The impact of psychiatric comorbidities on patient-reported surgical outcomes in adults treated for the median arcuate ligament syndrome.

OBJECTIVE: Median arcuate ligament syndrome (MALS) is an often overlooked, surgically correctable condition that mimics functional chronic abdominal pain. Patient-reported surgical outcomes are unpredictable in MALS. The objective of this study was to define the psychiatric comorbidities in a cohort of adults undergoing surgery for MALS and to determine whether these comorbidities are predictive of patient-reported quality of life (QOL) outcomes. METHODS: A prospective observational trial was conducted between April 1, 2010, and December 31, 2015, at a single tertiary care hospital. Adults with a diagnosis of chronic abdominal pain in the setting of celiac artery compression were enrolled in a prospective Institutional Review Board-approved observational trial. Patients completed psychological assessments before surgery for MALS and at 6 months after surgery. The primary outcome was patient-reported health-related QOL (young adult version of the Pediatric Quality of Life Inventory). RESULTS: A total of 51 patients (80% female; n = 41) with a mean age of 30.5 (±12.4) years were enrolled. Surgery significantly improved celiac artery hemodynamics in the entire cohort (P < .0001) as well as overall QOL (67.8 ± 14.6 [before surgery] vs 80.3 ± 13.7 [after surgery]; P < .001). Psychiatric diagnoses were common in this cohort, with 14 of 51 (28%) patients meeting criteria for a psychiatric diagnosis. There were no differences in the number of patients with psychiatric diagnoses between presurgical and postsurgical evaluations (14 [28%] vs 13 [26%]; P = .8). Exploratory analyses suggest that having a psychiatric diagnosis at the presurgical evaluation may predict significantly lower postsurgical QOL (R2 = 0.009; P = .01). CONCLUSIONS: Surgery improves patient-reported QOL in adults treated for MALS. Psychiatric diagnoses are common in adults with MALS and predict worse patient-reported QOL outcomes.

Psychological Factors and Outcomes in the Surgical Treatment of Pediatric Patients With Median Arcuate Ligament Syndrome.

OBJECTIVE: Median arcuate ligament syndrome (MALS) is a frequently overlooked cause of chronic abdominal pain (CAP), and results in many symptoms that mimic other gastrointestinal conditions that result in CAP. A small, but growing body of literature indicates that surgery improves quality of life (QOL) in patients with MALS. The purpose of the current study was to examine the psychological characteristics of pediatric patients with MALS to determine their prevalence and impact on surgical outcomes. METHODS: Thirty-two pediatric patients completed psychological assessments before surgery, and 6 months postsurgical intervention. Descriptive analyses and t tests were conducted to characterize the sample and compare psychosocial and QOL items. To explore possible associations between coping and ultimate changes in QOL, exploratory multiple regressions were conducted. RESULTS: Comorbid psychological conditions were common, occurring in about half the sample before and after surgery. Current pain significantly improved, as well as patient and parent-reported QOL constructs (Ps < 0.05). Parent-reported observations of patients using catastrophizing or helpless strategies to cope with pain before surgery was significantly associated with changes in patient and parent-reported QOL following surgery (Ps = 0.04). CONCLUSIONS: Comorbid psychological conditions are common in pediatric patients with MALS, and are maintained following surgery. While surgery improved pain and QOL, the need for presurgical psychological interventions for MALS is implicated.

Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study.

Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.

Contemporary outcomes in vascular patients who require preoperative coronary stent.

