Hybrid procedures for the treatment of aortic arch aneurysms.

Aortic arch aneurysms present a significant clinical challenge. Historically, open repair has been the mainstay of therapy, but it is associated with significant morbidity and mortality. In particular, the risk of stroke is not insignificant. The development of endovascular therapies has allowed for the less invasive treatment of thoracic aortic aneurysms using endograft therapy. This treatment is limited by the need for "healthy" aorta proximal and distal to the aneurysm in order to get an appropriate seal. This limits use of endografts in the aortic arch as treatment of aneurysms in this location would necessitate coverage of critical brachiocephalic vessels including the innominate and left carotid arteries. To overcome these limitations, hybrid approaches to arch aneurysm repair have been developed. These include partial arch reconstruction through a median sternotomy, or extra-anatomic arch vessel bypass depending on the location of the aneurysm and the patients overall medical condition. These are accompanied by the placement of a thoracic stent-graft at the same setting (either antegrade or retrograde) or at a subsequent procedure. Outcomes evaluating these procedures are just beginning to become available in significant numbers. The outcomes, however, demonstrate these are durable procedures that may provide a viable alternative to conventional aortic arch surgery. As experience with these procedures grows, our understanding of the factors affecting outcomes will be clearer, and the use of these procedures will become associated with even lower morbidities and mortality. The further evolution of aortic endograft technology, however, will ultimately allow for complete endovascular treatment of the entire aortic arch.

Spinal and visceral ischemia after endovascular aortic repair.

With the evolution of endovascular therapy, there is a broader application of this technology for the treatment of aortic disease. The span of treatment is no longer limited to the descending thoracic aorta and the infrarenal abdominal aorta. The development of branched aortic endograft therapies has allowed stent graft treatment of more extensive thoracoabdominal aortic aneurysms and more complex aortic pathologies. With this rapidly expanding experience it is possible to better assess the complications that arise with this surgery. Two devastating complications that can occur with conventional aortic surgery are spinal cord and visceral ischemia. The incidence of these complications is low, and is often related to periods of visceral or cord malperfusion during periods of hypotension or aortic cross-clamping. Unfortunately, however, these complications continue to occur despite the use of endovascular technology. As the volume of endovascular aortic procedures increases, it is possible to more accurately assess the incidence of these dreaded complications. In addition, it appears that the pathophysiology associated with their development may occasionally differ from that observed in open surgery. Enhancing our understanding of spinal and visceral ischemia development during aortic endovascular surgery will allow us to more effectively prevent and treat their occurrences. This article will review our current understanding of the incidence, pathophysiology, preventive and treatment options for spinal cord and visceral ischemia associated with endograft surgery of the aorta.

Decrease in fibrin content of venous thrombi in selectin-deficient mice.

The purpose of this study was to quantify the fibrin content of thrombi produced in a mouse model of venous thrombosis and correlate this to thrombus mass. The role of P-selectin, E-selectin, and IL-10 on thrombus fibrin content was analyzed using knockout (KO) mice. Five groups of mice were evaluated: control (N = 10), P-selectin KO (N = 7), E-selectin KO (N = 5), combined E-/P-selectin KO (N = 12), and IL-10 KO (N = 10). Venous thrombosis was induced by ligation of the infrarenal IVC. Mice were sacrificed on postoperative days (POD) 2 and 6. Thrombus mass was calculated. Sections of IVC were stained with an antibody that cross reacts with mouse fibrin. The distribution of RGB color pixels was generated from digitized micrographs of the thrombus of each animal. The mean pixel value for each group was compiled and analyzed using 2-way ANOVA. Mean pixel value per group was correlated with the mean thrombus mass per group. Color analysis demonstrated significant decreases in the analyzed fibrin content on POD-2 between the control vs E-/P-selectin KO (P < 0.05) and control vs IL-10 KO (P < 0.05) groups. In addition, significantly less fibrin staining was noted on POD-6 between the control vs E-selectin KO (P = 0.03), control vs P-selectin KO (P = 0.01), and control vs E-/P-selectin KO (P < 0.01). There was a strong overall correlation between the mean pixel value for each group and the thrombus mass (R = 0.964; P < 0.01). This study demonstrates a difference in fibrin content of thrombi produced in animals deficient in E-selectin, P-selectin, and IL-10, supporting their importance in thrombus amplification, fibrin formation, and the mass of thrombus formed.

