Genome wide association study of clinical duration and age at onset of sporadic CJD.

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.

BACKGROUND: The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters. METHODS: We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion. RESULTS: Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting. CONCLUSIONS: Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain.

An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1.

Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Prospective 25-year surveillance of prion diseases in France, 1992 to 2016: a slow waning of epidemics and an increase in observed sporadic forms.

BackgroundPrion diseases are rare, fatal disorders that have repeatedly raised public health concerns since the early 1990s. An active prion disease surveillance network providing national level data was implemented in France in 1992.AimWe aimed to describe the epidemiology of sporadic, genetic and infectious forms of prion diseases in France since surveillance implementation.MethodsWe included all suspected cases notified from January 1992 to December 2016, and cases who died during the period with a definite or probable prion disease diagnosis according to EuroCJD criteria. Demographic, clinical, genetic, neuropathological and biochemical data were collected.ResultsIn total, 25,676 suspected cases were notified and 2,907 were diagnosed as prion diseases, including 2,510 (86%) with sporadic Creutzfeldt-Jakob disease (sCJD), 240 (8%) genetic and 157 (6%) with infectious prion disease. Suspected cases and sCJD cases increased over time. Younger sCJD patients (≤ 50 years) showed phenotypes related to a distinct molecular subtype distribution vs those above 50 years. Compared to other European countries, France has had a higher number of cases with iatrogenic CJD after growth hormone treatment and variant CJD (vCJD) linked to bovine spongiform encephalopathy (second after the United Kingdom), but numbers slowly decreased over time.ConclusionWe observed a decrease of CJD infectious forms, demonstrating the effectiveness of measures to limit human exposure to exogenous prions. However, active surveillance is needed regarding uncertainties about future occurrences of vCJD, possible zoonotic potential of chronic wasting diseases in cervids and increasing trends of sCJD observed in France and other countries.

The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of prion diseases. The causes of sCJD are still unknown and exogenous factors may play a role. Worldwide, the number of patients with sCJD has progressively increased over time. This increase can be partly explained by increasing life expectancy and better case ascertainment, but a true increase in the number of sCJD cases cannot be excluded. We estimated mortality rates from sCJD in France (1992-2016) and studied variation in mortality rates by age, period, and time.We included all cases aged 45-89 years old who died with a probable/definite sCJD diagnosis based on the French national surveillance network. We used age-period-cohort (APC) Poisson regression models to study variation in mortality rates by sex, age, period, and time.A total of 2475 sCJD cases aged 45-89 years were included. Mortality rates increased with age, reached a peak between 75 and 79 years, and decreased thereafter. Mortality rates were higher in women than men at younger ages and lower at older ages. The full APC model with a sex×age interaction provided the best fit to the data, thus in favour of sex, age, period, and cohort effects on mortality rates. In particular, mortality rates increased progressively with successive birth cohorts.Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology.

Telomere length and mitochondrial DNA copy number in bipolar disorder: A sibling study.

OBJECTIVES: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences. METHODS: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA. RESULTS: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors. CONCLUSIONS: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.

Plasma tau, NfL, GFAP and UCHL1 as candidate biomarkers of alcohol withdrawal-associated brain damage: A pilot study.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.

Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence.

BACKGROUND: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. AIMS: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. METHODS: A cocaine-CPP paradigm in male Sprague-Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference. RESULTS: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between -85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes (Fos, Egr2, Nr4a1, and Zbtb37) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP. CONCLUSION: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine's rewarding effects.

A Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging.

BACKGROUND AND OBJECTIVES: To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging. METHODS: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF ß-amyloid (Aß) peptide biomarkers. These Aß cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients. RESULTS: A total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%. DISCUSSION: The proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.

Circulating IL-6 but not neutrophil extracellular traps levels can predict anakinra effectiveness in patients with severe COVID-19.

Added data on circulating IL-6 levels can predict COVID-19 severity and IL1RA efficiency.

Occurrence and severity of cocaine-induced hallucinations: Two distinct phenotypes with shared clinical factors but specific genetic risk factors.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.

INTRODUCTION: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. METHODS: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. RESULTS: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. DISCUSSION: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.

Childhood trauma and the severity of past suicide attempts in outpatients with cocaine use disorders.

Introduction: Suicide attempts have been associated with both cocaine use disorder (CocUD) and childhood trauma. We investigated how childhood trauma is an independent risk factor for serious and recurrent suicide attempts in CocUD. Method: 298 outpatients (23% women) with CocUD underwent standardized assessments of substance dependence (Diagnostic and Statistical Manual-mental disorders, fourth edition, text revised), impulsiveness, resilience, and childhood trauma, using validated tools. Suicide attempts history was categorized as single vs. recurrent or non-serious vs. serious depending on the lifetime number of suicide attempts and the potential or actual lethality of the worst attempt reported, respectively. Bivariate and multinomial regression analyses were used to characterize which childhood trauma patterns were associated with the suicide attempts groups. Results: 58% of CocUD patients reported childhood trauma. Recurrent and serious suicide attempts clustered together and were thus combined into "severe SA." Severe suicide attempt risk increased proportionally to the number of childhood traumas (test for trend, p = 9 × 10-7). Non-severe suicide attempt risk increased with impulsiveness and decreased with resilience. In multinomial regression models, a higher number of traumas and emotional abuse were independently and only associated with severe vs. non-severe suicide attempts (effect size = 0.82, AUC = 0.7). The study was limited by its cross-sectional design. Conclusion: These preferential associations between childhood trauma and severe suicide attempts warrant specific monitoring of suicide attempts risk in CocUD, regardless of the severity of addiction profiles.

