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Misfolded endoplasmic reticulum (ER) proteins are degraded through a process called ER-associated degradation (ERAD). Soluble, lumenal ERAD targets are recognized, retrotranslocated across the ER membrane, ubiquitinated, extracted from the membrane, and degraded by the proteasome using an ERAD pathway containing a ubiquitin ligase called Hrd1. To determine how Hrd1 mediates these processes, we developed a deep mutational scanning approach to identify residues involved in Hrd1 function, including those exclusively required for lumenal degradation. We identify several regions required for different Hrd1 functions. Most surprisingly, we find two cytosolic regions of Hrd1 required for lumenal ERAD substrate degradation. Using in vivo and in vitro approaches, we define roles for disordered regions between structural elements that are required for Hrd1 autoubiquitination and substrate interaction. Our results demonstrate that disordered cytosolic regions promote substrate retrotranslocation by controlling Hrd1 activation and establishing directionality of retrotranslocation for lumenal substrate across the ER membrane., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Misfolded proteins in the endoplasmic reticulum (ER) are removed through a process known as ER-associated degradation (ERAD). ERAD occurs through an integral membrane protein quality control system that recognizes substrates, retrotranslocates the substrates across the membrane, and ubiquitinates and extracts the substrates from the membrane for degradation at the cytosolic proteasome. While ERAD systems are known to regulate lipid biosynthetic enzymes, the regulation of ERAD systems by the lipid composition of cellular membranes remains unexplored. Here, we report that the ER membrane composition influences ERAD function by incapacitating substrate extraction. Unbiased lipidomic profiling revealed that elevation of specific very-long-chain ceramides leads to a marked increase in the level of ubiquitinated substrates in the ER membrane and concomitantly reduces extracted substrates in the cytoplasm. This work reveals a previously unrecognized mechanism in which ER membrane lipid remodeling changes the activity of ERAD.

Objective: We have reported the 5-year results of a pivotal prospective, multicenter study conducted in the United States of a specifically designed iliac branch endoprosthesis (IBE; W.L. Gore & Associates, Flagstaff, AZ) for endovascular repair of aortoiliac aneurysms and common iliac artery aneurysms., Methods: A total of 63 patients (98.4% male; mean age, 70 years) with aortoiliac or common iliac artery aneurysms had undergone implantation of a single IBE device and a bifurcated aortoiliac stent graft. Patients with bilateral common iliac artery aneurysms (n = 22; 34.9%) had undergone either staged occlusion or surgical revascularization of the contralateral internal iliac artery before study enrollment. At 5 years, 36 of the 63 patients had completed the final study follow-up examinations, including clinical examinations (n = 35) and computed tomography (n = 32), with the results evaluated by an independent core laboratory and adverse events adjudicated by a clinical events committee., Results: At 5 years, freedom from all-cause mortality was 85.7% and freedom from aneurysm-related mortality was 100%. The nine deaths that had occurred (range, 132-1898 days) were adjudicated as unrelated to the aneurysm or procedure. Primary patency of the internal and external iliac artery IBE limbs was 95.1% and 100%, respectively. No patients had experienced new-onset buttock claudication on the IBE side or self-reported new-onset erectile dysfunction. The common iliac artery diameter on the IBE side was either unchanged or had decreased by ≥5 mm in 30 of the 31 patients (96.8%) with a baseline (1 month) and 5-year (range, 1641-2006 days) computed tomography scan available. Of the 31 evaluable patients, 9 (29.0%) had had an increase of ≥5 mm in the aortic diameter, 5 of whom had had a concurrent type II endoleak. No type I or type III endoleaks or device migration were identified by the core laboratory. Six patients had undergone eight secondary interventions, including five interventions for a type II endoleak. The freedom from secondary intervention was 90.5%., Conclusions: The 5-year results of our prospective, multicenter study have confirmed the safety, efficacy, and durability of the IBE device for the treatment of aortoiliac and iliac artery aneurysms. The device effectively prevented common iliac artery aneurysm rupture, maintained the patency of the internal iliac artery, and avoided the complications associated with internal iliac artery sacrifice. Although common iliac artery aneurysm enlargement was rare, abdominal aortic enlargement was more common, suggesting that the outcomes of endovascular aneurysm repair might be different for patients with or without associated common iliac artery aneurysms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Aneurysm sac remodeling is a complex multifactorial process with unknown factors influencing sac regression after endovascular aortic aneurysm repair (EVAR). We sought to identify factors associated with this process by analyzing data obtained from patients treated with the GORE EXCLUDER endovascular aneurysm repair (EVAR) endoprosthesis from December 2010 to October 2016 enrolled in the Global Registry for Endovascular Aortic Treatment (GREAT)., Methods: All patients enrolled in GREAT with three years CT angiography (CTA) follow-up in each of the three successive years after EVAR were included. The percentage of sac size reduction toward device diameter was calculated and used as a surrogate for sac regression with the formula used being: sac size reduction = ((AAA baseline diameter - AAA diameter at follow-up)/(AAA baseline diameter - device diameter))∗100. The cohort was divided into two groups in accordance with the percentage of aneurysm sac reduction at three years; one with the top quartile of patients and the other with the lowest three quartiles. Demographic and procedural variables were analyzed using univariate and regression modeling to determine factors predictive of sac regression., Results: There were 3265 subjects enrolled with follow-up as of May 2018 of which 526 (16.2%) had three years of CTA surveillance. Overall aneurysm sac size decreased from a mean of 58.0 mm (Std Dev: 10.4, range: 34.2, 100.0) to a mean of 49.3 mm (Std Dev: 14.1, range: 0, 140) for a percentage reduction toward device diameter of a mean 28.2% (Std Dev: 39.0, range: -103.7, 183.9). On multivariate logistic regression model; two factors proved to be statistically significant contributors to a larger percentage reduction in aneurysm sac: a conical neck (odds ratio [OR] = 1.64, P-value = 0.023) and a larger proximal device diameter (OR = 1.09, P-value = 0.023). On the other hand, two factors were negative predictors of sac shrinkage, namely: old age (OR = 0.96, P-value = 0.002) and larger baseline aneurysm sac diameter (OR = 0.98, P-value = 0.028)., Conclusions: Aneurysms with conical necks and larger proximal device neck diameters have an increased percentage change in sac size over time after EVAR. Older age and larger initial diameters of aneurysms were negatively associated with percentage change in sac size as well as sac regression. Further study is needed to determine the clinical utility of these observations and applicability across multiple endoprosthesis platforms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

