Search

The COVID-19 pandemic has strained healthcare resources the world over, requiring healthcare providers to make resource allocation decisions under extraordinary pressures. A year later, our understanding of COVID-19 has advanced, but our process for making ethical decisions surrounding resource allocation has not. During the first wave of the pandemic, our institution uniformly ramped-down clinical activity to accommodate the anticipated demands of COVID-19, resulting in resource waste and inefficiency. In preparation for the second wave, we sought to make such ramp down decisions more prudently and ethically. We report the development of a tool that can be used to make fair and ethical decisions in times of resource scarcity. We formed an interprofessional team to develop and use this tool to ensure that a diverse range of stakeholder perspectives were represented in this development process. This team, called the clinical activity recovery team, established institutional objectives that were combined with well-established procedural values, substantive ethical principles and decision-making criteria by using a variation on the well-known accountability for reasonableness ethical framework. The result of this is a stepwise, semiquantitative, ethical decision tool that can be applied to resource allocation challenges in order to reach fair and ethically defensible decisions. This ethical decision tool can be applied in various contexts and may prove useful at both the institutional and the departmental level; indeed this is how it is applied at our centre. As the second wave of COVID-19 strains healthcare resources, this tool can help clinical leaders to make fair decisions.

Summary: Background: Survival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models. Methods: In this machine learning analysis, model development was done on a set of 42 146 liver transplant recipients (mean age 48·6 years [SD 17·3]; 17 196 [40·8%] women) from the Scientific Registry of Transplant Recipients (SRTR) in the USA. Transferability of the model was further evaluated by fine-tuning on a dataset from the University Health Network (UHN) in Canada (n=3269; mean age 52·5 years [11·1]; 1079 [33·0%] women). The primary outcome was cause of death, as recorded in the databases, due to cardiovascular causes, infection, graft failure, or cancer, within 1 year and 5 years of each follow-up examination after transplantation. We compared the performance of four deep learning models against logistic regression, assessing performance using the area under the receiver operating characteristic curve (AUROC). Findings: In both datasets, deep learning models outperformed logistic regression, with the Transformer model achieving the highest AUROCs in both datasets (p

BACKGROUND Burnout and distress have a negative impact on nurses and the treatment they provide. Our aim was to measure the prevalence of burnout and distress among nurses in a cardiovascular centre at 2 quaternary referral hospitals in Canada, and compare these outcomes to those for nurses at academic health science centres (AHSCs) in the United States. METHODS We conducted a survey of nurses practising in a cardiovascular centre at 2 quaternary referral hospitals in Toronto, Ontario, between Nov. 27, 2018, and Jan. 31, 2019. The survey tool included the Well-Being Index (WBI), which measures fatigue, depression, burnout, anxiety or stress, mental and physical quality of life, work-life integration, meaning in work and distress; a score of 2 or higher on the WBI indicated high distress. We also evaluated nurses' perception of the adequacy of staffing levels and of fair treatment in the workplace, and satisfaction with the electronic health record. We carried out standard univariate statistical comparisons using the χ2, Fisher exact or Kruskal-Wallis test as appropriate to perform univariate comparisons in the sample of respondents. We assessed the relation between a WBI score of 2 or higher and demographic characteristics. We compared univariate associations among WBI data for nurses at AHSCs in the US who completed the WBI to responses from our participants. RESULTS The response rate to the survey was 49.1% (242/493). Of the 242 respondents, 188 (77.7%) reported burnout in the previous month; 189 (78.1%) had a WBI score of 2 or higher, and 132 (54.5%) had a score of 4 or higher (indicative of severe distress). Ordinal multivariable analysis showed that lower WBI scores were associated with satisfaction with staffing levels (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.16-0.69) and the perception of fair treatment in the workplace (OR 0.41, 95% CI 0.23-0.74). Higher proportions of our respondents than nurses at AHSCs in the US reported burnout (77.7% v. 60.5%, p < 0.001) and had a WBI score of 2 or higher (78.1% v. 57.0%) or 4 or higher (54.5% v. 32.0%) (both p < 0.001). INTERPRETATION Although levels of burnout and distress were high among nurses, their perceptions of adequate staffing and fair treatment were associated with lower distress. Addressing inadequate staffing and unfair treatment may decrease burnout and other dimensions of distress among nurses, and improve their work experience and patient outcomes.

Background Burnout and distress negatively affect the well-being of health care professionals and the treatment they provide. Our aim was to measure the prevalence of burnout and distress among allied health care staff at a cardiovascular centre of a quaternary hospital network in Canada, and compare outcomes to those for nonphysician employees in the United States. Methods We conducted a survey of allied health care staff, including physical, respiratory and occupational therapists, pharmacists, social workers, dietitians and speech-language pathologists, in a cardiovascular centre at 2 quaternary referral hospitals in Toronto, Ontario, between Nov. 27, 2018, and Jan. 31, 2019. The survey tool included the Well-Being Index (WBI), which measures fatigue, depression, burnout, anxiety or stress, quality of life, work-life integration, meaning in work and overall distress; a score of 2 or higher indicated high distress. We carried out standard univariate statistical comparisons using the χ2, Fisher exact or Kruskal-Wallis test as appropriate to perform univariate comparisons in the sample of respondents. We assessed the relation between a WBI score of 2 or higher and demographic characteristics. We compared univariate associations among WBI data for nonphysician employees in the US who completed the WBI to responses from our participants. Results The response rate to the survey was 86% (45/52). Thirty-three respondents (73%) reported experiencing burnout in the previous month, and 31 (69%) reported emotional problems. Compared to respondents who perceived fair treatment in the workplace, those who perceived unfair treatment (20 [44%]) were more likely to report emotional problems (17 [85%] v. 13 [54%], p = 0.05), to worry that work was hardening them emotionally (15 [75%] v. 8 [33%], p = 0.008), and to feel down, depressed or hopeless (12 [60%] v. 4 [17%], p = 0.005). Twenty-five respondents (56%) and 13 respondents (29%) reported WBI scores consistent with high (≥ 2) or severe (≥ 5) distress, respectively. Respondents were more likely to have a high WBI score if they perceived unfair treatment or inadequate staffing levels. Our respondents had a higher prevalence of burnout (73.3% v. 53.6%, p = 0.008) and a higher average WBI score (2.6 [SD 2.8] v. 1.7 [SD 2.6], p = 0.05) than 9096 nonphysician employees in the US. Interpretation The prevalence of burnout, emotional problems and distress was high among allied health care staff. Fair treatment in the workplace and adequate staffing may lower distress levels and improve the work experience of these health care professionals.

