Aneurysm Severity is Increased by Combined Mmp-7 Deletion and N-cadherin Mimetic (EC4-Fc) Over-Expression.

There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N-cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation.

Surgical and procedural skills training at medical school - a national review.

This national study quantifies procedural and surgical skills training at medical schools in the United Kingdom (UK), a stipulated requirement of all graduates by the General Medical Council (GMC). A questionnaire recorded basic procedural and surgical skills training provided by medical schools and surgical societies in the UK. Skills were extracted from (1) GMC Tomorrows Doctors and (2) The Royal College of Surgeons Intercollegiate Basic Surgical Skills (BSS) course. Data from medical school curricula and extra-curricular student surgical societies were compared against the national GMC guidelines and BSS course content. Data were analysed using Mann-Whitney U tests. Representatives from 23 medical schools completed the survey (71.9% response). Thirty one skills extracted from the BSS course were split into 5 categories, with skills content cross referenced against GMC documentation. Training of surgical skills by medical schools was as follows: Gowning and gloving (72.8%), handling instruments (29.4%), knot tying (17.4%), suturing (24.7%), other surgical techniques (4.3%). Surgical societies provided significantly more training of knot tying (64.4%, P = 0.0013) and suturing (64.5%, P = 0.0325) than medical schools. Medical schools provide minimal basic surgical skills training, partially supplemented by extracurricular student surgical societies. Our findings suggest senior medical students do not possess simple surgical and procedural skills. Newly qualified doctors are at risk of being unable to safely perform practical procedures, contradicting GMC Guidelines. We propose a National Undergraduate Curriculum in Surgery and Surgical Skills to equip newly qualified doctors with basic procedural skills to maximise patient safety.

Surgical Safety Training of World Health Organization Initiatives.

Undergraduate training in surgical safety is essential to maximize patient safety. This national review quantified undergraduate surgical safety training. Training of 2 international safety initiatives was quantified: (1) World Health Organization (WHO) "Guidelines for Safe Surgery" and (2) Department of Health (DoH) "Principles of the Productive Operating Theatre." Also, 13 additional safety skills were quantified. Data were analyzed using Mann-Whitney U tests. In all, 23 universities entered the study (71.9% response). Safety skills from WHO and DoH documents were formally taught in 4 UK medical schools (17.4%). Individual components of the documents were taught more frequently (47.6%). Half (50.9%) of the additional safety skills identified were taught. Surgical societies supplemented safety training, although the total amount of training provided was less than that in university curricula (P < .0001). Surgical safety training is inadequate in UK medical schools. To protect patients and maximize safety, a national undergraduate safety curriculum is recommended.

Long-term reduction of medial and intimal thickening in porcine saphenous vein grafts with a polyglactin biodegradable external sheath.

OBJECTIVES: The development of neointimal hyperplasia with subsequent atherosclerotic deposition has been proposed to cause most late vein graft failures. Our unit has previously demonstrated that placement of a macroporous, loose-fitting polyester external stent prevents neointimal thickening in porcine vein grafts, and has been proposed as a therapeutic strategy to prevent late vein graft failure. To reduce any potential long-term complications of the permanent polyester stent, a study was undertaken to investigate the effect of a biodegradable external stent on porcine vein graft thickening at 1 month and to identify its longer term effects at 6 months. METHODS: Bilateral saphenous vein to common carotid artery interposition grafting was performed in Large White pigs (25-32 kg; n = 6 per time course group) according to UK Home Office guidelines. A commercially constructed loose-fitting 8-mm-diameter polyglactin stent was placed externally around the vein graft on one side, and the contralateral side remained unstented to serve as control. The external stent was designed to biodegrade and hence disappear within 90 days. Grafts were left in situ for 1 month in 1 group of animals, and for up to 6 months in the other group, before explantation. Graft morphometric features were assessed with computer-aided planimetry. RESULTS: At 1 month the vein grafts fitted with the polyglactin stent demonstrated a statistically significant decrease in neointimal thickening (0.038 mm; interquartile range [IQR], 0.035-0.039 mm) compared with the unstented control grafts (0.13 mm; IQR; 0.11-0.19; P = .0012), and also in medial thickening (0.09 mm; IQR, 0.086-0.093) compared with unsheathed control grafts (0.302 mm; IQR, 0.272-0.414; P = .0012). The 6-month polyglactin stented grafts also demonstrated a statistically significant reduction in neointimal thickening (0.049 mm; IQR, 0.047-0.07; P = .0012) compared with control grafts (0.178 mm; IQR, 0.164-0.19), and also in medial thickening (0.105 mm; IQR, 0.095-0.143) compared with unstented grafts (0.421 mm; IQR, 0.35-0.44; P = .0012, Mann-Whitney U test). CONCLUSION: The loose-fitting biodegradable polyglactin external stent reduces porcine vein graft thickening at 1 month, which persists in the long term, even after degradation of the stent itself. This effective removal of the stent may therefore reduce the long-term risks for infection and mechanical complications associated with implanted prosthetic material while still eliciting the primary objective of preventing graft thickening over the long term. Biodegradable external stents therefore have potential advantages over permanent stent material in clinical application. CLINICAL RELEVANCE: Arteriovenous bypass graft failure has a huge economic effect on health care resources, and a devastating effect o the patient. The attenuation of vein wall thickening, with subsequent luminal narrowing and occlusion, is a major goal in improving the longevity of the venous graft, to reduce secondary percutaneous and surgical interventions. The biodegradable external stent demonstrated in this study has possible clinical applications in bypass procedures with autogenous venous tissue, and represents a novel approach to ameliorating the problem of intimal hyperplasia that plagues these grafts.

