Johan Duflou

Major physical and psychological harms of methamphetamine use

ISSUES The major physical and psychological health effects of methamphetamine use, and the factors associated with such harms. APPROACH Comprehensive review. KEY FINDINGS Physical harms reviewed included toxicity and mortality, cardiovascular/cerebrovascular pathology, dependence and blood-borne virus transmission. Psychological harms include methamphetamine psychosis, depression, suicide, anxiety and violent behaviours. IMPLICATIONS While high-profile health consequences, such as psychosis, are given prominence in the public debate, the negative sequelae extend far beyond this. This is a drug class that causes serious heart disease, has serious dependence liability and high rates of suicidal behaviours. CONCLUSION The current public image of methamphetamine does not portray adequately the extensive, and in many cases insidious, harms caused.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults

BACKGROUND Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

Post‐Mortem Review and Genetic Analysis of Sudden Unexpected Death in Epilepsy (SUDEP) Cases

Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy‐related cause of death and is characterized by an absence of any identifiable cause of death at post‐mortem, suggesting an underlying arrhythmogenic predisposition. This study sought to identify SUDEP cases in a review of post‐mortem records and to undertake genetic studies in key familial long QT syndrome (LQTS) genes. All autopsies performed from 1993‐2009 at a forensic centre in Sydney, Australia were reviewed and SUDEP cases identified. DNA was extracted from post‐mortem blood and the three most common LQTS genes, ie, KCNQ1, KCNH2 (HERG) and SCN5A, were amplified and analyzed. Sixty‐eight SUDEP cases were identified (mean age of 40 ± 16 years). Genetic analysis revealed 6 (13%) non‐synonymous (amino acid changing) variants in KCNH2 (n = 2) and SCN5A (n = 4), all previously reported in LQTS patients. Specifically, KCNH2 Arg176Trp and SCN5A Pro1090Leu were identified once in SUDEP cases and absent in control alleles. Both DNA variants have been previously identified in the pathogenesis of LQTS. The cause of SUDEP is currently unknown. Our results indicate that investigation of key ion channel genes should be pursued in the investigation of the relationship between epilepsy and sudden death.

The comparative toxicology and major organ pathology of fatal methadone and heroin toxicity cases

In order to determine the comparative toxicology and systemic disease of cases of death due to methadone and heroin toxicity, 1193 coronial cases of opioid overdose that occurred in New South Wales, Australia between 1 January 1998 and 31 December 2007 were inspected. These comprised 193 cases in which cause of death involved methadone toxicity (METH) and 1000 cases in which cause of death involved heroin toxicity in the absence of methadone (HER). METH cases were significantly more likely to have benzodiazepines (63.7% vs. 32.2%), and less likely to have alcohol (23.6% vs. 42.7%) detected. METH cases were significantly more likely to be diagnosed with pre-existing systemic pathology (94.3% vs. 79.9%), and multiple organ system pathology (68.8% vs. 41.4%). Specifically, METH cases were more likely to have cardiac (58.9% vs. 34.5%), pulmonary (53.6% vs. 30.9%), hepatic (80.7% vs. 62.8%) and renal (25.0% vs. 9.5%) disease. Given the notable differences in toxicology and disease patterns, great caution appears warranted in prescribing benzodiazepines to methadone users, and regular physical examinations of methadone treatment patients would appear clinically warranted.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy

The leading cause of epilepsy‐related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome‐based analysis of rare variants.

Methamphetamine-related fatalities in Australia: Demographics, circumstances, toxicology and major organ pathology

AIM To examine the demographic characteristics, circumstances of death, toxicological results and major organ pathology of methamphetamine-related deaths in Australia. DESIGN Retrospective review of coronial files. SETTING Australia. METHODS Cases in which methamphetamine was listed as a cause of death were identified from the National Coronial Information System (NCIS). FINDINGS A total of 371 cases were identified. The mean age of decedents was 32.7 years; 77% were male and 35% were employed. Route of administration was predominantly by injection (89%). Drugs other than methamphetamine were detected in 89% of cases, most commonly benzodiazepines (41%) and morphine (36%). The median blood methamphetamine concentration was 0.2 mg/l (range 0.02-15.0 mg/l). Deaths were overwhelmingly accidental, with 14% determined to be suicides, and occurred in a private home (71%). Cardiovascular pathology, typically coronary artery atherosclerosis, was detected in 54% of decedents. Cerebrovascular pathology, most commonly cerebral haemorrhage and hypoxia, was present in 20% of cases. CONCLUSIONS Methamphetamine has contributed to a substantial number of deaths in Australia. Users need to be informed of the potential harms of methamphetamine use, particularly those associated with the cardiotoxicity of methamphetamine and the use of methamphetamine in conjunction with other drugs.