Background Waiting for procedures delayed by COVID‐19 may cause anxiety and related adverse consequences. Objective To synthesize research on the mental health impact of waiting and patient‐centred mitigation strategies that could be applied in the COVID‐19 context. Methods Using a scoping review approach, we searched 9 databases for studies on waiting lists and mental health and reported study characteristics, impacts and intervention attributes and outcomes. Results We included 51 studies that focussed on organ transplant (60.8%), surgery (21.6%) or cancer management (13.7%). Most patients and caregivers reported anxiety, depression and poor quality of life, which deteriorated with increasing wait time. The impact of waiting on mental health was greater among women and new immigrants, and those of younger age, lower socio‐economic status, or with less‐positive coping ability. Six studies evaluated educational strategies to develop coping skills: 2 reduced depression (2 did not), 1 reduced anxiety (2 did not) and 2 improved quality of life (2 did not). In contrast, patients desired acknowledgement of concerns, peer support, and periodic communication about wait‐list position, prioritization criteria and anticipated procedure date. Conclusions Findings revealed patient‐centred strategies to alleviate the mental health impact of waiting for procedures. Ongoing research should explore how to optimize the impact of those strategies for diverse patients and caregivers, particularly in the COVID‐19 context. Patient or Public Contribution Six patients and four caregivers waiting for COVID‐19‐delayed procedures helped to establish eligibility criteria, plan data extraction and review a draft and final report.

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1

Hematopoietic stem and progenitor cells reside within specialized niches. Colony stimulating factor 1 (CSF1) might serve as a monocyte niche factor given its critical role in regulating survival, proliferation, and differentiation of myeloid lineage cells. However, the role of CSF1 in adult monopoiesis and its functionally important cellular sources remain uncertain. Here, we show that conditional deletion of Csf1 in adulthood regulated monocyte abundance independent of its effects on bone development. Bone histology revealed monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular stromal cells. Concomitantly, targeted in vivo deletion of Csf1 from sinusoidal but not arteriolar ECs selectively reduced Ly6Cnegative monocytes in the bone marrow and blood. Combined depletion of Csf1 from both Lepr-expressing perivascular stromal cells and ECs had additive effects, further decreasing classical Ly6Chigh cells. Thus, different monocyte subsets are supported by distinct cellular sources of CSF1 within a perivascular bone marrow niche.%%%%M.Sc.

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.

BACKGROUND Pheochromocytoma, a catecholamine-producing tumor seldom encountered in pregnancy, is often heralded by nonspecific symptoms and undue mortality with delayed diagnosis. The presence of an aortic pseudoaneurysm poses a management challenge given the risk of aortic rupture amplified by hypertensive events. CASE A 30-year-old woman, gravida 3 para 1, presented at 23 6/7 weeks of gestation with vomiting, chest pain, and severe hypertension. Investigation revealed adrenal pheochromocytoma and pseudoaneurysm at the site of a previous aortic injury. Prazosin and phenoxybenzamine achieved α-blockade with subsequent addition of labetalol for β-blockade. Concerns for aortic dissection led to endovascular aortic repair at 30 2/7 weeks of gestation. A female neonate was delivered by urgent cesarean delivery for persistent postprocedure fetal bradycardia. An adrenalectomy followed with near-immediate symptom resolution. Mother and neonate remain well. CONCLUSION The case underscores the necessity of a meticulous approach to hypertension management and the pivotal role of diligent multidisciplinary collaboration to achieve a safe outcome.

Objectives This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. Background Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. Methods 18F-fluorodeoxyglucose (18FDG)–positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. Results Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). Conclusions Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.

Summary: Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease. : Shikatani et al. demonstrate that the nuclear transcription factor c-Myb exacerbates experimental atherosclerosis directly through its effects on B lymphocytes. Paradoxically, c-Myb promotes B2 cell development yet limits numbers of IgM-producing antibody-secreting cells and levels of atheroprotective OxLDL-specific IgM antibodies.

Background— Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other’s function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor–secreting cells of hitherto unknown function in atherosclerosis. Methods and Results— Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell–derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ–producing T helper-1 cells. This IRA B cell–dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins. Conclusions— Granulocyte macrophage colony-stimulating factor–producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1–associated milieu that aggravates atherosclerosis.

The role of Group X secreted phospholipase A2 (GX-sPLA2) during influenza infection has not been previously investigated. We examined the role of GX-sPLA2 during H1N1 pandemic influenza infection in a GX-sPLA2 gene targeted mouse (GX(-/-)) model and found that survival after infection was significantly greater in GX(-/-) mice than in GX(+/+) mice. Downstream products of GX-sPLA2 activity, PGD2, PGE2, LTB4, cysteinyl leukotrienes and Lipoxin A4 were significantly lower in GX(-/-) mice BAL fluid. Lung microarray analysis identified an earlier and more robust induction of T and B cell associated genes in GX(-/-) mice. Based on the central role of sPLA2 enzymes as key initiators of inflammatory processes, we propose that activation of GX-sPLA2 during H1N1pdm infection is an early step of pulmonary inflammation and its inhibition increases adaptive immunity and improves survival. Our findings suggest that GX-sPLA2 may be a potential therapeutic target during influenza.

Young children are typically considered a high-risk group for disease associated with influenza virus infection. Interestingly, recent clinical reports suggested that young children were the smallest group of cases with severe pandemic 2009 H1N1 (H1N1pdm) influenza virus infection. Here we established a newly weaned ferret model for the investigation of H1N1pdm infection in young age groups compared to adults. We found that young ferrets had a significantly milder fever and less weight loss than adult ferrets, which paralleled the mild clinical symptoms in the younger humans. Although there was no significant difference in viral clearance, disease severity was associated with pulmonary pathology, where newly weaned ferrets had an earlier pathology improvement. We examined the immune responses associated with protection of the young age group during H1N1pdm infection. We found that interferon and regulatory interleukin-10 responses were more robust in the lungs of young ferrets. In contrast, myeloperoxidase and major histocompatibility complex responses were persistently higher in the adult lungs; as well, the numbers of inflammation-prone granulocytes were highly elevated in the adult peripheral blood. Importantly, we observed that H1N1pdm infection triggered formation of lung structures that resembled inducible bronchus-associated lymphoid tissues (iBALTs) in young ferrets which were associated with high levels of homeostatic chemokines CCL19 and CXCL13, but these were not seen in the adult ferrets with severe disease. These results may be extrapolated to a model of the mild disease seen in human children. Furthermore, these mechanistic analyses provide significant new insight into the developing immune system and effective strategies for intervention and vaccination against respiratory viruses.

