Relevance of basic laboratory and clinical research activities as part of the vascular surgery fellowship: An assessment by program directors and postfellowship surgeons

AbstractIntroduction: Decreased federal monies for graduate medical education, increased clinical training demands, and a decreased pool of general surgery trainees applying to vascular surgery fellowships have brought into question the relevance of the fellowship research experience. This study sought to describe the recent laboratory experience of the fellows, the value of this experience to program directors (PDs) and the trainees, and what factors related to this experience contributed to the trainee entering an academic career versus a private practice career. Methods: A survey regarding the relevance of research experience during fellowship training was mailed in 2001 to all Accreditation Council for Graduate Medical Education-approved vascular surgery fellowship PDs and vascular surgery fellows (VSFs) from 1988 to 2000 applying for the American Board of Surgery Certificate of Added Qualification in General Vascular Surgery. Results: Survey responses were received from 89% of the PDs (74/83) and 69% of the VSFs (259/378). Among the PDs, 70% had completed an approved fellowship, and current bench research was performed by 46%. The PDs afforded protected research time to 69% of the VSFs (with a mean duration of 12 months). This research was in the basic science laboratory 34% of the time. Only 42% of the PDs considered basic laboratory research to be an important part of the fellowship, whereas 99% believed that clinical research was important. Among the PDs, 42% believed that more practice-oriented fellowships with no basic research were needed, whereas 35% believed that basic research should remain an integral component of the fellowship. VSF basic science productivity was significantly greater from those programs that offered protected research time as compared with those that did not (mean basic science paper published, 1.7 ± 0.1 versus 0.3 ± 0.6 per VSF; P < .001). At the time of the survey, 99 VSFs had entered academic careers and 136 were in private practice. Basic science research had been undertaken by 56% of the VSFs during medical school and by 53% during general surgery residency. Research during the fellowship was performed by 65% of the VSFs. This experience was considered helpful in choosing an academic or private practice career by 44% of the VSFs. A greater proportion of academic surgeons had research experience as VSFs when compared with VSFs who became private practitioners (71% versus 57%; P < .05). VSFs who entered academic careers had a more productive publication record in fellowship than did those who chose private practice (mean paper, 2.4 versus 1.5; P < .05). Overall, 78% of the VSFs believed that their research experience was maturing beyond the technical skills learned. Conclusion: This report provides a benchmark of the vascular surgery fellowship research experience. Most VSFs considered the research experience as it now exists to be worthwhile, and less than half of the PDs believed that it should remain as it is. Research experience in fellowship seemed more influential than that in medical school or general surgical residency in promoting an academic career. (J Vasc Surg 2002;36:1083-91.

A True Aneurysm of the Profunda Femoris Artery: A Case Report and Review of the English Language Literature

A rare case of true aneurysm of the profunda femoris artery (PFA) is reported. Surgical management consisted of ligation of the aneurysm and decompression of the sac. Presentation, diagnosis, and treatment of true PFA aneurysms are discussed and the English language literature is comprehensively reviewed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41367/1/10016_2004_Article_116.pd

Attenuation of Experimental Aortic Aneurysm Formation in P-Selectin Knockout Mice

