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Trace elements (TEs) status alterations in the brain have been linked to neurodegenerative diseases. However, data on TEs in living humans and in the post-traumatic conditions are scarce. Some TEs (copper - Cu, selenium - Se, zinc - Zn) are involved in essential antioxidant defence. This study aims to measure the evolution of TEs concentrations in the brain and serum of severe traumatic brain injury (TBI) patients over time. Twenty adult patients with severe TBI were monitored using cerebral microdialysis (CMD) and blood sampling within three days of intensive care unit admission. TEs levels were measured using inductively coupled plasma system coupled to mass spectrometry. TEs concentrations of chromium - Cr, Cu, cobalt - Co, manganese - Mn, molybdenum - Mo, Se, and Zn were quantified in brain interstitial fluid and serum. While serum and CMD levels did not differ significantly for Co, Mo and Mn, and modest differences was observed for Cr and Zn, significant differences were observed for Cu and Se with higher serum levels (8-10-fold higher) compared to CMD. No correlation was found between serum and brain TEs levels, except for Mo. This study provides novel TEs concentration data in living TBI patients, the largest differences between brain and serum being observed for Cu and Se, serving as a basis for further research on TEs dynamics in acute brain injury.

As a powerful phenotyping technology, metabolomics provides new opportunities in biomarker discovery through metabolome-wide association studies (MWAS) and the identification of metabolites having a regulatory effect in various biological processes. While mass spectrometry-based (MS) metabolomics assays are endowed with high throughput and sensitivity, MWAS are doomed to long-term data acquisition generating an overtime-analytical signal drift that can hinder the uncovering of real biologically relevant changes. We developed “ dbnorm ”, a package in the R environment, which allows for an easy comparison of the model performance of advanced statistical tools commonly used in metabolomics to remove batch effects from large metabolomics datasets. “ dbnorm ” integrates advanced statistical tools to inspect the dataset structure not only at the macroscopic (sample batches) scale, but also at the microscopic (metabolic features) level. To compare the model performance on data correction, “ dbnorm ” assigns a score that help users identify the best fitting model for each dataset. In this study, we applied “ dbnorm ” to two large-scale metabolomics datasets as a proof of concept. We demonstrate that “ dbnorm ” allows for the accurate selection of the most appropriate statistical tool to efficiently remove the overtime signal drift and to focus on the relevant biological components of complex datasets.

A growing number of evidence demonstrates that ancestral exposure to xenobiotics (pollutants, drugs of abuse, etc.) can perturb the physiology and behavior of descendants. Both maternal and paternal transmission of phenotype across generations has been proved, demonstrating that parental drug history may have significant implications for subsequent generations. In the last years, the burden of novel synthetic opioid (NSO) consumption, due to increased medical prescription of pain medications and to easier accessibility of these substances on illegal market, is raising new questions first in term of public health, but also about the consequences of the parental use of these drugs on future generations. Besides being associated to the neonatal abstinence syndrome, exposure to opioids has an impact on neuronal development with long-term repercussions that are potentially transmitted to subsequent generations. In addition, recent reports suggest that opioid use even before conception influences the reactivity to opioids of the progeny and the following generations, likely through epigenetic mechanisms. This review describes the current knowledge about the transgenerational effects of opioid consumption. We summarize the preclinical and clinical findings showing the implications for the subsequent generations of parental exposure to opioids earlier in life. Limitations of the existing data on NSOs and new perspectives of the research are also discussed, as well as clinical and forensic consequences.

