Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome.

INTRODUCTION: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. METHODS: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. RESULTS: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. CONCLUSION: SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.

Self-poisoning by E-cigarette and E-liquids: National Reports to French Poison Control Centers from July 2019 to December 2020: VIGIlance and VAPE: The VIGIVAPE Study.

INTRODUCTION: Exposure to e-cigarette liquids, whether intentional or accidental, might lead to adverse events. This study aimed to describe the prevalence and characteristics of exposures to e-liquids reported to French Poison Control Centers. METHODS: All e-liquids exposure cases reported to French Poison Control Centers from July 1, 2019, to December 31, 2020, were reviewed. Information was collected about the patient's characteristics, exposure circumstances, management and outcome. RESULTS: About 919 cases of exposure to e-liquids were reported. Ages ranged from one month to 89 years, with a mean age of 16.6 ± 18.6 years and a median age of 4 years. The highest number of exposures-50.7%-concerned infants (0-4 years), 3.1% children (5-11 years), 5.9% adolescents (12-17 years), and 40.1% of cases concerned adults. The majority of cases were accidental (95.0%). Intentional exposures (4.9%) were mainly observed in patients older than 12 years of age (P < 0.001). The route of exposure was ingestion in 73.7% of the cases. A total of 455 exposures showed no symptoms or signs related to poisoning. High nicotine concentration in e-liquids was associated with an increase in hospital management (Odds-ratio from 1.77 to 2.60). CONCLUSION: Involuntary exposures to e-liquids occurred more often in children under the age of five, mainly by ingestion. Unlike intentional ingestions, unintentional ingestions rarely resulted in severe adverse events. These findings highlight the importance of ongoing surveillance to prevent such exposures and associated injuries, emphasizing the need for effective regulation of these products.

What can we learn from PWS and SNORD116 genes about the pathophysiology of addictive disorders?

Addictive disorders have been much investigated and many studies have underlined the role of environmental factors such as social interaction in the vulnerability to and maintenance of addictive behaviors. Research on addiction pathophysiology now suggests that certain behavioral disorders are addictive, one example being food addiction. Yet, despite the growing body of knowledge on addiction, it is still unknown why only some of the individuals exposed to a drug become addicted to it. This observation has prompted the consideration of genetic heritage, neurodevelopmental trajectories, and gene-environment interactions in addiction vulnerability. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which children become addicted to food and show early social impairment. PWS is caused by the deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene was identified as the minimal gene responsible for the PWS phenotype. Several studies have also indicated the role of the Snord116 gene in animal and cellular models to explain PWS pathophysiology and phenotype (including social impairment and food addiction). We thus present here the evidence suggesting the potential involvement of the SNORD116 gene in addictive disorders.

Factors associated with hospitalization after self-poisoning in France: special focus on the impact of alcohol use disorder.

BACKGROUND: Previous studies have identified factors associated with admission to hospital after suicide spectrum behaviors. In this study, we aim to identify specific factors associated with psychiatric hospitalization after self-poisoning. Given earlier findings suggesting that alcohol use disorder is not associated with hospital admission, we also aim to consider its impact, as well as blood alcohol concentrations, on hospitalization decisions after a suicide attempt. METHODS: We studied the association between demographic features, suicide intent, psychiatric characteristics and admission to hospital in self-poisoning patients in an emergency department in France. RESULTS: Suicide intent, a past history of suicide attempts, bipolar disorder and depression were associated with psychiatric hospital admissions. Despite alcohol use disorder being known to be associated with a suicide risk, it was not linked with psychiatric hospitalization. A positive blood alcohol concentration in the emergency department likewise had no association with admission to a psychiatric ward for inpatient care. CONCLUSIONS: Our findings were similar to those reported for other suicide spectrum behaviors. Alcohol use disorder was not associated with admission for inpatient psychiatric care, whereas depression clearly was. The cause of this discrepancy must be determined in future research.

A 10-year review of cannabis exposure in children under 3-years of age: do we need a more global approach?

