Disordered eating as a repercussion of sexual assault: a consequence to consider.

PURPOSE: This study aims at clarifying the links between sexual violence and disordered eating (DE). METHODS: In a sample of 12,638 victims of self-reported sexual violence, we analyzed the situation of 546 victims that declared having developed DE. We assessed the characteristics of the assault (age, type of aggression) and the medical consequences (PTSD, depression, suicide attempts, anxiety disorders, etc.). RESULTS: DE prevalence was 4.3% in the victim sample. The age of the first assault in DE victims was significantly lower than that of the whole population (12 years vs 16 years for median; p < 0.001). A much higher prevalence of sexual assault consequences was present in victims developing DE with odd ratios (OR) for: self-mutilation (OR = 11.5 [8.29-15.95], p < 0.001); depression (OR = 5.7 [4.81-6.86], p < 0.001); self-medication (OR = 5.3 [3.86-7.19], p < 0.001); suicide attempts (OR = 4.5 [3.59-5.67], p < 0.001); post-traumatic stress disorder (OR = 3.8 [2.99-4.78], p < 0.001); anxiety troubles (OR = 5.2 [4.11-6.47], p < 0.001); alcoholism (OR = 4.0 [2.81-5.58], p < 0.001). CONCLUSION: This study confirms the link between DE and sexual violence, especially in childhood, leading to severe psychological consequences. In this context, DE should be envisaged as a coping strategy accompanying emotional dysregulation due to traumatic events, and be treated as such. LEVEL OF EVIDENCE: Level IV: Evidence obtained from multiple time series analysis such as case studies.

High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference.

BACKGROUND: High-dose biotin therapy is beneficial in progressive multiple sclerosis (MS) and is expected to be adopted by a large number of patients. Biotin therapy leads to analytical interference in many immunoassays that utilize streptavidin-biotin capture techniques, yielding skewed results that can mimic various endocrine disorders. We aimed at exploring this interference, to be able to remove biotin and avoid misleading results. METHODS: We measured free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), parathyroid homrone (PTH), 25-hydroxyvitamin D (25OHD), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, C-peptide, cortisol (Roche Diagnostics assays), biotin and its main metabolites (liquid chromatography tandem mass spectrometry) in 23 plasmas from MS patients and healthy volunteers receiving high-dose biotin, and in 39 biotin-unsupplemented patients, before and after a simple procedure (designated N5) designed to remove biotin by means of streptavidin-coated microparticles. We also assayed fT4, TSH and PTH in the 23 high-biotin plasmas using assays not employing streptavidin-biotin binding. RESULTS: The biotin concentration ranged from 31.7 to 1160 µg/L in the 23 high-biotin plasmas samples. After the N5 protocol, the biotin concentration was below the detection limit in all but two samples (8.3 and 27.6 µg/L). Most hormones results were abnormal, but normalized after N5. All results with the alternative methods were normal except two slight PTH elevations. In the 39 biotin-unsupplemented patients, the N5 protocol did not affect the results for any of the hormones, apart from an 8.4% decrease in PTH. CONCLUSIONS: We confirm that most streptavidin-biotin hormone immunoassays are affected by high biotin concentrations, leading to a risk of misdiagnosis. Our simple neutralization method efficiently suppresses biotin interference.

Unraveling the early molecular and physiological mechanisms involved in response to phenanthrene exposure.

BACKGROUND: Higher plants have to cope with increasing concentrations of pollutants of both natural and anthropogenic origin. Given their capacity to concentrate and metabolize various compounds including pollutants, plants can be used to treat environmental problems - a process called phytoremediation. However, the molecular mechanisms underlying the stabilization, the extraction, the accumulation and partial or complete degradation of pollutants by plants remain poorly understood. RESULTS: Here, we determined the molecular events involved in the early plant response to phenanthrene, used as a model of polycyclic aromatic hydrocarbons. A transcriptomic and a metabolic analysis strongly suggest that energy availability is the crucial limiting factor leading to high and rapid transcriptional reprogramming that can ultimately lead to death. We show that the accumulation of phenanthrene in leaves inhibits electron transfer and photosynthesis within a few minutes, probably disrupting energy transformation. CONCLUSION: This kinetic analysis improved the resolution of the transcriptome in the initial plant response to phenanthrene, identifying genes that are involved in primary processes set up to sense and detoxify this pollutant but also in molecular mechanisms used by the plant to cope with such harmful stress. The identification of first events involved in plant response to phenanthrene is a key step in the selection of candidates for further functional characterization, with the prospect of engineering efficient ecological detoxification systems for polycyclic aromatic hydrocarbons.

