The prevalence and selected characteristics of non-fatal opioid overdoses attended by ambulance in Australia

Key Points
1. Ambulance attendance at non-fatal opioid overdose is a common event in mainland Australia (among heroin users in particular).
2. The monthly rate of non-fatal opioid overdose attended by ambulance was generally highest in Victoria (Melbourne) followed by NSW with the rates substantially lower in the remaining mainland states over the period Jan  1999 - Feb 2001.
3. Non-fatal opioid overdose victims were most likely to be male in all states with the proportion of males highest in Victoria (77%).
4. Non-fatal opioid overdose victims were aged around 28 years with ages lowest in WA (26) and highest in NSW (30).
5. The rates of transportation varied according to ambulance service practice across the states with around 94% of cases transported in WA and around 19% and 30% of cases transported in Melbourne and NSW respectively.

Fatal women in renaissance tragedy, 1550-1650

Drawing upon the femme fatale of film noir, this thesis examines the presence of a fatal woman on the Renaissance stage. The thesis analyses the representation of emotionally and sexually independent women as fatally attractive to, yet ultimately destructive of, the men they entrap and seduce.

The making of modern scientific personae: the scientist as a moral person? Emil Du Bois-Reymond and his friends

This article examines the notion of the 'scientist as a moral person' in the light of the early stages of the commodification of science and the transformation of research into a big enterprise, operating on the principle of the division of labour. These processes were set in train at the end of the 19th century. The article focuses on the concomitant changes in the public persona and the habitus of scientific entrepreneurs. I begin by showing the significance of the professional networks that were built up and maintained to further a group's research ideas and the careers of its members, thus demonstrating one condition on which depended their practice of science and their ability to earn a living. This leads to a characterization of the changing styles of work, thought and life, and to a consideration of public perceptions and of the ways in which a new self-image of scholarship and science was fashioned. A critical discussion of the public role of these mandarin scientists follows in order to highlight the strains created by the commodification of science at a time of international tensions and conflicts, when shared beliefs in scholarly cosmopolitanism were subverted by appeals to science and scholarship to work in the service of one's own nation as its 'courtiers'. Various considerations of peculiar analogies between national styles of research and the style of social organization are then noted. In the final section, the article queries the long-term impact of these developments on the ideal of the scientist as a 'moral person'. Taking a cue from Max Weber and pursuing reflections by Zygmunt Bauman on 'science moralized', I argue that the emergence of a type of 'specialists without spirit' was an unintended but fatal consequence of the changes in research practices promoted by scientific entrepreneurs such as Du Bois-Reymond. I conclude that the temptation to sever the ties to a general ethos of civil virtues lay in the rationalization, specialization and potential de-humanization of the objectifying scientific outlook once advocated for its efficiency.

Bystander resuscitation attempts at heroin overdose: does it improve outcomes?

Study objective: To document the characteristics and effectiveness of cardiopulmonary resuscitation (CPR) at non-fatal heroin overdose events in Melbourne, Australia. Methods: A retrospective analysis of a computerised database of ambulance attendance records at non-fatal heroin overdose cases for the period 1/12/1998 to 31/7/2000 was undertaken.

Main outcome measures: The main outcome measure was the rate of patient hospitalisation. The rate of CPR administration at heroin overdose cases was also examined, along with characteristics of the attendance, such as the age and sex of the overdose case, the relationship of person providing CPR to the overdose case as well as the location, time and date of the event.

Results: CPR was administered prior to ambulance arrival in 579 heroin overdose cases (9.4% of total heroin overdose cases attended) between 1/12/98 and 31/7/2000. A greater proportion of female overdose cases were administered CPR than males and CPR administrations were evenly distributed across attendances occurring in private and public locations. Bystander administration of CPR prior to ambulance attendance resulted in a significantly lower rate of heroin user hospitalisation (14.5%) compared to cases where bystander CPR was not administered (18.8%).

Conclusions: While CPR administration prior to ambulance attendance at heroin overdose events is relatively uncommon (especially compared to out-of-hospital cardiac arrest), such administration was associated with a statistically significant improvement in clinical outcomes in cases of non-fatal heroin overdose. These findings suggest that the provision of CPR training to people likely to come into contact with heroin overdose events may be an effective strategy at minimising consequent overdose-related harm.

