Infected aortic endograft with an unusual microbe, Burkholderia cepacia.

With the growing use of endovascular aortic repair for aortic aneurysm pathology, multiple cases have been reported of associated endovascular graft infections. Explantation of the infected endograft and the revascularization procedure performed should be individualized with attention to the offending organism. We present the cases of two patients who underwent endovascular aortic repair with the same endograft and developed a graft infection with Burkholderia cepacia, a gram-negative organism with low virulence. Both endografts cultured Burkholderia cepacia complex; however, the organisms were genetically tested and found to be separate, unrelated strains. Both patients underwent successful explantation and revascularization procedures without any surgical-related complications to date.

Emotional Intelligence and Burnout Related to Resident-Assessed Faculty Teaching Scores.

OBJECTIVE: Emotional intelligence (EI) is associated with job success in multiple fields, in part, because EI may mitigate stress and burnout. Research suggests these relationships may include teaching. Our purpose is to further explore the relationships between EI, burnout, and teaching for faculty surgeons. DESIGN: With IRB approval, surgical faculty were offered the opportunity to complete personal demographics, the Maslach Burnout Inventory, the SETQ-SMART assessment of teaching ability, and the SEF:MED self-assessment of emotional intelligence. Surgical residents rated faculty teaching ability using the SETQ-SMART SETTING: A medium-sized academic medical center in the Southeast approved to graduate 6 residents per year. PARTICIPANTS: ACGME surgical faculty and general surgical residents PGY1 to PGY5 including preliminary residents, were given the opportunity to participate. RESULTS: Faculty self-assessed teaching scores were significantly different from resident scores for nine (60%) faculty; three (33%) overrated their and 6 (67%) under rated their overall teaching ability, relative to resident ratings. The 3 SEF:MED scales correlated low-moderate to strongly with the SETQ-OTS: IS (r = 0.41, p = 0.13), EM (r = 0.67, p < 0.01), and EA (r = 0.43, p = 0.11). Overall, 8(53%) faculty scored moderate to high on at least 1 of the 3 MBI subscales. Overall self-rated faculty teaching scores correlated negatively with higher EE and DP and positively with PA (r = -0.08, -0.21, and 0.52, p = 0.047; respectively). EI negatively correlated with MBI-EE and DP and positively with PA (r = -0.31, -0.18, 0.45, respectively), though due to the small sample none reach statistical significance with alpha set to 0.05. CONCLUSIONS: In this pilot study, EI is positively correlated to surgical faculty members' teaching ability. Burnout was less strongly correlated with resident-assessed faculty teaching scores, but with similar trends. Finally, EI was correlated with MBI EE, DP, and PA as expected given the literature in other fields. Expanded study is warranted.

Dietary supplementation with Zyflamend poly-herbal extracts and fish oil inhibits intimal hyperplasia development following vascular intervention.

The polyherbal blend Zyflamend™ has been shown to have anti-inflammatory properties and attenuate inflammatory-modulated pathologies. Fish oils have also been shown to have cardioprotective properties. However, the beneficial effects of their combination have not been investigated. Intimal hyperplasia (IH), a pathological remodeling response of a vessel to injury, is heavily regulated by an immune-mediated reaction. The objective of this study was to determine if dietary supplementation with Zyflamend and/or Wholemega could affect inflammatory-dependent vascular remodeling mechanisms when provided at human equivalent doses. Based on their anti-inflammatory properties and protective benefits demonstrated in previous pre-clinical studies, we hypothesized administration of these supplements would prevent IH in an animal model of vascular injury. The diets of aged male rats were supplemented with human equivalent doses of Zyflamend (Zyf) and/or Wholemega (WMega) or placebo (Plac) for 1wk prior to balloon angioplasty (BA)-induced injury of the left carotid artery. At 28d post-injury morphometric analysis of carotid tissue revealed IH was decreased in Zyf + WMega animals compared to placebo, while Zyf or WMega independently had no significant effect. Serum cytokine screening indicated injury-induced interleukin family isoforms, interferon-γ, and macrophage inflammatory proteins were downregulated by Zyf + WMega. Immunohistochemical staining for monocyte/macrophage phenotypic markers revealed that while overall monocyte/macrophage vessel infiltration was not affected, Zyf + WMega limited the alternative differentiation of M2 macrophages and reduced the presence of myofibroblasts in the injured vessel wall. In summary, dietary supplementation with Zyf + WMega attenuated the acute inflammatory response following vascular injury and inhibited IH development in vivo.