HIV-1 Vpr is necessary for maximal HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is a restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a host mannose-MR response system to facilitate infection while evading MR's normal role, which is to trap and destroy mannose-expressing pathogens., Competing Interests: JL, MV, MM, DC, MM, BP, ZL, MP, FG, VT, GZ, KC No competing interests declared, (© 2020, Lubow et al.)

Misfolded proteins in the lumen of the endoplasmic reticulum (ER) are retrotranslocated into the cytosol and polyubiquitinated before being degraded by the proteasome. The multi-spanning ubiquitin ligase Hrd1 forms the retrotranslocation channel and associates with three other membrane proteins (Hrd3, Usa1, Der1) of poorly defined function. The Hrd1 channel is gated by autoubiquitination, but how Hrd1 escapes degradation by the proteasome and returns to its inactive ground state is unknown. Here, we show that autoubiquitination of Hrd1 is counteracted by Ubp1, a deubiquitinating enzyme that requires its N-terminal transmembrane segment for activity towards Hrd1. The Hrd1 partner Hrd3 serves as a brake for autoubiquitination, while Usa1 attenuates Ubp1's deubiquitination activity through an inhibitory effect of its UBL domain. These results lead to a model in which the Hrd1 channel is regulated by cycles of autoubiquitination and deubiquitination, reactions that are modulated by the other components of the Hrd1 complex., Competing Interests: BP, MG, TR, RB No competing interests declared, (© 2019, Peterson et al.)