Molecular and cellular aspects of copper transport in developing mammals

Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ATPases play an important role in supplying copper to the developing fetus and neonate

Best practice in stabilisation of oral endotracheal tubes : a systematic review

Mechanical ventilation of patients in intensive care units is common practice. Artificial airways are utilised to facilitate ventilation and the endotracheal tube (ETT) is most commonly used for this purpose. The ETT must be stabilised to optimise ventilation and avoid displacement or unplanned extubation. Tube movement is a major factor in causing airway trauma. A destabilised tube can cause fatal complications. A systematic review was conducted to identify and analyse the best available evidence on ETT stabilisation to determine which stabilisation method resulted in reduced tube displacement and the least amount of unplanned or accidental extubations. The types of stabilisations included one or a combination of the following methods: twill or cotton tape, adhesive tape, gauze, or a manufactured device. All relevant randomised controlled and quasi-experimental studies of ETT stabilisation practices, identified through electronic and hand searching, were assessed for inclusion in the study. One published randomised controlled trial and six published quasi-experimental studies met the inclusion and exclusion criteria and were retrieved. Data were extracted independently by two reviewers. Results of the systematic review showed that no single method of ETT stabilisation could be identified as superior for minimising tube displacement and unplanned or accidental extubations. Rigorous randomised controlled trials with clearly identified and described ETT stabilisation methods are required to establish best practice. In addition, comparative research to evaluate cost effectiveness and nursing time requirements would also be of significant benefit to critical care nursing practice.

Generalising the Cinderella Effect to unintentional childhood fatalities

We investigated whether the repeatedly demonstrated increase in risk of child abuse and infanticide associated with living with a step parent generalized to cases of unintentional childhood fatal injury, the most common cause of death in children across the developed world. Reports were drawn from the Australian National Coroners' Information System (NCIS) on all cases of intentionally (n=32) and unintentionally (n=319) produced fatal injury in children aged under 5 years between 2000 and 2003. Even when using the most conservative possible analytic approach, in which all cases in which family type was unclear were classified as being from an ‘intact biological family’, step children under 5 years of age were found to be at significantly increased risk of unintentional fatal injury of any type, and of drowning in particular. Children from single-parented families were generally not found to be at significantly increased risk of intentional or unintentional fatal injury, while children who lived with neither of their biological parents were at greatest risk overall for fatal injury of any type.

Correction of a mouse model of Menkes disease by the human Menkes gene

The brindled mouse is an accurate model of the fatal human X-linked copper deficiency disorder, Menkes disease. Males carrying the mutant allele of the Menkes gene orthologue Atp7a die in the second week of life. To determine whether the genetic defect in the brindled mice could be corrected by expression of the human Menkes gene, male transgenic mice expressing ATP7A from the chicken β-actin composite promoter (CAG) were mated with female carriers of the brindled mutation (Atp7aMo-br). Mutant males carrying the transgene survived and were fertile but the copper defect was not completely corrected. Unexpectedly males corrected with one transgenic line (T25#5) were mottled and resembled carrier females, this effect appeared to be caused by mosaic expression of the transgene. In contrast, males corrected with another line (T22#2) had agouti coats. Copper concentrations in tissues of the rescued mutants also resembled those of the heterozygous females, with high levels in kidney (84.6 ± 4.9 μg/g in corrected males vs. 137.0 ± 44.3 μg/g in heterozygotes) and small intestine (15.6 ± 2.5 μg/g in corrected males vs. 15.7 ± 2.8 μg/g in heterozygotes). The results show that the Menkes defect in mice is corrected by the human Menkes gene and that adequate correction is obtained even when the transgene expression does not match that of the endogenous gene.

Zinc deficiency and its inherited disorders - A review

Zinc is an essential trace element required by all living organisms because of its critical roles both as a structural component of proteins and as a cofactor in enzyme catalysis. The importance of zinc in human metabolism is illustrated by the effects of zinc deficiency, which include a diminished immune response, reduced healing and neurological disorders. Furthermore, nutritional zinc deficiency can be fatal in newborn or growing animals. While zinc deficiency is commonly caused by dietary factors, several inherited defects of zinc deficiency have been identified. Acrodermatitis enteropathica is the most commonly described inherited condition found in humans. In several of the few cases that have been reported, this disorder is associated with mutations in the hZIP4 gene, a member of the SLC39 family, whose members encode membranebound putative zinc transporters. Mutations in other members of this family or in different genes may account for other cases of acrodermatitis in which defects in hZIP4 have not been detected. Another inherited form of zinc deficiency occurs in the lethal milk mouse, where a mutation in ZnT4 gene, a member of the SLC30 family of transmembrane proteins results in impaired secretion of zinc into milk from the mammary gland. A similar disorder to the lethal milk mouse occurs in humans. In the few cases studied, no changes in ZnT4 orthologue, hZnT4, were detected. This, and the presence of several minor phenotypic differences between the zinc deficiency in humans and mice, suggests that the human condition is caused by defects in genes that are yet to be identified. Taking into account the fact that there are no definitive tests for zinc deficiency and that this disorder can go undiagnosed, plus the recent identification of multiple members of the SCL30 and SLC39, it is likely that mutations in other genes may underlie additional inherited disorders of zinc deficiency.

