The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Alcohol-related emergency department injury presentations in Queensland adolescents and young adults over a 13-year period

Introduction and Aims. The rate of alcohol-related emergency department (ED) presentations in young people has increased dramatically in recent decades. Injuries are the most common type of youth alcohol-related ED presentation, yet little is known about these injuries in young people. This paper describes the characteristics of alcohol-related ED injury presentations in young people over a 13-year period and determines if they differ by gender and/or age group (adolescents: 12–17 years; young adults: 18–24 years). Design and Method. The Queensland Injury Surveillance Unit (QISU) database collects injury surveillance data at triage in participating EDs throughout Queensland, Australia. A total of 4667 cases of alcohol-related injuries in young people (aged 12–24 years) were identified in the QISU database between January 1999 and December 2011, using an injury surveillance code and nursing triage text-based search strategy. Results. Overall, young people accounted for 38% of all QISU alcohol-related ED injury presentations in patients aged 12 years or over. The majority of young adults presented with injuries due to violence and falls, whereas adolescents presented due to self-harm or intoxication without other injury. Males presented with injuries due to violence, whereas females presented with alcohol-related self-harm and intoxication. Discussion and Conclusions. There is a need for more effective ways of identifying the degree of alcohol involvement in injuries among young people presenting to EDs.

Addressing alcohol related harms within maxillofacial trauma practice

Background A brief intervention, conducted in the acute setting care setting after an alcohol-related injury, has been reported to be highly beneficial in reducing the risk of re-injury and in reducing subsequent level of alcohol consumption. This project aimed to understand Australasian Oral and Maxillofacial Surgeons' attitudes, knowledge and skills in terms of alcohol screening and brief intervention within acute settings for patients admitted with facial trauma. Materials and Methods A web-based survey was made available to all members (n=200-250) of the Australian and New Zealand Association of Oral and Maxillofacial Surgeons (ANZAOMS), promoted through a number of email bulletins sent by the Association to all members. Implied consent is assumed for participants who complete the online survey. The survey explored their current level of involvement in treating patients with alcohol-relatd facial trauma, as well as their knowledge of and attitudes towards alcohol screening and brief intervention. The survey also explored their willingness for further training and involvement in implementing a SBI program. Parts of the survey were based on a hypothetical case with facial injury and drinking history which was presented to the participants and the participants were asked to give their response to this scenario. Results A total of 58 surgeons completed the on-line survey. 91% of surgeons surveyed were males and 88% were consultant surgeons. 71% would take alcohol history; 29% would deliver a brief alcohol intervention and 14% would refer the patients to an alcohol treatment service or clinician. 40% agreed to have adequate training in managing patients with alcohol-related injuries, while 17% and 19% felt they had adequate time and resources. 76% of surgeons reported the need for more information on where to refer patients for appropriate alcohol treatment. Conclusion The study findings confirm the challenges and barriers to implementing brief alcohol intervention in current practice. There are service gaps that exist, as well as opportunities for training.

Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumours via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterised the effect on dendrimer disposition of conjugating α-carboxyl protected methotrexate (MTX) to a series of PEGylated 3H-labelled poly-L-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG570 dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG1100 dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumours and comparative disposition data in both rats (1 to 2% dose/g in tumour) and mice (11% dose/g in tumour) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-L-lysine dendrimers as long circulating vectors for the delivery and tumour-targeting of hydrophobic drugs.

The quik fix study : a randomised controlled trial of brief interventions for young people with alcohol-related injuries and illnesses accessing emergency department and crisis support care

Background: Alcohol is a major preventable cause of injury, disability and death in young people. Large numbers of young people with alcohol-related injuries and medical conditions present to hospital emergency departments (EDs). Access to brief, efficacious, accessible and cost effective treatment is an international health priority within this age group. While there is growing evidence for the efficacy of brief motivational interviewing (MI) for reducing alcohol use in young people, there is significant scope to increase its impact, and determine if it is the most efficacious and cost effective type of brief intervention available. The efficacy of personality-targeted interventions (PIs) for alcohol misuse delivered individually to young people is yet to be determined or compared to MI, despite growing evidence for school-based PIs. This study protocol describes a randomized controlled trial comparing the efficacy and cost-effectiveness of telephone-delivered MI, PI and an Assessment Feedback/Information (AF/I) only control for reducing alcohol use and related harm in young people. Methods/design: Participants will be 390 young people aged 16 to 25 years presenting to a crisis support service or ED with alcohol-related injuries and illnesses (including severe alcohol intoxication). This single blinded superiority trial randomized young people to (i) 2 sessions of MI; (ii) 2 sessions of a new PI or (iii) a 1 session AF/I only control. Participants are reassessed at 1, 3, 6 and 12 months on the primary outcomes of alcohol use and related problems and secondary outcomes of mental health symptoms, functioning, severity of problematic alcohol use, alcohol injuries, alcohol-related knowledge, coping self-efficacy to resist using alcohol, and cost effectiveness. Discussion: This study will identify the most efficacious and cost-effective telephone-delivered brief intervention for reducing alcohol misuse and related problems in young people presenting to crisis support services or EDs. We expect efficacy will be greatest for PI, followed by MI, and then AF/I at 1, 3, 6 and 12 months on the primary and secondary outcome variables. Telephone-delivered brief interventions could provide a youth-friendly, accessible, efficacious, cost-effective and easily disseminated treatment for addressing the significant public health issue of alcohol misuse and related harm in young people. Trial registration: This trial is registered with the Australian and New Zealand Clinical Trials Registry ACTRN12613000108718.