INTRODUCTION Multiple sclerosis (MS) is a disease of the white matter within the central nervous system, accepted as autoimmune in nature, and mediated by T and B cells [1,2]. A similar disorder, acute disseminated encephalomyelitis, shares this etiology, albeit being a single event often related to recent viral infection or inoculation. Experimental autoimmune encephalomyelitis, an animal model for both disorders, has been studied widely [3] since the 1930s. Interestingly, this experimental model in rodents did not show any increase incidence of the disease in iron-overloaded mice [4]. A totally different etiology for S was recently proposed by Zamoni et al [5], suggesting that, analgous to the pathophysiology of hronic venous insufficiency in the egs, cranial venous outflow restricion produces increased iron depoition in the perivenular regions of he deep white matter, inciting the isease. These and other authors sed balloon angioplasty of venous cclusive lesions initially identified y color flow duplex Doppler ultraound, in the jugular and azygos eins, as a form of therapy for MS 6]. This approach implies elevaion of intracranial venous pressure s a putative casual agent, as in the ower extremities. These trials acked control groups, and the inestigators were not blinded. The ypothetical causative factor has no ecognized grounds in empirical cience.

Purpose To describe early experience with the use of iliac branch grafts (IBGs) in aortoiliac aneurysm repair. Materials and Methods From July 2007 to August 2009 (25 months), 14 patients (13 men, one woman) with a mean age of 70.1 years (range, 59.3–80.0 y) were treated with IBGs. Indications were abdominal aneurysm with common iliac artery (CIA) involvement (n = 11), juxtarenal aortic aneurysm with CIA involvement (n = 1), and bilateral CIA and internal iliac artery (IIA) aneurysms (n = 1). Postoperative endoleaks and patency rate were determined with computed tomography within 1 month of implantation and 1 year thereafter, with concurrent clinical evaluation for pelvic ischemia. Mean follow-up period was 18.7 months (range, 6–35 mo). Results Technical success rate, as defined by successful implantation of IBG with no intraprocedural type I or type III endoleak, was 86% (12 of 14). A total of 14 IBGs were successfully deployed in 12 patients. Two cases of technical failure were related to excessive iliac tortuosity. The mean hospitalization duration was 6.5 days (range, 3–14 d), with zero mortality at 30 days. There were two cases of type II endoleak treated conservatively and a single case of IBG-related type III endoleak that required repeat intervention. The rest of the stent-implanted aortic and iliac aneurysms remained stable in size, with no aneurysm rupture or death recorded. All stent-implanted iliac branches remained patent on follow-up. None of the patients who received IBGs had new symptoms of pelvic ischemia. Conclusions Iliac branch graft placement is a feasible technique with excellent short-term results in the treatment of aortoiliac aneurysms.

A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E(2) (PGE(2)). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE(2) has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE(2) synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of E-prostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI(2) receptor (IP), thromboxane A(2) receptor (TP), PGD(2) receptor (DP), and PGF(2) receptor (FP), efficiently blocked LPS-induced tumor necrosis factor α (TNFα) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNFα, interleukin 1β (IL-1β), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNFα and IL-1β synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE(2) followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE(2) in resolution of neuroinflammation.

Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after HS and resuscitation (HS/R) with the administration of the MC stabilizers to prevent MC degranulation. Anesthetized male Sprague-Dawley rats were randomized to sham-operated control or HS/R groups and underwent 60 min of HS followed by 2 h of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline 15 min before shock. Hearts were excised following HS or 2 h of reperfusion, and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum β-hexosaminidase. Hearts were excised at 0 min (before HS) and following 60 min of HS (before resuscitation) for a histological evaluation of MC density and degranulation. In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure ( P < 0.05), contractility ( P < 0.05), and relaxation ( P < 0.05) compared with that of HS controls. Serum β-hexosaminidase increased during HS/R and was inhibited by MC stabilization ( P < 0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. The inhibition of MC degranulation can significantly improve cardiac function following HS/R.

Background— Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE 2 biosynthetic pathway. We caused acute MI in Ptges +/+ and Ptges −/− mice to define the role of mPGES-1 in cardiac ischemic injury. Methods and Results— Twenty-eight days after MI, Ptges −/− mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges +/+ mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges −/− than Ptges +/+ mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges −/− mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and α- and β-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges −/− than Ptges +/+ mice after MI. Ptges +/+ mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges −/− mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE 2 but not PGD 2 , thromboxane A 2 , PGI 2 , or PGF 2α are higher in the infarct and LV remote from the infarct after MI in Ptges +/+ than Ptges −/− mice. Conclusions— In Ptges +/+ mice, mPGES-1 in inflammatory cells catalyzes PGE 2 biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.

Objective This study determined the 30-day morbidity and mortality and in-hospital costs of elective fenestrated (fEVAR) and branched (bEVAR) endovascular aneurysm repairs at a single academic institution and determined factors that influence them. Methods All elective fEVAR or bEVAR patients treated between November 2007 and March 2014 in a Canadian academic hospital were included. Procedural details, 30-day morbidity and mortality rates, and cost of hospitalization were analyzed. Nonparametric bootstrap analysis was used to compare means between groups and calculate confidence intervals (CIs). Results There were 84 consecutive fEVAR (n = 61) and bEVAR (n = 23) procedures. The 30-day mortality was 3.3% for fEVAR and 4.3% for bEVAR. Mean hospital stay was 7.2 ± 0.8 days for fEVAR and 12.6 ± 2.2 days for bEVAR. The mean cost of the index hospitalization was $57,000 for fEVAR and $91,000 for bEVAR. Device-related costs accounted for 55% of the total costs. The occurrence of intraoperative or postoperative events were used to further divide each of the fEVAR and bEVAR groups into "complicated hospitalization" (fEVAR, n = 10; bEVAR, n = 13) and "uncomplicated hospitalization" (fEVAR, n = 51; bEVAR, n = 10) groups. Device-related costs were not significantly different between the complicated and uncomplicated hospitalization groups (mean difference [95% CI] fEVAR: $3383 [–$3405 to $9809], P = .3; and bEVAR: $1930 [−$7892 to $11,288], P = .68). However, there were significant differences between the complicated and uncomplicated hospitalization groups in hospital length of stay (mean difference [95% CI] fEVAR: 8.1 [3.0-13.2] days, P = .001; and bEVAR: 10.8 [5.9-19.9] days, P = .002) and nondevice-related costs (mean difference [95% CI,] fEVAR: $25,843 [$11,689-$43,247], P = .001; and bEVAR; $20,326 [$9362-$36,615], P = .002). Conclusions bEVAR and fEVAR are expensive interventions. Intraoperative adverse events and postoperative systemic complications dramatically increase costs and length of stay. Measures to minimize complications will reduce hospitalization costs and improve patient outcomes.