The Efficacy of Systemic Doxycycline Administration as an Inhibitor of Intimal Hyperplasia after Balloon Angioplasty Arterial Injury.

BACKGROUND: Intimal hyperplasia (IH) is the most common indicator for secondary intervention in peripheral vascular disease. Matrix metalloproteinases (MMPs) play a role in IH development due to their degradation of the extracellular matrix. Doxycycline (Doxy), a member of the tetracycline family of antibiotics, is a potent MMP inhibitor. We have previously shown that Doxy inhibits MMP activity and vascular smooth muscle cell migration in vitro. We hypothesized that Doxy would decrease MMP activity in vivo and inhibit the development of IH in a rodent model of vascular injury. METHODS AND RESULTS: Doxy (400 mg/pellet) was delivered by a slow-release pellet implanted 3 days prior to or at the time of balloon angioplasty (BA) of the common carotid artery in female rats. At 14 days post-BA, intima-to-media (I:M) ratios were 0.77 ± 0.21 and 1.04 ± 0.32 in the Doxy treated groups, respectively, compared to 1.25 ± 0.26 in the control group (P = not significant; n = 3). Additionally, the tested dose of Doxy in either group had no inhibitory effect on membrane type 1-MMP or MMP-2 tissue levels, as measured by immunohistochemistry, or on systemic levels of MMP, as measured by total MMP serum levels using enzyme-linked immunosorbent assay. At 14 days post-BA, VSMC proliferation in the injured artery was increased to Doxy treatment prior to and at the time of surgery (23.5 ± 3.4 and 27.2 ± 3.9%, respectively), compared to control (11.4 ± 0.4%; n = 3), as measured by proliferating cellular nuclear antigen immunostaining. CONCLUSIONS: In our in vivo model of vascular injury, systemic Doxy administration prior to or at the time of vascular injury does not significantly hinder the progression of IH development. Additional doses and routes of administration could be examined in order to correlate therapeutic serum levels of Doxy with effective MMP inhibition in serum and arterial tissue. However, alternative drug delivery systems are needed in order to optimize therapeutic administration of targeted MMP inhibitors for the prevention of IH development.

Systemic hypersensitivity reaction to endovascular stainless steel stent.

Endovascular intervention has become the mainstay for treatment of most patients suffering from peripheral vascular disease. We describe a patient with a known nickel allergy who underwent placement of a stainless steel stent for aortoiliac occlusive disease. Despite our attempt to avoid a nickel-containing stent, the patient developed a diffuse rash consistent with a nickel or metal allergy. A review of stainless steel metallurgy revealed that nickel, cobalt, and titanium are frequently used to provide anticorrosive properties to stainless steel. The clinical significance of the use of nickel-alloy stents in the setting of patients with a nickel allergy is discussed.

Effect of hormone replacement therapy in matrix metalloproteinase expression and intimal hyperplasia development after vascular injury.

