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The past 3 years have witnessed extraordinary progress in our understanding of mammalian iron transport and homeostasis. The first transmembrane iron transporter has been found. Mutations in this protein, in two animal models with iron-transport defects, have helped to define the roles of this protein in vivo. The gene defective in patients with hereditary hemochromatosis has been identified, and much has been learned about the structure and function of its gene product. Finally, our ability to make a molecular diagnosis of hereditary hemochromatosis has called attention to new iron-loading disorders, including African iron overload and juvenile hemochromatosis.

SummaryAdult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism.

The human and organizational factors affecting safety were examined on 10 offshore installations using the Offshore Safety Questionnaire. The questionnaire contained scales measuring work pressure and work clarity, job communication, safety behaviour, risk perception, satisfaction with safety measures and safety attitudes. A total of 722 UK offshore workers (33% response rate) from a range of occupations completed and returned the questionnaire. The ‘safety climates’ on the various installations were characterized by most respondents feeling ‘safe’ with respect to a range of offshore hazards and expressing ‘satisfaction’ with safety measures. Respondents reported little risk-taking behaviour and felt positive about levels of work clarity and job communication. There was a wider diversity of opinions on the safety attitudes scale, indicating a lack of a positive, concerted ‘safety culture’ and more evidence for a range offragmented ‘safety subcultures’, which varied mainly as a function of seniori...

Myelopoiesis is a developmental process through which stem cells give rise to mature monocytes and granulocytes by means of a tightly regulated cellular program. The molecular mechanisms controlling myelopoiesis are incompletely understood, as are the abnormalities in this process that give rise to myeloid cell diseases, such as leukemia, myelodysplasia, and myeloproliferative syndromes. These diseases are commonly associated with somatically acquired large chromosomal deletions, making the identification of the causative tumor suppressor genes difficult. To learn more about the genes required for normal myelopoiesis, which we postulated might be mutated during the molecular pathogenesis of myeloid malignancies, we performed a screen using a panel of insertional mutants provided by Nancy Hopkins (MIT) to identify zebrafish lines with deficiencies in myeloperoxidase (mpo), a gene specifically expressed in granulocytes. As part of this screen, we identified the line hi2648, in which homozygous mutants have a severe reduction in the numbers of mature myeloid cells expressing either mpo or l-plastin, and in which the small numbers of residual myeloid cells are abnormally large. We bred hi2648 mutant fish to a line carrying the pu.1:GFP transgene and found that the homozygous mutant embryos displayed decreased numbers but relatively large GFP-positive cells, which were also observed in cytospins of FACS-purified, GFP-expressing cells, consistent with our in situ analysis. Hi2648 harbors a retroviral insertion that disrupts the gene emi1 between exons one and two, resulting in decreased levels of emi1 RNA assayed by whole- mount in situ analysis. We confirmed that the hematopoietic phenotype in this line is due to disruption of emi1 by showing that we could phenocopy the mutant using emi1-specific morpholinos and also by rescuing the mutant phenotype using forced expression of emi1 RNA. The Emi1 gene product has been shown to inhibit anaphase-promoting complex during interphase of the cell cycle. We analyzed emi1-mutant embryos for cell cycle defects by FACS analysis of propidium-iodide stained cells at 21 hpf, and showed that impaired emi1 expression results in an accumulation of cells in G2 phase, presumably due to premature activation of APC during S- and G2-phase with an inability to accumulate adequate levels cyclin B. We also observed a range of increased of levels of cellular DNA content greater than the normal 4n complement, suggesting that loss of emi1 also promotes abortive endoreduplication. Mutational analysis indicated gene-specific disruption in of emi1 in a human leukemia cell line, suggesting that this gene represents one of the long-sought haploinsufficient tumor suppressors located on the long arm of human chromosome 6 (del 6q), whose loss promotes genomic instability during leukemogenesis and the progression of MDS to AML in man.

ObjectiveThe purpose of this study was to compare outcomes after endovascular repair (ER) and contemporary open repair (OR) of popliteal artery aneurysms (PAAs).MethodsClinical data of PAA patients treated between 2005 and 2012 were reviewed. Primary end points were major adverse events (MAEs) including mortality, major amputation, patency, complications, and reinterventions.ResultsA total of 149 PAAs were treated in 120 patients (mean age, 74 ± 10 years). ER was performed in 42 limbs of 35 men (mean age, 81 ± 6.5 years), in 32 electively and in 10 emergently. Technical success was 98%. The 30-day MAEs were more frequent after emergent repair (50% vs 9%; odds ratio [OR], 9.67; 95% confidence interval [CI], 1.74-54; P = .01); mortality and amputation rate was 0% after elective repair, 20% after emergent repair. Mean follow-up was 2.6 years (1 month-6.5 years); 3-year freedom from MAEs was lower after emergent repair than after elective repair (40% vs 66%; hazard ratio [HR], 3.13; 95% CI, 1.10-8.85; P = .03). OR was performed in 107 limbs of 91 patients (90 men; mean age, 71 ± 9.6 years), in 93 electively and in 14 emergently. The 30-day MAEs were more frequent after emergent repair (43% vs 5%; OR, 13; 95% CI, 3.29-53; P < .001); mortality was 1% after elective repair, 0% after emergent cases. Amputation rate was 0% for both elective and emergent repairs. Mean follow-up was 3.8 years (1 month-8.4 years); 3-year freedom from MAEs was lower after emergent repair (50% vs 80%; HR, 3.78; 95% CI, 1.55-9.20; P = .003). The 30-day MAE rates were equivalent between ER and OR independent of urgency of repair (elective: OR, 1.82; 95% CI, 0.41-8.09; P = .43; emergent: OR, 1.33; 95% CI, 0.26-6.81; P = .73). In elective interventions, ER had a trend to decreased freedom from MAEs (66% vs 80% at 3 years; HR, 1.93; 95% CI, 0.92-4.07; P = .08); freedom from reintervention was lower after ER (72% vs 88%; HR, 2.41; 95% CI, 1.02-5.70; P = .046). In emergent interventions, 1-year freedom from MAEs was similar (40% vs 50%; HR, 1.36; 95% CI, 0.49-3.74; P = .55). Emergent ER and poor runoff predicted MAEs.ConclusionsOur study failed to prove the superiority of ER over OR. If anatomy is suitable, ER of PAA in the elderly and high-risk patients is justified. For emergent PAA repairs, MAEs are frequent after both ER and OR; ER has not changed the severe prognosis of acute limb ischemia from PAA. A multicenter randomized controlled trial of PAA patients with acute presentation is warranted.