Pediatricians working in an emergency environment are confronted with children admitted to emergency departments for intoxication on a daily basis. We carried out a retrospective cohort study of children admitted to a pediatric emergency department due to unintentional cannabis exposure over a 10-year period from 2004 to 2014. Twenty-nine children under the age of 3 were admitted with a positive cannabis urine test. Eighty-seven percent of intoxications occurred at the family home. Resin was the main form of ingested cannabis (69%). The mean age was 16.5 ± 5.2 months, and mean weight was 11.1 ± 2.1 Kg. Sixty percent of admissions occurred between 2012 and 2014. More severe presentations, based on Poisoning Severity Score, occurred over the past 2 years. Four children experienced seizures before admission. Ten children (34%) had a decreased level of consciousness (GCS <12) and were admitted to a pediatric intensive care unit for 12-24 h. All of them had ingested hashish (resin). The majority (70%) of children suffering from neurological impairment were admitted in the last year, of whom three required assisted ventilation. There were no cases with major outcomes and no deaths. Parents were not assessed regarding their cannabis consumption. CONCLUSION: This study supports the impression that accidental child poisonings with cannabis have been more serious than previously thought for 2 years. This observation may be explained by (1) the increased THC concentration in cannabis and (2) the widespread use in young adults, even after they become parents. Introducing an addiction team inside the PED could help to improve the care links with these parents. What is Known: • Cases of unintentional cannabis intoxication in children have been increasing for many years due to an increase of potency. What is New: • We highlight an increase in more severe presentations in children under the age of 3 occurring over the past 2 years, which will indicate the importance of assessing cannabis abuse in parents by a specialized addiction team.

Cannabis Hyperemesis Syndrome in the Emergency Department: How Can a Specialized Addiction Team Be Useful? A Pilot Study.

BACKGROUND: Chronic cannabis users may experience cyclical episodes of nausea and vomiting and learned behavior of hot bathing. This clinical condition, known as cannabis hyperemesis syndrome, was first reported in 2004. OBJECTIVE: Our aim was to promote early recognition of this syndrome in emergency departments (EDs) and to increase referral to addiction specialists. METHODS: Cannabis abusers were admitted to the ED for vomiting or abdominal pain from June 1, 2014 to January 1, 2015 and diagnosed with cannabis hyperemesis syndrome by a specialized addiction team. Then, medical records were examined retrospectively. RESULTS: Seven young adults were included. Their mean age was 24.7 years (range 17-39 years) and the majority were men (male-to-female ratio 1.2). Biological and toxicological blood samples were taken in all patients. Tetrahydrocannabinol blood level was measured in 4 patients, with a mean blood concentration of 11.6 ng/mL. Radiographic examination including abdominal computed tomography and brain imaging were negative, as was upper endoscopy. Five patients compulsively took hot baths in an attempt to decrease the symptoms. Treatment was symptomatic. Five patients have started follow-up with the specialized addiction team. CONCLUSIONS: Cannabis hyperemesis syndrome is still under-diagnosed 10 years after it was first described. Physicians should be aware of this syndrome to avoid repeated hospitalizations or esophageal complications. Greater awareness should lead to prompt treatment and prevention of future recurrence through cannabis cessation. Addiction specialists, as well as medical toxicologists, are experts in the management of cannabis abusers and can help re-establish the role of medical care in this population in collaboration with emergency physicians.

Minoxidil topical solution: an unsafe product for children.

Minoxidil hair formulation is commonly used for the treatment of male or female androgenic alopecia. This over-the-counter product is wrongly considered safe. The ingestion of a few milliliters by a child can lead to significant intoxication. We report a case of significant intoxication after the ingestion of topical minoxidil (Alopexy; Pierre Fabre Laboratoires, SA, Switzerland). A 7-year-old girl, who accidentally ingested a teaspoon of minoxidil hair solution, presented to the pediatric emergency department for emesis. At admission, she had a blood pressure of 86/56 mm Hg and a pulse of 149 beats per minute. Hypotension lasted 40 hours with the lowest value 24 hours after ingestion (79/33 mm Hg). She presented electrocardiogram changes (sinus tachycardia and flattening T-waves) but normal cardiac enzymes. Infusion of 20 mL/kg of normal saline fluid had no hemodynamic effect. Her blood pressure normalized on day 2. Minoxidil topical solution is an unsafe product for children. This formulation should be strictly kept out of reach of children and manufacturers should enhance child-resistance security of packaging. The over-the-counter availability must be questioned.

Self-intoxication with baclofen in alcohol-dependent patients with co-existing psychiatric illness: an emergency department case series.