BACKGROUND: Postmenopausal women taking hormone replacement therapy (HRT) require secondary intervention after vascular reconstruction more frequently than women not taking HRT, often due to increased development of intimal hyperplasia (IH). Matrix metalloproteinases (MMPs) play a role in IH by degradation and remodeling of components of the vascular basement membrane. The MMP pathway is regulated by a balance between MMPs, membrane-type MMPs (MT-MMPs), and tissue inhibitor of MMPs (TIMPs). We have recently provided evidence for unbalanced regulation of the MT1-MMP/MMP-2 pathway in vascular smooth muscle cells (VSMCs) exposed to hormones in vitro. Herein we study the role of HRT in the development of IH in a postmenopausal rodent model of vascular injury and in the modulation of this MMP regulatory pathway in vivo. METHODS: Female rats were aged to 12 months. Animals were ovariectomized (OVX) and 4 weeks later hormones or placebo was delivered via a 90-day slow-release pellet. After 6 weeks of HRT each rat underwent balloon angioplasty of the left common carotid artery. At 14 days postinjury tissue samples were collected and stained with trichrome elastin and for isoform-specific MMPs. RESULTS: After vascular injury, the intima:media (I:M) ratio was decreased in OVX rats receiving placebos as compared with non-OVX controls (P < 0.05). In OVX animals receiving HRT, estrogen with and without progesterone and progesterone alone slightly increased I:M ratio compared with placebo, although no significant difference was found in any HRT group. Injury-induced intimal expression of MMP-2 and -9 was decreased in OVX placebo animals compared with non-OVX controls (P < 0.05). MMP-2 and -9 levels were subsequently increased by each type of hormone therapy compared with placebo, with a significant increase in MMP-9 in response to estrogen with and without progesterone (P < 0.05). Conversely, TIMP-2 was decreased by estrogen compared with placebo (P < 0.05). There was no effect on intimal MT1-MMP in any group. CONCLUSIONS: In this study we detected a statistically significant decrease in IH as a result of OVX. Subsequent HRT exposure resulted in increased I:M ratios compared with OVX animals given placebo, although significance was not reached with the doses given. Long-term exogenous exposure may have a more deleterious effect compared with acute exposure and should be examined further. We also demonstrated a significant reduction in MMP-2 and -9 and TIMP-2 in response to OVX. Subsequent hormone exposure resulted in the upregulation of MMP-2 and -9 without a counterregulatory increase in TIMP, indicating that HRT modulates the MMP regulatory pathway in vivo. The data suggest that the lack of hormones after OVX protects against pathologic remodeling in our aged model of disease and that exposure to both natural and exogenous hormones could be a negative risk factor resulting in an exaggerated vascular response to injury. Future studies should focus on in vivo manipulation of unbalanced MMP regulation for prevention of IH in response to HRT and in general. Furthermore, the age-associated difference in response to the presence of natural hormones in young vs aged models should be investigated.

Contemporary outcomes of vertebral artery injury.

OBJECTIVE: Vertebral artery injury (VAI) associated with cervical trauma is being increasingly recognized with more aggressive screening. Disparate results from previous literature have led to uncertainty of the significance, natural history, and optimal therapy for VAI. METHODS: To understand the natural history and treatment outcomes from our experience, we performed a retrospective, single-center review from a level I trauma center for the previous 10 years of all VAI. Injuries were identified from search of an administrative trauma database, a resident-run working database, and all radiology dictations for the same period. All VAI were classified according to segmental involvement, Denver grading scale, and laterality. Analysis of associated injuries, demographics, neurologic outcome, mortality, length of stay, treatment plan, and follow-up imaging was also performed. RESULTS: Fifty-one patients with VAI were identified from 2001 to 2011 from a total of 36,942 trauma admissions (0.13% incidence). Associated injuries were significant with an average New Injury Severity Score of 29.6. Penetrating trauma occurred in 14%. Cervical spine fracture was present in 88% with VAI. Diagnosis was obtained with computed tomographic angiography (CTA) in 95%. Screening was prompted by injury pattern or high-risk mechanism in all cases. Injuries classified according to the Denver grading scale were grade I = 24%, grade II = 35%, grade III = 4%, grade IV = 35%, and grade V = 2%. Distribution across segments included V1 = 18%, V2 = 67%, V3 = 31%, and V4 = 6%. Only one posterior circulation stroke was attributable to VAI. Overall mortality was 8%, with each mortality being associated with significant other organ injuries. Treatment rendered for VAI was antiplatelet therapy (50%), observation (31%), warfarin (17%), and stent (2%). There were no significant differences between treatment groups on any variable with the exception of body mass index (P = .047). Follow-up was obtained for 13% (n = 6) of survivors. The CTA demonstrated injury stability in four patients and resolution in two patients. Accuracy of the administrative trauma database was 53% compared with 96% for the resident-run working database. CONCLUSIONS: Neurologic sequelae attributable to VAI were rare. Grade of VAI or vertebral artery segment did not correlate with morbidity. We did not observe any differences in short-term outcomes between systemic anticoagulation and antiplatelet therapy. Of those patients seen at follow-up, injury resolution or stability was documented by CTA. A conservative approach with either observation or antithrombotic therapy is suggested. If the natural history of VAI includes a very low stroke rate, then therapies with a lower therapeutic index, such as systemic anticoagulation, in the severely injured trauma patient are not supported. Our search strategy urges awareness of the limitations of administrative databases for retrospective vascular study.