Multidrug resistance protein 1 (MRP1/ABCC1) actively transports a variety of drugs, toxic molecules and important physiological substrates across the plasma membrane. It can confer broad-spectrum multidrug resistance and can decrease the bioavailability of many important drugs. Substrates of MRP1 include anti-cancer agents, antibiotics, antivirals, antidepressants and anti-inflammatory drugs. Using calcein as a fluorescent reporter in a high content uptake assay, we recently reported the identification of 12 MRP1 inhibitors after screening an anti-cancer library of 386 compounds. Here, we describe the development of a new high content imaging-based uptake assay using doxorubicin as a fluorescent reporter. Screening the same anti-cancer library of 386 compounds, the new assay identified a total of 28 MRP1 inhibitors including 16 inhibitors that have not been previously reported as inhibitors of MRP1. Inhibition of MRP1 activity was confirmed using flow cytometry and confocal microscopy-based transport assays. Six drugs (afatinib, celecoxib, doramapimod, mifepristone, MK-2206 and rosiglitazone) were evaluated for their ability to reverse resistance of MRP1-overexpressing H69AR lung cancer cells against vincristine, doxorubicin and etoposide. Mifepristone and doramapimod were most effective in reversal of resistance against vincristine while mifepristone and rosiglitazone were most successful in resensitizing H69AR cells against doxorubicin. Furthermore, resistance towards etoposide was completely reversed in the presence of celecoxib or doramapimod. Selected drugs were also evaluated for resistance reversal in HEK cells that overexpress P-glycoprotein or breast cancer resistance protein. Our results indicate mifepristone and doramapimod as pan inhibitors of these three drug transporters while celecoxib exhibited selective MRP1 inhibition. Together, our findings signify the importance of MRP1 in drug discovery and demonstrate the effectiveness and value of doxorubicin-based high content screening approach. Anti-cancer agents that exhibit MRP1 inhibition may be used to reverse multidrug resistance or to improve the efficacy and reduce the toxicity of various cancer chemotherapies. On the other hand, anti-cancer drugs that did not interact with MRP1 carry a low risk for developing MRP1-mediated resistance., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: The GORE EXCLUDER Iliac Branch Endoprosthesis (IBE; W. L. Gore and Associates, Flagstaff, Ariz) is an iliac branch stent graft system designed to preserve internal iliac artery perfusion during endovascular repair of aortoiliac aneurysms (AIAs) and common iliac artery (CIA) aneurysms (CIAAs). We report the 6-month primary end point results of the IBE 12-04 United States pivotal trial for endovascular treatment of AIAs and CIAAs using the IBE device., Methods: The trial prospectively enrolled 63 patients with AIA or CIAA who underwent implantation of the IBE device at 28 centers in the United States from 2013 to 2015. All patients underwent placement of a single IBE device. Twenty-two patients (34.9%) with bilateral CIAs were enrolled after undergoing staged coil or plug embolization (21 of 22) or surgical revascularization (1 of 22) of the contralateral internal iliac artery. Follow-up at 30 days and 6 months included clinical assessment and computed tomography angiography evaluation as assessed by an independent core laboratory. The primary effectiveness end point was freedom from IBE limb occlusion and reintervention for type I or III endoleak and ≥60% stenosis at 6 months, and the secondary effectiveness end point was freedom from new onset of buttock claudication on the IBE side at 6 months., Results: Mean CIA diameter on the IBE side was 41.0 ± 11.4 mm (range, 25.2-76.3 mm). There were no procedural deaths, and technical success, defined as successful deployment and patency of all IBE components and freedom from type I or III endoleak, was 95.2% (60 of 63). Data for 61 patients were available for primary and secondary effectiveness end point analysis. Internal iliac limb patency was 95.1% (58 of 61), and no new type I or III endoleaks or device migrations were observed at 6 months. The three patients with loss of internal iliac limb patency were asymptomatic, and freedom from new-onset buttock claudication on the IBE side was 100% at 6 months. New-onset buttock claudication occurred on the non-IBE treatment side in six of 21 patients (28.6%) who underwent staged internal iliac artery coil embolization., Conclusions: These results confirm that the IBE device is effective at treating CIAAs and AIAs, maintaining blood flow into the internal iliac artery, and avoiding complications associated with internal iliac artery sacrifice. Follow-up will be continued for 5 years to establish the long-term durability of iliac aneurysm repair with the IBE device., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Multidrug resistance protein 1 (MRP1/ABCC1), an integral transmembrane efflux transporter, belongs to the ATP-binding cassette (ABC) protein superfamily. MRP1 governs the absorption and disposition of a wide variety of endogenous and xenobiotic substrates including various drugs across organs and physiological barriers. Additionally, its overexpression has been implicated in multidrug resistance in chemotherapy of multiple cancers. Here, we describe the development of a high content imaging-based screening assay for MRP1 activity. This live cell-based automated microscopy assay is very robust and allows simultaneous detection of cell permeable, non-toxic and potent inhibitors. The validity of the assay was demonstrated by profiling a library of 386 anti-cancer compounds, which are under clinical trials, for interactions with MRP1. The assay identified 12 potent inhibitors including two known MRP1 inhibitors, cyclosporine A and rapamycin. On the other hand, MRP1-inhibitory activity of tipifarnib, AZD1208, deforolimus, everolimus, temsirolimus, HS-173, YM201636, ESI-09, TAK-733, and CX-6258 has not been previously reported. Inhibition of MRP1 activity was further validated using flow cytometry and confocal microscopy for the respective detection of calcein and doxorubicin in MRP1-overexpressing cells. Among the identified compounds, tipifarnib, AZD1208, rapamycin, deforolimus, everolimus, TAK-733, and temsirolimus resensitized MRP1-overexpressing H69AR cells towards vincristine, a cytotoxic chemotherapeutic agent, by 2-6-fold. Using purified HEK293 membrane vesicles overexpressing MRP1, MRP2, MRP3, and MRP4, we also demonstrated that the identified compounds exert differential and selective response on the uptake of estradiol glucuronide, an endogenous MRP substrate. In summary, we demonstrated the effectiveness of the high content imaging-based high-throughput assay for profiling compound interaction with MRP1., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Renal artery anastomotic pseudoaneurysms are rare after renal transplantation. The etiology tends to be technical, infectious, or degenerative, and repair is difficult with a high postsurgical complication rate. We report the first case of a complex autotransplant renal artery pseudoaneurysm repaired with kissing covered stents. A 52-year-old woman presented with severe left lower quadrant abdominal pain 6 years after a renal autotransplant for ureteral stenosis and recurrent pyelonephritis. A computed tomographic angiography (CTA) scan revealed a bilobed aneurysm arising at the anastomosis between the renal and common iliac arteries. Kissing covered stents were placed within the common iliac artery proximally and extending into the transplant renal artery and external iliac artery. Postdeployment angiography confirmed complete exclusion of the pseudoaneurysm and excellent flow into the transplant kidney and left lower extremity. A follow-up CTA scan at 1 month revealed continued stent-graft patency and complete exclusion of the pseudoaneurysm. An endovascular approach to transplant anastomotic pseduoaneurysms using kissing covered stents is a viable option to exclude aneurysmal changes and preserve flow to the transplanted organ in carefully selected patients., (Copyright © 2013 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Background: Endovascular abdominal aortic aneurysm repair (EVAR) in patients with unfavorable proximal seal zones remains challenging. The purpose of this study was to identify the incidence of proximal extension cuff usage for type I endoleaks in patients with abdominal aortic aneurysms and unfavorable necks treated with the C3 Excluder repositionable endoprosthesis compared with the traditional Excluder stent-graft., Methods: This is a retrospective review of patients undergoing EVAR with unfavorable neck anatomy from January 2010 to October 2011 using the Excluder endoprosthesis on the traditional deployment system or the C3 repositionable system. Seventy-seven patients were treated with the Excluder device, with 44 (57%) having unfavorable neck anatomy defined as proximal aortic neck length of <15 mm, neck diameter of >28 mm, neck angulation of >60°, circumferential thrombus of >50% or calcification at the proximal seal zone, or a "reverse taper" on computed tomographic angiography. Of the 44 patients with unfavorable neck anatomy, 24 patients received the C3 Excluder and 20 received the traditional Excluder., Results: The groups' comorbidities, aneurysm characteristics, and high-risk neck criteria were comparable. Initial success was 100% in both groups. Sixteen of the 44 patients (36%) with high-risk neck criteria required proximal extension cuffs for type I endoleaks, with 3 of the 24 patients (13%) in the C3 group compared with 13 of the 20 patients (65%) in the traditional Excluder group requiring proximal extension (P = 0.0005). Operative variables between the two groups were similar. At mean follow-up of 2 months (range: 1-6 months), there were no type I endoleaks or renal artery occlusion, and sac size regression was similar., Conclusions: The C3 Excluder endoprosthesis significantly reduces the need for proximal extension cuffs in patients with unfavorable aortic neck anatomy compared with the traditional Excluder with identical short-term clinical outcomes. Repositionable grafts could increase the number of patients who can effectively be treated with EVAR., (Copyright © 2013 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is often limited by space-charge effects. Previously, particle-in-cell (PIC) simulations have been used to understand these effects on FTICR-MS signals. However, none have extended fully into the space-charge dominated (plasma) regime. We use a two-dimensional (2-D) electrostatic PIC code, which facilitates work at very high number densities at modest computational cost to study FTICR-MS in the plasma regime. In our simulation, we have observed peak coalescence and the rapid loss of signal coherence, two common experimental problems. This demonstrates that a 2-D model can simulate these effects. The 2-D code can handle a larger numbers of particles and finer spatial resolution than can currently be addressed by 3-D models. The PIC method naturally takes into account image charge and space charge effects in trapped-ion mass spectrometry. We found we can quantify the relative abundances of two closely spaced (such as (7)Be(+) and (7)Li(+)) species in the plasma regime even when their peaks have coalesced. We find that the frequency of the coalesced peak shifts linearly according to the relative abundances of these species. Space charge also affects more widely spaced lines. Singly-ionized (7)BeH and (7)Li have two separate peaks in the plasma regime. Both the frequency and peak area vary nonlinearly with their relative abundances. Under some conditions, the signal exhibited a rapid loss of coherence. We found that this is due to a high order diocotron instability growing in the ion cloud., (Copyright © 2010 American Society for Mass Spectrometry. Published by Elsevier Inc. All rights reserved.)