Background According to the World Health Organization, road traffic injuries lead to 1.3 million deaths each year and represent the leading cause of death for young adults under 30 years old. The use of psychoactive substances, including alcohol, drugs and pharmaceuticals, is a well-known risk factor for road traffic injuries. Our study aims to assess the prevalence of substances consumed by drivers in western Switzerland. Such studies are pivotal to improving prevention and developing public awareness campaigns. Methods To assess the prevalence of psychoactive substances among drivers, roadside controls were performed in collaboration with local police, using their classical sampling procedures to detect drivers under the influence of drugs or alcohol over two time periods (P1: 2006-2008, P2: 2017-2020). When impaired driving was not suspected by the police, minimally invasive sampling strategies (i.e., oral fluids during P1 and dried blood spots during P2) were performed on volunteer drivers after a road safety survey. A posteriori analyses and statistical interpretation were then performed . Results Among the 1605 drivers included in the study, 1048 volunteers provided an oral fluid sample, while 299 provided a dried blood spot sample. The percentage of drivers testing positive for at least one substance that can impact driving abilities was stable over time, with a rate of 10.5% positivity measured over both periods. Considering the different categories of substances, a slight variation was observed between both periods, with 7.6 and 6.3% of pharmaceuticals and 3.6 and 4.9% of illicit drugs for P1 and P2, respectively. Regarding the consumption of illicit drugs, the highest percentage of positivity was measured in biological fluids of drivers under the age of 35, during nights and week-ends, periods which are considered particularly prone to fatal accidents for this age group. Disturbingly, the road safety survey highlighted that drivers’ perception of the risk of getting positively controlled while driving after drug consumption is low (3.3 on a 1-to-10 scale, N  = 299). Conclusion The number of positive cases measured in voluntary drivers who passed the preliminary police check demonstrates the importance of systematic biofluid sampling strategies regarding driving under the influence of psychoactive substances. Although the number of fatal road accidents globally has decreased over time, the results of this study reveal the need for both better prevention and deterrent processes that could potentially reduce the risk of fatal road accidents associated with drug consumption.

Background In 1975, the mummified body of a female has been found in the Franciscan church in Basel, Switzerland. Molecular and genealogic analyses unveiled her identity as Anna Catharina Bischoff (ACB), a member of the upper class of post-reformed Basel, who died at the age of 68 years, in 1787. The reason behind her death is still a mystery, especially that toxicological analyses revealed high levels of mercury, a common treatment against infections at that time, in different body organs. The computed tomography (CT) and histological analysis showed bone lesions in the femurs, the rib cage, and the skull, which refers to a potential syphilis case. Results Although we could not detect any molecular signs of the syphilis-causing pathogen Treponema pallidum subsp . pallidum , we realized high prevalence of a nontuberculous mycobacterium (NTM) species in brain tissue sample. The genome analysis of this NTM displayed richness of virulence genes and toxins, and similarity to other infectious NTM, known to infect immunocompromised patients. In addition, it displayed potential resistance to mercury compounds, which might indicate a selective advantage against the applied treatment. This suggests that ACB might have suffered from an atypical mycobacteriosis during her life, which could explain the mummy’s bone lesion and high mercury concentrations. Conclusions The study of this mummy exemplifies the importance of employing differential diagnostic approaches in paleopathological analysis, by combining classical anthropological, radiological, histological, and toxicological observations with molecular analysis. It represents a proof-of-concept for the discovery of not-yet-described ancient pathogens in well-preserved specimens, using de novo metagenomic assembly.