Nitric oxide inhibition increases matrix metalloproteinase-9 expression by rat aortic smooth muscle cells in vitro.

OBJECTIVE: The hypothesis to be tested was that diminished bioavailable nitric oxide (NO) affects matrix metalloproteinase (MMP) expression and activation in vascular smooth muscle cells (SMCs). METHODS: Cultivated rat aortic SMCs (RA-SMCs) were exposed to increasing concentrations of L-N-monomethyl arginine (L-NMMA), a nonselective inhibitor of NO synthase, in the presence of proinflammatory cytokines (50 ng/mL interleukin [IL]-1beta, 50 ng/mL interferon-gamma, and 30 microg/mL lipopolysaccharide). Nitrite and nitrate, two of the final end products of NO metabolism, were measured in media collected at 48 hours with the use of the Saville assay (n = 4). MMP activity was measured with 1% gelatin zymography (n = 4). In separate experiments in which 2 ng/mL of IL-1beta and L-NMMA was used, MMP protein and messenger RNA (mRNA) levels were determined with Western blot analysis (n = 3) and semiquantitative reverse transcriptase-polymerase chain reaction (n = 3), respectively. Data were analyzed with nonparametric analysis of variance. RESULTS: Increasing concentrations of the NO synthase inhibitor L-NMMA caused a dose-dependent decrease (P <.05) in nitrite and nitrate production by RA-SMCs after cytokine exposure. Zymography documented an early dosedependent increase (P <.05 compared with cytokines alone) in 92-kd MMP activity, with no significant changes in 72-kd MMP activity after treatment with L-NMMA (P >.05 compared with cytokines alone). Reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that the addition of L-NMMA to IL-1beta-stimulated RA-SMCs led to significant increases in MMP-9 mRNA (n = 3, P <.01 for 1.0 mmol/L L-NMMA) and MMP-9 protein levels (n = 3, P <.05), respectively. No differences in MMP-2 mRNA or protein levels were demonstrated. CONCLUSIONS: Inhibition of cytokine-induced NO expression in RA-SMCs is associated with a selective, dose-dependent increase in MMP-9 expression and synthesis. These findings suggest that alterations in local NO synthesis may influence MMP-9-dependent vessel wall damage.

Alcohol withdrawal after open aortic surgery.

This study was designed to test the hypothesis that unexpected alcohol withdrawal-like syndrome (AWLS) is more common following aortic, but not other, vascular or nonvascular procedures. All patients undergoing open aortic surgery at our institution in 1997 who survived at least 48 hr were identified, as were those undergoing carotid endarterectomy, infrainguinal bypass, and total colectomy. AWLS was defined as prolonged confusion or agitation and response to conventional treatment for withdrawal, providing that all other sources had been ruled out or a significant history was present. Our results show that, for unknown reasons, AWLS is more common after aortic surgery than after other vascular and high-stress, nonaortic intraabdominal procedures at our institution, and is associated with increased length of stay and morbidity. Because prophylaxis may improve outcome, better efforts to identify patients at risk are required.

Premarket evaluation of the POCkit HSV-2 type-specific serologic test in culture-documented cases of genital herpes simplex virus type 2 [see comment].

BACKGROUND AND OBJECTIVES: The genital herpes epidemic continues, in part, because patients with subclinical or atypical presentations cannot be identified by most herpes simplex virus (HSV) antibody tests. A new product, POCkit HSV-2, has been developed to rapidly and accurately detect antibodies to HSV type 2 (HSV-2) in capillary blood or serum. GOAL: Sera from patients with culture-documented genital or oral herpes were tested to determine the sensitivity and specificity of the POCkit HSV-2 rapid point-of-care antibody test (Diagnology, Belfast, Northern Ireland). STUDY DESIGN: Sera from 50 patients with culture-documented HSV type 1 (9 oral, 41 genital) and from 253 patients with genital HSV-2 were tested by POCkit HSV-2 for HSV-2 antibodies. Each subject had a positive culture for HSV within 6 months of serum collection. Sera were preselected to include only those that were seropositive to the respective virus subtype by University of Washington Western blot. RESULTS: Compared with viral culture and Western blot analysis, sensitivity of the POCkit HSV-2 test for HSV-2 antibody was 96%; specificity was 98%. CONCLUSION: This test provides rapid, accurate identification of HSV-2 antibody in subjects with established HSV infections.

