Summary statistics for drug concentrations in post-mortem femoral blood representing all causes of death

Concentration distributions for 183 drugs and metabolites frequently found in post-mortem (PM) femoral venous blood were statistically characterized based on an extensive database of 122 234 autopsy cases investigated during an 18-year period in a centralized laboratory. The cases represented all causes of death, with fatal drug poisonings accounting for 8%. The proportion of males was 74% with a median age of 58 years compared with 26% females with a median age of 64 years. In 36% of these cases, blood alcohol concentration was higher than or equal to 0.2 parts per thousand, the median being 1.6 parts per thousand. The mean, median, and upper percentile (90th, 95th, 97.5th) drug concentrations were established, as the median PM concentrations give an idea of the "normal" PM concentration level, and the upper percentile concentrations indicate possible overdose levels. A correspondence was found between subsets of the present and the previously published PM drug concentrations from another laboratory that grouped cases according to the cause of death. Our results add to the knowledge for evidence-based interpretation of drug-related deaths.Peer reviewe

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRβ), CD73, CD271, alpha-smooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146+PDGFRβ+Ki67+ cells and CD73+CD271+PDGFRβ+Ki67– cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146+PDGFRβ+Ki67+ and CD73+CD271+PDGFRβ+Ki67– MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146+PDGFRβ+Ki67+ MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73+CD271+ adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS

Fatal drug poisonings in a Swedish general population

ABSTRACT: BACKGROUND: Pharmaceutical drug poisonings have previously been reported using single sources of information, either hospital data or forensic data, which might not reveal the true incidence. We therefore aimed to estimate the incidence of suspected fatal drug poisonings, defined as poisonings by pharmaceutical agents, by using all relevant case records from various sources in a Swedish population. METHODS: Every seventh randomly selected deceased in three counties in southeastern Sweden during a one-year period was identified in the Cause of Death Register. Relevant case records (death certificates, files from hospitals and/or primary care centres and medico-legal files) were reviewed for all study subjects. RESULTS: Of 1574 deceased study subjects, 12 cases were classified as pharmaceutical drug poisonings according to the death certificates and 10 according to the medico-legal files. When reviewing all available data sources, 9 subjects (0.57%; 95% confidence interval: 0.20-0.94%) were classified as drug poisonings, corresponding to an incidence of 6.5 (95% confidence interval: 2.3-10.7) per 100 000 person-years in the general population. The drug groups most often implicated were benzodiazepines (33%), antihistamines (33%) and analgesics (22%). CONCLUSIONS: Fatal drug poisonings is a relatively common cause of death in Sweden. By using multiple sources of information when investigating the proportion of fatal poisonings in a population, more accurate estimates may be obtained.Original Publication:Anna Jonsson, Olav Spigset, Micaela Tjäderborn, Henrik Druid and Staffan Hägg, Fatal drug poisonings in a Swedish general population., 2009, BMC clinical pharmacology, (9), 7, 1-5.http://dx.doi.org/10.1186/1472-6904-9-7Licensee: BioMed Centralhttp://www.biomedcentral.com

The Age of Human Cerebral Cortex Neurons

The traditional static view of the adult mammalian brain has been challenged by the realization of continuous generation of neurons from stem cells. Based mainly on studies in experimental animals, adult neurogenesis may contribute to recovery after brain insults and decreased neurogenesis has been implicated in the pathogenesis of neurological and psychiatric diseases in man. The extent of neurogenesis in the adult human brain has, however, been difficult to establish. We have taken advantage of the integration of {sup 14}C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral cortex. Together with the analysis of the cortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that whereas non-neuronal cells turn over, neurons in the human cerebral cortex are not generated postnatally at detectable levels, but are as old as the individual

A new model for the estimation of time of death from vitreous potassium levels corrected for age and temperature

