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Background: Delirium in trauma surgery is common, especially post-operatively, but medical characteristics, risk factors and residence post-discharge have not comprehensively been investigated in all trauma patients. Methods: Over 1 year, 2026 trauma patients were prospectively screened for delirium with the following tools: Delirium Observation screening scale (DOS), Intensive Care Delirium Screening Checklist (ICDSC) and a DSM (Diagnostic and Statistical Manual)-5, nursing tool (ePA-AC) construct. Risk factors—predisposing und precipitating—for delirium were assessed via multiple regression analysis. Results: Of 2026 trauma patients, 440 (21.7%) developed delirium, which was associated with an increased risk of assisted living (OR 6.42, CI 3.92–10.49), transfer to nursing home (OR 4.66, CI 3.29–6.6), rehabilitation (OR 3.96, CI 3.1–5.1), or death (OR 70.72, CI 22–227.64). Intensive care management (OR 18.62, CI 14.04–24.68), requirement of ventilation (OR 32.21, CI 21.27–48.78), or its duration (OR 67.22, CI 33.8–133.71) all increased the risk for developing delirium. Relevant predisposing risk factors were dementia (OR 50.92, CI 15.12–171.45), cardiac insufficiency (OR 11.76, CI 3.6–38.36), and polypharmacy (OR 5.9, CI 4.01–8.68).Relevant precipitating risk factors were brain edema (OR 40.53, CI 4.81–341.31), pneumonia (OR 39.66, CI 8.89–176.93) and cerebral inflammation (OR 21.74, CI 2.34–202.07). Conclusion: Delirium in trauma patients is associated with poor outcome as well as with intensive care management and various predisposing and/or precipitating factors. Three quarters of patients who had undergone delirium were not able to live independently at home any more. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to develop a molecular imaging strategy for response assessment of arginine deiminase (ADI) treatment in melanoma xenografts using 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]-FLT) positron emission tomography (PET).Procedures: F-FLT response to ADI therapy was studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was investigated, with a particular emphasis on biological pathways known to regulate (18)F-FLT metabolism.Results: Proliferation of SK-MEL-28 melanoma tumors was potently inhibited by ADI treatment. However, no metabolic response was observed in FLT PET, presumably based on the known ADI-induced degradation of PTEN, followed by instability of the tumor suppressor p53 and a relative overexpression of thymidine kinase 1, the enzyme mainly responsible for intracellular FLT processing.Conclusion: The specific pharmacological properties of ADI preclude using (18)F-FLT to evaluate clinical response in melanoma and argue for further studies to explore the use of other clinically applicable PET tracers in ADI treatment. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to develop a molecular imaging strategy for response assessment of arginine deiminase (ADI) treatment in melanoma xenografts using 3′-[ 18F]fluoro-3′-deoxythymidine ([ 18F]-FLT) positron emission tomography (PET). Procedures: F-FLT response to ADI therapy was studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was investigated, with a particular emphasis on biological pathways known to regulate 18F-FLT metabolism. Results: Proliferation of SK-MEL-28 melanoma tumors was potently inhibited by ADI treatment. However, no metabolic response was observed in FLT PET, presumably based on the known ADI-induced degradation of PTEN, followed by instability of the tumor suppressor p53 and a relative overexpression of thymidine kinase 1, the enzyme mainly responsible for intracellular FLT processing. Conclusion: The specific pharmacological properties of ADI preclude using 18F-FLT to evaluate clinical response in melanoma and argue for further studies to explore the use of other clinically applicable PET tracers in ADI treatment. [ABSTRACT FROM AUTHOR]

The Na+/H+ exchanger NHE1 is critical for cell vitality as it controls intracellular pH and cell volume. Its functionality is influenced by calcineurin B homologous proteins (CHPs). The human isoform CHP3 is important for transport of NHE1 to the plasma membrane and for its activity. Here, we characterized the binding interaction of human CHP3 with the regulatory domain of NHE1. The exact binding site of CHP3 was previously debated. CHP3 as well as both regions of NHE1 in question were produced and purified. CHP3 specifically formed stable complexes with the CHP-binding region (CBD) of NHE1 (residues 503-545) in size-exclusion chromatography (SEC), but not with the C-terminal region (CTD, residues 633-815). CTD was functional as shown by Ca2+-dependent binding of calmodulin in SEC analysis. CHP3 bound with high affinity to CBD with an equilibrium dissociation constant (KD) of 56 nM determined by microscale thermophoresis. The high affinity was substantiated by isothermal calorimetry analysis (KD = 3 nM), which also revealed that the interaction with CBD is strongly exothermic (ΔG° = −48.6 kJ/mol, ΔH = −75.3 kJ/mol, −TΔS° = 26.7 kJ/mol). The data provide insights in the molecular mechanisms that underlie the regulatory interaction of CHP3 and NHE1 and more general of calcineurin homologous proteins with their target proteins. [ABSTRACT FROM AUTHOR]