatment of HUVEC for 60 min with a selective p42/44MAPK inhibitor (AG126 at 2.7 and 27 microM) blocked 8-Br-cGMP-induced hyperpermeability. However, inhibition of p38MAPK (SB203580 at 0.6 microM) did not influence the cGMP-induced hyperpermeability response. AG126, administered at 27 microM, decreased baseline permeability from 7.9 +/- 0.5 x 10(-6) to 5.9 +/- 0.5 x 10(-6) cm/s (P < 0.05). Our results indicate that the p42/44MAPK signaling pathway is important in the regulation of baseline permeability and cGMP-induced hyperpermeability.

Cells, Cultured↗

PubMed2002

Carotid artery closure for endarterectomy does not influence results of angioplasty-stenting for restenosis.

OBJECTIVE: Carotid angioplasty and stenting (CAS) has been recommended by some authors for the management of postendarterectomy restenosis. However, some authors have expressed concern about the influence of primary closure and patch angioplasty performed during carotid endarterectomy (CEA) on the incidence rate of complications after CAS. METHODS: We analyzed our consecutive series of 54 CAS procedures performed for restenosis after prior CEA. These procedures accounted for 75% of the 72 CAS procedures performed at our institution for all indications during the last 4 years. Of these 54 patients, 28 (52%) were men and 26 (48%) were women, with a mean age of 69 years. The mean clinical follow-up period was 18 months (range, 1 to 48 months). The mean interval between prior CEA and CAS was 16 months (range, 6 to 62 months). Nineteen patients were symptomatic (35%), and 35 were asymptomatic (65%). The mean severity of restenosis was 84% +/- 7% (standard deviation). The mean residual stenosis after CAS was 8% +/- 3% (standard deviation). RESULTS: Among the 54 prior CEAs, eight cases were performed with primary closure (15%), five procedures used patch closure with autologous vein (9%), and 41 operations used Dacron patch closures (76%). All patients were managed successfully with CAS with predeployment angioplasty with low profile balloons, self-expanding stents, and poststent angioplasty to approximate the transverse diameter of the carotid artery. No instances of contrast extravasation, arterial disruption, or subintimal dissection were observed. One stroke (1.8%), a retinal infarction with partial field of vision loss, occurred in a patient with prior CEA and Dacron patch closure, and no deaths were observed in the series. CONCLUSION: Performance of CAS for restenosis after CEA with autologous or synthetic patch angioplasty was technically successful in all 54 procedures. The method of closure of the arteriotomy during CEA, primary closure or patch angioplasty, did not influence the incidence of complications.

Aged↗