Spaceflight Environment.

The safety and health of individuals who may be exposed to the spaceflight environment are first and foremost cared for through prevention. This environment, which encompasses microgravity, radiation, and alternobaric factors, can have physiologic impacts on every human system. Available medical care and resources in the spaceflight environment are currently limited by mass and volume constraints, with available medical resources thereby focusing on a patient's stabilization and evacuation. An understanding of the spaceflight environment and its possible effects is crucial for the treatment of individuals prior to, during, and after spaceflight.

Aviation Decompression Sickness in Aerospace and Hyperbaric Medicine.

INTRODUCTION: The U.S. Navy experienced a series of physiological events in aircrew involving primarily the F/A-18 airframe related to rapid decompression of cabin pressures, of which aviation decompression sickness (DCS) was felt to contribute. The underlying pathophysiology of aviation DCS is the same as that of diving-related. However, based on the innate multifactorial circumstances surrounding hypobaric DCS, in clinical practice it continues to be unpredictable and less familiar as it falls at the intersect of aerospace and hyperbaric medicine. This retrospective study aimed to review the case series diagnosed as aviation DCS in a collaborative effort between aerospace specialists and hyperbaricists to increase appropriate identification and treatment of hypobaric DCS.METHODS: We identified 18 cases involving high-performance aircraft emergently treated as aviation DCS at a civilian hyperbaric chamber. Four reviewers with dual training in aviation and hyperbaric medicine retrospectively reviewed cases and categorized presentations as "DCS" or "Alternative Diagnosis".RESULTS: Reviewers identified over half of presenting cases could be attributed to an alternative diagnosis. In events that occurred at flight altitudes below 17,000 ft (5182 m) or with rapid decompression pressure changes under 0.3 atm, DCS was less likely to be the etiology of the presenting symptoms.CONCLUSIONS: Aviation physiological events continue to be difficult to diagnose. This study aimed to better understand this phenomenon and provide additional insight and key characteristics for both flight physicians and hyperbaric physicians. As human exploration continues to challenge the limits of sustainable physiology, the incidence of aerospace DCS may increase and underscores our need to recognize and appropriately treat it.Kutz CJ, Kirby IJ, Grover IR, Tanaka HL. Aviation decompression sickness in aerospace and hyperbaric medicine. Aerosp Med Hum Perform. 2023; 94(1):11-17.

Histone Deacetylases Exert Class-Specific Roles in Conditioning the Brain and Heart Against Acute Ischemic Injury.

Ischemia-reperfusion (IR) injury comprises a significant portion of morbidity and mortality from heart and brain diseases worldwide. This enduring clinical problem has inspired myriad reports in the scientific literature of experimental interventions seeking to elucidate the pathology of IR injury. Elective cardiac surgery presents perhaps the most viable scenario for protecting the heart and brain from IR injury due to the opportunity to condition the organs prior to insult. The physiological parameters for the preconditioning of vital organs prior to insult through mechanical and pharmacological maneuvers have been heavily examined. These investigations have revealed new insights into how preconditioning alters cellular responses to IR injury. However, the promise of preconditioning remains unfulfilled at the clinical level, and research seeking to implicate cell signals essential to this protection continues. Recent discoveries in molecular biology have revealed that gene expression can be controlled through posttranslational modifications, without altering the chemical structure of the genetic code. In this scenario, gene expression is repressed by enzymes that cause chromatin compaction through catalytic removal of acetyl moieties from lysine residues on histones. These enzymes, called histone deacetylases (HDACs), can be inhibited pharmacologically, leading to the de-repression of protective genes. The discovery that HDACs can also alter the function of non-histone proteins through posttranslational deacetylation has expanded the potential impact of HDAC inhibitors for the treatment of human disease. HDAC inhibitors have been applied in a very small number of experimental models of IR. However, the scientific literature contains an increasing number of reports demonstrating that HDACs converge on preconditioning signals in the cell. This review will describe the influence of HDACs on major preconditioning signaling pathways in the heart and brain.

Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures.

Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2, respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2µM against the Calu-6 human lung adenocarcinoma line, and 4.8µM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b-6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents.

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors.

The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors are not toxic to mammalian cells in vitro, and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint Figure 1. Structures of LSD1 inhibitors 1, verlindamycin 2, (bis)thioureas 3, amidoxime 4, cyclic peptide 5, N3-(2-chloro-6-phenoxybenzyl)-4H-1,2,4-triazole-3,5-diamine 6 and N3,N5-bis(2-methoxybenzyl)-1H-1,2,4-triazole-3,5-diamine 7.