Haloperidol-Induced Neuroleptic Malignant Syndrome: A Case Report.

Neuroleptic malignant syndrome (NMS) is a severe reaction to antipsychotic medications characterized by fever, muscle rigidity, altered mental status, and autonomic dysfunction. Here, we describe the case of a 58-year-old female who presented with altered mental status two days after open reduction and internal fixation of the hip. A rapid response team was called when the patient appeared agitated with increased respiratory demand. After being intubated and moved to the ICU, she became febrile and rigid. A preliminary diagnosis of metabolic encephalopathy of unknown origin was made. Before being transported to the ICU, the patient was given multiple haloperidol doses in addition to her continued at-home medication, paroxetine, for major depressive disorder. The differential diagnosis included a workup for NMS, serotonin syndrome, and infectious processes. Once NMS was determined as the most likely etiology, all antipsychotic and serotonergic medications were discontinued. Then dantrolene and amantadine were administered, which resulted in clinically significant improvement. This case report demonstrates the importance of early identification of and intervention for NMS.

Brain Swelling versus Infarct Size: A Problematizing Review.

In human stroke, brain swelling is an important predictor of neurological outcome and mortality, yet treatments to reduce or prevent brain swelling are extremely limited, due in part to an inadequate understanding of mechanisms. In preclinical studies on cerebroprotection in animal models of stroke, historically, the focus has been on reducing infarct size, and in most studies, a reduction in infarct size has been associated with a corresponding reduction in brain swelling. Unfortunately, such findings on brain swelling have little translational value for treating brain swelling in patients with stroke. This is because, in humans, brain swelling usually becomes evident, either symptomatically or radiologically, days after the infarct size has stabilized, requiring that the prevention or treatment of brain swelling target mechanism(s) that are independent of a reduction in infarct size. In this problematizing review, we highlight the often-neglected concept that brain edema and brain swelling are not simply secondary, correlative phenomena of stroke but distinct pathological entities with unique molecular and cellular mechanisms that are worthy of direct targeting. We outline the advances in approaches for the study of brain swelling that are independent of a reduction in infarct size. Although straightforward, the approaches reviewed in this study have important translational relevance for identifying novel treatment targets for post-ischemic brain swelling.

High-Resolution Imaging of Human Cancer Proteins Using Microprocessor Materials.

Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of the p53 protein have been studied extensively, structural information for full-length p53 remains incomplete. Functionalized microprocessor chips (microchips) with properties amenable to electron microscopy permitted us to visualize complete p53 assemblies for the first time. The new structures revealed p53 in an inactive dimeric state independent of DNA binding. Residues located at the protein-protein interface corresponded with modification sites in cancer-related hot spots. Changes in these regions may amplify the toxic effects of clinical mutations. Taken together, these results contribute advances in technology and imaging approaches to decode native protein models in different states of activation.

Microchip-Based Structure Determination of Disease-Relevant p53.

The tumor suppressor protein TP53 (p53) plays a multifaceted role in all cells of the human body. Mutations in the TP53 gene are often involved in cancer induction and disease progression. Despite its important role in health and development, structural information for p53 remains incomplete. Here, we present a microchip-based technology to facilitate structural studies of p53 assemblies derived from human cancer cells. These devices do not introduce foreign sequences to the p53 gene and maintain naturally occurring post-translational modifications. Using cryo-electron microscopy, structures for the p53 monomer (∼50 kDa) and tetramer (∼200 kDa) were resolved to ∼4.8 and ∼7 Å, respectively. These structures revealed new insights for flexible regions of p53 along with biologically relevant ubiquitination sites. Collectively, the convergence of nanotechnology tools and structural imaging builds a strong framework to understand the oncogenic impact of p53 in human tissues.