The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine

Diabetes mellitus continues to grow in global prevalence and to consume an increasing amount of health care resources. One of the key areas of morbidity associated with diabetes is the diabetic foot. To improve the care of patients with diabetic foot and to provide an evidence-based multidisciplinary management approach, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine developed this clinical practice guideline.

From MgBr via single-electron transfer (SET) to a paramagnetic Mg(II) compound and back to Mg(I): [MgBr(L(1))˙]2 and [K(thf)3]2[Mg2(L(1))2], L(1) = RN=C(Me)C(Me)=NR, R = 2,6-diisopropylphenyl.

Since Mg(+) ions are isoelectronic to Na atoms, an easy single electron transfer (SET) can be expected for MgBr. Even at 190 K, the radical MgBr (obtained via its sophisticated condensation) in a metastable solution transfers its electron to a diazadiene entity. A paramagnetic Mg(II) compound [MgBr(L(1))˙]2 (4; L(1) = DippN=C(Me)C(Me)=NDipp) is formed consisting of a singly reduced ligand. As shown by EPR investigations, dimeric 4 dissociates in ethereal solvents to two monomeric subunits. In addition, 4 can subsequently be reduced with potassium to furnish again a Mg(I) compound, namely [K(thf)3]2[Mg2(L(1))2] (3).

Anion exchange nanofiber materials activated by daylight with a dual antibacterial effect.

Anion exchange polystyrene nanofiber materials (AE) were prepared by electrospinning followed by two-step functionalization of the nanofiber surface by chlorosulfonic acid and ethylendiamine. The photoactive character of these materials was introduced through adsorption of the tetra-anionic 5,10,15,20-tetrakis-(4-sulfonatophenyl)porphyrin photosensitizer (TPPS-AE) on the nanofiber surface or by encapsulation of the nonpolar 5,10,15,20-tetraphenylporphyrin photosensitizer (AE(TPP)) into the nanofibers. Anion exchange nanofiber materials with porphyrins are characterized by a high ion-exchange capacity, photogeneration of singlet oxygen O2((1)Δg), and singlet oxygen-sensitized delayed fluorescence. Due to the photogeneration of cytotoxic O2((1)Δg), the nanofibers exhibited oxidation of the external substrates in aqueous solution and an efficient antibacterial effect when activated by simulated daylight. Adsorption of both TPPS and I(-) on the surface of AE led to the formation of more efficient I-TPPS-AE materials. Rapid photooxidation of I(-) by O2((1)Δg), and the formation of another cytotoxic species, I3(-), on the surface of the nanofibers were responsible for the increased antibacterial properties of I-TPPS-AE and the prolonged antibacterial effect in the dark.

Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism.

BACKGROUND: Factors associated with postthrombotic syndrome are known clinically, but the underlying cellular processes at the vein wall are not well delineated. Prior work suggests that vein wall damage does not correlate with thrombus resolution but rather with plasminogen activator-1 (PAI-1) and matrix metalloproteinase (MMP) activity. OBJECTIVE: We hypothesized that PAI-1 would confer post venous thrombosis (VT) vein wall protection via a vitronectin (Vn)-dependent mechanism. METHODS: A stasis model of VT was used with harvest over 2 weeks, in wild-type, Vn(-/-) , and PAI-1-overexpressing mice (PAI-1 Tg). RESULTS: PAI-1 Tg mice had larger VT at 6 and 14 days, compared to controls, but Vn(-/-) mice had no alteration of VT resolution. Gene deletion of Vn resulted in an increase in, rather than the expected decrease in, circulating PAI-1 activity. While both Vn(-/-) and PAI-1 Tg had attenuated intimal fibrosis, PAI-1 Tg had significantly less vein wall collagen and a compensatory increase in collagen III gene expression. Both Vn(-/-) and PAI-1 Tg vein wall had less monocyte chemotactic factor-1 and fewer macrophages (F4/80), with significantly less MMP-2 activity and decreased TIMP-1 antigen. Ex vivo assessment of transforming growth factor ß-mediated fibrotic response showed that PAI-1 Tg vein walls had increased profibrotic gene expression (collagens I and III, MMP-2, and α-smooth muscle actin) compared with controls, opposite of the in vivo response. CONCLUSIONS: The absence of Vn increases circulating PAI-1, which positively modulates vein wall fibrosis in a dose-dependent manner. Translationally, PAI-1 elevation may decrease vein wall damage after deep vein thrombosis, perhaps by decreasing macrophage-mediated activities.