A simplified vacuum arc design [based on metal vapor vacuum arc (MeVVA) concepts] is employed as a plasma source for a study of a (7)Be non-neutral plasma. The design includes a mechanism for interchanging the cathode source. Testing of the plasma source showed that it is capable of producing on the order of 10(12) charges at confinable energies using a boron-carbide disk as the cathode target. The design is simplified from typical designs for lower energy and lower density applications by using only the trigger spark rather than the full vacuum arc in high current ion beam designs. The interchangeability of the cathode design gives the source the ability to replace only the source sample, simplifying use of radioactive materials in the plasma source. The sample can also be replaced with a completely different conductive material. The design can be easily modified for use in other plasma confinement or full MeVVA applications.

Large, family-based imaging studies can provide a better understanding of the interactions of environmental and genetic influences on brain structure and function. The interpretation of imaging data from large family studies, however, has been hindered by the paucity of well-developed statistical tools for that permit the analysis of complex imaging data together with behavioral and clinical data. In this paper, we propose to use two methods for these analyses. First, a variance components model along with score statistics is used to test linear hypotheses of unknown parameters, such as the associations of brain measures (e.g., cortical and subcortical surfaces) with their potential genetic determinants. Second, we develop a test procedure based on a resampling method to assess simultaneously the statistical significance of linear hypotheses across the entire brain. The value of these methods lies in their computational simplicity and in their applicability to a wide range of imaging data. Simulation studies show that our test procedure can accurately control the family-wise error rate. We apply our methods to the detection of statistical significance of gender-by-age interactions and of the effects of genetic variation on the thickness of the cerebral cortex in a family study of major depressive disorder.

Access-related limitations, namely small-caliber vessels and tortuous or calcified stenotic vessels, are often encountered during endovascular aneurysm repair (EVAR) and thoracic EVAR (TEVAR). Overcoming these limitations often requires the creation of a conduit through which the endovascular devices can be delivered. If these limitations are not recognized and respected preoperatively, significant morbidity and mortality may ensue because access-related complications are often addressed in emergent and chaotic situations. There are a variety of conduits described in the literature, each with their own advantages and disadvantages. The present report explores the use of conduits during EVAR and TEVAR by discussing the current literature, and the authors also describe a preferred method to address unfavorable iliac anatomy through the use of endoconduits.