This study compared the surgical, oncological, and functional outcomes of patients undergoing limb-salvage surgery for extremity soft tissue sarcoma with vascular resection and reconstruction with the outcomes of those undergoing limb-salvage without vascular reconstruction.Nineteen patients were identified from a prospective soft-tissue sarcoma database who underwent vascular resection and reconstruction as part of their limb-salvage surgery and who were followed up for at least 1 year or until death. Each of these 19 patients was case-matched to 2 additional patients on the basis of tumor location, size, and depth; patient age; and timing of radiation. To compare functional outcome, a subset of patients was case-matched with additional criteria including wound-complication status, motor nerve sacrifice, similar preoperative function as determined by the Toronto Extremity Salvage Score, and no metastases at diagnosis or the 1-year follow-up.Patients in the vascular reconstruction group were more likely to require a muscle transfer (53% vs. 18%; P = .008), experience a wound complication (68% vs. 32%; P = .03), experience deep venous thrombosis (26% vs. 0; P = .003), experience significant limb edema (87% vs. 20%; P = .001), and ultimately require an amputation (16% vs. 3%; P = .07). Patients who underwent vascular reconstruction had only slightly lower Toronto Extremity Salvage Score scores 1 year after surgery (78.5 vs. 84.2; P = .35). There were no significant differences in local or systemic tumor relapse between the two groups.Vascular reconstruction is a feasible option in limb-salvage surgery for soft tissue sarcoma but is associated with an increased risk for postoperative complications, including amputation. Although function is not significantly worse after vascular reconstruction, the results are less predictable.

BackgroundRuptured abdominal aortic aneurysm (RAAA) is associated with a systemic inflammatory response syndrome and multiple organ dysfunction. The potential role of a novel C5 complement inhibitor in attenuation of pathological complement activation and tissue injury was explored in a model of RAAA.MethodsAnaesthetized rats were randomized to sham (control) or shock and clamp (SC) groups. Animals in the SC group underwent 1 h of haemorrhagic shock (mean arterial pressure 50 mmHg or less), 45 min of supramesenteric aortic clamping and 2 h of reperfusion. They were randomized to receive an intravenous bolus of a functionally blocking anti-C5 monoclonal antibody (C5 inhibitor), at a dose of 20 mg/kg, or saline. Lung injury was assessed by permeability to 125I-labelled albumin, tissue myeloperoxidase (MPO) activity, and semiquantitative reverse transcriptase–polymerase chain reaction (RT–PCR) for mRNAs encoding tumour necrosis factor (TNF) α and interleukin (IL) 6.ResultsThe lung permeability index was significantly increased in the SC compared with the sham group (P = 0·032); this was prevented by the C5 inhibitor (P = 0·015). Lung MPO activity was significantly increased in the SC compared with the sham group (P < 0·001), and this increase was attenuated by treatment with the C5 inhibitor (P < 0·001). Semiquantitative RT–PCR in SC group demonstrated downregulation of TNF-α mRNA (P = 0·050) and upregulation of IL-6 mRNA (P < 0·001), which were both prevented by the C5 inhibitor (P = 0·014 and P < 0·001 respectively).ConclusionThese results indicated that C5 complement inhibition can reduce shock and acute lung injury in an experimental model of RAAA.

The role of a cytosolic phospholipase A2-α (cPLA2-α) in neutrophil arachidonic acid release, platelet-activating factor (PAF) biosynthesis, NADPH oxidase activation, and bacterial killing in vitro, and the innate immune response to bacterial infection in vivo was examined. cPLA2-α activity was blocked with the specific cPLA2-α inhibitor, Pyrrolidine-1 (human cells), or by cPLA2 -α gene disruption (mice). cPLA2-α inhibition or gene disruption led to complete suppression of neutrophil arachidonate release and PAF biosynthesis but had no effect on neutrophil NADPH oxidase activation, FcγII/III or CD11b surface expression, primary or secondary granule secretion, or phagocytosis of Escherichia coli in vitro. In contrast, cPLA2-α inhibition or gene disruption diminished neutrophil-mediated E. coli killing in vitro, which was partially rescued by exogenous arachidonic acid or PAF but not leukotriene B4. Following intratracheal inoculation with live E. coli in vivo, pulmonary PAF biosynthesis, inflammatory cell infiltration, and clearance of E. coli were attenuated in cPLA2-α(–/–) mice compared with wild type littermates. These studies identify a novel role for cPLA2-α in the regulation of neutrophil-mediated bacterial killing and the innate immune response to bacterial infection.

Objective Abdominal aortic aneurysm rupture is associated with a systemic inflammatory response syndrome and acute lung injury. Using a selective inducible nitric oxide synthase (iNOS) inhibitor, N6-(iminoethyl)-lysine (L-NIL), we explored the role of iNOS in the early pro-inflammatory signaling and acute lung injury in experimental abdominal aortic aneurysm rupture. Materials and methods Anesthetized rats were randomized to sham control or shock and clamp (s + c) groups, which underwent one hour of hemorrhagic shock, followed by 45 minutes of supramesenteric aortic clamping, and then two hours resuscitated reperfusion. Animals in s + c were randomized to receive intravenous L-NIL at 50 μg/kg/h or saline at the start of reperfusion. Pulmonary permeability to 125I-labeled albumin, myeloperoxidase (MPO) activity, cytokine levels, and semi-quantitative RT-PCR for mRNA were indicators of microvascular permeability, leuco-sequestration, and pro-inflammatory signaling, respectively. Results Lung permeability index were significantly increased in s + c compared to sham (4.43 ± 0.96 versus 1.30 ± 0.17, P Conclusions These data suggest that in our model of ruptured abdominal aortic aneurysm iNOS plays a crucial role in reperfusion lung injury. Selective inhibition of iNOS during early reperfusion prevents neutrophil mediated acute lung injury.

