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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.
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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.
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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.