Femoral-infrapopliteal bypass with prosthetic grafts.

BACKGROUND: Patients who require prosthetic infrapopliteal of the lower extremity have historically had dismal long-term results. This study examined the outcome of patients undergoing femoral-distal arterial bypass with expanded polytetrafluoroethylene (ePTFE) grafts. METHODS: Femoral to infrapopliteal artery bypasses with ePTFE performed between 1990 and 1997 were reviewed. Graft patency, limb salvage, and survival rates were calculated by actuarial analysis. Different anastomotic adjuncts (direct end-to-side anastomosis, vein patch anastomosis, and arteriovenous fistula [AVF] anastomosis) were compared with the log-rank test. RESULTS: Seventy-four femoral-infrapopliteal bypasses with ePTFE were performed in 67 patients for limb salvage. At 24 months the primary patency, assisted primary patency, and secondary patency rates were 40% +/- 10% (SEMAI), 48% +/- 11%, and 52% +/- 11%, respectively. Limb salvage was successful in 62 % +/- 10% of the bypasses at 24 months. Forty-six percent of the bypasses were performed with an AVF; 35% were performed with direct end-to-side anastomosis, and 19% were performed with a vein patch anastomosis. Apparent trends in favor of the AVF group did not attain statistical significance with 24-month patency rates of 65% +/- 19%, 44% +/- 16%, and 35% +/- 20%, respectively, in the 3 subgroups. Limb salvage rates were similar (64% +/- 17%, 56% +/- 15%, and 76% +/- 22%, respectively) at 24 months. CONCLUSIONS: Patency and limb salvage rates are sufficient to justify the use of ePTFE grafts in infrapopliteal bypass when adequate autogenous material is unavailable.

Ability of a rapid serology test to detect seroconversion to herpes simplex virus type 2 glycoprotein G soon after infection.

Sera (n = 188) from 29 patients with first-episode genital herpes simplex virus type 2 (HSV-2) infections were tested by POCkit-HSV-2 and Western blot (WB) to determine the speed of seroconversion. The median time to detection of HSV-2 antibody was 13 days (range, 3 to 102 days) by the POCkit-HSV-2 test versus 13 days (range, 2 to 58 days) for WB.

Effectiveness of fractionated external beam radiation in the inhibition of vascular restenosis.

BACKGROUND: From the clinical oncologic experience, fractionation of the radiation dose offers a better therapeutic window, both with respect to effectiveness and unwanted side effects. Thus, we undertook a pilot study in a rodent model, using a single dose of 15 Gy compared with fractionation schedules of 5 or 10 daily applications of 3 Gy. MATERIALS AND METHODS: Using a previously described rat angioplasty model, animals were randomly assigned to one of four groups: unilateral balloon injury, sham irradiation; unilateral balloon injury, bilateral 15 Gy single dose irradiation; unilateral balloon injury, bilateral 3 Gy x 5 daily fractions; or unilateral balloon injury, bilateral 3 Gy x 10 daily fractions. RESULTS AND CONCLUSIONS: All three radiation groups demonstrated a clear inhibition of neointimal hyperplasia. We therefore offer evidence for the effectiveness of fractionated radiation as a means to inhibit vascular restenosis in a rat carotid model. However, the 3 Gy x 5 schedule was less effective than either the 3 Gy x 10 schedule or the 15 Gy single dose. This study must be repeated using longer time points to provide proof of principle.

Tolerance of normal rabbit femoral arteries to single high dose external beam irradiation.