Maximal venous outflow velocity: an index for iliac vein obstruction.

Leg swelling is a common cause for vascular surgical evaluation, and iliocaval obstruction due to May-Thurner syndrome (MTS) can be difficult to diagnose. Physical examination and planar radiographic imaging give anatomic information but may miss the fundamental pathophysiology of MTS. Similarly, duplex ultrasonographic examination of the legs gives little information about central impedance of venous return above the inguinal ligament. We have modified the technique of duplex ultrasonography to evaluate the flow characteristics of the leg after tourniquet-induced venous engorgement, with the objective of revealing iliocaval obstruction characteristic of MTS. Twelve patients with signs and symptoms of MTS were compared with healthy control subjects for duplex-derived maximal venous outflow velocity (MVOV) after tourniquet-induced venous engorgement of the leg. The data for healthy control subjects were obtained from a previous study of asymptomatic volunteers using the same MVOV maneuvers. The tourniquet-induced venous engorgement mimics that caused during vigorous exercise. A right-to-left ratio of MVOV was generated for patient comparisons. Patients with clinical evidence of MTS had a mean right-to-left MVOV ratio of 2.0, asymptomatic control subjects had a mean ratio of 1.3, and MTS patients who had undergone endovascular treatment had a poststent mean ratio of 1.2 (P = 0.011). Interestingly, computed tomography and magnetic resonance imaging results, when available, were interpreted as positive in only 53% of the patients with MTS according to both our MVOV criteria and confirmatory venography. After intervention, the right-to-left MVOV ratio in the MTS patients was found to be reduced similar to asymptomatic control subjects, indicating a relief of central venous obstruction by stenting the compressive MTS anatomy. Duplex-derived MVOV measurements are helpful for detection of iliocaval venous obstruction, such as MTS. Right-to-left MVOV ratios and postengorgement spectral analysis are helpful adjuncts to duplex imaging for leg swelling. The MVOV maneuvers are well tolerated by patients and yields physiological data regarding central venous obstruction that computed tomography and magnetic resonance imaging fail to detect.

Role of MT1-MMP in estrogen-mediated cellular processes of intimal hyperplasia.

BACKGROUND: Hormone replacement therapy increases intimal hyperplasia (IH) following vascular intervention. Matrix metalloproteinases (MMPs) play a role in IH development. We have shown estrogen up-regulates MT1-MMP expression, a transmembrane protein that activates MMP-2, and increases vascular smooth muscle cell (VSMC) collagen invasion via increased MMP-2 activity. Here we hypothesize inhibition of MT1-MMP will prevent hormonally-stimulated increased MMP-2 activation and the downstream cellular processes of IH pathogenesis. METHODS: VSMCs from a postmenopausal donor were transfected with MT1-MMP or negative control siRNAs, treated with estrogen (Est), analyzed by q-PCR, Western blot, zymography, migration, invasion, and proliferation assays. RESULTS: Est treatment of MT1-MMP silenced cells still resulted in increased MT1-MMP expression (C = 41% ± 4%; Est = 52% ± 2%; P < 0.05). Silencing of MT1-MMP decreased basal MMP-2 activity (nonsilenced = 100%; MT1-silenced = 87% ± 3%; P < 0.05) but had no effect on basal invasion or proliferation. Est treatment of MT1-MMP silenced cells still resulted in increased MMP-2 activity (C = 87% ± 3%; Est = 101% ± 4%; P < 0.05) and invasion (C = 89% ± 6%; Est = 109% ± 3%; P < 0.05) compared with MT1-MMP silenced control cells. However, silencing of MT1-MMP did inhibit Est- and serum-stimulated proliferation (C = 106% ± 18%; Est = 104% ± 16%; FBS = 121% ± 24%; P = NS). CONCLUSION: Silencing of MT1-MMP in aged VSMCs results in impaired but not complete inhibition of basal and Est-stimulated increases in MMP-2 activity. Other mechanisms appear to be playing a role in hormonally-regulated cellular processes of IH pathogenesis. Future studies will target other signaling cascades, with the goal of identifying mechanisms responsible for hormonally-modulated unbalanced MMPs. In vivo manipulation of the expression patterns of MT1-MMP will be examined for the prevention of IH in animal models of vascular disease.