The aim of this study was to determine the role of P-selectin, an adhesion molecule found on the surface of activated platelets and endothelial cells during experimental aortic aneurysm formation. Infrarenal abdominal aortas of C57 black wild-type (WT) mice and P-selectin knockout (PKO) mice were measured in situ and then perfused with porcine pancreatic elastase (0.332 U mL). Whole blood was drawn from the tail artery on day 2 pre-perfusion to determine total and differential white blood cell (WBC) counts. On day 14 postperfusion, aortic diameters (AD) of WT mice ( N 19) and PKO mice ( N 9) were measured. An aortic aneurysm was defined as a 100 or greater increase in AD from pre-perfusion measurement. Immunohistochemistry, including H&E, trichrome and von Gieson staining, was performed on harvested aortic tissue. Statistical analysis was performed by t -test and Fisher's exact test. There were no significant differences in peripheral leukocyte counts at baseline between the two groups. WT mice had significantly larger AD compared to PKO mice at day 14 postperfusion (116 vs. 38 , P < 0.001). Aortic aneurysm penetrance was 52 in WT mice, while 0 ( P 0.01) of PKO mice formed aneurysms. On histologic examination, WT mouse aortas were associated with a significant inflammatory response and degradation of elastin and collagen fibers, while PKO mouse aortas lacked signs of inflammation or vessel wall injury. P-selectin deficiency attenuates aneurysm formation in the elastase aortic perfusion model. This was associated with a blunting of the inflammatory response and preserved vessel wall intergrity following elastase perfusion in the P-selectin knockout mice. Further investigation to elucidate the independent contributions of endothelial cell and platelet P-selectin in experimental aortic aneurysm formation is required.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73125/1/annals.1383.014.pd

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

Venous thromboembolism (VTE) is a major cause of morbidity and mortality. The impact of the Surgeon General’s Call to Action in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in VTE, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter‐based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence‐based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population‐based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of VTE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156163/2/rth212373_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156163/1/rth212373.pd

In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136296/1/art39938_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136296/2/art39938.pd

The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling

BackgroundVein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown.MethodsStasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed.ResultsThrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by ∼ threefold reduced TNFα and IL-1β at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/-mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor.ConclusionsIn stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy.Clinical RelevancePost-thrombotic syndrome has no direct therapies and causes significant morbidity. Anticoagulation limits thrombosis but does not clinically impact directly the vein wall response to injury as well as has bleeding risks. In this experimental study, we show that matrix metalloproteinase 2 genetic deletion lessens fibrotic injury and inflammation at the midterm timepoint, yet is also important for thrombus resolution. Future therapies that positively impact vein wall remodeling will need to account for how the thrombus responds as well

Decreased venous thrombosis with an oral inhibitor of P selectin

BackgroundP-selectin inhibition with protein therapeutics such as antibodies or soluble ligands given intravenously can decrease thrombosis in a mouse ligation model of venous thrombosis. In this study, we hypothesized that oral inhibition of P selectin with a novel oral nonprotein inhibitor (PSI-697) would decrease thrombosis and circulating microparticle populations. This study evaluated the effects on thrombosis and circulating microparticle populations in this murine venous thrombosis model.MethodsMice underwent inferior vena cava ligation to induce thrombosis. Mice with high circulating level of P selectin, Delta Cytoplasmic Tail (^CT), mice gene-deleted for both E- and P-selectin knockout (EPKO), and wild-type C57BL/6 mice (WT) were studied without and with administration of PSI-697 in food (100 mg/kg daily) from 2 days before thrombosis until the end of the study. Animals were killed 2 and 6 days later. Evaluations included thrombus weight (TW), vein wall morphometrics, microparticle quantification by using fluorescence-activated cell sorter analysis, and vein wall enzyme-linked immunosorbent assays for interleukin (IL)-10, P selectin, and monocyte chemotactic protein 1.ResultsPSI-697 significantly decreased TW in WT and ^CT mice, with a treated vs nontreated TW of 132 ± 24 vs 228 ± 29 × 10−4 g (P = .014) and 166 ± 19 vs 281 ± 16 × 10−4 g (P = .001), respectively. At day 6, the effect was significant only in the ^CT group (P < .05). Drug therapy at day 2 significantly increased vein wall monocytes in WT mice and increased monocytes and total inflammatory cells in ^CT animals. A significant decrease in neutrophils and total inflammatory cells was seen in EPKO mice at day 2 with therapy. Therapy significantly increased platelet-derived microparticles and total microparticles in ^CT mice on day 2. Changes in treated WT and treated EPKO animals were not significant compared with respective vehicle treatments at day 2. On day 6, therapy significantly decreased total microparticles in EPKO animals. Vein wall expression of IL-10 increased in all groups with therapy at day 2 (n = 18) and was significantly increased in WT (2687.5 ± 903 pg/mL vs 636 ± 108 pg/mL total protein; P = .038) and ^CT (2078 ± 295 pg/mL vs 432 ± 62 pg/mL total protein; P = .001) mice. Therapy significantly decreased vein wall P selectin, monocyte chemotactic protein 1, and IL-10 levels at day 6.ConclusionsPSI-697 decreased thrombosis. P-selectin inhibition allowed vein wall inflammatory cell extravasation in this model of complete ligation. Circulating microparticles (platelet-derived microparticles and total microparticles) increased with P-selectin inhibition, possibly because of decreased consumption into the thrombus. In summary, the oral administration of an inhibitor to P selectin provides significant TW reduction.Clinical RelevanceDeep venous thrombosis is a significant national health problem in the general population. The average annual incidence of deep venous thrombosis is approximately 250,000 cases per year. The selectin family of adhesion molecules is thought to be largely responsible for the initial attachment and rolling of leukocytes on stimulated vascular endothelium. Recent studies have explored the possible therapeutic implications of P-selectin inhibition to modulate venous thrombosis. For example, prophylactic dosing of a recombinant P-selectin ligand decreases venous thrombosis in a dose-dependent fashion in both feline and nonhuman primate animal models. Additionally, treatment of 2-day iliac thrombi with a recombinant protein, P-selectin inhibitor, significantly improves vein reopening in nonhuman primates. It is interesting to note that P-selectin inhibition decreases thrombosis without adverse anticoagulation. On the basis of the results from these previous studies, the use of P-selectin antagonism is a logical therapeutic approach to treat venous thrombosis. All inhibitors developed to date are either proteins or small molecules with low oral bioavailability that require intravenous or subcutaneous injection. This study evaluates, for the first time, a novel orally bioavailable inhibitor of P-selectin (PSI-697)