The benefits of the use of embolic protection devices (EPDs) in saphenous vein coronary artery bypass grafts and carotid arteries have been shown, but the utility of their application during infrainguinal endovascular interventions is somewhat unclear. Patients with specific anatomical features or lesion characteristics, or patients undergoing specific types of endovascular interventions may benefit from the off-label use of EPDs, but this has yet to be determined. This report will examine the current literature related to the use of EPDs in infrainguinal endovascular interventions and attempt to identify the patients who would most likely benefit from their use. In addition, the setting in which EPDs have been used at one institution is briefly described. This discussion will serve as a general guideline for the use of EPDs and act as an impetus for the development of future clinical trials to help elucidate the patients who will truly benefit from EPDs use when undergoing lower extremity endovascular revascularization procedures.

Various strategies have been used to combat arterial access limitations encountered during thoracic endovascular aortic repair (TEVAR). Most require retroperitoneal dissection or aggressive angioplasty techniques that can lead to devastating complications. We describe a novel technique using an "internal endoconduit." Deployment of an iliac stent graft across the prohibitively stenotic area, followed by angioplasty and controlled rupture of the iliac artery, allows for safe passage of the delivery sheath. Adverse events associated with decreased pelvic perfusion or hemorrhage from iliac artery rupture are theoretically possible but have not been observed. Faced with unfavorable iliac anatomy, we use internal endoconduits rather than retroperitoneal access procedures and believe their use will increase the number of procedures that will be able to be performed through femoral access and substantially reduce the frequency of access-related complications.

Two techniques of vena cava filter placement with intravascular ultrasound (IVUS) guidance have been described previously. Placement with real-time IVUS imaging requires two venous access sites, one for the filter delivery system and one for the IVUS catheter, which makes the procedure more invasive. Alternatively, a single-access technique of IVUS imaging of the vena cava requires measuring the distance from the access site to the desired location for filter placement and then delivering the filter to that distance blindly, risking filter misplacement. We describe in this article a single puncture technique that allows for real-time imaging to position the filter delivery sheath using IVUS and reduces the uncertainty of the blind positioning of the filter delivery system.

Infection of bare metal stents in the vasculature is rare, but associated with significant morbidity and mortality. We report two cases of bare metal stent infections and review the literature regarding infected bare metal stents with respect to risk factors, pathophysiology, diagnosis, treatment, and prevention. Overall, this article highlights the need to have a high index of suspicion of bare metal stent infection, since prompt diagnosis and treatment can ultimately decrease the morbidity and mortality associated with this devastating problem.

Objective: Compare long-term results of endovascular treatment and standard open repair of abdominal aortic aneurysms in a multicenter, concurrent-controlled trial., Methods: 334 subjects were treated with standard open repair (control, n = 99) or the original EXCLUDER Bifurcated Endoprosthesis (test, n = 235). Five-year clinical evaluations and corelab radiographic results are analyzed., Results: Overall and aneurysm-related survival are similar. There have been ten open conversions, most frequently for enlarging sacs without endoleak. Two patients died after conversion. Including reinterventions and complications of reinterventions as adverse events, there is significant, persistent long-term reduction in major adverse events. At 5 years, corelab reported 0% limb narrowing, 0% trunk migration, 0% component (contralateral leg, aortic extender, and iliac extender) migration, 0% fracture, endoleak in 3% (2 type II/68), and aneurysm growth (>5 mm compared to baseline) in 38% (30/78) of the test group. There are no aneurysm ruptures in either test or control group., Conclusions: After 5 years follow-up, endovascular repair is a safer and effective treatment compared with open surgical repair for abdominal aortic aneurysms. Major adverse events are less frequent with the endograft despite the need for late reinterventions. Aneurysm expansion is observed in nearly two-fifths of patients but is not associated with endoleak or aneurysm rupture. Multicenter clinical trials are evaluating a newer version of this device designed to avoid this high rate of sac expansion.

These studies were undertaken to evaluate human microvascular endothelial cell (MEC) synthesis of interleukin-8 (IL-8), a potent neutrophil chemoattractant, under in vitro conditions of ischemia and reperfusion. IL-8 and other related CXC chemokines are believed to mediate tissue injury in a variety of pathologic conditions in humans. MEC grown on microcarrier beads were exposed to 3 or 6 h of in vitro ischemia followed by 2 h of reperfusion. Conditioned medium, MEC protein, and total RNA extracts were assayed for IL-8 using an ELISA. During ischemia alone, MEC increased intracellular, but not extracellular levels of IL-8 secretion. In contrast, reperfusion markedly stimulated both intracellular and extracellular IL-8 secretion. Neither 3 h of ischemia alone or followed by reperfusion altered steady-state levels of IL-8 mRNA when compared to pre-ischemic levels. In contrast, after 6 h of ischemia alone and ischemia followed by reperfusion, IL-8 mRNA was increased eight- and sixfold, respectively, when compared to pre-ischemic levels. These studies demonstrate an inverse relationship between the rate of IL-8 protein secretion and the steady-state levels of IL-8 mRNA during ischemia and reperfusion. During ischemia and reperfusion both the increase in cell-associated IL-8 protein and the release of IL-8 into the medium is dependent on de novo protein synthesis rather than the intracellular accumulation of IL-8. These experiments indicate that post-ischemic modulation of IL-8 release and synthesis following ischemia reperfusion will require strategies directed towards inhibition of IL-8 transcription and in depth knowledge of the mechanisms regulating IL-8 secretion.