BACKGROUND: The documented risks of preoperative coronary revascularization prior to vascular surgery have led to a marked reduction in the role of percutaneous coronary intervention (PCI) during preoperative risk stratification. However, many patients with peripheral arterial disease are first identified immediately after a PCI for an acute coronary syndrome. We sought to determine the risks associated with these patients who then go on to have a peripheral arterial intervention (open operation or endovascular procedure). We hypothesized that there was no difference in outcomes in patients whose medical condition required PCI with coronary stent placement prior to a vascular operation compared with a control cohort of nonstented patients who underwent a vascular operation alone. We report the vascular operative outcomes in a contemporary cohort of vascular patients who had PCI with coronary stent placement for an acute event. METHODS: We performed a retrospective cohort analysis, utilizing administrative data, of 3,678 vascular patients from 2005 to 2010 at a tertiary care hospital. Two groups were defined: patients with preoperative PCI and coronary stent placement within 1 year prior to vascular operation (N = 101, mean age 66 ± 1.22 years, 51.5% men); and patients with no PCI prior to vascular operation (N = 3,577, mean age 60 ± 0.27 years, 46.37% men). Cardiovascular risk factors and complications derived from ICD-9 codes were used to parse data after open peripheral vascular surgery, endovascular repair, or amputation. Primary outcomes were death, nonfatal myocardial infarction, major adverse cardiac event (MACE, defined as death, myocardial infarction, or subsequent coronary revascularization) or bleeding. RESULTS: Univariate analysis showed significant differences in both demographic and outcome analysis in patients with and without prior coronary stent. Patients with a recent PCI followed by a vascular procedure were more likely to undergo an endovascular procedure (75.3% vs. 64.5%, odds ratio = 1.67, P = 0.028). These patients also had 11 of 20 cardiovascular risk factors, significantly higher than in those without a prior PCI. Multivariate subgroup analysis indicated that patients with a prior coronary stent were more likely to have an episode of congestive heart failure (CHF) after 1 year of surgery (16.8%, P = 0.045). In addition, an acute cardiac ischemic event was more likely within 1 year (2.0%, P = 0.036) and beyond 1 year (4.0%, P = 0.022) of surgery. Importantly, there was no significant increase in death, myocardial infarction, MACE, or bleeding in patients with a preoperative coronary stent. CONCLUSIONS: Patients who underwent PCI with coronary stent and then went on to require a vascular procedure had significantly more cardiovascular (CV) risk factors and were more likely to have an endovascular procedure than those patients without preoperative PCI. When controlling for CV risk factors and procedure type, there was no significant difference in death, MI, MACE, or bleeding complications between the groups.

Natural history of carotid artery occlusion.

Carotid artery occlusion (CAO) is a risk factor for stroke ipsilateral to the occlusion and puts patients in a high-risk category when contralateral endarterectomy is performed. The purpose of this study was to evaluate the long-term outcomes of patients with internal CAO and to determine risk factors predictive of subsequent neurological event, contralateral carotid intervention, or death. Patients with internal CAO shown by duplex ultrasonography were retrospectively identified and followed between January 2002 and June 2010 (follow-up: 1-101 months, mean: 52 months) at a tertiary care hospital. All had multiple duplex examinations available for review. Chi-square analysis was used to determine risk factors for neurologic event, contralateral intervention, or all-cause morality. Multivariate Cox proportional hazard analysis was conducted using univariate risk factors with P values <0.1. Survival was estimated using the Kaplan-Meier method (P < 0.05 significant). Eighty patients with internal CAO were identified and available for analysis. On initial encounter, 30 (38%) were symptomatic, with 26 (87%) having symptoms referable to the side of the occluded internal carotid artery. During follow-up, seven (9%) had a neurologic event, of which six (86%) were referable to the occluded side; 14 (18%) patients underwent a contralateral operation. Nineteen (24%) patients died during the period of study. Although numerous variables of multivessel disease were significant with χ(2) analysis, there was no significant risk factor associated with neurologic event on multivariate analysis. However, the development of a hemodynamically significant stenosis (>50%) or occlusion of the external carotid artery (ECA) ipsilateral to the occlusion on follow-up (P < 0.027) was associated with increased risk of death. Kaplan-Meier analysis showed 7-year survival for patients with ECA disease at follow-up was significantly worse (16.2% ± 10.3% [n = 21] vs. 79% ± 8.7% [n = 59]; P < 0.00001). Frequently, patients present with neurological symptoms referable to the side of the internal CAO. Eighty-six percent of neurologic events that occur in follow-up are attributable to the side of the occluded carotid, indicating that the occluded side continues to contribute to neurologic morbidity over time. Multivariate analysis revealed no single factor to be predictive of subsequent neurologic events. With significant risk of death in patients found to have ipsilateral ECA stenosis during follow-up, it seems reasonable to continue surveillance of the occluded carotid.

Median arcuate ligament syndrome: a cost analysis to determine the economic burden of a rarely diagnosed disease.