AIMS: The aim of the study was to describe the characteristics and management of alcohol-dependent patients with co-existing psychiatric illness seen after self-intoxication with oral baclofen in an emergency department (ED). METHODS: A retrospective review of medical records of such patients over a 12-month period from January 2012. RESULTS: Twelve such patients were identified, median age 39.5 years. The median supposed ingested dose of baclofen was 340 mg (range 140-800 mg). Three patients who had co-ingested benzodiazepines had a decreased level of consciousness (Glasgow Coma Scale <8) and flumazenil had been given to reverse coma. Blood alcohol concentration, requested for all patients, was positive in three (ranging from 153 to 495 mg/100 ml). Gastric lavage was performed in two cases. All patients made a full recovery. They were discharged from the ED or intensive care unit after psychiatric assessment. CONCLUSION: Baclofen overdose affects the autonomic and central nervous system. Supportive care is symptom based. Care should be taken when prescribing baclofen with other central nervous system depressants and to patients with past attempted suicide.

Parental cannabis abuse and accidental intoxications in children: prevention by detecting neglectful situations and at-risk families.

OBJECTIVES: Cannabis intoxication in toddlers is rare and mostly accidental. Our objectives were to focus on the characteristics and management of children under the age of 6 years who were admitted to our emergency department with cannabis poisoning reported as accidental by parents, and to point out the need to consider accidental cannabis ingestions as an indicator of neglect. METHODS: The medical records of children hospitalized for cannabis poisoning in a pediatric emergency department from January 2007 to November 2012 were retrospectively evaluated. Data collected included age, sex, drug ingested, source of drug, intentional versus accidental ingestion, pediatric intensive care unit or hospital admission, treatment and length of hospital stay, toxicology results, and rate of child protectives services referral. RESULTS: Twelve toddlers (4 boys and 8 girls; mean age, 16.6 months) were included. All had ingested cannabis. Their parents reported the ingestion. Seven children experienced drowsiness or hypotonia. Three children were given activated charcoal. Blood screening for cannabinoids, performed in 2 cases, was negative in both, and urine samples were positive in 7 children (70%). All children had favorable outcomes after being hospitalized from 2 to 48 hours. Nine children were referred to social services for further assessment before discharge. CONCLUSIONS: Cannabis intoxication in children should be reported to child protection services with the aim of prevention, to detect situations of neglect and at-risk families. Legal action against the parents may be considered. Accidental intoxication and caring parents should be no exception to this rule.

Low-dose ketamine infusion to facilitate opioid tapering in chronic non-cancer pain with opioid-use disorder: a historical cohort study.

BACKGROUND: Long-term opioid use is associated with pharmacological tolerance, a risk of misuse and hyperalgesia in patients with chronic pain (CP). Tapering is challenging in this context, particularly with comorbid opioid-use disorder (OUD). The antihyperalgesic effect of ketamine, through N-methyl-D-aspartate (NMDA) antagonism, could be useful. We aimed to describe the changes in the dose of opioids consumed over 1 year after a 5-day hospitalisation with ketamine infusion for CP patients with OUD. METHODS: We performed a historical cohort study using a medical chart from 1 January 2014 to 31 December 2019. Patients were long-term opioid users with OUD and CP, followed by the Pain Center of the University Hospital of Toulouse, for which outpatient progressive tapering failed. Ketamine was administered at a low dose to initiate tapering during a 5-day hospitalisation. RESULTS: 59 patients were included, with 64% of them female and a mean age of 48±10 years old. The most frequent CP aetiologies were back pain (53%) and fibromyalgia (17%). The baseline opioid daily dose was 207 mg (±128) morphine milligram equivalent (MME). It was lowered to 92±72 mg MME at discharge (p<0.001), 99±77 mg at 3 months (p<0.001) and 103±106 mg at 12 months. More than 50% tapering was achieved immediately for 40 patients (68%), with immediate cessation for seven patients (12%). 17 patients were lost to follow-up. CONCLUSIONS: A 5-day hospitalisation with a low-dose ketamine infusion appeared useful to facilitate opioid tapering in long-term opioid users with CP and OUD. Ketamine was well tolerated, and patients did not present significant withdrawal symptoms. Prospective and comparative studies are needed to confirm our findings.

The consumption of psychoactive substances among French physicians: how do they perceive the creation of a dedicated healthcare system?