Background: Standard treatment of traumatic thoracic aortic transection (TTAT) is open repair by left thoracotomy with or without the use of partial cardiopulmonary bypass. However, open repair is associated with high rates of morbidity and mortality, particularly in multiply injured trauma patients. We reviewed our experiences of endovascular repair of acute TTAT., Methods: Between February 2001 and February 2006, 30 patients (male 24, female 6, mean age 43 years) who had sustained severe blunt trauma with multiple injuries (mean injury severity score = 42) underwent endovascular repair for TTAT. Devices used included commercially available proximal abdominal aortic extension cuffs and thoracic stent-grafts. Either low dose or no systemic heparin was used. Arterial access was obtained by femoral-iliac cutdown (n = 19) or completely percutaneous through the femoral artery (n = 11). Mean follow-up was 11.6 months (range, 1 to 48 months)., Results: Technically success was achieved in 100% of patients, as determined by angiographic and computed tomographic (CT) scan exclusion of TTAT. Mean operating time was 132 minutes. Mean blood loss was 300 cm3. Three patients had complications: 1 iliac artery rupture, 1 cerebellar stroke, and 1 partial stent collapse. There were 2 perioperative deaths. There were no instances of procedure-related paralysis. Clinical and CT follow-up did not reveal evidence of endoleak, stent migration, or late pseudoaneurysm formation., Conclusions: The adaptation of commercially available stent-graft devices to treat TTAT is technically feasible, and can be performed with low rates of morbidity and mortality. The long-term durability of endovascular repair of TTAT remains unknown, but early and midterm results appear promising.

Complex thoracoabdominal aortic aneurysm repair remains a difficult problem from both open and endoluminal approaches. The reduced morbidity and mortality rates reported to be associated with aortic stent-graft procedures makes this option more attractive, but it is hampered by the need for adequate proximal and distal seal zones. While branched and fenestrated aortic stent-grafts are being refined, an alternative is a two-stage surgical and endoluminal approach that is particularly useful for aneurysms involving the aortic visceral segment. The present report describes stent-graft repair in two patients after complete visceral artery revascularization or "debranching."

Hypothesis: Endovascular interventions have revolutionized the contemporary treatment of peripheral vascular occlusive disease. Traditional management of supra-aortic trunk disease has employed surgical extra-anatomic bypass via a cervical approach or median sternotomy. Endoluminal therapy may be a less morbid alternative., Design and Setting: A retrospective review of procedures performed by vascular surgeons in an operating room angiosuite at a single university-based, tertiary referral center., Patients: Eighteen consecutive patients with 20 brachiocephalic-origin stenoses., Interventions: From December 2001 through September 2005, 20 brachiocephalic-origin stenoses were treated endoluminally with balloon-expandable stents. Treated vessels were innominate (n = 8), common carotid (n = 9), and subclavian (n = 3). The target lesion was accessed by one of the following methods: antegrade via the femoral artery (n = 5), retrograde through the brachial artery (n = 1), or via a retrograde cut-down on the common carotid artery (n = 14). Cerebral protection was achieved with either a distal embolic filter device or with open surgical occlusion of the distal common carotid artery., Main Outcome Measures: We report immediate and midterm outcomes of all aortic arch vessel stenting procedures with mean follow-up of 12 months., Results: Mean age was 68 years (6 men and 12 women) and overall mean stenosis was 85%. Preprocedural symptoms including stroke, transient ischemic attack, arm fatigue, digital ischemia, and angina were present in 16 of 20 cases (80%). The 4 asymptomatic patients all had more than 90% stenosis on angiography. At 30-day follow-up, there were no deaths, myocardial infarctions, or strokes. During follow-up, there were no cases of restenosis., Conclusion: Endoluminal arterial stenting of brachiocephalic arch vessels may be a viable alternative to traditional open bypass in cases of focal stenotic disease.