Serum levels of matrix metalloproteinase-2 as a marker of intimal hyperplasia.

BACKGROUND: A primary component in the development of intimal hyperplasia (IH) in response to vascular injury is basement membrane remodeling. Matrix metalloproteinases (MMPs) play a major role in this process by degradation of basement membrane proteins, mainly collagen type IV. Vascular injury initiates an inflammatory cascade with the release of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and C-reactive protein (CRP). We hypothesize serum levels of these elements may serve as biomarkers of the development of IH. METHODS AND RESULTS: At baseline, 2, 7, 10, and 14 days post-balloon angioplasty of the carotid artery, rat tissue samples were stained with Masson trichrome elastin to examine IH. Intima:media ratios (I:M) increased significantly over time postinjury. Serum samples were collected at the time of tissue sampling, and levels of MMP-2, MMP-9, collagen type IV, TNFalpha, IL-1beta, and CRP were assayed using sandwich enzyme-linked immunosorbent assay (ELISA). MMP-2 serum levels at 7, 10, and 14 days postinjury were significantly elevated compared with baseline. Other elements were not significantly elevated. CONCLUSION: Early and persistent elevation in the serum levels of MMP-2 may be a useful biomarker of basement membrane remodeling and the presence of IH.

Development and validation of the Rapid Estimate of Adult Literacy in Vascular Surgery (REAL_VS).

The purposes of this study were to develop and validate the (1) Rapid Estimate of Adult Literacy in Vascular Surgery (REAL_VS) for researchers studying the impact of literacy skills as related to vascular surgery-related knowledge and outcomes and (2) short version of the REAL_VS (REAL_VSs) to allow clinicians to gauge their patients' familiarity with vascular surgery-related terms. A three-phase process was used to identify potential words for inclusion in the REAL_VS, including reviewing Internet-based patient education material content and listening to a random sample of 50 archived audiorecordings of vascular surgeon-patient encounters. The REAL_VS was composed of 75 terms (e.g., stent, gangrene, invasive, aneurysm) of varying pronunciation difficulty. One hundred fifty-two English-speaking patients (>or=18 years of age) attending a university-based vascular surgery clinic were recruited to participate in this study (mean age = 61.4 +/- 14.6 years). During face-to-face interviews, patients' sociodemographic information was collected, and patients were administered the widely used Rapid Estimate of Adult Literacy in Medicine (REALM) and REAL_VS. Mean scores on the REALM (56.9 +/- 14.0) and REAL_VS (63.3 +/- 15.6) were highly correlated (Spearmans rank correlation [rho] = 0.91; p < 0.00). Internal consistency of the REAL_VS (Cronbachs alpha = 0.98) was excellent. Mean scores on the REAL_VSs (4.1 +/- 2.7) were highly correlated with both the REALM (rho = 0.82; p < 0.00) and REAL_VS (rho = 0.94; p < 0.00). Internal consistency, measured using Cronbachs alpha, of the REAL_VSs was 0.86. This study demonstrates that both the REAL_VS and REAL_VSs are both promising tools for use in vascular surgery research and clinical practice, respectively.

Regulation of vascular smooth muscle cell expression and function of matrix metalloproteinases is mediated by estrogen and progesterone exposure.