SIMulation of Medication Error induced by Clinical Trial drug labeling: the SIMME-CT study.

OBJECTIVE: To assess the impact of investigational drug labels on the risk of medication error in drug dispensing. DESIGN: A simulation-based learning program focusing on investigational drug dispensing was conducted. SETTING: The study was undertaken in an Investigational Drugs Dispensing Unit of a University Hospital of Lyon, France. PARTICIPANTS: Sixty-three pharmacy workers (pharmacists, residents, technicians or students) were enrolled. INTERVENTION: Ten risk factors were selected concerning label information or the risk of confusion with another clinical trial. Each risk factor was scored independently out of 5: the higher the score, the greater the risk of error. From 400 labels analyzed, two groups were selected for the dispensing simulation: 27 labels with high risk (score ≥3) and 27 with low risk (score ≤2). Each question in the learning program was displayed as a simulated clinical trial prescription. MAIN OUTCOME MEASURE: Medication error was defined as at least one erroneous answer (i.e. error in drug dispensing). For each question, response times were collected. RESULTS: High-risk investigational drug labels correlated with medication error and slower response time. Error rates were significantly 5.5-fold higher for high-risk series. Error frequency was not significantly affected by occupational category or experience in clinical trials. CONCLUSIONS: SIMME-CT is the first simulation-based learning tool to focus on investigational drug labels as a risk factor for medication error. SIMME-CT was also used as a training tool for staff involved in clinical research, to develop medication error risk awareness and to validate competence in continuing medical education.

The DUF59 family gene AE7 acts in the cytosolic iron-sulfur cluster assembly pathway to maintain nuclear genome integrity in Arabidopsis.

Eukaryotic organisms have evolved a set of strategies to safeguard genome integrity, but the underlying mechanisms remain poorly understood. Here, we report that asymmetric leaves1/2 enhancer7 (AE7), an Arabidopsis thaliana gene encoding a protein in the evolutionarily conserved Domain of Unknown Function 59 family, participates in the cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway to maintain genome integrity. The severe ae7-2 allele is embryo lethal, whereas plants with the weak ae7 (ae7-1) allele are viable but exhibit highly accumulated DNA damage that activates the DNA damage response to arrest the cell cycle. AE7 is part of a protein complex with CIA1, NAR1, and MET18, which are highly conserved in eukaryotes and are involved in the biogenesis of cytosolic and nuclear Fe-S proteins. ae7-1 plants have lower activities of the cytosolic [4Fe-4S] enzyme aconitase and the nuclear [4Fe-4S] enzyme DNA glycosylase ROS1. Additionally, mutations in the gene encoding the mitochondrial ATP binding cassette transporter ATM3/ABCB25, which is required for the activity of cytosolic Fe-S enzymes in Arabidopsis, also result in defective genome integrity similar to that of ae7-1. These results indicate that AE7 is a central member of the CIA pathway, linking plant mitochondria to nuclear genome integrity through assembly of Fe-S proteins.

A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression.

A growing number of long nuclear-retained non-coding RNAs (ncRNAs) have recently been described. However, few functions have been elucidated for these ncRNAs. Here, we have characterized the function of one such ncRNA, identified as metastasis-associated lung adenocarcinoma transcript 1 (Malat1). Malat1 RNA is expressed in numerous tissues and is highly abundant in neurons. It is enriched in nuclear speckles only when RNA polymerase II-dependent transcription is active. Knock-down studies revealed that Malat1 modulates the recruitment of SR family pre-mRNA-splicing factors to the transcription site of a transgene array. DNA microarray analysis in Malat1-depleted neuroblastoma cells indicates that Malat1 controls the expression of genes involved not only in nuclear processes, but also in synapse function. In cultured hippocampal neurons, knock-down of Malat1 decreases synaptic density, whereas its over-expression results in a cell-autonomous increase in synaptic density. Our results suggest that Malat1 regulates synapse formation by modulating the expression of genes involved in synapse formation and/or maintenance.

Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia.

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.

Cytogenetic and Genetic Abnormalities with Diagnostic Value in Myelodysplastic Syndromes (MDS): Focus on the Pre-Messenger RNA Splicing Process.

Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed.

Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells' proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography-tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/ß-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.

Nuclear reformation after mitosis requires downregulation of the Ran GTPase effector RanBP1 in mammalian cells.

