A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury.

Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.

Emphysema-associated Autoreactive Antibodies Exacerbate Post-Lung Transplant Ischemia-Reperfusion Injury.

Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.

Implications of 25% to 50% coronary stenosis with cardiac computed tomographic angiography in ED patients.

OBJECTIVE: The aim of this study was to determine if patients presenting with symptoms of acute coronary syndrome and found to have 25% to 50% diameter reduction with coronary computed tomographic angiography (CCTA) are likely to benefit from further diagnostic testing. METHODS: A registry study of 213 subjects (median age, 51 years; 53% women) with symptoms concerning for possible acute coronary syndrome with low-risk features found to have 25% to 50% maximal diameter stenosis on CCTA was performed at 2 academic medical centers. The analysis was approved by an institutional review board and was conducted with waiver of consent. The potential contribution of additional testing was determined by measuring the major adverse cardiac events (MACEs) from presentation through 30 days. The MACEs included myocardial infarction, coronary revascularization, unstable angina, and cardiovascular death. Sample size calculations were predicated on a 0% MACE rate leading to upper bounds of a 2-sided exact 95% confidence interval less than 2%. RESULTS: Thrombolysis in myocardial infarction risk score of less than 2 was present in 92% subjects, 70% (150 of 213) had 2 or more serial cardiac markers performed, and 40% (87 of 213) had stress testing or cardiac catheterization. The MACEs occurred in 1 (0.5%) of 213 subjects (95% confidence interval, 0%-2.6%) and was identified by an elevation of serial cardiac markers during the index hospitalization. No patients experienced cardiovascular death or required revascularization. CONCLUSIONS: In patients with emergent low-risk chest pain and 25% to 50% diameter coronary stenosis by CCTA, the rate of near-term MACE is very low. Serial cardiac markers may be beneficial in this subgroup. Routine provocative testing is unlikely to be beneficial during the index visit.

A Case-Based Overview of the Role of Radiological Imaging in Emergency General Surgery.

This article aims to give an overview of some of the common conditions seen in emergency general surgery and the recommended choice of imaging. For junior doctors, choosing the correct imaging modality can be difficult so we aim to provide a summary of the evidence behind radiology for emergency general surgery. Four of the most important acute surgical conditions were chosen, alongside abdominal aortic aneurysm. A literature search was carried out to review the most up-to-date evidence regarding imaging choices. Cases were chosen from everyday practice to put the imaging into context. This article gives an overview of the most common imaging modalities used in emergency general surgery. It can be used by medical students and junior doctors to help understand the reasoning behind imaging choices on the acute surgical take.

Hyperbaric oxygen does not prevent neurologic sequelae after carbon monoxide poisoning.

UNLABELLED: Delayed neurologic sequelae occur in up to 40% of severe carbon monoxide (CO) poisonings. Conflicting clinical data support the efficacy of hyperbaric oxygen (HBO) therapy in the acute treatment of CO poisoning. OBJECTIVE: To determine whether oxygen therapy reduces neurologic sequelae after CO poisoning in mice. METHODS: Male Swiss-Webster mice were exposed to CO at 1,000 ppm for 40 minutes and then 50,000 ppm until loss of consciousness (LOC) (4-9 additional minutes). Total time of both phases of CO exposure was 40-49 minutes. Treatment included HBO with 3 atmospheres (ATA) 100% oxygen, normobaric oxygen (NBO) with 1 ATA 100% oxygen, or ambient air 15 minutes after LOC. All animals underwent passive avoidance training and memory was assessed by measuring step-down latency (SDL) and step-up latency (SUL) seven days following CO exposure. RESULTS: Carbon monoxide poisoning induced significant memory deficits (SDL(CO) = 156 sec; SUL(CO) = 75%) compared with nonpoisoned (NP) animals (SDL(NP) = 272 sec; SUL(NP) = 100%). Both HBO and NBO did not prevent these neurologic sequelae. Furthermore, no significant neurobehavioral differences were found between HBO and NBO. Histologic examination of the CA1 layer of the hippocampus for pyknotic cells showed significant damage from CO in the air-treated animals (9.6%) but not in the nonpoisoned animals (3.8%). No significant neuroprotection was seen histologically with NBO and HBO compared with ambient air. CONCLUSIONS: These results suggest that HBO is not effective in preventing neurologic sequelae in mice and that there is no benefit of HBO over NBO following severe CO neurotoxicity.