OBJECTIVE: Postmenopausal women receiving hormone replacement therapy (HRT) have been reported to have more adverse outcomes after vascular reconstructions, including increased intimal hyperplasia development and bypass graft failure. HRT may be affecting the pathway contributing to intimal hyperplasia. An important component of this pathway involves matrix metalloproteinases (MMPs), implicated in vascular remodeling due to their ability to degrade components of the extracellular matrix. We hypothesize that estrogen (Est) and progesterone (Prog) upregulate the MMP pathway in vascular smooth muscle cells (VSMCs) thereby increasing MMP activity and function. METHODS AND RESULTS: VSMCs were incubated with Est (5 ng/mL), Prog (50 ng/mL), Est + Prog combination (Est/Prog), and/or doxycycline (40 microg/mL; Doxy). Using reverse transcriptase polymerase chain reaction (RT-PCR) analysis we have previously shown membrane type 1-MMP (MT1-MMP) messenger ribonucleic acid (mRNA) levels are significantly increased by Est. Here, Western blot analyses indicated MT1-MMP and MMP-2 protein levels, not tissue inhibitor of MMP-2 (TIMP-2), were increased in response to Est and Est/Prog (P < .05 vs control). In-gel zymography revealed that Est and Est/Prog resulted in increased MMP-2 activity (hormone groups, P < .05 vs control) with no significant difference among the hormone groups. VSMC migration was increased by 45 +/- 14% in response to Est (P < .05 vs control), as measured using a modified Boyden chamber assay. Doxycycline significantly inhibited basal and Est/Prog-stimulated increases in MMP-2 activity (P < .05 vs control; P < .05 vs hormone groups), and partially blocked basal and hormonally stimulated migration (P < .05 vs control and Est). CONCLUSION: Estrogen and progesterone affects the MMP pathway by increasing MMP-2 enzymatic activity, possibly via the upregulation of MT1-MMP expression without a corresponding increase in TIMP expression. This increased collagenase activity increases VSMC motility and their ability to migrate through a collagen type IV lattice. Est/Prog upregulation of MT1-MMP may contribute to the adverse effect of HRT on vascular interventions.

Effect of hormones on matrix metalloproteinases gene regulation in human aortic smooth muscle cells.

BACKGROUND: Postmenopausal women receiving hormone replacement therapy have more adverse outcomes after vascular reconstructions. Estrogen-binding receptors have been identified on vascular smooth muscle cells (VSMCs), indicating that vascular function may be under direct hormonal control. A key group of enzymes involved in vascular remodeling are matrix metalloproteinases (MMPs). Here we studied the effect of estrogen (Est) and progesterone (Prog) on MMP gene expression in human VSMCs. METHODS AND RESULTS: VSMCs were incubated with Est (5 ng/mL), Prog (50 ng/mL), Est+Prog combination (Est/Prog), and interleukin-1beta (100 U/mL; IL-1beta). Gene array analysis indicated Est+IL-1beta increased the expression of MMP-3. Reverse transcriptase-polymer chain reaction (RT-PCR) analyses revealed MMP-3 mRNA levels were significantly increased by Est/Prog+IL-1beta treatment. However, Western blot and further RT-PCR analyses indicated no change in MMP-3 in response to hormones alone. RT-PCR analyses revealed membrane type 1 (MT1)-MMP mRNA levels, not MMP-2 or tissue inhibitor of MMP (TIMP), were significantly increased by Est/Prog+IL-1beta, and Western blot analyses confirmed a significant increase in MT1-MMP protein in response to Est alone. CONCLUSION: Estrogen and progesterone affect the MMP pathway of VSMCs via isoform specific mechanisms and may lead to unbalanced MMP regulation. Estrogen up-regulates MT1-MMP without a corresponding increase in TIMP-2, known activator and inhibitor of MMP-2, respectively. Additionally, estrogen up-regulates MMP-3 only in the presence of IL-1beta. This differential regulation, combined with case-specific variations in degree of inflammatory response, may explain why some women receiving exogenous hormone therapy at the time of vascular interventions are more susceptible to complications.

Can screening items identify surgery patients at risk of limited health literacy?

BACKGROUND: Health literacy skills (HLS) have been shown to have a major impact on patient outcomes. To identify patients with limited or marginal HLS, the accuracy of three established screening items were examined. MATERIALS AND METHODS: We studied English-speaking adults (>or=21 years) attending a university-based vascular surgery clinic. Structured interviews were conducted to assess sociodemographic characteristics, screening items, and HLS. Area under the receiver operating characteristic (AUROC) curves were plotted to assess the discriminatory capacity of each screening item in detecting patients with limited/marginal HLS. RESULTS: One hundred patients agreed to enter the study and met inclusion criteria. The mean age was 62.0 +/- 12.9; 65 were female; 96 were Caucasian; and 32 had not completed high school. The three screening items were effective in detecting patients with limited (n=18) or marginal (n=21) HLS. "How often do you have someone (like a family member, friend, or hospital worker) help you read hospital materials?" (AUROC of 0.83; 95% confidence interval [CI]=0.73, 0.92), "How often do you have problems learning about your medical condition because of difficulty understanding written information?" (AUROC of 0.77; 95% CI=0.67, 0.86), and "How confident are you filling out medical forms by yourself?" (AUROC of 0.76; 95% CI=0.66, 0.86) were effective in detecting those with limited/marginal HLS skills. CONCLUSIONS: Our findings provide further evidence of the clinical usefulness of these screening items for detecting inadequate HLS in this patient population. Surgeons should consider administering these easy screening items to identify patients at greatest risk of limited or marginal HLS.