Introduction: Substance use among physicians can have negative impacts on their health, quality of life, and patient care. While Physician Health Programs (PHPs) have proven effective, many physicians with substance use disorders (SUDs) still face obstacles in seeking help. Our study explores the expectations, attitudes, and experiences of French physicians regarding the implementation of a specialized healthcare system (SHS) for addiction, and their opinions on the factors that could improve the effectiveness of such a service, with a focus on substance use disorders (SUDs). Methods: We conducted a web-based survey from April 15 to July 15, 2021, which included questions about sociodemographic characteristics, substance use, and attitudes toward a specialized healthcare system (SHS) for physicians with SUDs. Results: Of the 1,093 respondents (62.5% female), 921 consumed alcohol (84.2%), and 336 (36.4%) were categorized as hazardous drinkers (AUDIT-C ≥ 4 for women and ≥ 5 for men). The mean AUDIT-C score was 3.5 (±1.7 SD), with a range from 1 to 12. Factors associated with hazardous alcohol consumption included coffee consumption [OR 1.53 (1.11-2.12)], psychotropic drug use [OR 1.61 (1.14-2.26)], cannabis use [OR 2.96 (1.58-5.55)], and other drug use [OR 5.25 (1.92-14.35)]. On the other hand, having children was associated with non-hazardous alcohol consumption [OR 0.62 (0.46-0.83)]. Only 27 physicians (2.9%) had consulted a specialist in addiction medicine, while 520 (56.4%) expressed interest in such a consultation. The main barriers to accessing a dedicated consultation were denial (16.3%), physician self-medication (14.3%), fear of judgment (12.8%), and confidentiality concerns (10.2%). Conclusion: A specialized consultation with trained professionals in a neutral location can improve access to care for healthcare workers and maintain patient confidentiality and anonymity. Prevention and awareness can reduce addiction stigma and help peers in need. The improvement of healthcare workers' addiction culture and detection of addictive behavior in peers depends on academic addiction medicine.

Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database.

AIM: Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD). METHODS: All reports of adverse drug reactions (ADR) recorded in the FPVD between 1 January 1985 and 31 July 2008 and including the terms aggressiveness or violence were selected. We compared proportion of exposure to different drugs between cases (reports with violence) and noncases (other reports in the database). RESULTS: Among 537 cases, 56 were included (48 men, mean age 46 years). Misuse was observed in ten cases (18%). In 25 cases (44.6%), a previous psychiatric history was documented. Main drugs involved were nervous system (63.6%) followed by respiratory (7.8%), alimentary tract and metabolism (7.8%), dermatological (5.2%) and anti-infective (5.2%) agents. Case/noncase analysis found an association with dopaminergic agonists (pergolide, pramipexole, bromocriptine, piribedil), benzodiazepines (alprazolam, bromazepam) and serotoninergic antidepressants (taken as a whole), but not antipsychotics or antiepileptics. Association was also found with varenicline, isotretinoin, interferon alpha-2b, rimonabant, benfluorex, topiramate and antiviral drugs (ribavirin, efavirenz). CONCLUSION: Dopaminergic agonists, benzodiazepines and serotoninergic antidepressants are the main pharmacological classes able to induce aggressive behaviour. This study also emphasises the putative role of other drugs less known to be involved in such ADR.

Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory.

BACKGROUND: Prader-Willi syndrome is a rare genetic neurodevelopmental disorder caused by a paternal deficiency of maternally imprinted gene expression located in the chromosome 15q11-q13 region. Previous studies have demonstrated that several classes of neurodevelopmental disorders can be attributed to either over- or under-expression of specific genes that may lead to impairments in neuronal generation, differentiation, maturation and growth. Epigenetic changes that modify gene expression have been highlighted in these disorders. One recent study focused on epigenetic analysis and compared patients with PWS with patients with other imprinting disorders. No study, however, has yet focused on epigenetics in patients with PWS specifically by comparing the mutations associated with this syndrome. OBJECTIVE: This study investigated the epigenetic modifications in patients with PWS and patients with PWS-related disorders caused by inactivation of two genes of the PWS chromosomal region, SNORD116 and MAGEL2. Our approach also aimed to compare the epigenetic modifications in PWS and PWS-related disorders. METHODS: We compared genome-wide methylation analysis (GWAS) in seven blood samples from patients with PWS phenotype (five with deletions of the PWS locus, one with a microdeletion of SNORD116 and one with a frameshift mutation of MAGEL2 presenting with Schaaf-Yang syndrome), as well as two control patients. Controls were infants that had been studied for suspicion of genetic diseases that was not confirmed by the genetic analysis and the clinical follow-up. RESULTS: The analysis identified 29,234 differentially methylated cytosines, corresponding to 5,308 differentially methylated regions (DMRs), which matched with 2,280 genes. The DMRs in patients with PWS were associated with neurodevelopmental pathways, endocrine dysfunction and social and addictive processes consistent with the key features of the PWS phenotype. In addition, the separate analysis for the SNORD116 and MAGEL2 deletions revealed that the DMRs associated with the SNORD116 microdeletion were found in genes implicated in metabolic pathways and nervous system development, whereas MAGEL2 mutations mostly concerned genes involved in macromolecule biosynthesis. CONCLUSION: The PWS is associated with epigenetic modifications with differences in SNORD116 and MAGEL2 mutations, which seem to be relevant to the different associated phenotypes.

