Effect of hypoxia on mortality and disability in traumatic brain injury according to shock status: A cross-sectional analysis.

OBJECTIVES: This study aimed to test the association between hypoxia level and outcomes according to shock status in traumatic brain injury (TBI) patients. METHODS: Adult TBI patients transported by emergency medical services in 10 provinces were enrolled. Hypoxia was a main exposure; three groups by oxygen saturation (SaO2, non-hypoxia (≥94%), mild hypoxia (90 ≤ SaO2 < 94%)), and severe hypoxia (<90%). Shock status (

Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development.

Autonomic parasympathetic neurons (parasymNs) control unconscious body responses, including "rest-and-digest." ParasymN innervation is important for organ development, and parasymN dysfunction is a hallmark of autonomic neuropathy. However, parasymN function and dysfunction in humans are vastly understudied due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void as a versatile platform. Here, we developed a differentiation paradigm detailing the derivation of functional human parasymNs from Schwann cell progenitors. We employ these neurons (1) to assess human autonomic nervous system (ANS) development, (2) to model neuropathy in the genetic disorder familial dysautonomia (FD), (3) to show parasymN dysfunction during SARS-CoV-2 infection, (4) to model the autoimmune disease Sjögren's syndrome (SS), and (5) to show that parasymNs innervate white adipocytes (WATs) during development and promote WAT maturation. Our model system could become instrumental for future disease modeling and drug discovery studies, as well as for human developmental studies.

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.

Identification of physiological modulators of nuclear hormone receptor (NHR) activity is paramount for understanding the link between metabolism and transcriptional networks that orchestrate development and cellular physiology. Using libraries of metabolic enzymes alongside their substrates and products, we identify 1-deoxysphingosines as modulators of the activity of NR2F1 and 2 (COUP-TFs), which are orphan NHRs that are critical for development of the nervous system, heart, veins, and lymphatic vessels. We show that these non-canonical alanine-based sphingolipids bind to the NR2F1/2 ligand-binding domains (LBDs) and modulate their transcriptional activity in cell-based assays at physiological concentrations. Furthermore, inhibition of sphingolipid biosynthesis phenocopies NR2F1/2 deficiency in endothelium and cardiomyocytes, and increases in 1-deoxysphingosine levels activate NR2F1/2-dependent differentiation programs. Our findings suggest that 1-deoxysphingosines are physiological regulators of NR2F1/2-mediated transcription.

Signals of Adverse Drug Reactions of Paliperidone Compared to Other Atypical Antipsychotics Using the Korean Adverse Event Reporting System Database.

BACKGROUND AND OBJECTIVES: Schizophrenia is a severe public health problem and one of the top ten causes of disability, affecting about 1.1% of the world's population. Paliperidone is a new atypical antipsychotic used to treat schizophrenia. Several case reports about unexpected adverse drug reactions of paliperidone have been consistently reported around the world. The purpose of this study was to detect signals of adverse events (AEs) after paliperidone treatment using the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System database (KIDS-KD). METHODS: We applied data-mining techniques based on a disproportionality analysis to KIDS-KD consisting of spontaneously reported AE reports related to atypical antipsychotics between January 2009 and December 2018. We calculated three data-mining indices of paliperidone compared to all other atypical antipsychotics. We defined signals that satisfied all three criteria of the indices. We checked if the signals identified were included in the drug labels for South Korea, the USA, the UK, Japan, Germany, and France. RESULTS: The total number of suspected AE reports related to all atypical antipsychotics in the KIDS-KD from January 2009 to December 2018 was 43,970. Among those, the number of AE reports related to paliperidone was 9453. Overall, 13 signals such as seborrhea, hallucination, obesity, gingivitis, and intervertebral disorder were classified into newly detected meaningful signals. CONCLUSION: We detected new AE signals of paliperidone that were not listed on the drug labels of six countries, and many that were related to psychotic symptoms, metabolic problems, and endocrine disorders.

Nuclear Hormone Receptors and Their Ligands: Metabolites in Control of Transcription.

Nuclear hormone receptors are a family of transcription factors regulated by small molecules derived from the endogenous metabolism or diet. There are forty-eight nuclear hormone receptors in the human genome, twenty of which are still orphans. In this review, we make a brief historical journey from the first observations by Berthold in 1849 to the era of orphan receptors that began with the sequencing of the Caenorhabditis elegans genome in 1998. We discuss the evolution of nuclear hormone receptors and the putative ancestral ligands as well as how the ligand universe has expanded over time. This leads us to define four classes of metabolites-fatty acids, terpenoids, porphyrins and amino acid derivatives-that generate all known ligands for nuclear hormone receptors. We conclude by discussing the ongoing efforts to identify new classes of ligands for orphan receptors.