The importance of thrombophilia in the treatment of Paget-Schroetter syndrome.

Venous thoracic outlet syndrome (V-TOS) and associated subclavian vein thrombosis (SVT) result in significant patient morbidity and can be difficult to manage. Previous studies have suggested that both mechanical compressive factors and pathological alterations in patient coagulation may contribute to the development of SVT; however, no study has specifically evaluated the role of thrombophilia in the treatment of V-TOS and the need for long-term anticoagulation as an adjunct to surgical decompression. This retrospective study describes the clinical courses of 18 patients treated for V-TOS with and without acute SVT. In this review, 67% of patients with SVT are found to have relatively common coagulation disorders and 90% of postoperative complications were associated with some form of thrombophilia. This study suggests that thrombophilia may play an important role in the pathogenesis of V-TOS and may be a determinant of the success of surgical decompression. Clotting disorders should therefore be aggressively evaluated in this patient population and can improve therapeutic outcome.

Nitric oxide mediates the effect of fluvastatin on intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression on human endothelial cells.

Leukocyte and platelet adhesion to endothelial cells, an early step in the pathogenesis of atherosclerosis, is mediated through adhesion molecules. It has been shown that statins decrease adhesion molecule expression. We examined the hypothesis that fluvastatin decreased intercellular adhesion molecule-1 (ICAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression through a nitric oxide-mediated pathway. Human iliac artery endothelial cells were exposed to fluvastatin in the presence or absence of 2 mM N-monomethyl-L-arginine (L-NMMA). Flow cytometry analysis was used to measure ICAM-1 and PECAM-1 expression. In a separate experiment, confluent cell cultures were exposed in a serum-free medium to fluvastatin 20 microM, and the supernatant was collected for nitrate/nitrite determination after 6 and 48 hr of incubation. Protein was isolated and processed for immunoblotting with monoclonal antibodies specific for endothelial nitric oxide synthase (eNOS), Ser(1177)-phosphorylated eNOS, and AMP kinase. Relative band intensity was assessed with densitometry. Results are presented as the mean +/- standard deviation (SD), and p < 0.05 was considered significant. ICAM-1 and PECAM-1 were expressed constitutively. Human iliac artery endothelial cells (HIAECS) treated with 5 microM fluvastatin did not exhibit reduced expression of PECAM-1 or ICAM-1. Incubation with 10 microM fluvastatin reduced basal expression of both ICAM-1 and PECAM-1. Fluorescence intensity (FI) for these substance was as follows: 3638 +/- 1671, p = 0.01 and PECAM-1 vs. control FI 276 +/- 52 vs. 522 +/- 78, p = 0.02. In the presence of 2 mM L-NMMA, fluvastatin failed to decrease the expression of ICAM-1 (fluvastatin 10 microM + L-NMMA: FI was 3042 +/- 1378 vs. 3638 +/- 1671 for the control p = 0.01) or PECAM-1 (fluvastatin 10 microM + L-NMMA: FI was 415 +/- 188 vs. 522 +/- 78 for the control, p = 0.1). Incubation with 20 microM fluvastatin similarly reduced ICAM-1 expression (FI was 2014 +/- 1595 vs. 3638 +/- 1671 for the control, p = 0.02) and PECAM-1 expression (FI was 196 +/- 109 vs. 522 +/- 78 for the control, p = 0.02). This reduction was prevented in the presence of 2 mM L-NMMA. L-NMMA in a concentration of 2 mM had no significant effect on adhesion molecule expression (p > 0.05 for all comparisons of the control FI versus 2 mM L-NMMA mean FI). After a 48 hr incubation with 20 microM fluvastatin there was a 219 +/- 35% increase in the cell eNOS protein content (p = 0.01) and a 170 +/- 26% increase in the cell AMPK protein content (p = 0.02). Ser(1177)-phosphorylated eNOS protein levels were increased by 41 +/- 8% (p = 0.03). The nitric oxide concentration in the medium of the HIAEC treated with 20 microM fluvastatin for 48 hr was significantly higher than that in the control (p = 0.0004), pointing to increased production during the incubation period. Fluvastatin thus decreases basal expression of ICAM-1 and PECAM-1. Competitive inhibition of eNOS with L-NMMA abolishes the effect of fluvastatin on ICAM-1 and PECAM-1 expression. The statin up-regulates eNOS and AMP kinase, one of the enzymes that activates eNOS via phosphorylation at Ser(1177). We have shown that after a 48-hr exposure to fluvastatin there is an increased amount of the phosphorylated enzyme in the endothelial cells.