Plasma DNA is Elevated in Patients with Deep Vein Thrombosis.

OBJECTIVE: To investigate if plasma DNA is elevated in patients with deep vein thrombosis (DVT) and to determine whether there is a correlation with other biomarkers of DVT. BACKGROUND: Leukocytes release DNA to form extracellular traps (ETs), which have recently been linked to experimental DVT. In baboons and mice, extracellular DNA co-localized with von Willebrand factor (VWF) in the thrombus and DNA appeared in circulation at the time of thrombus formation. ETs have not been associated with clinical DVT. SETTING: From December 2008 to August 2010, patients were screened through the University of Michigan Diagnostic Vascular Unit and were divided into three distinct groups: 1) the DVT positive group, consisting of patients who were symptomatic for DVT, which was confirmed by compression duplex ultrasound (n=47); 2) the DVT negative group, consisting of patients that present with swelling and leg pain but had a negative compression duplex ultrasound, (n=28); and 3) a control group of healthy non-pregnant volunteers without signs or symptoms of active or previous DVT (n=19). Patients were excluded if they were less than 18 years of age, unwillingness to consent, pregnant, on an anticoagulant therapy, or diagnosed with isolated calf vein thrombosis. METHODS: Blood was collected for circulating DNA, CRP, D-dimer, VWF activity, myeloperoxidase (MPO), ADAMTS13 and VWF. The Wells score for a patient's risk of DVT was assessed. The Receiver Operating Characteristic (ROC) curve was generated to determine the strength of the relationship between circulating DNA levels and the presence of DVT. A Spearman correlation was performed to determine the relationship between the DNA levels and the biomarkers and the Wells score. Additionally the ratio of ADAMTS13/VWF was assessed. RESULTS: Our results showed that circulating DNA (a surrogate marker for NETs) was significantly elevated in DVT patients, compared to both DVT negative patients (57.7±6.3 vs. 17.9±3.5ng/mL, P<.01) and controls (57.7±6.3 vs. 23.9±2.1ng/mL, P<.01). There was a strong positive correlation with CRP (P<.01), D-dimer (P<.01), VWF (P<.01), Wells score (P<.01) and myeloperoxidase (MPO) (P<.01), along with a strong negative correlation with ADAMTS13 (P<.01) and the ADAMTS13/VWF ratio. The logistic regression model showed a strong association between plasma DNA and the presence of DVT (ROC curve was determined to be 0.814). CONCLUSIONS: Plasma DNA is elevated in patients with deep vein thrombosis and correlates with biomarkers of DVT. A strong correlation between circulating DNA and MPO suggests that neutrophils may be a source of plasma DNA in patients with DVT.

Renal artery aneurysms: diagnosis, management and outcomes.

Renal artery aneurysms are an uncommon vascular entity and are more likely to affect younger patients without significant atherosclerotic risk factors as compared to patients with renal artery occlusive disease. Hypertension is a commonly associated disease and the renal artery aneurysm may be causal, exclusive of renal artery occlusive disease. Diagnosis is often made incidentally but arteriography is essential for good operative planning. The main complication of RAA is rupture, which is increased in peripartum females. Operative therapy is primarily in situ aneurysmectomy and angioplastic closure or exclusion and bypass, usually with autologous conduit. It is currently recommended that in good operative risk patients, repair is recommended for RAA >1.0 cm when hypertension present and RAA >1.5 to 2.0 cm when no hypertension present. Given the anatomic complexity of these lesions, little role for endovascular therapy is forecast.

Computed tomographic venography is specific but not sensitive for diagnosis of acute lower-extremity deep venous thrombosis in patients with suspected pulmonary embolus.