Young Australian adults' beliefs about alcohol's role in sexual aggression and victimisation

Beliefs and misconceptions about sex, gender, and rape have been explored extensively to explain people’s attributions concerning alcohol-involved sexual violence. However, less is known about the specific beliefs that people hold about how alcohol facilitates sexual aggression and victimisation. The present study aimed to identify these alcohol-related beliefs among young Australian adults. Six men and nine women (N = 15; 18-24 years) in focus groups (n = 13) and interviews (n = 2) were asked to discuss the role of alcohol in a hypothetical alcohol-involved rape. Using a consensual qualitative research methodology, the effects of alcohol that were seen to introduce, progress, and intensify risks for rape were: increased confidence; character transformation: impaired cognition; behavioural disinhibition; altered sexual negotiation; enhanced self-centredness; impaired awareness of wrongdoing; increased/decreased sexual assertiveness; and compromised self-protection. Some of the beliefs identified in this study are not currently captured in alcohol expectancy measures which assess people’s beliefs about alcohol’s effects on cognition, emotion, and behaviour. This study’s findings offer a conceptual basis for the development of a new alcohol expectancy measure that can be used in future rape-perception research.

Explicating the role of sexual coercion and vulnerability: Alcohol expectancies in rape attributions

Despite evidence suggesting that alcohol expectancies may influence people’s rape perceptions, no study to date has measured context-specific expectancies comprehensively. This study represents an initial investigation of the role of sexual coercion and vulnerability alcohol expectancies in young Australian adults’ rape blame attributions. Using a vignette method, it was hypothesised that participants’ stronger expectancy endorsement would predict lesser perpetrator blame and greater victim blame. Participants (N = 210; 34.9% males; 18-25 years) read a hypothetical rape scenario and rated dimensions of blameworthiness attributed to the intoxicated sexual perpetrator and victim. Participants completed the Sexual Coercion and Sexual Vulnerability sub-scales of the Drinking Expectancy Sexual Vulnerabilities Questionnaire for the targets self, men, and women in addition to measures of traditional gender role attitudes and rape myth acceptance. Hierarchical multiple regressions revealed that, as expected, stronger sexual coercion expectancy predicted lower perpetrator blame and greater victim blame. Self-oriented expectancy predicted evaluations of the perpetrator whereas other-oriented expectancy predicted victim evaluations. These effects were robust after controlling for gender role attitudes and rape myth acceptance. Alcohol expectancies appear to be part of a network of beliefs and attitudes which perpetuate biased rape attributions and may be useful to challenge in altering rape perceptions.

Young adults' perceptions of alcohol-involved sexual violence : explicating alcohol expectancies relating to sexual aggression and victimisation

Based on a mixed-methods research program, this thesis identifies the nature and impact of young Australian adults' alcohol-related beliefs relevant to intoxicated sexual aggression and victimisation. The thesis describes the development and validation of the Drinking Expectancy Sexual Vulnerabilities Questionnaire and demonstrates that sexual violence-related alcohol expectancies are linked to rape blame attributions. Findings show how Alcohol Expectancy Theory can be applied in rape-perception research and illuminate the reasons underlying negative responses to rape disclosure, the underreporting of sexual victimisation, cultural discourse about alcohol and rape, and biased decision-making in the criminal justice system.

Alcohol use in South Africa : findings from the first demographic and health survey (1998)

Objective This study formed part of the 1998 South African Demographic and Health Survey, which included questions assessing the extent of alcohol use, risky drinking and alcohol problems among South Africans to obtain up-to-date baseline estimates of consumption and risky drinking and to inform intervention efforts. Method A two-stage random sample of 13,826 persons ages 15 or older (59% women) was included in the survey. Alcohol use was assessed through eight questions, including the CAGE questionnaire. Frequency analyses for different age groups, geographic setting, education level, population group and gender were calculated, as were odds ratios for these variables in relation to symptoms of alcohol problems. Results Current alcohol consumption was reported by 45% of the men and 17% of the women. White men (71%) were most likely and Asian women (9%) least likely to be current drinkers. Urban residents were more likely than nonurban dwellers to report current drinking. One third of the current drinkers reported risky drinking over weekends, and 28% of the men and 10% of the women scored above the cutoff level on the CAGE questionnaire. Symptoms of alcohol problems were significantly associated with lower socioeconomic status, no school education in women and being older than 25 years of age. Conclusions A comprehensive strategy is required to address the high levels of risky drinking and reported symptoms of alcohol problems.