Background: Chronic abdominal pain (CAP) is a medical condition resulting in enormous economic burden and healthcare utilization costs. One understudied source of CAP is the median arcuate ligament syndrome (MALS). MALS is often not diagnosed and treated for a variety of reasons, including the fact that MALS is highly comorbid with psychological symptoms and psychiatric disorders similar to CAP. To better inform future work on the study of MALS, we undertook a pilot study to estimate the economic impact and public health burden of this condition. We hypothesized that MALS imposes a significant public health burden. Methods: Pediatric and adult patients enrolled in a prospective study undergoing multidisciplinary evaluation and treatment for MALS at a tertiary care facility were invited to participate in a brief self-report survey, the Direct and Indirect Medical Care Impact of MALS Form, to capture health care resources including procedures, surgeries, health care visits, and absenteeism (school and work). To estimate costs from the Direct and Indirect Medical Care Impact of MALS Form, the medical care usage data self-reported by patients were converted to dollar value utilizing FSC-93 billing data and corresponding current procedural terminology (CPT) codes for procedures and provider visits one year prior to surgery and then following surgery. Descriptive analyses were conducted to characterize the sample in terms of demographics and reported absences from school and work. Results: One hundred and nineteen patients (mean age = 30.9 ± 13.0) completed the questionnaires, yielding a 57% response rate. 82.4% (n = 98) of the participants were female and 90.8% (n = 108) were non-Hispanic/Latine white. The mean and median surgical follow-up periods were 5.3 and 5.4 years, respectively. Overall, median cost of provider and ancillary healthcare provider visits for each patient was (US)$19,119 including the pre-operative and post-operative visits. The mean cost for providers alone was (US)$28,908. Wilcoxon signed-ranks tests indicated that the postoperative missed number of days of school were significantly lower than the pre-surgical number of missed school days (Z = -3.36, p = 0.001). Similarly, there were significantly less missed work-days following surgery than before for the entire sample (Z = -2.86, p = 0.004). Conclusion: Median arcuate ligament syndrome imposes a large economic burden on patients and the healthcare system. The current findings, although reflective of a homogenous population, are adding to a growing body of literature suggesting that healthcare disparities play a role in the low rates of diagnosis and treatment of MALS.

Evaluation and treatment of suspected type II endoleaks in patients with enlarging abdominal aortic aneurysms.

PURPOSE: To evaluate angiographic diagnosis and embolotherapy of patients with enlarging abdominal aortic aneurysms and computed tomographic (CT) diagnosis of type II endoleak. MATERIALS AND METHODS: A retrospective review was performed of all patients referred to a single vascular and interventional radiology section from January 1, 2003, to June 1, 2011, with a diagnosis of enlarging aneurysm and type II endoleak. Twenty-five patients underwent 40 procedures between 12 and 82 months after endograft insertion (mean, 48 mo) for diagnosis and/or treatment of endoleaks. RESULTS: Type II endoleaks were treated with cyanoacrylate, coils, and ethylene vinyl alcohol copolymer in 16 patients. Technical success rate was 88% (14 of 16 patients) and clinical success rate was 100% (16 of 16 patients). Aneurysm growth was arrested in all cases over a mean follow-up of 27.5 months (range, 6-88 mo). Endoleaks in nine patients were misclassified on CT; two had type I endoleaks and seven had type III endoleaks. Four of the nine patients (two type I endoleaks and two type III endoleaks) were correctly classified after initial angiography. The other five type III endoleaks were correctly classified on CT after coil embolization of the inferior mesenteric artery. Direct embolization was performed via sac puncture with ethylene vinyl alcohol copolymer in two of the latter five patients and eliminated endoleaks in both. CONCLUSIONS: Aneurysm growth caused by type II endoleaks was arrested by embolization. CT misclassification occurred relatively commonly; type III endoleaks purported to be type II endoleaks were found in 28% of patients (seven of 25).

Patient-Reported Experiences With Median Arcuate Ligament Syndrome: Resilience and Resources Required.

Objective: Median arcuate ligament syndrome (MALS) is a vascular condition that is treated surgically. MALS is a diagnosis of exclusion and therefore often requires that pediatric patients undergo an exhaustive number of tests and potential experiences with misdiagnosis before receiving an accurate diagnosis and treatment. The purpose of the current mixed-methods study was to assess the pediatric patient- and parent-reported experience of (a) coping with and managing symptoms associated with MALS and (b) the diagnostic, treatment, and recovery process for pediatric MALS. Methods: Nine postsurgical pediatric patients (M age = 20.11 ± 3.59; all <18 at time of surgery) and 6 parents participated in semistructured focus groups and completed self-report questionnaires about their experiences and current functioning. Results: Four themes emerged: (a) the impact of MALS (physical and psychosocial), (b) uncertainties and feeling misunderstood, (c) extensive medical tests, and (d) mental health impacts, with an additional three themes related to specific querying (i.e., appreciation, recommendations, and interdisciplinary treatment team). With the exception of variable long-term physical impacts, patients and their parents reported fairly consistent experiences, and the content of these themes was consistent with self-reported quantitative data. Conclusions: The current study highlights the resilience and resources seemingly required for effective diagnosis and intervention for pediatric MALS. The need for increased knowledge about MALS, the inclusion of an interdisciplinary treatment team, and long-term follow-up for pediatric patients with MALS are implicated.

