Biological Effects of HDAC Inhibitors Vary with Zinc Binding Group: Differential Effects on Zinc Bioavailability, ROS Production, and R175H p53 Mutant Protein Reactivation.

The coordination of zinc by histone deacetylase inhibitors (HDACi), altering the bioavailability of zinc to histone deacetylases (HDACs), is key to HDAC enzyme inhibition. However, the ability of zinc binding groups (ZBGs) to alter intracellular free Zn+2 levels, which may have far-reaching effects, has not been explored. Using two HDACis with different ZBGs, we documented shifts in intracellular free Zn+2 concentrations that correlate with subsequent ROS production. Next, we assayed refolding and reactivation of the R175H mutant p53 protein in vitro to provide greater biological context as the activity of this mutant depends on cellular zinc concentration. The data presented demonstrates the differential activity of HDACi in promoting R175H response element (RE) binding. After cells are treated with HDACi, there are differences in R175H mutant p53 refolding and reactivation, which may be related to treatments. Collectively, we show that HDACis with distinct ZBGs differentially impact the intracellular free Zn+2 concentration, ROS levels, and activity of R175H; therefore, HDACis may have significant activity independent of their ability to alter acetylation levels. Our results suggest a framework for reevaluating the role of zinc in the variable or off-target effects of HDACi, suggesting that the ZBGs of HDAC inhibitors may provide bioavailable zinc without the toxicity associated with zinc metallochaperones such as ZMC1.

A Twisted Cecum: Herniation and Volvulus of the Cecum Through the Epiploic Foramen.

Herniation of the cecum, terminal ileum, and ascending colon through the epiploic foramen is an uncommon presentation of an internal hernia. An 82-year-old female presented with a small bowel obstruction; Computed Tomography (CT) imaging showed a herniation of the terminal ileum, cecum, and ascending colon through the foramen of Winslow into the lesser sac, with cecal volvulus. Prompt surgical treatment included laparotomy and reduction of the hernia, followed by an extended right hemicolectomy with primary anastomosis and functional closure of the epiploic foramen. This report reviews the natural history and management of this rare pathology.

Staphylococcal Scalded Skin Syndrome in a Ten-Month-Old Male.

A 10-month-old male presented with rhinorrhea and decreased oral intake and was diagnosed with an upper respiratory infection. Two days later, he returned to the clinic due to a lack of improvement and the onset of new symptoms, including facial edema and perioral skin irritation. That evening, he became febrile at 100.4 °F and went to the emergency department at the local children's hospital. No further workup was done and the parents were instructed to continue with the current treatment regimen. Over the next 48 hours, the patient's symptoms worsened with the new onset of bilateral extremity edema and desquamation. The patient was returned to the emergency department. A physical exam was notable for a blanching, desquamating, erythematous rash on the face and creases of the arms, legs, and groin. A positive Nikolsky sign was reported. A clinical diagnosis of staphylococcal scalded skin syndrome (SSSS) was made, and the patient was started on intravenous clindamycin. This case illustrates a severe presentation of SSSS in a pediatric patient, demonstrating the challenges it poses to diagnosis and treatment.