S OF THE 2013 VASCULAR ANNUAL MEETING V1: Peripheral Vascular Surgery Society Paper Session I

Objectives: To compare long-term outcomes after OR vs EVAR of AAAs at a tertiary center. Methods: Clinical data of consecutive AAA patients treated electively between 2000 and 2011 were retrospectively reviewed. Primary endpoint was all-cause mortality, secondary endpoints were complications, reinterventions and ruptures. Propensity score-based matching included age, gender, year of intervention and comorbidities was performed to compare outcomes. Results: There were 1350 matched cohorts (mean age 74 6 7 years). Thirty-day mortality was 1.3% after OR, 1.0% after EVAR (P 1⁄4 .40). Early complications were lower after EVAR (13% vs 25%; P < .0001). Mean follow-up was 4.2 years (30 days-12.7 years). At 5 years, all-cause mortality was lower, freedom from reintervention higher after OR (23% vs 32%, 87% vs 74%); freedom from complications the same (66%). In multi-variable analysis, SVS-comorbidity score and age were associated with allcause mortality. Results were similar in 1791 unmatched cohorts. There were 2 ruptures after OR, 8 after EVAR (P 1⁄4 .02). Conclusions: Both elective OR and EVAR have low early mortality, EVAR has fewer early complications. Advanced age and comorbidities predict high late mortality. This study failed to support long-term benefits of EVAR, since the procedure was associated with increased rates of late all-cause mortality, reinterventions and small but definite risk of late rupture.

Objectives: To determine the utility of routine postoperative troponin (PO Tn) measurements in patients undergoing major vascular surgical reconstructions (VSRs). Methods: Data from consecutive patients undergoing VSRs and routine PO Tn measurement over one year, January 1 to December 31, 2010, were retrospectively analyzed. A positive troponin (Tn) panel included a baseline level immediately after the procedure of $ .20 ng/mL, or a delta at 3 and/or 6 hours of $ .30 ng/mL/$ 20%. Patients without complete Tn panels and research authorization were excluded. Cox Proportional hazards model was used to evaluate the effect of preoperative risk factors and postoperative Tn levels on early and mid-term mortality. Results: Of 725 patients undergoing VSRs 678 (462 males, 216 females; mean age 69 years) satisfied criteria for inclusion. Procedures included 408 open, 196 endovascular and 73 hybrid (306 abdominal, 197 infrainguinal, 40 thoracoabdominal, 117 cerebrovascular and 18 upper extremity). Tn levels were elevated in 67 patients (10%; M: 42, F: 25) and after consultation with a cardiologist were ascribed to non-ST elevation myocardial infarction (NSTEMI) in 26, STEMI in six, demand ischemia in 29 and renal insufficiency in six. Sixty-one patients were managed medically; six underwent cardiac catheterization and intervention. Thirty-day mortality was significantly higher in Tn+ compared to Tnpatients (7.6% vs 1.7%; P 1⁄4 .08). On multivariate analysis abnormal delta Tn (P 1⁄4 .008; HR, 2.0; 95% CI, 1.2-3.4) and SVS/AAVS comorbidity score >9 were associated with mortality. The cumulative probability of death in Tn+ patients remained significantly higher at 1 (27.6% vs 10.6%; P 1⁄4 .004) and 2 years (40.8% vs 18.5%; P 1⁄4 .002). Conclusions: Elevated delta troponin levels following major vascular surgical procedures are independently associated with higher 30 day and mid-term mortality, and this marker should be considered an important prognostic indicator. Author Disclosures: T. C. Bower: Nothing to disclose; R. David: Nothing to disclose; A. A. Duncan: Nothing to disclose; M. D. Fleming: Nothing to disclose; P. Gloviczki: Nothing to disclose; W. Harmsen: Nothing to disclose; M. Kalra: Nothing to disclose; J. Manunga: Nothing to disclose; G. S. Oderich: Nothing to disclose. PS62.