Ascorbic Acid Deficiency Prevalence and Associated Cognitive Impairment in Alcohol Detoxification Inpatients: A Pilot Study.

Malnutrition has been reported in alcohol use disorder patients as having a possible influence on cognitive function. The aim of this study was to analyse the prevalence of ascorbic acid (AA) deficiency in inpatients admitted for alcohol detoxification and the associated factors, including cognitive impairment in the early period of abstinence. A retrospective chart review was conducted. The AA level was categorised into three groups: deficiency (AAD) (<2 mg/L), insufficiency (AAI) (2-5 mg/L) and normal level. The cognitive impairment was screened using the Montreal Cognitive Assessment (MoCA). Ninety-six patients were included (74 men; mean age 49.1 years (±11.5)). Twenty-seven AAD (28.1%) and twenty-two AAI (22.9%) were observed. In multivariate analysis, risk factors for AAD versus normal AA level were men (OR 17.8, 95%CI (1.63-194)), compensated cirrhosis (OR 9.35, 95%CI (1.60-54.6)) and street homelessness (OR 5.76, 95%CI (1.24-26.8) versus personal housing). The MoCA score was available for 53 patients (mean MoCA score: 25.7 (±3.3)). In multivariate analysis, the natural logarithm of AA (ß = 1.18, p = 0.037) and sedative use disorder (ß = -2.77, p = 0.046) were associated with the MoCA score. AAD and AAI are frequent in inpatients admitted for alcohol detoxification. A low level of AA was associated with cognitive impairment in the early period of abstinence.

An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases.

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival. Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system. Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood-brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals. This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.

Risk and Protective Factors of Lifetime Cocaine-Associated Chest Pain.

Introduction: Cocaine users often present with repetitive events of cocaine-associated chest pain (CACP), clinically resembling acute coronary syndromes. The aim of the study is to describe the specific risk factors for CACP. Method: Cocaine users (n = 316) were recruited for a multicenter cross-sectional study. Lifetime CACP history, sociodemographic factors, and lifetime use of cocaine and other substances were assessed. Thirty single nucleotide polymorphisms (SNPs) of NOS3, ROCK2, EDN1, GUCY1A3, and ALDH2 genes, suggested by the literature on coronary spasms, were selected. The associations with CACP history were tested using the chi-square test, Student's t-test and logistic regression. Results: Among the 316 subjects [78.5% men, mean age 37.5 years, (standard-deviation ±8.7)], 190 (60.1%) were daily cocaine users and 103 (32.6%) reported a lifetime CACP history. Among those with a lifetime CACP history, the median was 10 events per individual. In multivariate analysis, lifetime CACP history was associated with daily cocaine use [odds-ratio (OR) 3.24; 95% confidence intervals (1.29-9.33)], rapid route of cocaine use [OR 2.33 (1.20-4.64) vs. intranasal use], and lifetime amphetamine use [daily amphetamine use: OR 2.80 (1.25-6.32) and non-daily amphetamine use: OR 2.14 (1.15-4.04) vs. never used]. Patients with lifetime opioid maintenance treatment (OMT) reported significantly less lifetime CACP history [OR 0.35 (0.16-0.76)]. None of the selected SNPs was associated with CACP history after multiple testing corrections. Conclusions: Clinical variables describing the intensity of stimulant use were positively associated with lifetime CACP history, while OMT was negatively associated with it. Specific harm reduction strategies can target these risk factors.

Clustering suicidal phenotypes and genetic associations with brain-derived neurotrophic factor in patients with substance use disorders.

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances.

Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = -0.965 and -2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.

Acute Poisoning with Rhabdomyolysis in the Intensive Care Unit: Risk Factors for Acute Kidney Injury and Renal Replacement Therapy Requirement.

Acute kidney injury (AKI) is the major complication of rhabdomyolysis. We aimed to identify the predictive factors for AKI and renal replacement therapy (RRT) requirement in poisoning-associated rhabdomyolysis. We conducted a cohort study including 273 successive poisoned patients (median age, 41 years) who developed rhabdomyolysis defined as creatine kinase (CK) >1000 IU/L. Factors associated with AKI and RRT requirement were identified using multivariate analyses. Poisonings mainly involved psychotropic drugs. AKI occurred in 88 patients (37%) including 43 patients (49%) who required RRT. Peak serum creatinine and CK were weakly correlated (R2 = 0.17, p < 0.001). Death (13%) was more frequent after AKI onset (32% vs. 2%, p < 0.001). On admission, lithium overdose (OR, 44.4 (5.3-371.5)), serum calcium ≤2.1 mmol/L (OR, 14.3 (2.04-112.4)), female gender (OR, 5.5 (1.8-16.9)), serum phosphate ≥1.5 mmol/L (OR, 2.0 (1.0-4.2)), lactate ≥ 3.3 mmol/L (OR, 1.2 (1.1-1.4)), serum creatinine ≥ 125 µmol/L (OR, 1.05 (1.03-1.06)) and age (OR, 1.04 (1.01-1.07)) independently predicted AKI onset. Calcium-channel blocker overdose (OR, 14.2 (3.8-53.6)), serum phosphate ≥ 2.3 mmol/L (OR, 1.6 (1.1-2.6)), Glasgow score ≤ 5 (OR, 1.12; (1.02-1.25)), prothrombin index ≤ 71% (OR, 1.03; (1.01-1.05)) and serum creatinine ≥ 125 µmol/L (OR, 1.01; (1.00-1.01)) independently predicted RRT requirement. We identified the predictive factors for AKI and RRT requirement on admission to improve management in poisoned patients presenting rhabdomyolysis.