ObjectiveAbdominal aortic aneurysm (AAA) rupture is associated with a systemic inflammatory response syndrome, characterized by increased microvascular permeability and neutrophil sequestration, leading to multiorgan dysfunction. We examined the role of a novel complement factor 5a (C5aR) receptor antagonist, the cyclic peptide AcF-(OpdChaWR), in attenuation of pathologic complement activation and tissue injury in a model of AAA rupture.MethodsAnesthetized rats were randomized to sham (control) or shock and clamp (s+c) groups. Animals in the s+c group underwent 1 hour of hemorrhagic shock (mean arterial blood pressure ≤50 mm Hg), followed by 45 minutes of supramesenteric aortic clamping, then 2 hours of resuscitated reperfusion. Animals in the s+c group were randomized to receive an intravenous bolus of C5aR antagonist at 1 mg/kg or saline solution control at the end of hemorrhagic shock. Intestinal and pulmonary permeability to iodine 125–labeled albumin was measured as an indicator of microvascular permeability. Tissue myeloperoxidase activity, proinflammatory cytokine tissue necrosis factor-α (TNF-α) protein and mRNA, and C5aR mRNA levels were measured as indicators of neutrophil sequestration and inflammatory signaling, respectively.ResultsLung permeability index was significantly increased in the s+c group compared with the sham group (4.43 ± 0.96 vs 1.30 ± 0.17; P < .01), and prevented with treatment with C5aR antagonist (1.74 ± 0.50; P < .03). Lung myeloperoxidase activity was significantly increased in the the s+c group compared with the sham group (2.41 ± 0.34 U/mg vs 1.03 ± 0.29 U/mg; P < .009), and significantly attenuated with treatment with C5aR antagonist (1.11 ± 0.09 U/mg; P < .006). Lung TNF-α protein levels were significantly elevated in both s+c groups, whereas lung TNF-α mRNA expression was significantly downregulated in both s+c groups compared with the sham group. Intestinal permeability index was significantly increased in animals in the s+c groups during reperfusion, compared with sham (P < .001), which was attenuated in early reperfusion with treatment with C5a receptor antagonist. Data represent mean ± SEM, group comparisons with analysis of variance and post hoc Scheffé test.ConclusionsThese results indicate that a potent antagonist of C5a receptor protects the rat intestine and lung from neutrophil-associated injury in a model of AAA rupture. These data suggest that complement-mediated inflammation can be modulated at the C5a receptor level, independent of proinflammatory TNF-α production, and prevent acute local and remote organ injury.

Advances in renal transplantation have allowed for improved survival and an increased age of recipients. This has resulted in more aortoiliac lesions requiring intervention. The optimal approach for renal protection during aortoiliac surgery remains unknown. A retrospective review of transplant patients admitted to Toronto General Hospital for aortoiliac reconstruction between 1990 and 2000 was performed. A total of 20 aortic reconstructions were carried out in 18 patients: 5 patients with ascending aortic repairs and 15 patients with aortoiliac reconstructions. Of the five ascending repairs, all had cardiopulmonary bypass and four were performed under hypothermic arrest. There was one allograft loss in the postoperative period and one mortality. Of the 15 aortoiliac reconstructions 12 had protection: 10 temporary axillofemoral artery bypasses and 2 renal cold perfusion. In the 10 patients with temporary bypass protection, there were no graft losses. There was no graft loss in the hypothermic perfusion group. Of the three patients without protection, there was one graft loss. The postoperative rise in serum creatinine was significantly higher (p0.05) in the no-protection group than in those receiving temporary bypass protection. Our algorithm of (1). temporary axillofemoral bypass, (2). cold perfusion if temporary bypass cannot be performed, and (3). clamp and sew if the patient is too unstable allows for surgery with excellent graft survival.

The bacterial tripeptide formyl-Met-Leu-Phe (fMLP) induces the secretion of enzyme(s) with phospholipase A2 (PLA2) activity from human neutrophils. We show that circulating human neutrophils express groups V and X sPLA2 (GV and GX sPLA2) mRNA and contain GV and GX sPLA2 proteins, whereas GIB, GIIA, GIID, GIIE, GIIF, GIII, and GXII sPLA2s are undetectable. GV sPLA2 is a component of both azurophilic and specific granules, whereas GX sPLA2 is confined to azurophilic granules. Exposure to fMLP or opsonized zymosan results in the release of GV but not GX sPLA2 and most, if not all, of the PLA2 activity in the extracellular fluid of fMLP-stimulated neutrophils is due to GV sPLA2. GV sPLA2 does not contribute to fMLP-stimulated leukotriene B4 production but may support the anti-bacterial properties of the neutrophil, because 10–100 ng per ml concentrations of this enzyme lead to Gram-negative bacterial membrane phospholipid hydrolysis in the presence of human serum. By use of a recently described and specific inhibitor of cytosolic PLA2-α (group IV PLA2α), we show that this enzyme produces virtually all of the arachidonic acid used for the biosynthesis of leukotriene B4 in fMLP- and opsonized zymosan-stimulated neutrophils, the major eicosanoid produced by these pro-inflammatory cells.

The purpose of this study was to define the role of secretory phospholipase A2 (sPLA2), calcium-independent PLA2, and cytosolic PLA2 (cPLA2) in arachidonic acid (AA) release from fMLP-stimulated human neutrophils. While fMLP induced the release of extracellular sPLA2 activity and AA, 70% of sPLA2 activity remained associated with the cell. Treatment with the cell-impermeable sPLA2 inhibitors DTT or LY311-727, or the anti-sPLA2 Ab 3F10 all inactivated extracellular sPLA2 activity, but had minimal effect on neutrophil AA mass release. In contrast, coincubation of streptolysin-O toxin-permeabilized neutrophils with DTT, LY311-727, or 3F10 all decreased [3H8]AA release from [3H8]AA-labeled, fMLP-stimulated cells. Exposure to fMLP resulted in a decrease in the electrophoretic mobility of cPLA2, a finding consistent with cPLA2 phosphorylation, and stimulated the translocation of cPLA2 from cytosolic to microsomal and nuclear compartments. The role of cPLA2 was further evaluated with the cPLA2 inhibitor methyl arachidonyl fluorophosphonate, which attenuated cPLA2 activity in vitro and decreased fMLP-stimulated AA mass release by intact neutrophils, but had no effect on neutrophil sPLA2 activity. Inhibition of calcium-independent PLA2 with haloenol lactone suicide substrate had no effect on neutrophil cPLA2 activity or AA mass release. These results indicate a role for cPLA2 and an intracellular or cell-associated sPLA2 in the release of AA from fMLP-stimulated human neutrophils.