Median arcuate ligament syndrome - Current state of management.

Symptomatic celiac artery compression syndrome (CACS) or median arcuate ligament syndrome (MALS) is a controversial diagnosis that should be considered in patients with chronic abdominal pain of unknown etiology despite an extensive medical evaluation. Once suspected, patients should undergo mesenteric duplex ultrasound. Diagnosis is confirmed with elevated celiac artery velocities which normalize with deep inspiration followed by CT angiogram showing the typical "J-hook" conformation of the celiac artery. Patients should then undergo evaluation by a multi-disciplinary team to appropriately select and prepare patients for potential surgical treatment. Surgical options include release of the median arcuate ligament, with or without neurolysis of the celiac nerve plexus, and with or without concomitant revascularization procedures. Approaches can be open, laparoscopic, or robotic. Surgical treatment has an overall success rate of 70-80% with patients reporting improved abdominal pain and quality of life. Post-operatively, patients can have persistent or recurrent abdominal pain and should undergo re-evaluation for possible need for a revascularization procedure for stenosis of the celiac artery or celiac plexus block if the celiac artery flow is normalized. Additionally, some patients will have persistent pain consistent with functional gastrointestinal disorder (FGID) that will then require medical management. Psychiatric comorbidities have been identified as a predisposing factor that may predict poorer outcomes, and there are preliminary findings suggesting that patients with dysautonomia diagnoses may have worse outcomes as well.

Targeting Coping to Improve Surgical Outcomes in Pediatric Patients With Median Arcuate Ligament Syndrome: Feasibility Study.

Background: Median arcuate ligament syndrome (MALS) is a vascular compression syndrome leading to postprandial epigastric pain, nausea, and weight loss; it can be treated surgically. While most patients report improved quality of life following surgical intervention, 30% continue to experience chronic abdominal pain. Pre-surgical diagnoses of depression and/or anxiety have been found to significantly predict post-surgical: quality of life, highest experience of pain, anxiety, and parent- and self-reported coping strategies. As such, increasing the coping strategies of pediatric patients with MALS may impact their post-surgical outcomes. The purpose of the current study was to: (1) implement a pre-operative cognitive behavioral therapy protocol with a focus on psychoeducation and coping strategies; and (2) determine feasibility of a pre-surgical intervention for this population. Method: Children (<18 years of age) with a diagnosis of MALS who were eligible for surgical intervention were invited to participate in a 7-week in-person or video-based pre-surgical cognitive behavioral therapy intervention. Psychiatric comorbidities were assessed at baseline and post-surgery; patient-reported distress, pain interference and intensity, health-related quality of life, and health status were assessed at four time points (baseline, week 4, week 7, and post-surgery). Descriptive analyses were used to characterize the sample, assess feasibility outcomes (i.e., attrition rates), and explore symptom-based outcomes across time. Results: Twelve pediatric patients (M age = 15.2 ± 1.7; 91.7% female) and their parents (91.7% mothers) participated. Feasibility metrics based on protocol completion were exceeded for engagement at the stages of consent (68.4% vs. goal of ≥50%), treatment initiation (92.3% vs. 85%), and treatment completion (84.6% vs. 75%). Out of the 12 participants, nine (75%) met criteria for at least one comorbid psychiatric diagnosis at baseline and nine (75%) elected to undergo MALS surgery after completing the intervention. Conclusion: The intervention implementation was feasible, despite chronic pain symptoms experienced by the sample, a high prevalence of psychiatric diagnoses, and an international pandemic, suggesting that it would be beneficial to further evaluate the efficacy of the intervention. Future research should include stakeholder input in the design, deployment, and evaluation of a pilot efficacy trial of pre-surgical cognitive behavioral therapy for pediatric patients with MALS.