A bioabsorbable (polyglactin), nonrestrictive, external sheath inhibits porcine saphenous vein graft thickening.

OBJECTIVE: External, nonrestrictive, macro-porous polyester stents prevent neointima formation in porcine vein grafts and have been proposed as a therapeutic approach to the prevention of late vein graft failure. These stents are nonbiodegradable and therefore may promote long-term foreign body problems including infection and inflammation. The effect of external macro-porous biodegradable (polyglactin) sheaths on neointimal and medial thickening in porcine vein grafts was therefore investigated. METHODS: Bilateral saphenous vein-carotid artery interposition grafting was performed in white Landrace pigs (n = 8) with external placement of polyglactin (Vicryl) sheaths (8 mm in diameter) on 1 side, with the contralateral side acting as a control. One month after surgery, grafts were explanted and wall dimensions measured on histological sections using computer-aided planimetry, and an immunocytochemical appraisal was carried out. RESULTS: All grafts were patent at explantation. Polyglactin sheaths significantly reduced intimal thickness, medial thickness, and the percentage of proliferating cells compared with unsheathed controls. There was a pronounced accumulation of macrophages, giant cells, endothelial cells, and microvessels within and surrounding the biodegradable sheath compared with controls. CONCLUSIONS: A nonrestrictive, biodegradable (polyglactin), external sheath reduces medial and intimal thickening in experimental saphenous vein grafts, possibly through inflammatory cell-mediated angiogenesis. If subsequent long-term studies confirm preservation of this beneficial effect, once the sheath biodegrades, this approach may have an advantage over the permanent polyester stent when applied clinically.

The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts.

OBJECTIVE: Late saphenous vein graft failure after coronary artery bypass graft surgery is initiated by medial thickening and neointima formation, both of which are mediated by the proliferation of vascular smooth muscle cells. Because porcine vein grafts contain high levels of endothelin 1 receptor subtypes and endothelin 1 promotes the proliferation of vascular smooth muscle cells, the effect of administration of the endothelin 1(A) receptor antagonist BSF 302146 ([+]-[S]-2-[4,6-dimethyl-pyrimidin-2-yloxy]-3,3-diphenyl-butanoic acid) on porcine vein graft thickening was investigated. METHODS: Saphenous vein-carotid artery interposition grafting was performed in 4 groups of large white pigs (30-35 kg, n = 10 for each group). BSF 302146 was administered orally (3, 10, and 30 mg x kg(-1) x d(-1)) for 4 weeks to one group of pigs, and placebo was administered to the other group (control animals). Pigs were then anesthetized, and the grafts were removed and fixed at 100 mm Hg with 4% paraformaldehyde. Histologic sections were prepared, and graft morphometry was carried out by using computer-aided planimetry. RESULTS: In vein grafts from animals treated with BSF 302146 compared with grafts from control animals (untreated), there were significant dose-dependent reductions in the increase in medial thickness and neointimal thickness, an increase in luminal area, and a decrease in proliferating cell nuclear antigen-positive cells in the medial-intimal area. CONCLUSIONS: The administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1(A)-mediated effect on vascular smooth muscle cell replication. The administration of this endothelin 1(A) receptor antagonist might therefore be therapeutically effective in preventing late vein graft failure in patients undergoing coronary artery bypass grafting.