High mobility group box 1 protein (HMGB1) is a non-histone nuclear protein with dual function. Inside the cell, HMGB1 binds DNA and regulates transcription, whereas outside the cell, it serves as a cytokine and mediates the late effects of LPS. The movement of HMGB1 into the extracellular space has been demonstrated for macrophages stimulated with LPS as well as cells undergoing necrosis but not apoptosis. The differential release of HMGB1 during death processes could reflect the structure of chromatin in these settings as well as the mechanisms for HMGB1 translocation. Since apoptotic cells can release some nuclear molecules such as DNA to which HMGB1 can bind, we therefore investigated whether HMGB1 release can occur during apoptosis as well as necrosis. For this purpose, Jurkat cells were treated with chemical inducers of apoptosis (staurosporine, etoposide, or camptothecin), and HMGB1 release into the medium was assessed by Western blotting. Results of these experiments indicate that HMGB1 appears in the media of apoptotic Jurkat cells in a time-dependent manner and that this release can be reduced by Z-VAD-fmk. Panc-1 and U937 cells treated with these agents showed similar release. In addition, HeLa cells induced to undergo apoptosis showed HMGB1 release. Furthermore, we showed using confocal microscopy that HMGB1 and DNA change their nuclear location in Jurkat cells undergoing apoptosis. Together, these studies indicate that HMGB1 release can occur during the course of apoptosis as well as necrosis and suggest that the release process may vary with cell type.

High-mobility group protein 1 (HMGB1) is a nonhistone nuclear protein whose function depends on cellular location. Inside the cell, HMGB1 modulates a variety of important cellular processes, including transcription, whereas outside the cell, HMGB1 acts as a cytokine that can promote inflammation and mediate sepsis and arthritis in animal models. In in vitro studies, proinflammatory molecules such as LPS, lipoteichoic acid, polyinosinic-polycytidylic acid (poly(I:C)), TNF-α, and type I and II IFNs can induce HMGB1 release from macrophages. Although these agents can activate cells, they can also induce apoptosis under certain circumstances. Therefore, because of evidence that apoptotic as well as necrotic cells can contribute to HMGB1-mediated events in sepsis, we have investigated the relationship between apoptosis and HMGB1 release in macrophages and other cells. In these experiments, using RAW 264.7 cells as a model, LPS and poly(I:C) caused HMGB1 release into the medium whereas CpG ODN failed to induce this response. With both LPS and poly(I:C), the extent of HMGB1 release correlated with the occurrence of apoptosis as measured by caspase 3 activation, lactate dehydrogenase release, and TUNEL staining. Similar results were obtained with primary murine macrophages as well as human Jurkat T cells. For Jurkat cells, poly(I:C) and NO donors induced apoptosis as well as HMGB1 release. Together, these results indicate that HMGB1 release from macrophages is correlated with the occurrence of apoptosis and suggest that these processes reflect common mechanisms and can occur concomitantly.

Background The association between physician self-reported empathy and burnout has been studied in the past with diverse findings. We aimed to determine the association between empathy and burnout among United States emergency medicine (EM) physicians using a novel combination of tools for validation. Methods This was a prospective single-center observational study. Data were collected from EM physicians. From December 1, 2018 to January 31, 2019, we used the Jefferson scale of empathy (JSE) to assess physician empathy and the Copenhagen burnout inventory (CBI) to assess burnout. We divided EM physicians into different groups (residents in each year of training, junior/senior attendings). Empathy, burnout scores and their association were analyzed and compared among these groups. Results A total of 33 attending physicians and 35 EM residents participated in this study. Median self-reported empathy scores were 113 (interquartile range (IQR): 105 - 117) in post-graduate year (PGY)-1, 112 (90 - 115) in PGY-2, 106 (93 - 118) in PGY-3 EM residents, 112 (105 - 116) in junior and 114 (101 - 125) in senior attending physicians. Overall burnout scores were 43 (33 - 50) in PGY-1, 51 (29 - 56) in PGY-2, 43 (42 - 53) in PGY-3 EM residents, 33 (24 - 47) in junior attending and 25 (22 - 53) in senior attending physicians separately. The Spearman correlation (ρ) was -0.11 and β-weight was -0.23 between empathy and patient-related burnout scores. Conclusion Self-reported empathy declines over the course of EM residency training and improves after graduation. Overall high burnout occurs among EM residents and improves after graduation. Our analysis showed a weak negative correlation between self-reported empathy and patient-related burnout among EM physicians.

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