Axonal Injury in Children after Motor Vehicle Crashes: Extent, Distribution, and Size of Axonal Swellings Using β-APP Immunohistochemistry

The brains of 32 children (3 months to 16 years) who died as a result of motor vehicle collisions were examined for axonal injury using beta-APP immunohistochemistry. The extent and distribution of axonal injury was assessed and quantified throughout the forebrain, brainstem and cerebellum. The mean diameter of immunoreactive axons in the corpus callosum was measured for this pediatric group and, for comparison, a small adult sample. beta-APP immunoreactivity was seen in 14 pediatric cases (survival 35 mins to 87 h), most frequently in the parasagittal white matter (12/14), the corpus callosum (11/14), the brainstem (10/14) and cerebellum (9/14). In 2 cases, axon swelling was visualized in the internal capsule after only 35-45-min survival, earlier than has previously been reported. No immunoreactivity was seen in the remaining 18 cases who died within 1 h. The extent and distribution of axonal injury throughout the brain showed a rapid early increase with increasing survival time and then a slower progression. The diameter of individual callosal axons increased with increasing survival times, rapidly over the first 24 h and then more slowly. There was no statistical difference (p < 0.05) for callosal axon diameters at different survival times between the children and the adults sampled here. The extent and distribution of axonal injury throughout the brain appears to be similar in children to that previously reported in adults. The spatial and temporal spread of axonal damage suggests there may be therapeutic potential for the process to be arrested or slowed in its early stages.

Toxicology and circumstances of death of homicide victims in New South Wales, Australia 1996-2005

Abstract:  To determine the prevalence and circumstances of psychoactive substances amongst homicide victims, 485 consecutive cases autopsied at the NSW Department of Forensic Medicine (1/1/1996–12/31/2005) were analyzed. Substances were detected in 62.6% of cases, and illicit drugs in 32.8%. Alcohol, cannabis, opioids, and psychostimulants were most commonly detected. Alcohol and cannabis were both more prevalent amongst males. Mean ages were significantly younger for decedents who tested positive for a substance and for an illicit drug. Cases where death resulted from a physical altercation were more likely to have had alcohol and cannabis present. Illicit drugs were prominent amongst firearms deaths. The proportion of alcohol positive cases increased from 25.0% on Monday to 49.4% for Saturdays/Sundays. Alcohol was more common in incidents in the 0001–0600 h and 1800–2400 h periods. Psychoactive substances appear to substantially increase the risk of homicide, although there are important differences between drug classes in the circumstances of such incidents.

A comparison of the needle biopsy post mortem with the conventional autopsy

&NA; Tru‐cut biopsy post mortems were compared with the standard full autopsy at a large city mortuary. Subjects consisted of coronial cases excluding suspicious deaths, obvious trauma cases and children under the age of 14 yrs. The following comparisons were made: the ability to collect tissue from each of the organs; any abnormalities detected on histology; correlation of the Tru‐cut biopsy results with the results of the conventional post mortem; and determination of cause of death with both techniques. Twenty‐one cases were examined by both techniques. Tissue collection by biopsy varied from 100% for liver to 9.5% for kidney with heart, lung and brain giving intermediate results. The cause of death was determined in 9 cases (43%) by biopsy and in 20 cases (95%) by conventional post mortem; the cause of death was not ascertainable in 1 case. In 8 of the 9 cases (89%) where death could be determined by biopsy the cause of death was consistent with the findings of the full autopsy. The cause of death at needle biopsy examination was incorrect in 1 case (11%) compared to the findings of the standard post mortem. Clearly the needle post mortem is inferior to the conventional autopsy in determining the cause of death.

Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis.

Objectives:To determine whether tryptophan metabolism to kynurenine contributes to the direct regulation of vascular tone in human septic shock. Background:Indoleamine 2,3-dioxygenase 1 is an inducible enzyme that converts tryptophan to kynurenine and shares functional similarities with inducible nitric oxide synthase. Recently, kynurenine has been identified as an endothelium-derived relaxing factor produced during inflammation, raising the possibility that this novel pathway may contribute to hypotension in human sepsis. Design:Prospective, matched, single-center, cohort study. Settings:Intensive care unit of a tertiary teaching hospital matched to control subjects from the general medical ward and healthy volunteers. Subjects:Patients (n = 16) with septic shock had indoleamine 2,3-dioxygenase activity assessed as the kynurenine-to-tryptophan ratio, and the severity of hypotension was determined by their inotrope requirements. Healthy and blood pressure-matched nonseptic control subjects were also studied. Interventions:None. Measurements and Main Results:Tissues from septic and control patients were stained for the presence of indoleamine 2,3-dioxygenase 1. Indoleamine 2,3-dioxygenase activity increased up to ninefold in patients with septic shock and was significantly higher than in the two control groups (p < .01). Indoleamine 2,3-dioxygenase activity was strongly correlated with inotrope requirements (p < .001). Indoleamine 2,3-dioxygenase protein was expressed in inflamed cardiac tissue as well as in endothelial cells of resistance vessels in hearts and kidneys from subjects who died from sepsis. Conclusions:Indoleamine 2,3-dioxygenase 1 is expressed in resistance vessels in human sepsis and Indoleamine 2,3-dioxygenase activity correlates with hypotension in human septic shock. Indoleamine 2,3-dioxygenase 1 is thus a potential novel contributor to hypotension in sepsis.