PURPOSE: We gave high single doses of external radiation to normal vessels to produce vascular injury and establish the dose tolerance in an animal model. We also performed immunohistochemical staining for macrophages and smooth muscle cells to assess qualitative changes in their populations. METHODS: Following direct bilateral inguinal cutdown in New Zealand white rabbits, single doses of 15, 20 and 30 Gy were delivered to one vessel. At predetermined time intervals following treatment, the animals underwent angiography and were sacrificed. Both systems were harvested and analyzed, and their luminal and medial areas compared. RESULTS: No statistically significant differences were found between any treatment vessel and its contralateral control at any time point. In addition, no alterations in subintimal or medial content of macrophages or smooth muscle cells were observed. CONCLUSIONS: Our data suggest that single radiation doses as high as 30 Gy appear to be well tolerated in the normal, uninjured rabbit vessel over a 6-month follow-up. However, the use of a diseased vessel model and longer follow-up times need to be studied to provide a better clinical understanding of the basic radiobiology of this technique.

Apolipoprotein B RNA sequence 3' of the mooring sequence and cellular sources of auxiliary factors determine the location and extent of promiscuous editing.

Apolipoprotein B (apoB) RNA editing involves a cytidine to uridine transition at nucleotide 6666 (C6666) 5' of an essential cis -acting 11 nucleotide motif known as the mooring sequence. APOBEC-1 (apoB editing catalytic sub-unit 1) serves as the site-specific cytidine deaminase in the context of a multiprotein assembly, the editosome. Experimental over-expression of APOBEC-1 resulted in an increased proportion of apoB mRNAs edited at C6666, as well as editing of sites that would otherwise not be recognized (promiscuous editing). In the rat hepatoma McArdle cell line, these sites occurred predominantly 5' of the mooring sequence on either rat or human apoB mRNA expressed from transfected cDNA. In comparison, over-expression of APOBEC-1 in HepG2 (HepG2-APOBEC) human hepatoma cells, induced promiscuous editing primarily 5' of the mooring sequence, but sites 3' of the C6666 were also used more efficiently. The capacity for promiscuous editing was common to rat, rabbit and human sources of APOBEC-1. The data suggested that differences in the distribution of promiscuous editing sites and in the efficiency of their utilization may reflect cell-type-specific differences in auxiliary proteins. Deletion of the mooring sequence abolished editing at the wild type site and markedly reduced, but did not eliminate, promiscuous editing. In contrast, deletion of a pair of tandem UGAU motifs 3' of the mooring sequence in human apoB mRNA selectively reduced promiscuous editing, leaving the efficiency of editing at the wild type site essentially unaffected. ApoB RNA constructs and naturally occurring mRNAs such as NAT-1 (novel APOBEC-1 target-1) that lack this downstream element were not promiscuously edited in McArdle or HepG2 cells. These findings underscore the importance of RNA sequences and the cellular context of auxiliary factors in regulating editing site utilization.

Ruptured popliteal artery aneurysm.

Popliteal artery aneurysms rarely rupture. We treated a 91-year-old man who presented with a deep venous thrombosis and anemia; rupture of a popliteal artery aneurysm was suspected only after compartment syndrome isolated to the thigh developed as the result of bleeding. Although fasciotomy was required on the basis of the clinical examination alone, the cause of the problem, operative strategy, and definitive treatment (i.e., resection and bypass) were clarified by the preoperative computed tomography scan. Ruptured popliteal aneurysm can manifest as a massively swollen leg with anemia and should be suspected if no other cause is evident.

Impact of inflow reconstruction on infrainguinal bypass.

PURPOSE: This study assessed whether multisegmental disease that is severe enough to require an inflow procedure adversely affects infrainguinal bypass patency, limb salvage, or patient survival rates. METHODS: The records of 495 patients who underwent 551 infrainguinal bypass grafting procedures were reviewed. Saphenous vein and prosthetic grafts were evaluated separately. Graft patency rates, patient limb salvage rates, and patient survival rates in those grafts that arose from a reconstructed inflow source were compared with those that arose from normal, nonreconstructed inflow sources. When grafts had either hemodynamic failure or occlusion, the cause of failure was identified. RESULTS: Four-year primary patency rates in vein grafts that arose from a reconstructed inflow sources were lower than those in grafts that arose from nonreconstructed inflow sources (41% vs 54%; p = 0.006). Assisted primary patency rates and secondary patency rates, however, were similar (62% vs 74% and 64% vs 77%, respectively). The 4-year primary patency rate (45% vs 55%), assisted primary patency rate (60% vs 60%), and secondary patency rate (60% vs 61%) in prosthetic grafts did not vary based on inflow source. The most common cause of graft failure was inflow failure, except in the vein grafts that did not require an inflow procedure, in which the most common cause of failure was graft failure. Inflow failure occurred in 24% and 22% of the vein and prosthetic grafts with multisegmental disease, respectively, but in only 7% (p < 0.001) and 10% (p < 0.05), respectively, of those that arose from normal nonreconstructed inflow. The presence of an inflow procedure did not affect limb salvage rates or patient survival rates, regardless of graft material. CONCLUSIONS: Long-term patency rates, patient limb salvage rates, and survival rates in patients with a reconstructed inflow source were similar to those of patients with a normal nonreconstructed inflow. A major cause of occlusion is inflow failure, and this occurs in a greater proportion of patients with multisegmental disease. These patients, in particular, may benefit from patient surveillance to screen for progression of their inflow disease and to allow for intervention before infrainguinal graft occlusion.

