L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes

L-selectin mediates rolling of lymphocytes in high endothelial venules (HEVs) of peripheral lymph nodes (PLNs). Cross-linking of L-selectin causes proteolytic shedding of its ectodomain, the physiological significance of which is unknown. To determine whether L-selectin shedding regulates lymphocyte migration, a mutant form that resists shedding (LdDeltaP-selectin) was engineered. Transgenic mice expressing either LDeltaP or wild-type (WT) L-selectin on T cells were crossed with L-selectin knockout (KO) mice. The cellularity and subset composition of secondary lymphoid organs did not differ between LDeltaP and WT mice, however, they were different from C57BL/6. Plasma levels of soluble L-selectin in LDeltaP mice were reduced to <5% of WT and C57BL/6 mice. The rolling properties of T lymphocytes from LDeltaP and WT mice on immobilized L-selectin ligands were similar. Furthermore, similar numbers of LDeltaP and WT T lymphocytes were recruited from the bloodstream into PLNs in mice, although LDeltaP T cells transmigrated HEVs more slowly. WT, but not LDeltaP-selectin, underwent rapid, metalloproteinase-dependent shedding after TCR engagement, and LDeltaP T cells retained the capacity to enter PLNs from the bloodstream. These results suggest that the ability to shed L-selectin is not required for T cell recirculation and homing to PLNs. However, L-selectin shedding from antigen-activated T cells prevents reentry into PLNs.     

The Rate of Clinically Significant Plain Radiograph Misinterpretation by Faculty in an Emergency Medicine Residency Program

Objective: To estimate the rate of clinically significant discrepancies between radiograph interpretations by attending radiologists and emergency medicine (EM) faculty in 2 academic EDs, using a unique scoring system.
Methods: A retrospective comparison of radiographic agreement between EM and radiology faculty members was performed. All plain films initially interpreted by EM faculty or by EM residents with immediate rein-terpretation by EM faculty were subsequently reviewed by attending radiologists. All discrepancies between these readings were reported to the ED on the following day for review by an EM faculty member (usually different from the initial EM faculty reader) who determined the need for treatment or follow-up changes. A secondary chart review by a quality assurance faculty member determined whether radiographic findings not noted on the x-ray log were present on the ED record. All discrepancies from February to June 1994 were reviewed. A severity score was assigned based on the following criteria. Q-0: There was no change in treatment or follow-up; or the initial interpretation by EM faculty was validated by repeat or additional views. Q-1: Discrepancy is minor. Q-2: Discrepancy is significant, with potential for injury or bad outcome. 4–3: Discrepancy is significant, with actual injury or bad outcome.
Results: Of 14,046 radiographic studies eligible for enrollment, there were 134 discrepancies (0.95%). Only 28 cases (0.2%) were found to be clinically significant. Of these, 25 were scored Q-1, 3 were scored Q-2, and 0 were scored 4–3. These clinically significant discrepancy rates were highest for the finger, skull, elbow, hand, and lumbar spine.
Conclusion: Emergency medicine faculty provide highly accurate rates of plain radiograph interpretation, particularly when adjusted for clinical significance and actual impact on patient care.     

Impact of perioperative myocardial infarction on angiographic and clinical outcomes following coronary artery bypass grafting (from PRoject of Ex-vivo Vein graft ENgineering via Transfection [PREVENT] IV)

Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase >or=10 times the upper limit of normal or >or=5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.     

The Effects of Severe Hypoxia and Hypoxic Postconditioning on the Glutathione-Dependent Antioxidant System of the Rat Brain

In this study we investigated the effects of severe hypobaric hypoxia (SH) and severe hypobaric hypoxia accompanied by postconditioning using mild hypobaric hypoxia (PostC) on the glutathione-dependent antioxidant system in the rat hippocampus and neocortex. SH (3 h, 180 mmHg, 5% O₂) led to oxidative stress that was associated with a decrease in the total glutathione level, as well as in antioxidant capacity. PostC (2 h, 360 mmHg, 10% O₂) led to incomplete recovery of the total glutathione level and up-regulated glutathione peroxidase activity. In the neocortex, SH did not lead to the development of posthypoxic pathology. A small decrease in total glutathione, glutathione peroxidase activity, and antioxidant capacity on the 1st day after SH was corrected by the 2nd day. In contrast, glutathione reductase activity decreased by the 4th day after exposure to SH. PostC led to a consistent decrease in the total glutathione level but normalized glutathione reductase activity. We found that the studied brain structures develop a specific response to SH. In the hippocampus, SH led to oxidative stress, whereas the neocortex was not affected by exposure to SH. Partial differences between brain areas are based on better antioxidant defense of the neocortex in comparison with the hippocampus. PostC corrects posthypoxic pathology in the hippocampus with involvement of the glutathione- dependent antioxidant system. In the neocortex, PostC did not lead to a significant biochemical response.     

Distinct Antibody Responses to Endemic Coronaviruses Pre- and Post-SARS-CoV-2 Infection in Kenyan Infants and Mothers

Pre-existing antibodies that bind endemic human coronaviruses (eHCoVs) can cross-react with SARS-CoV-2, which is the betacoronavirus that causes COVID-19, but whether these responses influence SARS-CoV-2 infection is still under investigation and is particularly understudied in infants. In this study, we measured eHCoV and SARS-CoV-1 IgG antibody titers before and after SARS-CoV-2 seroconversion in a cohort of Kenyan women and their infants. Pre-existing eHCoV antibody binding titers were not consistently associated with SARS-CoV-2 seroconversion in infants or mothers; however, we observed a very modest association between pre-existing HCoV-229E antibody levels and a lack of SARS-CoV-2 seroconversion in the infants. After seroconversion to SARS-CoV-2, antibody binding titers to the endemic betacoronaviruses HCoV-OC43 and HCoV-HKU1, and the highly pathogenic betacoronavirus SARS-CoV-1, but not the endemic alphacoronaviruses HCoV-229E and HCoV-NL63, increased in the mothers. However, eHCoV antibody levels did not increase following SARS-CoV-2 seroconversion in the infants, suggesting the increase seen in the mothers was not simply due to cross-reactivity to naively generated SARS-CoV-2 antibodies. In contrast, the levels of antibodies that could bind SARS-CoV-1 increased after SARS-CoV-2 seroconversion in both the mothers and infants, both of whom were unlikely to have had a prior SARS-CoV-1 infection, supporting prior findings that SARS-CoV-2 responses cross-react with SARS-CoV-1. In summary, we found evidence of increased eHCoV antibody levels following SARS-CoV-2 seroconversion in the mothers but not the infants, suggesting eHCoV responses can be boosted by SARS-CoV-2 infection when a prior memory response has been established, and that pre-existing cross-reactive antibodies are not strongly associated with SARS-CoV-2 infection risk in mothers or infants.