Coercion and Compulsory Treatment in Anorexia Nervosa: a Systematic Review on Legal and Ethical Issues.

BACKGROUND: The aim of this systematic review is to critically summarize current literature concerning ethical and legal issues related compulsory treatment (CT) in patients with anorexia nervosa (AN). SUBJECTS AND METHODS: Relevant articles were identified following the PRISMA guidelines after performing title/abstract screening and full text screening. We built the search string using the following terms: "coercion", "compulsory/involuntary treatment", "eating disorders", "anorexia nervosa", "mental capacity", "ethical/legal issues". Research was conducted on original articles published from any time until June 2023. RESULTS: Out of 302 articles retrieved, seven were included for the analysis, including five studies on mental health practitioners, and two on hospital records. The results show that mental health practitioners a) favor the use of CT, but the support is weaker in AN vs other psychiatric conditions (i.e., schizophrenia or depression); b) support of mental capacity is controversial and some variability was found between different categories of psychiatrists; in particular, both ED-treating and CT experienced mental health practitioners support higher use of CT and lack of capacity of AN patients vs. general psychiatrists; c) use of CT is more supported in the early vs. chronic AN, when chances of success are lower. The analysis of hospital records identified 1) comorbidities, previous admissions and current health risk as CT predictors in 96 Australian patients; 2) family conflicts association with longer hospitalizations in 70 UK patients. CONCLUSION: CT is usually intended for patients with AN at the onset of disease, mainly to prevent risk of death and self-injury. However, there is some variability in the attitude to perform CT among psychiatrists working in different setting, also related to the concept of mental capacity. There are also cross-national variabilities regarding CT. We can conclude that forcing patients to treatment is a conceivable option, but the balance between protection respect for patient's autonomy should be evaluated on individual bases.

The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75(NTR)-dependent apoptosis.

Nerve growth factor (NGF) receptors, TrKA and p75(NTR), are being investigated in cancer therapy. Our previous data show that, in HTB114 uterine leiomyosarcoma cells, p75(NTR)-dependent apoptosis is inducible by cytotoxic drugs and can suppress nerve growth factor-dependent growth. Although amitriptyline can kill cancer cells and bind TrKA/B, its effects on p75-dependent apoptosis are unknown. The aim of this paper was to evaluate the antineoplastic potential of amitriptyline, and the role of p75(NTR)-dependent apoptosis in the chemoresistant uterine HTB114 leiomyosarcoma. Using proliferation assays and fluorescence-activated cell sorting analysis, we found that amitriptyline caused a marked reduction in HTB114 cell viability, associated with the parallel upregulation of p75(NTR) expression. This converted the TrKA⁺-proliferating cells into TrKA⁺/p75(NTR⁺), leading to downregulation of TrKA-prosurvival signaling (AKT) and activation of p75(NTR)-dependent apoptosis (through caspase-3). Overall, we provide novel evidence that HTB114 uterine leiomyosarcoma cells are highly sensitive to amitriptyline, supporting the role of p75(NTR)-dependent apoptosis as a novel cytotoxic mechanism of this drug and of p75(NTR) as an inducible stress receptor and a novel target in clinical oncology.

S100B-stimulated NO production by BV-2 microglia is independent of RAGE transducing activity but dependent on RAGE extracellular domain.

The Ca(2+)-modulated protein, S100B, is expressed in high abundance in and released by astrocytes. At the low levels normally found in the brain, extracellular S100B acts as a trophic factor, protecting neurons against oxidative stress and stimulating neurite outgrowth through its binding to the receptor for advanced glycation end products (RAGE). However, upon accumulation in the brain extracellular space, S100B might be detrimental to neurons. At relatively high concentrations, S100B stimulates NO release by microglia in the presence of lipid A or interferon-gamma (IFN-gamma). We analyzed further the S100B-microglia interaction to elucidate the molecular mechanism by which the protein brings about this effect. We found that S100B increased NO release by BV-2 microglia by stimulating reactive oxygen species (ROS) production and activating the stress-activated kinases, p38 and JNK. However, S100B stimulated NO production to the same extent in microglia overexpressing a transduction-incompetent mutant of RAGE and in microglia overexpressing full-length RAGE, with a significantly smaller effect in mock-transfected microglia. This suggests that the RAGE transducing activity has little or no role in S100B-stimulated NO production by microglia, whereas RAGE extracellular domain is important, probably serving to concentrate S100B on the BV-2 cell surface. On the other hand, S100B stimulated NF-kappaB transcriptional activity in BV-2 microglia in a manner that was strictly dependent on RAGE transducing activity, pointing to additional, RAGE-mediated effects of the protein on microglia that remain to be investigated.