Severe Chronic Venous Insufficiency: Magnitude of the Problem and Consequences

The aim of this study was to characterize patients requiring hospitalization for severe chronic venous insufficiency (CVI) at the local and national levels and to analyze factors related to primary amputation. An administrative database (Nationwide Inpatient Sample, 1988-2000) and a single institution (1992-2000) were reviewed using the International Classification of Diseases, 9th ed., Clinical Modification , codes for CVI, excluding phlegmasia and concomitant peripheral vascular occlusive disease codes. Demographics, clinical course, and outcomes were assessed. Descriptive, univariate, and multivariate statistical analyses were used; p < 0.05 was considered significant. Nationally, CVI occurred with a mean incidence of 92/100,000 admissions, of which 55% were women, having a mean age of 65 years and a median length of stay of 7 days. Mean hospital charges were $13,900 and did not change significantly over time. Acute deep vein thrombosis affected 1.3%, amputation was performed in 1.2%, and in-hospital mortality was 1.6% The local cohort included 67 patients with a mean age of 51 years; a majority were men (60%), and 85% were C6 (of Clinical-Etiologic-Anatomic-Pathophysiology [CEAP]). Patients averaged 23 clinic visits and a median of one hospitalization for CVI care over a 44-month follow-up. Twelve patients (18%) underwent a CVI-related amputation (one transmetatarsal amputation, nine below-knee amputations, and two above-knee amputations). They had fourfold more CVI-related hospitalizations, greater preoperative chronic narcotic use than nonamputee patients (85% vs. 58%), but less ongoing wound care needs (25% vs. 89%) (all p values < 0.05). However, no significant difference in long-term mortality, number of clinic visits, duration of symptoms, antibiotic courses, or prior venous-related surgeries was found. In those with amputation, ambulatory status was maintained in 75% at 15-month follow-up. The physiological and economic costs of severe CVI are significant and have not decreased over more than a decade. Amputation for CVI-related nonhealing wounds has a reasonable outcome. Future therapy must focus on prevention of CVI sequelae.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41369/1/10016_2005_Article_5425.pd