Apoptosis may underlie the pathology of zinc-deficient skin

The trace element zinc is essential for the survival and function of all cells. Zinc deficiency, whether nutritional or genetic, is fatal if left untreated. The effects of zinc deficiency are particularly obvious in the skin, seen as an erythematous rash, scaly plaques, and ulcers. Electron microscopy reveals degenerative changes within keratinocytes. Despite the well-documented association between zinc deficiency and skin pathology, it is not clear which cellular processes are most sensitive to zinc deficiency and could account for the typical pathological features. We used the cultured HaCaT keratinocyte line to obtain insight into the cellular effects of zinc deficiency, as these cells show many characteristics of normal skin keratinocytes. Zinc deficiency was induced by growing cells in the presence of the zinc chelator, TPEN, or by growth in zinc-deficient medium. Growth of cells in zinc-deficient medium resulted in a 44% reduction of intracellular zinc levels and a 75% reduction in the activity of the zinc-dependent enzyme, 5'-nucleotidase, relative to the control cells. Over a period of 7 days of exposure to zinc-deficient conditions, no changes in cell viability and growth, or in the cytoskeletal and cell adhesion systems, were found in HaCaT cells. At 7 days, however, induction of apoptosis was indicated by the presence of DNA fragmentation and expression of active caspase-3 in cells. These results demonstrate that apoptosis is the earliest detectable cellular change induced by zinc deficiency in HaCaT keratinocytes. Our observations account for many of the features of zinc deficiency, including the presence of degenerate nuclei, chromatin aggregates and abnormal organization of keratin, that may represent the later stages of apoptosis. In summary, a major causal role for apoptosis in the pathology of zinc deficiency in the skin is proposed. This role is consistent with the previously unexplained diverse range of degenerative cellular changes seen at the ultrastructural level in zinc-deficient keratinocytes.

Purification and membrane reconstitution of catalytically active Menkes copper-transporting P-type ATPase (MNK; ATP7A)

The MNK (Menkes disease protein; ATP7A) is a major copper- transporting P-type ATPase involved in the delivery of copper to cuproenzymes in the secretory pathway and the efflux of excess copper from extrahepatic tissues. Mutations in the MNK (ATP7A) gene result in Menkes disease, a fatal neurodegenerative copper deficiency disorder. Currently, detailed biochemical and biophysical analyses of MNK to better understand its mechanisms of copper transport are not possible due to the lack of purified MNK in an active form. To address this issue, we expressed human MNK with an N-terminal Glu-Glu tag in Sf9 [Spodoptera frugiperda (fall armyworm) 9] insect cells and purified it by antibody affinity chromatography followed by size-exclusion chromatography in the presence of the non-ionic detergent DDM (n-dodecyl b-D-maltopyranoside). Formation of the classical vanadate-sensitive phosphoenzyme by purified MNK was activated by Cu(I) [EC50=0.7 µM; h (Hill coefficient) was 4.6]. Furthermore, we report the first measurement of Cu(I)-dependent ATPase activity of MNK (K0.5=0.6 µM; h=5.0). The purified MNK demonstrated active ATP-dependent vectorial 64Cu transport when reconstituted into soya-bean asolectin liposomes. Together, these data demonstrated that Cu(I) interacts with MNK in a co-operative manner and with high affinity in the sub-micromolar range. The present study provides the first biochemical characterization of a purified full-length mammalian copper-transporting P-type ATPase associated with a human disease.

The DALY, context and the determinants of the severity of disease: an exploratory comparison of paraplegia in Australia and Cameroon

This paper summarises the findings of an empirical investigation of some of the technical and social assumptions on which the disability adjusted life year (DALY) is based. The objectives of the study were to examine the notion that the burden of disease is broadly similar without regard to country, environment, gender or socio-economic status and to develop detailed descriptions of the experiences of the burden of disease as they related to these contextual factors. The study was a multi-factorial exploratory study employing qualitative and quantitative techniques to obtain data on the effects of country (development), environment (urban versus rural), gender and socio-economic status on people with paraplegia. The data provided an extensive and detailed compilation of context rich descriptions of living with paraplegia. Striking features of the data were the differences between countries with respect to the impact of the health conditions on functioning and highlight a context in which paraplegia of like clinical severity can be fatal in one environment and not in another. While there has been some focus on the control of social determinants of disease, there has been little work on the social determinants of the severity of disease. The underlying assumptions of the DALY, which ignore context in the assessment of the burden of disease, risk exacerbating inequalities by undervaluing the burden of disease in less-developed countries. There is a need to continue to subject the development of indicators to rigorous debate to determine a balance between the assumption of a global “average social milieu” and the treatment of each individual as belonging to their own context in the assessment of population health in order for indicators to be meaningful cross-culturally.

Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Background and Aim: The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. The tx mouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct the tx mouse phenotype.

Methods: Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-old tx mice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplanted tx mice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.

Results: Repopulation in recipient tx mice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g, n = 11) compared to non-repopulated animals (866 ± 62 µg/g, n = 14) and untreated controls (910 ± 103 µg/g, n = 6; P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.

Conclusion: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

Drug-herb interactions: eliminating toxicity with hard drug design.

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called ”hard drugs” that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.