Concomitant proliferation and caspase-3 mediated apoptosis in response to low shear stress and balloon injury.

BACKGROUND: Arterial remodeling occurs as a response to hemodynamic change and direct vessel wall injury through the process of neointimal hyperplasia (NH). A concomitant response of vascular smooth muscle cell (VSMC) proliferation and apoptosis exists. The purpose of this study is to assess the cellular response of vessels following exposure to low shear stress (tau) and balloon injury in order to further elucidate the mechanisms underlying vascular injury. Our hypothesis is that the combination of low tau and balloon injury results in NH approximating that seen in clinical arterial restenosis, and that quantitative analysis of VSMC proliferation and apoptosis correlates with the associated increase in arterial remodeling. METHODS AND RESULTS: New Zealand White rabbits underwent surgery on the carotid artery creating low tau (n =11), balloon injury (n = 11), combined low tau and balloon injury (n =11), and sham (n = 13) groups. Experiments were terminated at 1, 3, and 28 d. Day 1 and 3 arteries were analyzed with immunohistochemistry for apoptotic markers, terminal transferase dUTP nick end labeling (TUNEL), and activated caspase-3, and a cellular proliferation marker, accumulated proliferating cell nuclear antigen (PCNA), as well as immunoblot analysis for activated caspase-3 and PCNA at day 3. There was significantly greater apoptosis in the combined group as compared with the other groups assessed by quantitative TUNEL and activated caspase-3 levels at both days 1 and 3. Similarly, an increase in cellular proliferation assessed by PCNA expression, was significantly greater in the combined group as compared with the other groups. At 28 d there was no difference in NH observed in the low tau (26 +/- 3 microm) and balloon injury (51 +/- 17 microm) groups. However, significantly more NH was observed in the combined group (151 +/- 35 microm) as compared with the other groups. CONCLUSIONS: An increase in VSMC apoptosis via a caspase-3 dependent pathway is up-regulated by 24 h in the face of combined low shear stress and balloon-induced vessel wall injury. Paradoxically, this increase in VSMC apoptosis is associated with a significant increase in neointimal thickening at 28 d. The concomitant increase of both apoptosis and proliferation are indicative of a robust arterial remodeling response.

Use of internal endoconduits as an adjunct to endovascular aneurysm repair in the setting of challenging aortoiliac anatomy.

The combination of Trans-Atlantic Intersociety Consensus (TASC) D aortoiliac occlusive disease as well as a symptomatic abdominal aortic aneurysm (AAA) is not a common occurrence. Extensive calcified atherosclerotic disease, occlusions, and small iliofemoral segmental arteries make transfemoral access difficult, if not impossible, for endovascular aneurysm repair (EVAR) in these patients. We present a case in which "controlled rupture" of the external iliac artery with a covered stent allowed transfemoral delivery of an aortouni-iliac stent graft with a completion femoral-to-femoral bypass. The patient is a 60-year-old male with a 5.3 cm symptomatic infrarenal AAA and a history of one block right leg claudication. Preoperative computed tomography angiography revealed the patient to have occlusion of the right common iliac artery, extensive calcified stenoses of his aortoiliac segments, and a prohibitively small left external iliac artery, which measured 4.5 mm at its narrowest diameter. The patient, despite discussions concerning the suitability of his iliac arteries as conduits for the delivery of the stent graft, insisted on an endovascular approach to lessen his chances of postoperative sexual dysfunction as well as minimize his length of stay. Access was obtained through bilateral femoral artery cutdowns, and attempts at dilating the left external iliac artery using 16-French dilators were performed without success. An 8 mm x 5 cm covered self-expanding stent was deployed in the diseased 4.5 mm left external iliac artery, followed by angioplasty performed with an 8 mm noncompliant balloon to disrupt the vessel. This endoconduit now allowed accommodation of our 18-French introducer for the aortouni-iliac stent graft. The operation was completed with a femoral-femoral bypass. Flow to both hypogastric arteries was preserved. We believe use of such techniques will ultimately expand the number of patients eligible for EVAR and avoid devastating access-related complications.

Microsurgical vascular bypass in the setting of pediatric limb length discrepancy.