Purpose: Ruptured abdominal aortic aneurysm (RAAA) remains a lethal condition despite improvements in perioperative care. The consequences of RAAA are hypothesized to result from a combination of two ischemia/reperfusion events: hemorrhagic shock and lower torso ischemia. Ischemia/reperfusion results in tissue injury by diverse mechanisms, which include oxygen free radical–mediated injury produced from activated neutrophils, xanthine oxidase, and mitochondria. Oxygen-free radicals attack membrane lipids, resulting in membrane and subsequently cellular dysfunction that contributes to postoperative organ injury/failure. The purpose of this investigation was to quantify the oxidative injury that occurs as a result of the ischemia/reperfusion events in RAAAs and elective AAAs. Methods: Blood samples were taken from 22 patients for elective AAA repair and from 14 patients for RAAA repair during the perioperative period. Plasma F2 -isoprostanes were extracted, purified, and measured with an enzyme immunoassay. Aldehydes and acyloins were purified and quantified. Neutrophil oxidative burst was measured in response to a receptor independent stimulus (phorbol 12-myristate 13-acetate) with luminol-based chemiluminescence. Results: Plasma from patients with RAAAs showed significantly elevated F2 -isoprostane levels on arrival at hospital and were significantly elevated as compared with the levels of patients for elective repair throughout the perioperative period (two-way analysis of variance, P < .0001). Multiple regression showed a significant relationship between the phagocyte oxidative activity and F2 -isoprostane levels (P < .013). Total acyloin levels were significantly higher in patients with RAAAs as compared with the levels in elective cases. Conclusion: The F2 -isoprostane levels, specific markers of lipid peroxidation, showed that patients with RAAAs had two phases of oxidative injury: before arrival at hospital and after surgery. The significant relationship between the postoperative increases in F2 -isoprostane levels and the neutrophil oxidant production implicates neutrophils in the oxidative injury that occurs after RAAA. New therapeutic interventions that attenuate neutrophil-mediated oxidant injury during reperfusion may decrease organ failure and ultimately mortality in patients with RAAAs. (J Vasc Surg 1999;30:219-28.)

Exposure of neutrophils to inflammatory stimuli such as the chemoattractant FMLP leads to activation of responses including cell motility, the oxidative burst, and secretion of proteolytic enzymes. A signaling cascade involving sequential activation of Raf-1, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) is also rapidly activated after agonist exposure. The temporal relationship between these events suggests that the kinases may be involved in triggering the effector functions, but direct evidence of a causal relationship is lacking. To assess the role of the MEK/ERK pathway in the activation of neutrophil responses, we studied the effects of PD098059, a potent and selective inhibitor of MEK. Preincubation of human neutrophils with 50 μM PD098059 almost completely (>90%) inhibited the FMLP-induced activation of MEK-1 and MEK-2, the isoforms expressed by neutrophils. This dose of PD098059 virtually abrogated chemoattractant-induced tyrosine phosphorylation and activation of ERK-1 and ERK-2, implying that MEKs are the predominant upstream activators of these mitogen-activated protein kinases. Pretreatment of neutrophils with the MEK antagonist inhibited the oxidative burst substantially and phagocytosis only moderately. In addition, PD098059 antagonized the delay of apoptosis induced by exposure to granulocyte-macrophage CSF. However, the effects of PD098059 were selective, as it failed to inhibit other responses, including chemoattractant-induced exocytosis of primary and secondary granules, polymerization of F-actin, chemotaxis, or activation of phospholipase A2. We conclude that MEK and ERK contribute to the activation of the oxidative burst and phagocytosis, and participate in cytokine regulation of apoptosis.

The role of Group X secreted phospholipase A2 (GX-sPLA2) during influenza infection has not been previously investigated. We examined the role of (Reviewer 2 Minor Comment 2) GX-sPLA2 during H1N1 pandemic influenza infection in a GX-sPLA2 gene targeted mouse (GX−/−) model and found that survival after infection was significantly greater in GX−/− mice than in GX+/+ mice. Downstream products of GX-sPLA2 activity, PGD2, PGE2, LTB4, cysteinyl leukotrienes and Lipoxin A4 were significantly lower in GX−/− mice BAL fluid. Lung microarray analysis identified an earlier and more robust induction of T and B cell associated genes in GX−/− mice. Based on the central role of sPLA2 enzymes as key initiators of inflammatory processes, we propose that activation of GX-sPLA2 during H1N1pdm infection is an early step of pulmonary inflammation and its (Reviewer 2 Minor Comment 2) inhibition increases adaptive immunity and improves survival. Our findings suggest that GX-sPLA2 may be a potential therapeutic target during influenza.

Introduction: Chemokines are small proteins that regulate different cellular functions, such as leukocyte activation, chemoattraction and inflammation. The chemokine CXCL14 (BRAK) is a highly conserved gene among species and through evolution. It has been shown that CXCL14 is locally upregulated during viral infections, also, it has been found that this chemokine possesses direct antibacterial activities. Nonetheless, the exact role that CXCL14 plays during infection remains elusive. Methodology: CXCL14 deficient mice were generated in a C57B6/129 background and followed by phenotypic characterization. Later, the effect of CXCL14 deficiency during influenza infection and E. coli challenge was assessed. Results: Other than a slight weight reduction, CXCL14 deficient mice exhibited no phenotypic alterations. CXCL14 deficiency did not influence the outcome of influenza virus infection or challenge with E. coli, and no statistically significant differences in clinical signs, cellular responses and histopathological findings were observed. Conclusions: CXCL14 does not seem to play a pivotal role during influenza and E. coli infections of the lung; these results are suggestive of functional overlap between CXCL14 and other chemokines that are present during lung infection.