Background: A rapidly increasing number of thoracic aortic lesions are now treated by endoluminal exclusion by using stent grafts. Many of these lesions abut the great vessels and limit the length of the proximal landing zone. Various methods have been used to address this issue. We report our experience with subclavian artery revascularization in association with endoluminal repair of acute and chronic thoracic aortic pathology., Methods: Thirty (43%) of 70 patients undergoing thoracic endovascular stent-graft placement from January 2001 to August 2005 had lesions adjacent to or involving the origin of the subclavian artery. The mean age was 62 years (range, 22-85 years; 63% were men, and 37% were women). This subgroup of 30 patients had indications for repair that included thoracic aortic aneurysm (n = 15), traumatic transection (n = 6), chronic dissection with pseudoaneurysm (n = 5), and acute dissection with intramural hematoma (n = 4). All 30 patients had the subclavian origin covered by the stent graft. In eight cases (27%), no effort was made to revascularize the subclavian artery before or during the endograft placement procedure. Twenty-three (77%) of 30 patients underwent subclavian to carotid artery transposition (n = 21) or bypass (n = 2) before (n = 12; average of 14 days before stent-graft placement), concomitant with (n = 10), or after (n = 1) the endovascular procedure. Physical examination and computed tomography scans were performed after surgery at 1, 6, and 12 months and annually thereafter. The mean follow-up was 18 months (range, 1-51 months)., Results: Five acute complications occurred in the eight patients (63%) who had the subclavian artery covered without pre-endograft revascularization and included four patients who experienced stroke (accounting for the only death) and one patient who developed symptomatic subclavian-vertebral steal that necessitated transposition 7 months later. Two (9%) of the 23 patients who had subclavian revascularization experienced left-sided vocal cord palsies, and 1 patient (4%) developed lower extremity paraparesis secondary to spinal cord ischemia. No late endoleaks related to retrograde sac perfusion from the most distal great vessel have been identified in any patient., Conclusions: Subclavian revascularization procedures can be performed with relatively low risk. Complications are rare, and patient recovery is rapid. Although this is not necessary in all cases, we advocate subclavian to carotid transposition when the aortic lesion is within 15 mm of the left subclavian orifice to prevent type II endoleak or perfusion of a dissected false lumen when the ipsilateral vertebral artery is patent and dominant or when coronary revascularization using an ipsilateral internal mammary artery is anticipated and in cases that necessitate extensive coverage of intercostals that contribute to spinal cord perfusion. Carotid to subclavian artery bypass should be reserved for patients with a patent internal mammary artery conduit perfusing a coronary vessel and should be combined with proximal subclavian ligation.

Transluminal arterial stenting reduces vessel compliance and may alter accurate interpretation of flow velocities. We reviewed duplex ultrasonography (DUS) following carotid stenting to identify criteria indicative of severe recurrent stenosis. This is a single-center retrospective review of 158 carotid stenoses treated with carotid angioplasty and stenting (CAS) from April 2001 to December 2004. DUS was obtained preoperatively, postoperatively, and at 3-month intervals thereafter. Peak systolic velocity (PSV) and end diastolic velocity (EDV) were analyzed. Mean follow-up was 12 months (range 1-40). Mean age was 71 +/- 9 years (range 51-91; 74% men, 26% women). Three patients (1.9%) developed restenosis and one (0.6%) developed an asymptomatic occlusion during follow-up. Average preoperative PSV was 373 +/- 123 cm/sec (mean +/- SD) and EDV was 148 +/- 63 cm/sec. Immediate postoperative PSV and EDV decreased by an average of 70% (average 118 +/- 45 cm/sec) and 72% (average 32 +/- 15 cm/sec), respectively. In patients free from restenosis or occlusion, these reductions (range 65-80%) were maintained throughout follow-up and remained within 1-25% of immediate postoperative values. In patients suffering restenosis or occlusion, follow-up PSV and EDV increased 34% and 28%, respectively, compared to preoperative values. PSV and EDV increased by an average of 287% and 500%, respectively, compared to immediate postoperative values. Using criteria of PSV >170 cm/sec and a 50% increase of PSV over immediate postoperative values, restenosis or occlusion was detected with 100% sensitivity and specificity in our patients. Additionally, EDV >120 cm/sec and a 50% increase in EDV over immediate postoperative values detected restenosis and occlusion with 100% sensitivity and specificity. Presumed restenosis and occlusion detected by DUS were confirmed in all cases with angiography. Restenosis or occlusion after CAS at our institution can reliably be detected by carotid duplex using cut-off values of 170 cm/sec PSV, 120 cm/sec EDV, and >50% increase over immediate postoperative values. While these criteria are applied to patients undergoing CAS at our institution, they serve only as suggested guidelines for patient populations at other centers and must be customized to each Intersocietal Commission for the Accreditation of Vascular Laboratories-accredited vascular laboratory.

Background: Untreated traumatic aortic transection carries a mortality rate higher than 85%. Standard therapy has been open repair via a left thoracotomy with systemic heparin and is associated with a high risk of paralysis. We reviewed our experience of endoluminal stent-graft repair for treatment of acute traumatic thoracic aortic transection., Methods: Between February 2001 and February 2005, 11 patients sustaining severe blunt trauma with multiple injuries underwent acute endovascular repair for thoracic aortic transection with 'off-the-shelf' commercially available proximal aortic cuffs. No systemic heparin was used. Access to the aorta was obtained either through a femoral/iliac cutdown (n = 4) or percutaneously through the femoral artery (n = 7). Mean follow-up was 21 months (range, 3-49 months)., Results: Technically successful repair was achieved in 100% of patients, as determined by completion angiography demonstrating apposition of the stent-grafts to the aortic wall, normal perfusion of the aortic branches, and exclusion of the aortic transection without evidence of extravasation. None of the patients required secondary interventions, and there were no instances of death or paralysis. Patient follow-up, using computed tomography angiography, demonstrated durability of endovascular repair without evidence of endoleak, stent migration, or late pseudoaneurysm formation., Conclusion: Adaptation and use of commercially available abdominal devices in the thoracic aorta has proven to be technically feasible. Urgent repair of thoracic aortic transection in the setting of blunt trauma can be transformed into a well-tolerated surgical intervention using endovascular techniques. Long-term durability of endovascular repair of traumatic thoracic transections remains unknown, but early and midterm results are promising.

