Efficacy, Tolerability, and Acceptance of Long-Lasting Antipsychotics in Children and Adolescents: A Systematic Review.

Objectives: While long-lasting antipsychotics (LLA) were specifically developed to address the problem of adherence in patients with chronic psychiatric disorders, their role in pediatric populations is not clear. Methods: To document the efficacy, tolerance, and acceptance of LLAs in children and adolescents, a literature search was conducted using several databases for published studies (PubMed, PsycINFO) from January 1965 to December 2020. Twenty-two studies were identified (16 case reports/series, 3 open label studies, 2 controlled studies, and 1 retrospective analysis of national database). Results: Demographic features were widely heterogeneous across studies (total N = 480, 58% male, mean age = 15.0 ± 1.8). Case reports/series presented positive therapeutic outcomes in noncompliant youths with severe mental illness. Three open-label one-arm studies supported the clinical efficacy of risperidone long-acting injection in patients previously stabilized with oral risperidone. One study showed lower clinical symptoms and higher functioning at 12 months in youths treated for an acute psychotic episode with paliperidone palmitate compared to oral risperidone. The types and rates of side effects of LLA were comparable to those observed for oral antipsychotics. Two studies suggested better metabolic and neurological tolerance of LLA compared to an oral form. Preliminary evidence supported a satisfactory level of treatment satisfaction in patients treated with LLA and their families, while concerns were raised regarding practical administration in outpatient services. However, the average quality of the evidence based on the RoB2 tool was low. Conclusions: The level of evidence was low for the efficacy of LLA in pediatric populations and very low for the tolerance and acceptance. It concerned mostly the effect of risperidone long-acting injection in adolescents with psychotic disorders. Randomized maintenance clinical trials using noninferiority analysis would be more appropriate for further research.

FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition.

BACKGROUND: Cystic fibrosis (CF) lung disease severity is highly variable and dependent on several factors including genetic modifiers. Family with sequence similarity 13 member A (FAM13A) has been previously associated with lung function in the general population as well as in several chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), we examined whether FAM13A is a modifier gene of CF lung phenotype. We also studied how FAM13A may contribute to the physiopathological mechanisms associated with CF. METHODS: We investigated the association of FAM13A with lung function in CF French patients (n=1222) by SNP-wise analysis and Versatile Gene Based Association Study. We also analyzed the consequences of FAM13A knockdown in A549 cells and primary bronchial epithelial cells from CF patients. RESULTS: We found that FAM13A is associated with lung function in CF patients. Utilizing lung epithelial A549 cells and primary human bronchial epithelial cells from CF patients we observed that IL-1ß and TGFß reduced FAM13A expression. Knockdown of FAM13A was associated with increased RhoA activity, induction of F-actin stress fibers and regulation of epithelial-mesenchymal transition markers such as E-cadherin, α-smooth muscle actin and vimentin. CONCLUSION: Our data show that FAM13A is a modifier gene of CF lung phenotype regulating RhoA activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition.

Transcriptional and cellular effects of benzotriazole UV stabilizers UV-234 and UV-328 in the freshwater invertebrates Chlamydomonas reinhardtii and Daphnia magna.

Benzotriazole ultra violet stabilizers (BZT-UVs) are compounds used in many applications and products to prevent photochemical degradation. Despite their widespread presence in aquatic ecosystems and persistence in the environment, there are very limited data on their effects and toxicity, and their modes of action remain largely unknown. The objectives of the present study were to evaluate the chronic effects of 2 BZT-UVs, 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (UV-234) and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328), on the freshwater green algae Chlamydomonas reinhardtii and the freshwater crustacean Daphnia magna. Organisms were exposed to 0.01 and 10 µg/L of UV-234, UV-328, as well as a mixture of the 2 compounds. Life-history endpoints (viability, reproduction, and growth) and oxidative stress-related biomarkers (gene transcription, reactive oxygen species [ROS] production, and lipid peroxidation) were measured. Daphnia magna growth, reproduction, and gene transcription were not impacted by 21-d individual or mixed exposure. After 96-h of exposure, no differences were observed on the cellular viability of C. reinhardtii for either of the 2 BZT-UVs. In the algae, results showed increased ROS production in response to UV-328 and lipid peroxidation following exposure to UV-234. Synergistic effects of the 2 BZT-UVs were evident at the transcriptional level with 2 to 6 times up-regulation of glutathione peroxidase (gpx ) in response to the mixture for all treatment conditions. The transcription of superoxide dismutase (sod), catalase (cat), and ascorbic peroxidase (apx) was also regulated by UV-234 and UV-328 in the green algae, most likely as a result of ROS production and lipid peroxidation. Results from the present study suggest potential impacts of UV-234 and UV-328 exposure on the antioxidant defense system in C. reinhardtii. Environ Toxicol Chem 2017;36:3333-3342. © 2017 Crown in the Right of Canada. Published by Wiley Periodicals Inc., on behalf of SETAC.

Transcriptomic, cellular and life-history responses of Daphnia magna chronically exposed to benzotriazoles: Endocrine-disrupting potential and molting effects.

Benzotriazoles (BZTs) are ubiquitous aquatic contaminants used in a wide range of industrial and domestic applications from aircraft deicers to dishwasher tablets. Acute toxicity has been reported in aquatic organisms for some of the BZTs but their mode of action remains unknown. The objectives of this study were to evaluate the transcriptomic response of D. magna exposed to sublethal doses of 1H-benzotriazole (BTR), 5-methyl-1H-benzotriazole (5MeBTR) and 5-chloro-1H-benzotriazole (5ClBTR) using RNA-sequencing and quantitative real-time PCR. Cellular and life-history endpoints (survival, number of neonates, growth) were also investigated. Significant effects on the molting frequency were observed after 21-d exposure to 5MeBTR and 5ClBTR. No effects on molting frequency were observed for BTR but RNA-seq results indicated that this BZT induced the up-regulation of genes coding for cuticular proteins, which could have compensated the molting disruption. Molting in cladocerans is actively controlled by ecdysteroid hormones. Complementary short-term temporal analysis (4- and 8-d exposure) of the transcription of genes related to molting and hormone-mediated processes indicated that the three compounds had specific modes of action. BTR induced the transcription of genes involved in 20-hydroxyecdysone synthesis, which suggests pro-ecdysteroid properties. 5ClBTR exposure induced protein activity and transcriptional levels of chitinase enzymes, associated with an impact on ecdysteroid signaling pathways, which could explain the decrease in molt frequency. Finally, 5MeBTR seemed to increase molt frequency through epigenetic processes. Overall, results suggested that molting effects observed at the physiological level could be linked to endocrine regulation impacts of BZTs at the molecular level.