Objectives We and others have reported the early experience with off-label use of thoracic aortic endografts to facilitate the resection of tumors infiltrating the aorta. We describe our extended experience and long-term outcome using this innovative approach. Methods Patients with preoperative suspected thoracic aortic infiltration who underwent endografting followed by en bloc tumor resection including the aortic wall were retrospectively reviewed and data were analyzed. Results Between 2008 and 2012, 5 patients (4 female) with a median age of 52 years (34-63 years) were included. Tumors infiltrating the aorta were non–small cell lung carcinomas (n = 3) and sarcomas (n = 2). Both patients with sarcoma had neoadjuvant radiation, whereas patients with non–small cell lung carcinomas had neoadjuvant (n = 2) or adjuvant chemoradiation (n = 1). Aortic endografting was performed 1 to 17 days before resection of the tumor. The proximal end of the stent-graft was deployed in the aortic arch (n = 2) or the descending aorta (n = 3). The tumor was resected en bloc in all patients and combined with chest wall and 2 to 3 levels of spinal resection in 4 of the 5 patients. Two patients with full-thickness aortic wall resection had additional buttressing of the defect. Cardiopulmonary bypass was never required. One patient had an empyema requiring debridements and thoracic window. After a median follow-up of 39 months (range, 9-62 months), all patients were alive and disease-free. None of them had overt endograft-related complications. Conclusions Thoracic aortic endografting allowed safe en bloc resection of tumors invading the aortic wall. Therefore, the indication for thoracic aortic endografts could be extended to specific oncologic cases.

Management of vascular surgical emergencies requires rapid access to a vascular surgeon and hospital with the infrastructure necessary to manage vascular emergencies. The purpose of this study was to assess the impact of regionalization of vascular surgery services in Toronto to University Health Network (UHN) and St Michael's Hospital (SMH) on the ability of CritiCall Ontario to transfer patients with life- and limb-threatening vascular emergencies for definitive care. A retrospective review of the CritiCall Ontario database was used to assess the outcome of all calls to CritiCall regarding patients with vascular disease from April 2003 to March 2010. The number of patients with vascular emergencies referred via CritiCall and accepted in transfer by the vascular centers at UHN or SMH increased 500% between 1 April 2003-31 December 2005 and 1 January 2006-31 March 2010. Together, the vascular centers at UHN and SMH accepted 94.8% of the 1002 vascular surgery patients referred via CritiCall from other hospitals between 1 January 2006 and 31 March 2010, and 72% of these patients originated in hospitals outside of the Toronto Central Local Health Integration Network. Across Ontario, the number of physicians contacted before a patient was accepted in transfer fell from 2.9 ± 0.4 before to 1.7 ± 0.3 after the vascular centers opened. In conclusion, the vascular surgery centers at UHN and SMH have become provincial resources that enable the efficient transfer of patients with vascular surgical emergencies from across Ontario. Regionalization of services is a viable model to increase access to emergent care.

Evolution of H1N1 influenza A outbreaks of the past 100 years is interesting and significantly complex and details of H1N1 genetic drift remains unknown. Here we investigated the clinical characteristics and immune cross-reactivity of significant historical H1N1 strains. We infected ferrets with H1N1 strains from 1943, 1947, 1977, 1986, 1999, and 2009 and showed each produced a unique clinical signature. We found significant cross-reactivity between viruses with similar HA sequences. Interestingly, A/FortMonmouth/1/1947 antisera cross-reacted with A/USSR/90/1977 virus, thought to be a 1947 resurfaced virus. Importantly, our immunological data that didn't show cross-reactivity can be extrapolated to failure of past H1N1 influenza vaccines, ie. 1947, 1986 and 2009. Together, our results help to elucidate H1N1 immuno-genetic alterations that occurred in the past 100 years and immune responses caused by H1N1 evolution. This work will facilitate development of future influenza therapeutics and prophylactics such as influenza vaccines.

taken, namely that the length of the trimmed catheter was approximately the same length as the wire fragment, and that a ball weld was not seen at either end of the wire fragment (Fig 5). In conclusion, care must be taken to withdraw the Jtipped wire sufficiently out of a PICC before the length is trimmed, and the extension line clamp must be left open until the J-tipped wire has been removed. Also, visual inspection of the wire should be done to confirm that the wire was removed intact. Simultaneous failure to accomplish these three simple tasks may result in an intravascular foreign body.

Pandemic H1N1 influenza A (H1N1pdm) is currently a dominant circulating influenza strain worldwide. Severe cases of H1N1pdm infection are characterized by prolonged activation of the immune response, yet the specific role of inflammatory mediators in disease is poorly understood. The inflammatory cytokine IL-6 has been implicated in both seasonal and severe pandemic H1N1 influenza A (H1N1pdm) infection. Here, we investigated the role of IL-6 in severe H1N1pdm infection. We found IL-6 to be an important feature of the host response in both humans and mice infected with H1N1pdm. Elevated levels of IL-6 were associated with severe disease in patients hospitalized with H1N1pdm infection. Notably, serum IL-6 levels associated strongly with the requirement of critical care admission and were predictive of fatal outcome. In C57BL/6J, BALB/cJ, and B6129SF2/J mice, infection with A/Mexico/4108/2009 (H1N1pdm) consistently triggered severe disease and increased IL-6 levels in both lung and serum. Furthermore, in our lethal C57BL/6J mouse model of H1N1pdm infection, global gene expression analysis indicated a pronounced IL-6 associated inflammatory response. Subsequently, we examined disease and outcome in IL-6 deficient mice infected with H1N1pdm. No significant differences in survival, weight loss, viral load, or pathology were observed between IL-6 deficient and wild-type mice following infection. Taken together, our findings suggest IL-6 may be a potential disease severity biomarker, but may not be a suitable therapeutic target in cases of severe H1N1pdm infection due to our mouse data., This work was supported by the Li Ka Shing Foundation and Immune Diagnostics & Research. Dr. Alyson A. Kelvin is the Scientific Director for Immune Diagnostics & Research and had input into experimental design and write-up of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background— Microsomal prostaglandin E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E 2 biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges −/− mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges +/+ mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow–derived leukocytes in the recovery of LV function after coronary ligation. Methods and Results— Cardiac structure and function in Ptges +/+ mice with Ptges +/+ bone marrow ( BM +/+ ) and Ptges +/+ mice with Ptges −/− BM ( BM −/− ) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography–tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM −/− mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM +/+ mice. BM −/− mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM +/+ mice. Levels of prostaglandin E 2 were higher in the infarct and viable myocardium of BM −/− mice than in BM +/+ mice. Conclusions— Lack of mPGES-1 in bone marrow–derived leukocytes negatively regulates COX-1 expression, prostaglandin E 2 biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction.

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.

