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.

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.

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.

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.

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.

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.

[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.

The RDoC approach for translational psychiatry: Could a genetic disorder with psychiatric symptoms help fill the matrix? the example of Prader-Willi syndrome.

The Research Domain Criteria project (RDoc) proposes a new classification system based on information from several fields in order to encourage translational perspectives. Nevertheless, integrating genetic markers into this classification has remained difficult because of the lack of powerful associations between targeted genes and RDoC domains. We hypothesized that genetic diseases with psychiatric manifestations would be good models for RDoC gene investigations and would thereby extend the translational approach to involve targeted gene pathways. To explore this possibility, we reviewed the current knowledge on Prader-Willi syndrome, a genetic disorder caused by the absence of expression of some of the genes of the chromosome 15q11-13 region inherited from the father. Indeed, we found that the associations between genes of the PW locus and the modification identified in the relevant behavioral, physiological, and brain imaging studies followed the structure of the RDoC matrix and its six domains (positive valence, negative valence, social processing, cognitive systems, arousal/regulatory systems, and sensorimotor systems).

[Substance use disorder in the elderly and specified DSM-5 criteria]. / Tous les critères DSM-5 du trouble lié à l'usage de substance se valent-ils chez les sujets âgés ?

BACKGROUND: Substance use disorder (SUD) is commonly thought to be less frequent among the elderly than among younger adults. However, this disorder could be insufficiently screened in this population. And the diagnosis could be difficult to make especially because of specificities of this population. The diagnosis is based on the criteria of the DSM-5. Nevertheless, DSM-5 criteria were elaborated for younger adults and some of them could be inappropriate for older adults. METHODS: We studied the frequency of the DSM-5 criteria in a population of 59 patients aged around of 80 years, non-dependent and exposed to alcohol or benzodiazepines. We collected data relative to age, gender, type of residence (self-home or retirement house), medical past history, current treatment. Patient were also asked about their alcohol consumption, time of exposition, quantity of alcohol ingested or dose of benzodiazepines ingested and frequency of consumption. Alcohol consumption was reported as alcohol unit per day (one unit containing 10-gram alcohol). Frequency consisted in number of days with consumption in a week. Concerning benzodiazepine with evaluated the quantity by converting dose in equivalent diazepam per day. We determine the frequency of each criterion and the association with SUD diagnosis. RESULTS: We found that 45% of patients presented a diagnosis of SUD. DSM criteria 1, 2, 4, 9, 10 and 11 were found significantly more frequently in patients with addiction than in those without addiction. On the regression analysis criteria 1, 4, 6, 9, 10 and 11 as well as the number of units of alcohol consumed per day were associated with the diagnosis of addiction. The other socio-demographic factors were not associated with the diagnosis. CONCLUSION: This pilot study highlights that certain DSM-5 addiction criteria seem to be more relevant to seek in the elderly.