Management of pediatric iatrogenic arterial occlusions can be challenging clinically, leading to chronic complications such as claudication and limb length discrepancy. We report the case of a 6-month-old female patient who had experienced iatrogenic right external iliac and common femoral arterial occlusion. At the age of 8 years, she had developed claudication and a limb length discrepancy of 3.2 cm. She underwent common iliac artery to superficial femoral artery and profunda artery bypass via a branched autologous reverse great saphenous vein using microsurgical techniques for the distal anastomoses. In the present report, we have focused on the musculoskeletal improvements, benefits of microsurgery in pediatric vessels, and maximization of epiphyseal perfusion.

Metachronous giant brachial artery pseudoaneurysms: a case report and review of the literature.

Brachial artery pseudoaneurysms secondary to intravenous drug abuse represent a limb-threatening problem to patients and a technical challenge to the vascular surgeon. Here information is reported about a patient with metachronous bilateral giant brachial artery pseudoaneurysms secondary to intravenous drug use that were successfully treated with excision of the aneurysm and ligation of the brachial artery. Furthermore, a review of the current literature on the treatment of brachial artery aneurysm is presented.

Ruptured popliteal artery aneurysm: a case report.

A high index of suspicion for popliteal aneurysms must be present when evaluating a popliteal mass. Though typically pulsatile, in the presence of chronic thrombosis, the absence of a pulse may make the diagnosis even more difficult. A case is presented that illustrates this point, where an 83-year-old man presents following the biopsy of what turned out to be a very large popliteal aneurysm. In the presence of chronic thrombosis and adequate collateral flow, decompression and ligation of any feeding vessels is typically sufficient. These patients must be followed lifelong for the development of other associated aneurysms.

Pediatric Chronic Abdominal Pain and Median Arcuate Ligament Syndrome: A Review and Psychosocial Comparison.

Chronic abdominal pain (CAP) occurs in children and adolescents with a reported prevalence of 4% to 41% with significant direct and indirect costs to the child, family, and society. Median arcuate ligament syndrome (MALS) is a vascular compression syndrome of the celiac artery that may cause symptoms of epigastric pain and weight loss and is a frequently overlooked cause of CAP in the pediatric population. We have observed that the psychosocial presentation of patients with MALS is notable for various psychiatric comorbidities. In this article, we review MALS as well as our study results of the psychosocial profile of 30 MALS patients. Our data suggest that children and adolescents with MALS have similar psychosocial profiles to children with other gastrointestinal disorders resulting in CAP. The overlap of physical and psychosocial symptoms of patients who have MALS with other CAP disorders leads us to recommend that patients with CAP should be evaluated for MALS. [Pediatr Ann. 2016;45(7):e257-e264.].

Evidence for the Use of Multiple Mechanisms by Herpes Simplex Virus-1 R7020 to Inhibit Intimal Hyperplasia.

Intimal hyperplasia (IH) is the primary cause of vein bypass graft failure. The smooth muscle cell (SMC) is a key element of IH as it phenotypically switches from a contractile to a synthetic state which can become pathological. R7020, which is an engineered strain of Herpes Simplex Virus-1, inhibits IH in animal models. Although it has many characteristics which make it a strong candidate for use as a prophylactic agent how it inhibits IH is not well understood. The objective of this study was to identify modes of action used by R7020 to function in blood vessels that may also contribute to its inhibition of IH. The cytopathic effect of R7020 on SMCs was determined in vitro and in a rabbit IH model. In vitro assays with R7020 infected SMCs were used to quantify the effect of dose on the release kinetics of the virus as well as the effects of R7020 on cell viability and the adhesion of peripheral blood mononuclear cells (PBMCs) to SMCs in the absence and presence of tumor necrosis factor alpha (TNF-α). The observed cytopathic effect, which included R7020 positive filopodia that extend from cell to cell and the formation of syncytia, suggests that R7020 remains cell associated after egress and spreads cell to cell instead of by diffusion through the extracellular fluid. This would allow the virus to rapidly infect vascular cells while evading the immune system. The directionality of the filopodia in vivo suggests that the virus preferentially travels from the media towards the intima targeting SMCs that would lead to IH. The formation of syncytia would inhibit SMC proliferation as incorporated cells are not able to multiply. It was also observed that R7020 induced the fusion of PBMCs with syncytia suggesting the virus may limit the effect of macrophages on IH. Furthermore, R7020 inhibited the proliferative effect of TNF-α, an inflammatory cytokine associated with increased IH. Thus, the results of this study suggest that R7020 inhibits IH through multiple mechanisms.