A nationwide study of prenatal exposure to illicit drugs and risk of neurodevelopmental disorders and disruptive behavioral disorders.

This cohort study aimed to examine the association between prenatal exposure to illicit drugs and neurodevelopmental and disruptive behavioral disorders (DBD) in children aged 7-12 years, using data from four national databases in Taiwan from 2004 to 2016. We linked parental and child IDs from the Taiwan Maternal and Child Health database to track children's health status from birth to at least age 7 and identify those diagnosed with neurodevelopmental disorders. The study included 896,474 primiparous women who gave birth between 2004 and 2009, with 752 pregnant women with illicit drug use history and 7520 matched women without. The results of the study showed that prenatal illicit drug exposure was significantly associated with the development of neurodevelopmental disorders and DBD in offspring. The adjusted hazard ratios for developmental delay, mild-to-severe intellectual disability, attention deficit hyperactivity disorder, and DBD were 1.54 (95 % CI: 1.21-1.95), 2.63 (95 % CI: 1.64-4.19), 1.58 (95 % CI: 1.23-2.03), and 2.57 (95 % CI: 1.21-5.48), respectively. Furthermore, prenatal exposure to methamphetamine increased the risk of neurodevelopmental disorders and DBD in offspring, while opioid use was significantly associated with a higher risk of three types of neurodevelopmental disorders, but not with DBD. The use of sedative hypnotic drugs alone was not associated with any increased risk of the three types of neurodevelopmental disorders or DBD. However, we found a significant interaction effect between prenatal illicit drug exposure and the use of sedative hypnotic drugs, which increased the risk of developmental delay.

Emergency department visits due to new psychoactive substances and other illicit drugs in Taiwan: preliminary results of the Taiwan Emergency Department Drug Abuse Surveillance (TEDAS) project.

INTRODUCTION: The use of new psychoactive substances (NPSs) has markedly increased worldwide; thus, it is important to monitor NPS-related effects. The Taiwan Emergency Department Drug Abuse Surveillance (TEDAS) project aims to assess the patterns of recreational drug use in patients presenting to emergency departments (EDs) across the country. Here, we report the preliminary results of this project. METHODS: This observational study included the collection and analysis of urine samples and assessment of the clinical presentation of patients from 79 EDs across Taiwan. Clinical features were recorded through a questionnaire filled by attending doctors or nurses who collected urine samples for clinical diagnosis. Urine samples were analyzed for 110 drugs and metabolites using electrospray ionization liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Between February and November 2019, a total of 2649 patients were enrolled for urine drug analysis. A total of 675 cases older than 12 years (males, n = 480) had NPS or other illicit drugs detected in their urine samples. Overall, 1271 counts of drugs, among which 717 (56.4%) were NPS. At least one NPS was detected in 340 patients (50.4%), and 292 cases were positive for multiple drugs. The most frequently detected drug was methamphetamine/amphetamine, followed by synthetic cathinones, ketamine and its two analogs, and opioids. The most common drug combination was cathinones plus ketamine and/or its analogs (n = 56). Younger patients (OR = 3.3, p≤.0001) and women (OR = 1.5, p = .01) were more likely to have NPS detected in their urine samples. NPS-positive cases frequently experienced chest pain (OR = 2.6, p = .03), tachycardia (OR = 2.6, p = .0002), and suicide attempt/non-suicidal self-harm (OR = 1.8, p = .004), whereas depressed consciousness (OR = 0.5, p = .001) was less frequent among NPS-positive cases than among other illicit drug-positive cases. CONCLUSIONS: The TEDAS project provides a nationwide epidemiological profile of recreational drug use in Taiwan. More than half of the recreational drugs were NPSs, which were comprehensively detected using LC-MS/MS.

The Affinity of Elongated Membrane-Tethered Ligands Determines Potency of T Cell Receptor Triggering.

T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I and II pMHC molecules. The dimensions of membrane-tethered anti-CD3 and pMHC molecules were progressively increased by insertion of different extracellular domains. In agreement with previous studies, elongation of pMHC molecules or low-affinity anti-CD3 scFv caused progressive loss of T cell activation. However, elongation of high-affinity ligands (BC3 and OKT3 scFv) did not abolish TCR phosphorylation and T cell activation. Mutation of key amino acids in OKT3 to reduce binding affinity to CD3 resulted in restoration of topological dependence on T cell activation. Our results show that high-affinity TCR ligands can effectively induce TCR triggering even at large interspatial distances between T cells and APCs.

IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha.

IL-10 is an immunosuppressive cytokine in the immune system. It was in clinical trial as an anti-inflammatory therapy for inflammatory bowel disease and various autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis. IL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene (MDA-7, IL-24), and AK155 (IL-26). Despite a partial homology in their amino acid sequences, they are dissimilar in their biologic functions. Little is known about the biologic function and gene regulation of IL-19. To understand the gene regulation of human IL-19, we identified a human IL-19 genomic clone and analyzed its promoter region. Five fusion genes containing different regions upstream of exon 1 linked to a luciferase reporter gene were expressed in the canine kidney epithelial-like Madin-Darby canine kidney cells. A fusion gene containing 394 bp showed luciferase activity 7- to 8-fold higher than the negative control of the promoterless fusion gene. We also isolated a full-length mouse cDNA clone. Mouse IL-19 shared 71% amino acid identity with human IL-19. Treatment of monocytes with mouse IL-19 induced the production of IL-6 and TNF-alpha. It also induced mouse monocyte apoptosis and the production of reactive oxygen species. Taken together, our results indicate that mouse IL-19 may play some important roles in inflammatory responses because it up-regulates IL-6 and TNF-alpha and induces apoptosis.