In a case of a driving ability assessment, hair analysis for ethyl glucuronide (EtG) was requested by the authorities. The person concerned denied alcohol consumption and did not present any clinical sign of alcoholism. However, EtG was found in concentrations of up to 910pg/mg in hair from different sampling dates suggesting an excessive drinking behavior. The person declared to use a hair lotion on a regularly base. To evaluate a possible effect of the hair lotion, prospective blood and urine controls as well as hair sampling of scalp and pubic hair were performed. The traditional clinical biomarkers of ethanol consumption, CDT and GGT, were inconspicuous in three blood samples taken. EtG was not detected in all collected urine samples. The hair lotion was transmitted to our laboratory. The ethanol concentration in this lotion was determined with 35g/L. The EtG immunoassay gave a positive result indicating EtG, which could be confirmed by GC–MS/MS-NCI. In a follow-up experiment the lotion was applied to the hair of a volunteer over a period of six weeks. After this treatment, EtG could be measured in the hair at a concentration of 72pg/mg suggesting chronic and excessive alcohol consumption. Overnight incubation of EtG free hair in the lotion yielded an EtG concentration of 140pg/mg. In the present case, the positive EtG hair findings could be interpreted as the result of an EtG containing hair care product. To our knowledge, the existence of such a product has not yet been reported, and it is exceptionally unusual to find EtG in cosmetics. Therefore, external sources for hair contamination should always be taken into account when unusual cosmetic treatment is mentioned. In those cases, it is recommended to analyze the hair product for a possible contamination with EtG. The analysis of body hair can help to reveal problems occurring from cosmetic treatment of head hair. As a consequence, the assessment of drinking behavior should be based on more than one diagnostic parameter.

Diagnostics of myocardial infarction in human post-mortem hearts can be achieved only if ischemia persisted for at least 6–12 h when certain morphological changes appear in myocardium. The initial 4 h of ischemia is difficult to diagnose due to lack of a standardized method. Developing a panel of molecular tissue markers is a promising approach and can be accelerated by characterization of molecular changes. This study is the first untargeted metabolomic profiling of ischemic myocardium during the initial 4 h directly from tissue section. Ischemic hearts from an ex-vivo Langendorff model were analysed using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) at 15 min, 30 min, 1 h, 2 h, and 4 h. Region-specific molecular changes were identified even in absence of evident histological lesions and were segregated by unsupervised cluster analysis. Significantly differentially expressed features were detected by multivariate analysis starting at 15 min while their number increased with prolonged ischemia. The biggest significant increase at 15 min was observed for m/z 682.1294 (likely corresponding to S-NADHX—a damage product of nicotinamide adenine dinucleotide (NADH)). Based on the previously reported role of NAD + /NADH ratio in regulating localization of the sodium channel (Na v 1.5) at the plasma membrane, Na v 1.5 was evaluated by immunofluorescence. As expected, a fainter signal was observed at the plasma membrane in the predicted ischemic region starting 30 min of ischemia and the change became the most pronounced by 4 h. Metabolomic changes occur early during ischemia, can assist in identifying markers for post-mortem diagnostics and improve understanding of molecular mechanisms.

Psychotropic drugs can induce strong metabolic adverse effects, potentially increasing morbidity and/or mortality of patients. Metabolomic profiling, by studying the levels of numerous metabolic intermediates and products in the blood, allows a more detailed examination of metabolism dysfunctions. We aimed to identify blood metabolomic markers associated with weight gain in psychiatric patients. Sixty‐two patients starting a treatment known to induce weight gain were recruited. Two hundred and six selected metabolites implicated in various pathways were analyzed in plasma, at baseline and after 1 month of treatment. Additionally, 15 metabolites of the kynurenine pathway were quantified. This latter analysis was repeated in a confirmatory cohort of 24 patients. Among the 206 metabolites, a plasma metabolomic fingerprint after 1 month of treatment embedded 19 compounds from different chemical classes (amino acids, acylcarnitines, carboxylic acids, catecholamines, nucleosides, pyridine, and tetrapyrrole) potentially involved in metabolic disruption and inflammation processes. The predictive potential of such early metabolite changes on 3 months of weight evolution was then explored using a linear mixed‐effects model. Of these 19 metabolites, short‐term modifications of kynurenine, hexanoylcarnitine, and biliverdin, as well as kynurenine/tryptophan ratio at 1 month, were associated with 3 months weight evolution. Alterations of the kynurenine pathway were confirmed by quantification, in both exploratory and confirmatory cohorts. Our metabolomic study suggests a specific metabolic dysregulation after 1 month of treatment with psychotropic drugs known to induce weight gain. The identified metabolomic signature could contribute in the future to the prediction of weight gain in patients treated with psychotropic drugs.