PURPOSE: Duplex ultrasound scanning (US) is the accepted standard means of diagnosis for lower-extremity suprageniculate deep venous thrombosis (LE-DVT). Computed tomographic venography (CTV) has been proposed as an alternative modality for diagnosis of LE-DVT in patients with suspected pulmonary embolism (PE). This study compared CTV with US as a means of diagnosing acute LE-DVT. METHODS: A retrospective review of US and CTV scans from 136 patients with suspected PE who underwent both studies to exclude acute LE-DVT at a single institution was performed. Studies were reviewed and coded in a blinded manner. US was considered to be the reference test. Direct costs of each study were determined by using commercial software. RESULTS: The sensitivity and specificity rates of CTV were 71% and 93%, respectively. The positive predictive value, negative predictive value, and accuracy rates of CTV were 53%, 97%, and 90%, respectively. DVT localization was the same in eight of 10 cases in which the results of both US and CTV were positive. CTV costs and charges per study were greater than those of US by $46.88 and $602.00, respectively. CONCLUSION: CTV is specific, but has a lower sensitivity rate and positive predictive value for the diagnosis of acute LE-DVT compared with US. Additionally, CTV is more costly than US scanning. Because of the lower sensitivity rate and positive predictive value and the increased cost of CTV, US remains the screening study of choice in cases of suspected acute LE-DVT.

Renal artery aneurysms: a 35-year clinical experience with 252 aneurysms in 168 patients.

OBJECTIVE: To define the relevance of treating renal artery aneurysms (RAAs) surgically. SUMMARY BACKGROUND DATA: Most prior definitions of the clinical, pathologic, and management features of RAAs have evolved from anecdotal reports. Controversy surrounding this clinical entity continues. METHODS: A retrospective review was undertaken of 168 patients (107 women, 61 men) with 252 RAAs encountered over 35 years at the University of Michigan Hospital. Aneurysms were solitary in 115 patients and multiple in 53 patients. Bilateral RAAs occurred in 32 patients. Associated diseases included hypertension (73%), renal artery fibrodysplasia (34%), systemic atherosclerosis (25%), and extrarenal aneurysms (6.5%). Most RAAs were saccular (79%) and noncalcified (63%). The main renal artery bifurcation was the most common site of aneurysms (60%). RAAs were often asymptomatic (55%), with a diagnosis made most often during arteriographic study for suspected renovascular hypertension (42%). RESULTS: Surgery was performed in 121 patients (average RAA size 1.5 cm), including 14 patients undergoing unilateral repair with contralateral RAA observation. The remaining 47 patients (average RAA size 1.3 cm) were not treated surgically. Operations included aneurysmectomy and angioplastic renal artery closure or segmental renal artery reimplantation, aneurysmectomy and renal artery bypass, and planned nephrectomy for unreconstructable renal arteries or advanced parenchymal disease. Eight patients underwent unplanned nephrectomy, being considered a technical failure of surgical therapy. Dialysis-dependent renal failure occurred in one patient. There were no perioperative deaths. Late follow-up (average 91 months) was available in 145 patients (86%). All but two arterial reconstructions remained clinically patent. Secondary renal artery procedures included percutaneous angioplasty, branch embolization, graft thrombectomy, and repeat bypass for late aneurysmal change of a vein conduit. Among 40 patients with clearly documented preoperative and postoperative blood pressure measurements, 60% had a significant decline in blood pressure after surgery while taking fewer antihypertensive medications. Late RAA rupture did not occur in the nonoperative patients, but no lessening of this group's hypertension was noted. CONCLUSION: Surgical therapy of RAAs in properly selected patients provides excellent long-term clinical outcomes and is often associated with decreased blood pressure.

Efficacy and durability of autogenous saphenous vein conduits for lower extremity arterial reconstructions in preadolescent children.