International audience; Group V-secreted phospholipase A(2) (GV sPLA(2)) hydrolyzes bacterial phospholipids and initiates eicosanoid biosynthesis. Here, we elucidate the role of GV sPLA(2) in the pathophysiology of Escherichia coli pneumonia. Inflammatory cells and bronchial epithelial cells both express GV sPLA(2) after pulmonary E. coli infection. GV(-/-) mice accumulate fewer polymorphonuclear leukocytes in alveoli, have higher levels of E. coli in bronchoalveolar lavage fluid and lung, and develop respiratory acidosis, more severe hypothermia, and higher IL-6, IL-10, and TNF-α levels than GV(+/+) mice after pulmonary E. coli infection. Eicosanoid levels in bronchoalveolar lavage are similar in GV(+/+) and GV(-/-) mice after lung E. coli infection. In contrast, GV(+/+) mice have higher levels of prostaglandin D(2) (PGD(2)), PGF(2α), and 15-keto-PGE(2) in lung and express higher levels of ICAM-1 and PECAM-1 on pulmonary endothelial cells than GV(-/-) mice after lung infection with E. coli. Selective deletion of GV sPLA(2) in non-myeloid cells impairs leukocyte accumulation after pulmonary E. coli infection, and lack of GV sPLA(2) in either bone marrow-derived myeloid cells or non-myeloid cells attenuates E. coli clearance from the alveolar space and the lung parenchyma. These observations show that GV sPLA(2) in bone marrow-derived myeloid cells as well as non-myeloid cells, which are likely bronchial epithelial cells, participate in the regulation of the innate immune response to pulmonary infection with E. coli.

Skeletal muscle ischemia results in energy depletion and intracellular acidosis. Reperfusion is associated with impaired adenine nucleotide resynthesis, edema formation, and myocyte necrosis. The purpose of these studies was to define the time course of cellular injury and adenine nucleotide depletion and resynthesis in postischemic skeletal muscle during prolonged reperfusion in vivo. The isolated canine gracilis muscle model was used. After 5 h of ischemia, muscles were reperfused for either 1 or 48 h. Lactate and creatine phosphokinase (CPK) release during reperfusion was calculated from arteriovenous differences and blood flow. Adenine nucleotides, nucleosides, bases, and creatine phosphate were quantified by high-performance liquid chromatography, and muscle necrosis was assessed by nitroblue tetrazolium staining. Reperfusion resulted in a rapid release of lactate, which paralleled the increase in blood flow, and a delayed but prolonged release of CPK. Edema formation and muscle necrosis increased between 1 and 48 h of reperfusion (P less than 0.05). Recovery of energy stores during reperfusion was related to the extent of postischemic necrosis, which correlated with the extent of nucleotide dephosphorylation during ischemia (r = 0.88, P less than 0.001). These results suggest that both adenine nucleotide resynthesis and myocyte necrosis, which are protracted processes in reperfusing skeletal muscle, are related to the extent of nucleotide dephosphorylation during ischemia.

In this clinical study we have prospectively measured plasma phospholipase A2 (PLA2) activity and tumor necrosis factor (TNF) levels in ventilated intensive care unit (ICU) patients with (n = 9) and without (n = 12) evidence of respiratory distress syndrome (ARDS) and multiple-organ failure (MOF). The median peak TNF concentration in control patients was 40 ng/L (range less than 40-100 ng/L) and in ARDS patients 231 ng/L (range 100-2550 ng/L; p less than 0.001). All of the control patients were discharged alive from the ICU, whereas 6 of 9 ARDS patients died in the ICU. In 6 ARDS patients, it was possible to measure more than 4 consecutive plasma TNF levels. Of these 6 patients, the 3 with persistent elevations in systemic TNF above 230 ng/L succumbed (p less than 0.05, one-tailed). Patients with ARDS also had parallel elevations in plasma PLA2 activity above controls. These elevations were significant for arterial PLA2 activity but not for venous PLA2 activity. Our study suggests that serial measurement of plasma (arterial or venous) TNF levels may have (1) prognostic and (2) etiologic significance in ICU patients with ARDS and MOF.

BACKGROUND: Transcatheter aortic valve implantation (TCAVI) is an emerging alternative therapy to open-heart surgery in high-risk patients with symptomatic aortic stenosis. METHODS: Between January 2007 and May 2009, 46 patients underwent TCAVI with the 23 mm or 26 mm Edwards Sapien bioprosthesis via either the transapical (TA-AVI) or transfemoral (TF-AVI) approach. All patients had an estimated operative mortality risk of >15%. RESULTS: A total of 46 patients (30 TA-AVI, 16 TF-AVI) with a mean aortic valve area (AVA) of 0.63 +/- 0.2 cm(2) and mean gradient of 54 +/- 16 mm Hg were treated. Predicted operative mortality was 25.3% by logistic Euroscore and 8.7% by Society of Thoracic Surgeons risk score. Procedural success was 93% in the TA-AVI group and 88% in the TF-AVI group. There was one intraprocedural death in the TA-AVI group. Overall 30-day mortality was 6.5% (2-TA-AVI, 1-TF-AVI). Four patients (9.5%) died from noncardiac causes after 30 days. Successful TCAVI was associated with a significant increase in AVA from 0.6 +/- 0.1 cm(2) to 1.6 +/- 0.6 cm(2) in the TA-AVI group and 0.6 +/- 0.1 cm(2) to 1.4 +/- 0.2 cm(2) in the TF-AVI group at a mean follow up of 7.4 +/- 4.4 and 8.3 +/- 5.0 months, respectively. At discharge, there was significant improvement in AVA (P < 0.0001), transaortic mean gradient (P < 0.0001), and mitral regurgitation (P = 0.01). At medium term follow up, the valve area was maintained and there was significant improvement in NYHA class in both groups (P < 0.0001). CONCLUSION: At medium term follow-up, both transcatheter approaches demonstrated good valve durability with no cardiac-related mortality post hospital discharge.

The advent and success of endovascular repair of abdominal aneurysms led to the development of catheter-based techniques to treat thoracic aortic pathology. Such diseases, including thoracic aortic aneurysms, acute and chronic type B dissections, penetrating aortic ulcers, and traumatic aortic transection, challenge surgeons to perform complex open operative repairs in high-risk patients. The minimally invasive nature of thoracic endografting provides an attractive alternative therapy. We present two cases of covered stent grafts deployed in the thoracic aorta to perform resection of the aortic wall infiltrated by malignancy in order to avoid a major vascular intervention and a traditional vascular graft interposition. This may become a potential new utility for aortic endografts.