The GTPase Ran regulates nucleocytoplasmic transport in interphase and spindle organisation in mitosis via effectors of the importin beta superfamily. Ran-binding protein 1 (RanBP1) regulates guanine nucleotide turnover on Ran, as well as its interactions with effectors. Unlike other Ran network members that are steadily expressed, RanBP1 abundance is modulated during the mammalian cell cycle, peaking in mitosis and declining at mitotic exit. Here, we show that RanBP1 downregulation takes place in mid to late telophase, concomitant with the reformation of nuclei. Mild RanBP1 overexpression in murine cells causes RanBP1 to persist in late mitosis and hinders a set of events underlying the telophase to interphase transition, including chromatin decondensation, nuclear expansion and nuclear lamina reorganisation. Moreover, the reorganisation of nuclear pores fails associated with defective nuclear relocalisation of NLS cargoes. Co-expression of importin beta, together with RanBP1, however mitigates these defects. Thus, RanBP1 downregulation is required for nuclear reorganisation pathways operated by importin beta after mitosis.

Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA.

Deregulation of pre-mRNA splicing is observed in many cancers and hematological malignancies. Genes encoding splicing factors are frequently mutated in myelodysplastic syndromes, in which SF3B1 mutations are the most frequent. SF3B1 is an essential component of the U2 small nuclear ribonucleoprotein particle that interacts with branch point sequences close to the 3' splice site during pre-mRNA splicing. SF3B1 mutations mostly lead to substitutions at restricted sites in the highly conserved HEAT domain, causing a modification of its function. We found that SF3B1 was aberrantly spliced in various neoplasms carrying an SF3B1 mutation, by exploring publicly available RNA sequencing raw data. We aimed to characterize this novel SF3B1 transcript, which is expected to encode a protein with an insertion of eight amino acids in the H3 repeat of the HEAT domain. We investigated the splicing proficiency of this SF3B1 protein isoform, in association with the most frequent mutation (K700E), through functional complementation assays in two myeloid cell lines stably expressing distinct SF3B1 variants. The yeast Schizosaccharomycespombe was also used as an alternative model. Insertion of these eight amino acids in wild-type or mutant SF3B1 (K700E) abolished SF3B1 essential function, highlighting the crucial role of the H3 repeat in the splicing function of SF3B1.

Too much iron: A masked foe for leukemias.

The role of iron in non-erythroid hematopoietic lineages and its implication in hemato-oncogenesis are still debated. Iron exerts an important role on hematopoietic stem cell transformation and on mature white blood cell differentiation. Iron acts experimentally as an oncogenic cofactor but its exact role in the transformation of the myelodysplastic syndrome into leukemia continues to be discussed. Body iron overload frequently develops mainly as the result of multiple erythrocyte transfusions in patients with leukemia or myelodysplastic syndrome, and, in the latter, as a result of increased ineffective erythropoiesis. Iron overload, especially through the deleterious effects of reactive oxygen species, leads to organ damage that likely impacts the global outcome of patients, especially after hematopoietic stem cell transplantation (HSCT). In these pathological settings (before and after HSCT), oral iron chelation should be considered whenever body iron overload has been firmly established, ideally by magnetic resonance imaging.

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues.

Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding "splicing and myeloproliferative neoplasms". We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor.

In several brain regions, microglia actively promote neuronal apoptosis during development. However, molecular actors leading microglia to trigger death remain mostly unknown. Here, we show that, in the developing hippocampus, apoptotic neurons are contacted by microglia expressing both the integrin CD11b and the immunoreceptor DAP12. We demonstrate that developmental apoptosis decreases in mice deficient for CD11b or DAP12. In addition, function-blocking antibodies directed against CD11b decrease neuronal death when injected into wild-type neonates, but have no effect when injected into DAP12-deficient littermates. This demonstrates that DAP12 and CD11b act in converging pathways to induce neuronal death. Finally, we show that DAP12 and CD11b control the production of microglial superoxide ions, which kill the neurons. Thus, our data show that the process of developmental neuronal death triggered by microglia is similar to the elimination of pathogenic cells by the innate immune cells.

Rare anemias due to genetic iron metabolism defects.