Endovascular exclusion of saphenous vein graft aneurysms complicating abdominal aortic aneurysm repair--a case report.

A 64-year-old man was referred for vascular evaluation before renal transplantation for ischemic nephropathy. In the past he had undergone bilateral renal artery revascularizations using saphenous vein. At the time of transplant evaluation, he was found to have bilateral aneurysms of the saphenous veins used to bypass his renal artery stenoses. He underwent successful endovascular exclusion of the aneurysms with 2 endovascular AneuRx extension cuffs. This case highlights both the versatility of endovascular treatments as well as the importance of a comprehensive vascular examination.

Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.

Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.

Open versus endo: early experience with endovascular abdominal aortic aneurysm repair beyond the clinical trials.

OBJECTIVE: To analyze and compare open (OR) versus endovascular (EVAR) abdominal aortic aneurysm repair at our institution. METHODS: EVAR was attempted in 256 patients at the University of Tennessee Medical Center, Knoxville, between December 1999 and November 2002. One hundred forty patients underwent attempted EVAR, and 116 underwent OR. All patients were included on an intent-to-treat basis, and results were reviewed retrospectively. Statistical methods included the Student t test and chi-square analysis. RESULTS: Patients were age matched between the 2 groups (70.2 years versus 69.0 years; P = .936). Patients in the OR group had significantly higher American Society of Anesthesiologists classes than the EVAR group (2.96 versus 3.07; P = .006). However, there was no difference between the groups, OR versus EVAR, with respect to the presence of chronic obstructive pulmonary disease (55% versus 46%; P = .129), coronary artery disease (69% versus 66%; P = .638), diabetes mellitus (12% versus 18%; P = .167), mean left ventricular ejection fraction (51.8% versus 53.9%; P = .28), or mean preoperative creatinine level (1.2 mg/dL versus 1.1 mg/dL; P = .167). Tobacco use was more prevalent in the OR group (78.4% versus 64.2%; P = .013), and known carotid artery disease was more prevalent in the EVAR group (20.0% versus 6.9%; P = .003). The EVAR group had significantly shorter lengths of stay ( 4.2 versus 9.0 days; P = .000), intensive care unit days (0 versus 3.2; P = .000), time in the operating room (119.6 minutes versus 225.7 minutes; P = .000), and estimated blood loss (189.1 mL versus 897.9 mL; P = .000). Mean aneurysm size was larger in the OR group (5.6 cm versus 4.9 cm; P = .000). Perioperative complications occurred in 31 patients in the OR group and 5 in the EVAR group (P = .000). Two perioperative deaths occurred in the OR group and none in the EVAR group. As of this writing there has been no significant difference in all-cause mortality in the 2 groups (OR 9.6% versus EVAR 8.0%; P = .651). Seven patients in the EVAR group needed secondary interventions. Six were managed with endovascular techniques, and 1 underwent femoral-femoral bypass. CONCLUSIONS: Patients who undergo EVAR have significantly less morbidity and mortality in the perioperative period than do equally matched patients undergoing open repair. In midterm follow-up (2-5 years), mortality is no different. Morbidity conferred by the need for secondary intervention in the endovascular group is minimal.