Bench-to-bedside review: Mechanisms and management of hyperthermia due to toxicity

Body temperature can be severely disturbed by drugs capable of altering the balance between heat production and dissipation. If not treated aggressively, these events may become rapidly fatal. Several toxins can induce such non-infection-based temperature disturbances through different underlying mechanisms. The drugs involved in the eruption of these syndromes include sympathomimetics and monoamine oxidase inhibitors, antidopaminergic agents, anticholinergic compounds, serotonergic agents, medicaments with the capability of uncoupling oxidative phosphorylation, inhalation anesthetics, and unspecific agents causing drug fever. Besides centrally disturbed regulation disorders, hyperthermia often results as a consequence of intense skeletal muscle hypermetabolic reaction. This leads mostly to rapidly evolving muscle rigidity, extensive rhabdomyolysis, electrolyte disorders, and renal failure and may be fatal. The goal of treatment is to reduce body core temperature with both symptomatic supportive care, including active cooling, and specific treatment options

Pulsating star research and the Gaia revolution

In this article we present an overview of the ESA Gaia mission and of the unprecedented impact that Gaia will have on the field of variable star research. We summarise the contents and impact of the first Gaia data release on the description of variability phenomena, with particular emphasis on pulsating star research. The Tycho-Gaia astrometric solution, although limited to 2.1 million stars, has been used in many studies related to pulsating stars. Furthermore a set of 3,194 Cepheids and RR Lyrae stars with their times series have been released. Finally we present the plans for the ongoing study of variable phenomena with Gaia and highlight some of the possible impacts of the second data release on variable, and specifically, pulsating stars.Comment: 12 pages, 4 figures, proceedings for the 22nd Los Alamos Stellar Pulsation Conference Series Meeting "Wide field variability surveys: a 21st-century perspective", held in San Pedro de Atacama, Chile, Nov. 28 - Dec. 2, 201

Acute recreational drug toxicity: Comparison of self-reports and results of immunoassay and additional analytical methods in a multicenter European case series

The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity.We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project.Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively.In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives

The rs429358 locus in apolipoprotein E is associated with hepatocellular carcinoma in patients with cirrhosis

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P=2.9×10−5). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P=3.1×10−6). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P=0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P=0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis

Evaluation of laboratory tests for cirrhosis and for alcohol use, in the context of alcoholic cirrhosis

International audienceLaboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91~\textpm~0.01 and 0.88~\textpm~0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88~\textpm~0.01 for INR and 0.85~\textpm~0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85~units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288~units/L in men and 138~units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used

Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors

International audienceBackground and aims - Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and results - We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions - Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC

Dose-related hypoglycemia in venlafaxine poisoning: a retrospective cohort study.

CONTEXT Several case reports describe hypoglycemia in the context of venlafaxine overdose, while investigations at therapeutic dose suggested a neutral effect on glucose homeostasis. Studies on hypoglycemia in venlafaxine intoxication are lacking. METHODS Single-center retrospective cohort study of non-diabetic patients presenting with a laboratory-confirmed antidepressant overdose to the department of clinical toxicology of a tertiary care hospital over a 12-year period. Our main goal was to investigate the association of hypoglycemia as the primary outcome with venlafaxine exposure using multiple logistic regression. Multi-drug exposures were included. We further aimed to describe the association of blood glucose (BG)/hypoglycemia with antidepressant dose, seizures and length of hospital stay. RESULTS 525 antidepressant intoxications were included, 85 of which involved venlafaxine. Hypoglycemia occurred in 34.1% (29/85) of venlafaxine intoxications and in 10.7% (47/440) of non-venlafaxine antidepressant overdoses. Venlafaxine exposure was significantly associated with hypoglycemia (adjusted odds ratio (OR): 6.6, 95% confidence interval (CI): 3.5-12.6). Venlafaxine-associated hypoglycemia was mainly mild (BG: 51-70 mg/dL), in 75.8% of cases, to moderate (BG: 31-50 mg/dL), in 20.7%, with one case of severe hypoglycemia (BG: 30 mg/dL). BG was significantly inversely correlated with dose in the venlafaxine group (Spearman's correlation coefficient: -0.47, p = 0.002) but not in other commonly prescribed antidepressants. Regardless of venlafaxine exposure, hypoglycemia was associated with seizures (adjusted OR: 5.3, 95% CI: 2.6-10.6) and with a 2.7 day increase in hospital length of stay (95% CI: 1.3-4.2). CONCLUSION A dose-related, mild to moderate hypoglycemia occurred in over one-third of venlafaxine poisonings. In overdose of other antidepressants, hypoglycemia was seen less frequently and without significant dose-dependency. Regardless of venlafaxine exposure, hypoglycemia was associated with seizures and prolonged length of stay, although these factors are likely primarily determined by other toxicities. BG monitoring in venlafaxine overdose should be considered

Ibuprofen plasma concentration profile in deliberate ibuprofen overdose with circulatory depression treated with therapeutic plasma exchange: a case report

Background Inquiries relating to ibuprofen overdose have more than tripled in the last ten years in our poison control center. Although the vast majority of cases have a benign clinical course, there are few severe or even fatal cases present with refractory circulatory failure. Case presentation We describe a case of a 48 year-old male with suicidal mono-ingestion of approximately 72 g ibuprofen. Despite an initial rapid spontaneous drop in the total ibuprofen plasma concentration (IPC) from 550 to 275 mcg/mL within the first 5 h after admission, the patient developed a circulatory failure, refractory to aggressive fluid resuscitation and high doses of vasopressors. Due to ibuprofen’s favorable pharmacokinetics (>95% bound to albumin, low volume of distribution) and in the absence of specific therapeutic alternatives thereby avoiding escalating vasopressor doses, therapeutic plasma exchange (TPE) for extracorporeal elimination of ibuprofen was considered as a therapeutic rescue option. An improvement of hemodynamics with a significant reduction of vasopressors was observed with TPE-initiation. However, neither the observed IPC-profile nor a pharmacokinetic (PK) simulation provided evidence for a quantitative effective elimination of ibuprofen by TPE. Based on PK-modeling we calculated an overall ibuprofen half-life of 17.2 h for the entire observation period over 5 days. Conclusions To our knowledge this is the first report of a severe ibuprofen-mono intoxication treated with TPE and providing serial IPCs over a period of five days, indicating an estimated fivefold overall-elimination half-life of 17.2 h. Despite TPE clinically improved persistent hemodynamic instability, this procedure was neither consistent with the observed IPC-profile nor correlated with a meaningful quantitative elimination of ibuprofen