OBJECTIVE: Limb length discrepancies (LLDs) in growing children may accompany extremity arterial occlusions. Revascularization with vein grafts has been questioned because of degenerative graft changes observed at other sites. This study was undertaken to define vein graft durability and efficacy in lower extremity revascularizations in preadolescent children. STUDY DESIGN: Fourteen children (10 boys, 4 girls) with a mean age of 7.3 years (range, 2-11 years) who underwent 16 lower extremity revascularizations with greater saphenous vein grafts were subjected to follow-up with graft ultrasonography, ankle/brachial indices (ABIs) with and without exercise, and limb length determinations. A mean of 5.7 years elapsed between the onset of ischemia and operation. Arterial occlusions resulted from cardiac catheterizations (11), arteritis (1), dialysis cannulation (1), and penetrating trauma (1). Indications for operation included LLD (6), claudication (4), both LLD and claudication (3), markedly diminished ABIs with a potential for LLD (2), and a traumatic transection with hemorrhage (1). The reconstructions with 15 reversed and one in situ vein grafts included iliofemoral (11), femorofemoral (1), aortofemoral (1), femoropopliteal (1), popliteal-popliteal (1), and popliteal-posterior tibial (1) arterial bypass grafts. RESULTS: Among patent grafts available for follow-up, 36% (5 of 14) remained unchanged, 50% (7 of 14) developed nonaneurysmal dilatation, and 14% (2 of 14) exhibited nonprogressive aneurysmal expansion. One graft became occluded, and one graft was lost to follow-up. Collectively, the grafts manifest an 11.2% expansion at an average of 10.7 years postoperatively. ABIs increased from 0.75 preoperatively to 0.97, at an average of 11.0 years postoperatively. LLDs were reduced from 1.66 to 1.24 cm, at an average of 11.4 years postoperatively. CONCLUSION: Vein graft reconstructions of lower extremity arteries in preadolescent children are durable. They provide an efficacious means of restoring normal blood flow, and in 70% of children their preexisting LLDs were reduced.

Interleukin-8 administration enhances venous thrombosis resolution in a rat model.

BACKGROUND: Therapy for deep vein thrombosis (DVT) resolution in those patients in whom a complication or contraindication to anticoagulation occurs is limited. As prior work suggests that thrombus maturation involves early influx of neutrophils (PMN) and neovascularization, we hypothesized that administering the proinflammatory/proangiogenic chemokine interleukin (IL)-8 might accelerate thrombus resolution. MATERIALS AND METHODS: An established rodent model of DVT (inferior vena cava [IVC] ligation) was used whereby daily intravenous recombinant human IL-8 (1 microg) or vehicle control was administered, with sacrifice at 4 and 8 days. Prior to sacrifice and at harvest, duplex ultrasound of the DVT and femoral venous pressure measurements were performed. Thrombi were analyzed by immunohistochemical techniques for PMN, monocytes, and neovascularization; for chemokines, by enzyme-linked immunoassay; and fibrosis, by hydroxyproline assay and trichrome staining. RESULTS: IL-8 accelerated thrombus dissolution 4 days after IVC ligation, with 6-fold increased thrombus blood flow by duplex ultrasound and a 23% increased absolute femoral venous pressure compared with controls (both P < 0.05). These findings may be partially explained by the fact that animals receiving IL-8, as compared with controls, had 2.5-fold greater thrombus neovascularization (with a trend continuing to 8 days) and increased PMN at 4 days. Thrombus vascular endothelial growth factor was significantly reduced at 8 days postligation, while monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha were not altered by IL-8 administration. At 8 days post-IVC-ligation, fibrosis was 12-fold greater with IL-8 treatment compared with controls. CONCLUSIONS: A proinflammatory/proangiogenic thrombus milieu, as conferred by IL-8, enhances thrombus resolution and underscores the important relationship between neovascularity and inflammation.

Impact of chronic obstructive pulmonary disease on elective and emergency abdominal aortic aneurysm repair.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is associated with abdominal aortic aneurysm (AAA) expansion and is considered by some to be a relative contraindication to conventional aortic surgery. This study was undertaken to determine if COPD increases operative death, morbidity, intensive care unit (ICU) length of stay (LOS), and hospital LOS, after AAA repair. METHODS: Data from national administrative records supplemented with laboratory data previously obtained for a system-wide study were analyzed in a retrospective review of 1053 consecutive patients (264 with and 789 without COPD) undergoing operation for intact or ruptured AAAs in Veterans Administration Hospitals from 1997 to 1998. Bivariate comparisons and multivariate regression were used to evaluate the impact of COPD on the number of days of ventilation, ICU LOS, total hospital LOS, and death, while controlling for other known risk factors, including acute myocardial infarction, renal failure, and age. RESULTS: The mortality rate in elective aneurysm patients did not differ (P =.99) between patients with (3.7%) or without COPD (3.7%). However, elective AAA repair was associated with longer hospital LOS (14.4 vs 12.3 days, P =.01), longer ICU LOS (6.5 vs 5.4 days, P =.01), and a higher incidence of requiring 96 hours or more ventilation (6.9% vs 3.6%, P =.02) in patients with COPD. Ruptured AAA affected 4.9% of patients and was strongly associated with COPD (P =.02); however, COPD did not result in a statistically significant increase in death (P =.25). CONCLUSIONS: Although COPD does not appear to increase operative death, it is associated with an increased risk of rupture. Elective repair of AAA should not be deferred in patients with COPD despite their higher LOSs and need for postoperative ventilation.

Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule expression in a rat model of venous thrombosis.

Post-thrombotic inflammation probably contributes to chronic venous insufficiency, and little effective treatment exists. IL-10 is an anti-inflammatory cytokine that previously has been shown to decrease perithrombotic inflammation and thrombosis. We investigated in a rat model whether local expression of viral IL-10 (vIL-10) in a segment of vein that undergoes thrombosis would confer an anti-inflammatory effect and how this effect might be mediated. Rats underwent inferior vena cava isolation, cannulation, and instillation of saline or adenovirus encoding either beta-galactosidase or vIL-10. Two days after transfection, thrombosis was induced, 2 days after this the rats underwent gadolinium (Gd)-enhanced magnetic resonance venography exam, and the vein segments were harvested. Tissue transfection was confirmed by either RT-PCR of vIL-10 or positive 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside (X-Gal) staining. vIL-10 significantly decreased both leukocyte vein wall extravasation and area of Gd enhancement compared with those in controls, suggesting decreased inflammation. Immunohistochemistry demonstrated decreased endothelial border staining of P- and E-selectin, while ELISA of vein tissue homogenates revealed significantly decreased P- and E-selectin and ICAM-1 levels in the vIL-10 group compared with those in controls. Importantly, native cellular IL-10 was not significantly different between the groups. However, neither clot weight nor coagulation indexes, including tissue factor activity, tissue factor Ag, or von Willebrand factor levels, were significantly affected by local vIL-10 expression. These data suggest that local transfection of vIL-10 decreases venous thrombosis-associated inflammation and cell adhesion molecule expression, but does not directly affect local procoagulant activity.

Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy.

OBJECTIVE: This study was performed to determine the effectiveness of recombinant P-selectin glycoprotein ligand Ig (rPSGL-Ig) pretreatment to decrease thrombosis and inflammation in experimental venous thrombosis. rPSGL-Ig, a unique mucin-like glycoprotein, has a high affinity for P-selectin. METHODS: Twelve juvenile baboons underwent inferior vena cava (IVC) thrombosis with temporary 6-hour IVC balloon occlusion. Before balloon placement, the animals received rPSGL-Ig (4 mg/kg; n = 8) or saline solution for control (n = 4). The animals underwent evaluation with duplex ultrasound scan imaging, magnetic resonance venography (MRV), phlebography, coagulation profile, and tissue analysis at death for cytokines and vein wall leukocyte morphometrics. With the MRV results, thrombus development, thrombus resolution, and inflammation (gadolinium; square millimeters of enhancement) were assessed. RESULTS: Each animal provided two time points for evaluation (days 2 and 6 after balloon occlusion). A significant decrease in IVC thrombosis between balloons was found in the rPSGL-Ig animals (1 of 16) versus the control animals (5 of 8; P <.01). The MRV results showed significantly less enhancement in the rPSGL-Ig animals at days 2 and 6 (P <.05). Spontaneous thrombus resolution (including balloon sites) was significantly greater from day 2 to day 6 in the rPSGL-Ig animals versus the control animals (23% vs 2%; P <.001), without pulmonary embolism. Lower interleukin-8, platelet factor IV, and monocyte chemotactic protein-1 levels were found in rPSGL-Ig vein walls without significant differences in vein wall leukocyte morphometrics. There were significantly lower D-dimer levels in the rPSGL-Ig-treated animals (P <.05), but there were no differences in measurements of coagulation. Adequate circulating rPSGL-Ig levels were documented. CONCLUSION: Pretreatment with rPSGL-Ig results in: (1) a significant inhibition of thrombosis and vein wall inflammation; (2) a decrease in vein wall cytokine expression; and (3) a promotion of thrombus resolution. Inflammatory inhibition by rPSGL-Ig without anticoagulation therapy provides effective venous thrombosis prophylaxis in experimental venous thrombosis.