International audienceAnalysis of potassium concentration in the vitreous fluid of the eye is frequently used by forensic pathologists to estimate the postmortem interval (PMI), particularly when other methods commonly used in the early phase of an investigation can no longer be applied. The postmortem rise in vitreous potassium has been recognized for several decades and is readily explained by a diffusion of potassium from surrounding cells into the vitreous fluid. However, there is no consensus regarding the mathematical equation that best describes this increase. The existing models assume a linear increase, but different slopes and starting points have been proposed. In this study, vitreous potassium levels, and a number of factors that may influence these levels, were examined in 462 cases with known postmortem intervals that ranged from 2 hours to 17 days. We found that the postmortem rise in potassium followed a non-linear curve and that decedent age and ambient temperature influenced the variability by 16% and 5%, respectively. A long duration of agony and a high alcohol level at the time of death contributed less than 1% variability, and evaluation of additional possible factors revealed no detectable impact on the rise of vitreous potassium. Two equations were subsequently generated, one that represents the best fit of the potassium concentrations alone, and a second that represents potassium concentrations with correction for decedent age and/or ambient temperature. The former was associated with narrow confidence intervals in the early postmortem phase, but the intervals gradually increased with longer PMIs. For the latter equation, the confidence intervals were reduced at all PMIs. Therefore, the model that best describes the observed postmortem rise in vitreous potassium levels includes potassium concentration, decedent age, and ambient temperature. Furthermore, the precision of these equations, particularly for long PMIs, is expected to gradually improve by adjusting the constants as more reference data are added over time. A web application that facilitates this calculation process and allows for such future modifications has been developed

Retrospective Birth Dating of Cells

The generation of cells in the human body has been difficult to study and our understanding of cell turnover is limited. Extensive testing of nuclear weapons resulted in a dramatic global increase in the levels of the isotope {sup 14}C in the atmosphere, followed by an exponential decrease after the test ban treaty in 1963. We show that the level of {sup 14}C in genomic DNA closely parallels atmospheric levels, and can be used to establish the time point when the DNA was synthesized and cells were born. We use this strategy to determine the age of cells in the cortex of the adult human brain, and show that whereas non-neuronal cells are exchanged, occipital neurons are as old as the individual, supporting the view that postnatal neurogenesis does not take place in this region. Retrospective birth dating is a generally applicable strategy that can be used to measure cell turnover in man under physiological and pathological conditions

Toxicological findings and manner of death in autopsied users of anabolic androgenic steroids

With the aim to characterize patterns in toxicological profile and manner of death in deceased users of anabolic androgenic steroids (AAS), a retrospective autopsy protocol study of 52 deceased users of AAS was undertaken. The AAS users were compared to 68 deceased users of amphetamine and/or heroin who were consecutively tested and found to be negative for AAS. Use of AAS was in the majority of cases (79%) associated with concomitant use of psychotropic substances. AAS-related deaths differed in several respects from deaths among users of heroin or amphetamine, most strikingly with regard to: (a) the median age at death, which was significantly lower for AAS users (24.5 years) than for users of heroin and/or amphetamine (34 and 40 years, respectively); (b) the manner of death, with AAS users dying significantly more often from homicide or suicide than users of other drugs; and (c) the body mass index (BMI), with AAS users exhibiting significantly higher BMI than users of other drugs. These results support the earlier reported association between use of AAS and use of other psychoactive substances. In addition, the data suggest that AAS users are more likely to become involved in incidents leading to violent death and have a higher risk of dying at a younger age than users of other drugs. (c) 2005 Elsevier Ireland Ltd. All rights reserved

The importance of sample size with regard to the robustness of postmortem reference values

Evaluating postmortem toxicological results is a challenging task due to multiple factors affecting blood concentrations after death. In order to improve the diagnostic accuracy in cases of suspected fatal intoxication different compilations of postmortem reference drug concentrations are often used. However, it is not clear what constitutes a reliable postmortem reference value. The current study presents reference concentrations for 13 substances from seven substance groups according to a standardized protocol. The reference concentrations were gathered from 3767 autopsy cases and subdivided into intoxications by one substance only (Group A, n= 611), multi-substance intoxications (Group B, n = 1355) and postmortem controls, in which incapacitation by drugs were excluded (Group C, n = 1801). In particular, this study presents statistical information about the precision and conformity change with various sample sizes. Based on the present data &amp;gt;10 detections are usually needed, for the substances examined, to differentiate between intoxication cases and controls. Repeated samplings show that the median of small samples (N= &amp;lt;= 5) has a high variation (normalized interquartile range 138-75%) and that a high number of detections (N = &amp;gt;20) in each group are needed to reduce the variation. (C) 2020 The Author(s). Published by Elsevier B.V.Funding Agencies|Swedish National Board of Forensic Medicine</p