Appraisal by Year Six French medical students of the teaching of forensic medicine and health law.

Legal medicine is a cross-sectional specialty in which medico-legal situations very frequently combine with routine medical practice. A total of 132 students in the last year of the second cycle of medical studies (Year 6) replied anonymously and voluntarily to a questionnaire corresponding to the topics in the curriculum for the national ranking examination: law relating to death and the dying, examination of assault victims, medical malpractice liability rules, writing death certificates, respect of medical confidentiality and the principles of medical deontology. The most frequently cited activities of the forensic physician were autopsy (87.9%), writing certificates (75.8%) and consultations with victims of violence (60.6%). Students did not often come into contact with a medico-legal situation during Years 2-6 of medical studies. Assiduity in attending lectures was low. Students preferred the standard textbooks available in specialized bookshops. They were severe in their appraisal of their own competence at the end of the second cycle, and did not feel ready to examine a corpse (95.5%) or to examine victims of assault (92.4%). Knowledge of the law and of the risks of medical practice was felt to be inadequate by 60.5% of students, and of the writing of a medical certificate by 56.8%. Training medical students in this field is a major challenge in view of the limited number of teaching hours and the need to acquire increasingly specialized knowledge. Complementary initiatives appear to be necessary, such as partnership with other clinical specialties which are frequently confronted with medico-legal situations.

Mitral valve prolapse and out-of-hospital sudden death: a case report and literature review.

The emergency medical services were called to the workplace of a 25-year-old woman who appeared to be dead. The alarm was raised by employees who had found her unconscious at her desk. There was no semi-automatic defibrillator on the premises and no member of staff had received specific training in management of cardiac arrest. External cardiac massage was immediately started as advised by telephone by the emergency physician and ventricular fibrillation was diagnosed on arrival of the medical team. Despite continuous resuscitation, the victim did not revive. The death certificate was signed with a medicolegal objection to burial, leading to an inquiry. Several causes were suggested by the emergency physician who had been called to the patient, and who was unable to account for the death. Autopsy established the diagnosis of mitral valve prolapse. The authors stress that autopsy is imperative and detail the implications of such a procedure.

[Cannabis use and somatic consequences]. / Complications somatiques du cannabis.

Cannabis use and somatic consequences. Cannabis is the most frequently used illicit psychoactive substance in the world. It is perceived as a low-risk drug, as it is a plant, although many warnings in the medical literature underlined increased complications of cannabis use. Acute and chronic cannabis use is known to be harmful inducing psychiatric and addictive effects. An increase in the potency of cannabis as defined by a high ratio between the more important components, tetrahydrocannabinol and cannabidiol has been observed for years, which leads to more serious complications. Evidence indicates that both acute and chronic consumptions of cannabis can be detrimental to both mental and physical health. Effects of cannabis use include mood disorders, exacerbation of psychotic disorders in vulnerable people, cannabis use disorders, withdrawal syndrome, neurocognitive impairments, cardiovascular and respiratory and other diseases. Synthetic cannabinoid has rapidly spread for the last few years; they are chemical substances inducing similar psychoactive effects to cannabis. Although, cannabis users call these substances "cannabis", synthetic cannabinoids have different pharmacological properties, which make them dangerous substances leading to more serious complications. Physicians dealing with cannabis users should be aware of these differences between vegetal cannabis and synthetic cannabinoids.

Complications somatiques du cannabis. Le cannabis reste la substance illicite la plus consommée dans le monde. La perception du cannabis comme une substance peu dangereuse au regard de son origine végétale participe à l'augmentation de son usage. La puissance du cannabis est définie par un ratio élevé entre les composants les plus importants du cannabis, c'est-à-dire letétrahydrocannabinol et le cannabidiol. Les effets aigus et chroniques de l'usage du cannabis comportent un risque majoré de troubles psychiatriques, mais aussi de complications cardiovasculaires, neurovasculaires et neurocognitives, respiratoires et de sevrage en cas de dépendance. Avec l'apparition récente des cannabinoïdes de synthèse qui sont des substances chimiques contrairement au cannabis issu de la plante, des complications plus sévères sont décrites même lors d'usage unique. Ces nouvelles substances de synthèse, bien qu'appelées aussi cannabis par les utilisateurs, ont conduit à une modification des prises en charge des usagers en raison d'une toxicité aiguë et chronique plus sévère.