Induction of the proliferative phenotype in differentiated myogenic cells by hypoxia.

The effect of cellular differentiation on the response of cells to hypoxic stress has been evaluated using the myogenic cell line BC3H1. Aerobic myocytes were predominantly in G0/G1 of the cell cycle and could be induced into S and G2/M of the cell cycle only by replating in high serum-containing medium at subconfluent cell density. In contrast, hypoxic myocytes demonstrated marked progression into S and G2/M upon reoxygenation without replating in the presence of serum. This modulation of myocytes by hypoxia was suggested further by the induction of 100-kDa and 9-kDa proteins (PSP 100 and PSP 9) which were otherwise only detectable in myoblasts. Two-dimensional gel analysis of newly synthesized proteins demonstrated that the five major glucose/oxygen-regulated proteins (GRP/ORP 260, 150, 100, 80, and 33) were induced in hypoxic myogenic cells independent of their state of differentiation. In addition to the GRP/ORPs, synthesis of 20 and 23 other major proteins was influenced in myocytes and myoblasts, respectively. The bulk of these alterations in myoblasts (70%) were inhibitions. In contrast, 75% of the alterations in myocyte protein synthesis were either enhancements or inductions. The data show that hypoxia can modulate the myocyte phenotype and invoke proliferative characteristics. Moreover, the data suggest that ischemia will have a different effect on and prognosis for tissues with a high mitotic index compared with differentiated tissues.

Quantitation of endogenous liver apolipoprotein B mRNA editing.

The mRNA for apolipoprotein B is translated into either a high molecular weight (apo BH) or low molecular weight (apo BL) form of the protein depending on a novel form of RNA processing known as RNA editing. Apo BH mRNA editing is both tissue-specific and hormonally regulated and involves transition of cytidine to uridine at codon 2153 thereby converting a glutamine codon (CAA) to a translational stop codon (UAA). Three methods for quantitating the endogenous levels of liver apo B mRNA editing were compared: (1) Southern blot hybridization with discriminative thermal washes, (2) competimer-hybridization with discriminative thermal washes and (3) competimer-polymerase chain reaction (competimer-PCR). The data suggest that hybridization and PCR can yield similar quantitation when competing oligonucleotides are used. Based on competimer-PCR it is proposed that 40% and 85% of normal rat liver and small intestine apo B mRNA (respectively) are edited.

Relationship of clinical and immunological abnormalities in haemophilia A to F VIII therapy and HIV exposure: a longitudinal study.

This study was established to examine the longitudinal consequences of F VIII therapy on immune function in 24 patients with haemophilia A. Antibodies to the human immunodeficiency virus (HIV) were found in 15 of 16 patients with severe haemophilia and in 2 of 8 patients with mild disease. The principal clinical and immunological abnormalities were restricted to the HIV antibody-positive patients: T helper cell lymphopenia (less than 0.55 x 10(9)/l) in 10 patients, persistent glandular lymphadenopathy in 4 patients and depressed response to skin recall antigens in 7 of 9 HIV-positive patients tested. Although no extension of these immunological and clinical abnormalities developed in the 18-month period of monitoring, T helper cell counts and platelet counts were significantly lower in a group of patients with established long duration HIV seropositivity (since 1982/1983) in comparison with the remaining seropositive patients. This suggests that a progressive pathological process is associated with infection by this virus, but the factors which determine the long-term sequelae are still unknown.