35 research outputs found
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
The “Body Packer Syndrome”—Toxicity Following Ingestion of Illicit Drugs Packaged for Transportation
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National Association of Medical Examiners position paper on the certification of cocaine-related deaths
The National Association of Medical Examiners Committee on Cocaine-related Deaths recommends that the following guidelines be applied in the process of documenting, interpreting, and certifying potential cocaine-related fatalities. The committee cautions that the investigation of any drug-related death requires a complete investigation of the circumstances of death, the death scene, and past medical history. It is also necessary to have the results of the forensic toxicological analysis and those of a complete forensic autopsy examination prior to formulating an opinion as to the cause and manner of death. Cocaine should be considered the underlying cause of the death when 1 or more of the following is true: (1). the circumstances surrounding the death can be associated with an acute cocaine exposure and there are no supervening causes of death; (2). the immediate cause of death is directly due to a readily identifiable mechanism or disease such as a gunshot wound or a stroke, yet the acute use of cocaine was the direct underlying cause of the trauma or the disease process; and (3). chronic cocaine use leads to a disease that results in an ultimately fatal pathologic process leading to organ injury and death. The committee further cautions that reported drug levels may not directly relate to the toxic or lethal effects of the drug upon the patient. These guidelines are intended for use by practicing medical examiners and physicians who certify drug deaths, as well as providing education tools for students
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Criteria for the interpretation of cocaine levels in human biological samples and their relation to the cause of death
The determination that cocaine is directly responsible for the immediate cause of death should be considered only when there is a reasonably complete understanding of the circumstances or facts surrounding the death. Another, more obvious and immediate cause of death must be absent, or, at least cocaine must be shown to be a significant contributing factor in the chain of medical findings that lead directly to the immediate cause of death. Not all death investigation requires the sequential steps described in this paper, but these steps must be considered early on in the investigation whenever there is scene, investigational, medical or a historical basis to believe that cocaine is directly related to the cause of death. A relatively high profile death when cocaine is known to be involved, or a death involving unusual behavior on the part of the deceased with police involvement are examples where these considerations may well apply. Information needs to be obtained as soon as possible to have the highest chance of successfully documenting the toxicologic basis for the diagnosis. These facts would include, but would not necessarily be limited to, a scene investigation (whenever possible), a careful review of the investigative reports from all involved agencies, the initial core temperature of the body as well as that of the environment at the time of the collapse or death, the past medical history of the individual, and the results of a complete forensic autopsy and toxicologic studies. Knowledge of and an understanding of the current relevant forensic literature on this subject should be available to the reviewer prior to any interpretation of the significance of cocaine upon a specific death
Fatal Excited Delirium Following Cocaine Use: Epidemiologic Findings Provide New Evidence for Mechanisms of Cocaine Toxicity
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Cocaethylene: A Unique Cocaine Metabolite Displays High Affinity for the Dopamine Transporter
: Concurrent cocaine and alcohol use is common practice in the general population, as indicated by recent prevalence studies. In the presence of ethyl alcohol, cocaine is metabolized to its ethyl homolog, cocaethylene. The transesterification of cocaine and ethanol to cocaethylene takes place in the liver and represents a novel metabolic reaction. Cocaethylene was detected in postmortem blood, liver, and neurological tissues in concentrations equal to and sometimes exceeding those of cocaine. In vitro binding studies demonstrate that cocaethylene has a pharmacological profile similar but not identical to that of cocaine at monoamine transport sites assayed in the human brain. Cocaethylene was equipotent to cocaine at inhibiting [3H]mazindol binding to the dopamine transporter. The blockade of dopamine reuptake in the synaptic cleft by cocaethylene may account for the enhanced euphoria associated with combined alcohol and cocaine abuse
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Brain biomarkers for identifying excited delirium as a cause of sudden death
Excited delirium (ED) syndrome is a serious medical condition associated with acute onset of agitated violent behavior that often culminates in a sudden unexplained death. While the contribution of restraint, struggle and the use of conductive energy devices (CED) to the cause and manner of death raise controversy, a CNS dysfunction of dopamine signaling may underlie the delirium and fatal autonomic dysfunction. We conducted a mortality review for a case series of ninety excited delirium deaths and present results on the association of a 2-protein biomarker signature. We conducted quantitative analyses of the dopamine transporter and heat shock protein 70 validated for specificity and degree of interindividual variation. Incident circumstances, force measures, autopsy and toxicology results were determined for all subjects. A majority of the victims in this case series tested positive for cocaine in blood and brain, although four had no licit or illicit drugs or alcohol measured at autopsy. Mean core body temperature where recorded was 40.7
°C. The expression of the heat shock protein HSPA1B transcript was elevated 1.8–4-fold in postmortem brain. The elevation of Hsp70 in autopsy brain specimens confirms that hyperthermia is an associated symptom and often a harbinger of death in these cases. Dopamine transporter levels were below the range of values measured in age-matched controls, providing pathologic evidence for increased risk of chaotic dopamine signaling in excited delirium. When combined with descriptions of the decedents’ behavior prior to death, a 2-protein biomarker signature can serve as a reliable forensic tool for identifying the excited delirium syndrome at autopsy