Background: Open repair of thoracic aortic aneurysms (TAAs) is fraught with high morbidity and mortality rates. The availability of endoprostheses for treating thoracic aortic pathology has not kept pace with those for treating abdominal aneurysms. Technical feasibility, durability, and safety of custom-made stent-grafts for the treatment of TAAs and dissections are evaluated., Methods: From July 2002 to October 2004 there were 15 patients with TAAs, intramural hematoma, or dissections treated with custom-made endografts. Grafts were deployed after brief adenosine-induced cardiac arrest. Computed tomography scans were obtained 1 month postoperatively and every 6 months thereafter. The mean follow-up period was 15 months (range, 3-31 mo)., Results: The mean age of patients was 67 +/- 11 years (range, 47-81 y; 67% men, 33% women). Indications for repair included TAA (10), chronic type B dissection (3), penetrating ulcer (1), and acute dissection (1). Planned concomitant procedures included subclavian-carotid transposition (2) and aortosplenic bypass (2) to achieve adequate proximal or distal landing seal zones, respectively. The mean length of hospital stay was 8 days (range, 1-49 d). Immediate complications included 2 access-related events, 1 cerebellar infarction treated expectantly, and 1 death from a large hemispheric stroke. There were no cases of postoperative paralysis and on follow-up imaging no cases of endoleak, endograft migration, or stent fractures were found. No late deaths occurred caused by stent-graft repair or aneurysm-related causes., Conclusions: Endoluminal exclusion of thoracic aortic aneurysms and dissections can be achieved successfully using custom-made stent-grafts. The use of specially designed devices appears to be technically feasible and durable, with acceptable morbidity and mortality rates.

Endoluminal aortic stent-grafts have revolutionized the contemporary management of abdominal aortic aneurysms. The application of this treatment option for aortic dissections has been hampered by the difficult anatomic constraints frequently encountered with both acute and chronic forms of the disease. Although the data are sparse, it is rapidly growing as technologic advances are made in the design and delivery of various stent-grafts. Reviewed is our current understanding of the pathophysiology of descending thoracic aortic dissections, available stent-graft designs, techniques of implantation, and alternatives for complex anatomy. The section concludes with an overview of published data on stent-graft repair of both acute and chronic aortic dissections.

Pancreaticoduodenal arcade aneurysms are rare. Untreated, these lesions enlarge progressively and have the potential for spontaneous rupture. Aneurysmal degeneration of pancreaticoduodenal arcade vessels is known to be associated with celiac artery occlusion, vasculitis, and certain connective tissue disorders. Given their precarious location, surgical expiration is a challenging endeavor. Innovations in endovascular techniques offer a possible alternative. We report a case of a 55-year-old gentleman with a 2.2x2.1-cm aneurysm of one of the inferior pancreaticoduodenal arteries and a concomitant finding of occlusion of the celiac artery trunk. Percutaneous coil embolization of the aneurysm was employed as the treatment in this case with the successful exclusion of the aneurysm sac, while maintaining continuity of the native circulation. This case report demonstrates that, due to the success rate of aneurysm exclusion and the relatively low morbidity and mortality rates seen with endovascular repair as compared to surgical intervention, endovascular treatment has become the treatment of choice for pancreaticoduodenal artery aneurysms.

This paper describes a combined theoretical and experimental approach to understanding the capillary spark discharge with specific application to use as a soft x-ray or extreme ultraviolet laser source. Atomic physics calculations have identified several potential laser lines in a collisionally pumped neon-like or nickel-like plasma, and magnetohydrodynamic (MHD) modeling has shown that a capillary discharge device should be capable of producing the correct plasma conditions to achieve a population inversion in some of these lines. An experiment is constructed to evaluate the accuracy of the MHD model and investigate the potential of observing inversion in a neon-like argon or a nickel-like krypton plasma.

We have measured the response of WC/C multilayers to x-ray fluxes on the order of 200 MW/cm2 using laser-generated plasmas and found that these multilayers will maintain near peak reflectivity for at least 1 ns but are eventually destroyed. A description of the experiments and data analysis methods is given. Transmission electron micrographs of WC/C multilayers before and after irradiation show melting to be the dominant damage mechanism. The results of the experiments will be compared with simulations.

Neurones containing VIP, substance P, or enkephalin were studied by immunocytochemistry in intestinal specimens from 27 patients with Crohn's disease. Also several endocrine cell systems in the gut were examined. The results were compared with those from a control group of 26 patients. The relative frequency of various endocrine cells did not differ overtly from that in controls. Vasoactive intestinal polypeptide and substance P nerve fibres were distributed in all layers of the gut wall, including the submucosal and myenteric plexuses, whereas enkephalin fibres were restricted to the smooth muscle layer and the myenteric plexus. The distribution and frequency of the peptide-containing nerve fibres were the same in Crohn's disease patients as in control patients. A proportion of these nerve fibres, however, were notably coarse in the Crohn's disease patients. This was particularly apparent in the afflicted parts of the intestine although it was noted also in non-afflicted parts. The concentration of VIP and substance P (expressed as pmol/g wet weight) did not, however, exceed that of the control group.