An Evaluation of the Impact of Mental Illness on Postoperative Breast Reconstruction Revision Surgery.

Breast cancer impacts millions of people yearly affecting various aspects of their lives-including but not limited to mental health. Patients with a known psychiatric history, specifically generalized anxiety disorder (GAD) and/or depression, have previously been shown to have an increased number of revisions after breast reconstruction. Methods: A commercially available database of 91 million unique patients, PearlDiver, was used to identify patients with breast cancer who underwent autologous free flap breast reconstruction. An average number of revisions were calculated from each group of patients-those with a history of anxiety and/or depression and patients without a history of anxiety and/or depression. A logistic regression was performed to determine risk factors associated with patients undergoing revision surgery. Results: A total of 39,683 patients with a history of breast cancer underwent autologous breast reconstruction between 2010 and 2020, of which 6308 (15.9%) patients had a history of GAD and/or depression before autologous reconstruction. A total of 13,422 (33.8%) patients received at least one revision surgery. Patients with GAD only, depression only, and concomitant GAD and depression received 1.40 revisions each with no significant differences between the control and any of the study groups (P = 0.956). Logistic regression did not find psychiatric history to be associated with patients undergoing revision surgery (OR, 0.94; 95% CI, 0.89-1.00). Conclusion: Patients who underwent autologous reconstruction for breast cancer demonstrated no difference in rates of secondary surgical revision, regardless of a concurrent mental health history.

Mechanism of Mitochondrial Transcription Factor A Attenuation of CpG-Induced Antibody Production.

Mitochondrial transcription factor A (TFAM) had previously been shown to act as a damage associated molecular pattern with the ability to enhance CpG-A phosphorothioate oligodeoxynucleotide (ODN)-mediated stimulation of IFNα production from human plasmacytoid dendritic cells. Examination of the mechanism by which TFAM might influence CpG ODN mediated innate immune responses revealed that TFAM binds directly, tightly and selectively to the structurally related CpG-A, -B, and -C ODN. TFAM also modulated the ability of the CpG-B or -C to stimulate the production of antibodies from human B cells. TFAM showed a dose-dependent modulation of CpG-B, and -C -induced antibody production from human B cells in vitro, with enhancement of high dose and inhibition of low doses of CpG stimulation. This effect was linked to the ability of TFAM to directly inhibit the binding of CpG ODNs to B cells, in a manner consistent with the relative binding affinities of TFAM for the ODNs. These data suggest that TFAM alters the free concentration of the CpG available to stimulate B cells by sequestering this ODN in a TFAM-CpG complex. Thus, TFAM has the potential to decrease the pathogenic consequences of exposure to natural CpG-like hypomethylated DNA in vivo, as well as such as that found in traumatic injury, infection, autoimmune disease and during pregnancy.

Insights into electron leakage in the reaction cycle of cytochrome P450 BM3 revealed by kinetic modeling and mutagenesis.

As a single polypeptide, cytochrome P450 BM3 fuses oxidase and reductase domains and couples each domain's function to perform catalysis with exceptional activity upon binding of substrate for hydroxylation. Mutations introduced into the enzyme to change its substrate specificity often decrease coupling efficiency between the two domains, resulting in unproductive consumption of cofactors and formation of water and/or reactive species. This phenomenon can correlate with leakage, in which P450 BM3 uses electrons from NADPH to reduce oxygen to water and/or reactive species even without bound substrate. The physical basis for leakage is not yet well understood in this particular member of the cytochrome P450 family. To clarify the relationship between leakage and coupling, we used simulations to illustrate how different combinations of kinetic parameters related to substrate-free consumption of NADPH and substrate hydroxylation can lead to either minimal effects on coupling or a dramatic decrease in coupling as a result of leakage. We explored leakage in P450 BM3 by introducing leakage-enhancing mutations and combining these mutations to assess whether doing so increases leakage further. The variants in this study provide evidence that while a transition to high spin may be vital for coupled hydroxylation, it is not required for enhanced leakage; substrate binding and the consequent shift in spin state are not necessary as a redox switch for catalytic oxidation of NADPH. Additionally, the variants in this study suggest a tradeoff between leakage and stability and thus evolvability, as the mutations we investigated were far more deleterious than other mutations that have been used to change substrate specificity.