Anemia is defined by a deficiency of hemoglobin, an iron-rich protein that binds oxygen in the blood. It can be due to multiple causes, either acquired or genetic. Alterations of genes involved in iron metabolism may be responsible, usually at a young age, for rare forms of chronic and often severe congenital anemia. These diseases encompass a variety of sideroblastic anemias, characterized by the presence of ring sideroblasts in the bone marrow. Clinical expression of congenital sideroblastic anemia is either monosyndromic (restricted to hematological lineages) or polysyndromic (with systemic expression), depending on whether iron metabolism, and especially heme synthesis, is directly or indirectly affected. Beside sideroblastic anemias, a number of other anemias can develop due to mutations of key proteins acting either on cellular iron transport (such as the DMT1 transporter), plasma iron transport (transferrin), and iron recycling (ceruloplasmin). Contrasting with the aforementioned entities which involve compartmental, and sometimes, systemic iron excess, the iron refractory iron deficiency anemia (IRIDA) corresponds to a usually severe anemia with whole body iron deficiency related to chronic increase of plasma hepcidin, the systemic negative regulator of plasma iron. Once clinically suggested, these diseases are confirmed by genetic testing in specialized laboratories.

Coadsorption of HIV-1 p24 and gp120 proteins to surfactant-free anionic PLA nanoparticles preserves antigenicity and immunogenicity.

Biodegradable micro- or nanoparticles with surface adsorbed antigens represent a promising method for in vivo delivery of vaccines. Most vaccines, licensed or under development, are based on combined delivery of multiple antigens. Thus, we investigated the feasibility of combining two vaccine antigens, HIV-1 p24 and gp120 proteins, on the surface of surfactant-free anionic PLA nanoparticles obtained by an improved solvent diffusion method. The analysis of adsorption isotherms has shown that both proteins had similar and high affinities for the nanoparticles. Coadsorption of p24 and gp120 onto the same PLA particle was evidenced by sandwich ELISA, using antibodies directed against one protein for particle capture and the other one for detection. To assess structural integrity, the antigenicity of free and PLA-adsorbed antigens was compared by competition ELISA, using a set of 6 anti-p24 and 7 anti-gp120 antibodies, as well as soluble CD4. The antigenicity of proteins on the nanoparticle surface was well preserved, adsorbed either individually or in combination. Furthermore, both antigens maintained their immunogenicity, since high antibody titres (10(6) for p24 and 10(5) for gp120) were elicited in mice with monovalent and divalent PLA formulations. Taken together our results show that development of multivalent vaccines based on anionic PLA nanoparticles is possible. Moreover, coadsorption of a ligand for cell-specific targeting or of an immunostimulatory molecule will further extend the field of application of delivery systems based on charged micro- and nanoparticles.

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. AREAS COVERED: High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. EXPERT OPINION: A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

[Pre-mRNA splicing: when the spliceosome loses ground]. / L'épissage des ARN pré-messagers : quand le splicéosome perd pied.

Pre-mRNA splicing is an obligatory step required to assemble the vast majority of mRNAs in eukaryotes. In humans, each gene gives rise to at least two transcripts, with an average 6-8 spliced transcripts per gene. Pre-mRNA splicing is not unequivocal. Variations may occur, such that splicing can become alternative, thereby participating in increasing protein variability and restricting the gap that exists between the relatively low number of genes - between 20,000 and 25,000 in humans - and the much higher number of distinct proteins - at least 100,000. In addition, although alternative pre-mRNA splicing often fulfils cell-specific needs, many aberrant splicing events can happen and lead to either hereditary or acquired diseases such as neurodegenerative diseases or cancers. In those cases, alternative splicing events may serve as disease-associated markers, or even as targets for corrective approaches. In this review, we will summarize the main aspects of regulated alternative splicing. We will present the spliceosome, a large ribonucleoprotein complex that orchestrates the splicing reactions and that was recently identified as a preferential target for mutations in several pathologies. We shall discuss some spliceosome-associated defects linked to either cis (i.e on the DNA) or trans (e.g. in proteins) alterations of splicing machinery, like those that have been reported in genetic or acquired diseases.

Tumor necrosis factor-alpha and neuronal development.

Tumor necrosis factor-alpha (TNFalpha) is a prototypic inflammatory cytokine up-regulated in most if not all neurodegenerative diseases. Many studies have reported variable roles in the adult or pathological brain. In contrast, the implication of TNFalpha in developmental neuronal cell death has been well documented in few studies. In sympathetic and trigeminal neurons, TNFalpha acts in an autocrine manner to induce immediate cell death on neurotrophic factor deprivation. In the spinal cord, TNFalpha is transiently produced by macrophages and commits motoneurons to become competent to die 2 days later. TNFalpha is also likely to induce immediate and delayed prodeath effects in adult and pathological tissues. Data obtained in embryonic systems will thus help to develop new therapeutic approaches to pathological neuronal death in adults.