Background:Carbon monoxide (CO) poisoning is an important cause of morbidity and mortality worldwide. Symptoms are mostly aspecific, making it hard to identify, and its diagnosis is usually made through blood gas analysis. However, the bulkiness of gas analyzers prevents them from being used at the scene of the incident, thereby leading to the unnecessary transport and admission of many patients. While multiple-wavelength pulse oximeters have been developed to discriminate carboxyhemoglobin (COHb) from oxyhemoglobin, their reliability is debatable, particularly in the hostile prehospital environment.Objective:The main objective of this pilot study was to assess whether the Avoximeter 4000, a transportable blood gas analyzer, could be considered for prehospital triage.Methods:This was a monocentric, prospective, pilot evaluation study. Blood samples were analyzed sequentially with 2 devices: the Avoximeter 4000 (experimental), which performs direct measurements on blood samples of about 50 µL by analyzing light absorption at 5 different wavelengths; and the ABL827 FLEX (control), which measures COHb levels through an optical system composed of a 128-wavelength spectrophotometer. The blood samples belonged to 2 different cohorts: the first (clinical cohort) was obtained in an emergency department and consisted of 68 samples drawn from patients admitted for reasons other than CO poisoning. These samples were used to determine whether the Avoximeter 4000 could properly exclude the diagnosis. The second (forensic) cohort was derived from the regional forensic center, which provided 12 samples from documented CO poisoning.Results:The mean COHb level in the clinical cohort was 1.7% (SD 1.8%; median 1.2%, IQR 0.7%-1.9%) with the ABL827 FLEX versus 3.5% (SD 2.3%; median 3.1%, IQR 2.2%-4.1%) with the Avoximeter 4000. Therefore, the Avoximeter 4000 overestimated COHb levels by a mean difference of 1.8% (95% CI 1.5%-2.1%). The consistency of COHb readings by the Avoximeter 4000 was excellent, with an intraclass correlation coefficient of 0.97 (95% CI 0.93-0.99) when the same blood sample was analyzed repeatedly. Using prespecified cutoffs (5% in nonsmokers and 10% in smokers), 3 patients (4%) had high COHb levels according to the Avoximeter 4000, while their values were within the normal range according to the ABL827 FLEX. Therefore, the specificity of the Avoximeter 4000 in this cohort was 95.6% (95% CI 87%-98.6%), and the overtriage rate would have been 4.4% (95% CI 1.4%-13%). Regarding the forensic samples, 10 of 12 (83%) samples were positive with both devices, while the 2 remaining samples were negative with both devices.Conclusions:The limited difference in COHb level measurements between the Avoximeter 4000 and the control device, which erred on the side of safety, and the relatively low overtriage rate warrant further exploration of this device as a prehospital triage tool.

Tolperisone (Mydocalm®) is a centrally acting muscle relaxant with few sedative side effects that is used for the treatment of chronic pain conditions. We describe three cases of suicidal tolperisone poisoning in three healthy young subjects in the years 2006, 2008 and 2009. In all cases, macroscopic and microscopic autopsy findings did not reveal the cause of death. Systematic toxicological analysis (STA) including immunological tests, screening for volatile substances and blood, urine and gastric content screening by GC–MS and HPLC–DAD demonstrated the presence of tolperisone in all cases. In addition to tolperisone, only the analgesics paracetamol (acetaminophen), ibuprofen and naproxen could be detected. The blood ethanol concentrations were all lower than 0.10g/kg. Tolperisone was extracted by liquid–liquid extraction using n-chlorobutane as the extraction solvent. The quantification was performed by GC–NPD analysis of blood, urine and gastric content. Tolperisone concentrations of 7.0mg/l, 14mg/l and 19mg/l were found in the blood of the deceased. In the absence of other autopsy findings, the deaths in these three cases were finally explained as a result of lethal tolperisone ingestion. To the best of our knowledge, these three cases are the first reported cases of suicidal tolperisone poisonings.