Sulfur mustard (HD) is a potent cutaneous vesicant that penetrates rapidly through the skin, causing prolonged injuries and leading to severe incapacitation. Although there has been long and intensive efforts to find a treatment for HD skin lesions, no effective treatment is available for HD-induced skin injuries. Recently, ointments containing calmodulin antagonists were found to be effective in preventing skin injuries induced by HD in hairless mice. The present study was designed to investigate the beneficial effects of topical treatments with calmodulin antagonists against HD skin lesions in the pig model. The pig is used as a preferred animal model for human skin in many studies, including vesicants. Neat HD, either in liquid form (0.2-1 microl droplets) or as vapour, was applied to the back skin of female pigs (a cross Large White & Landrace, 10-12 kg) for various exposure durations. Evaluation was based on quantitative analysis of the degree of erythema and area of the lesions, as well as histological evaluation. Calmodulin antagonists (10% pentamide, 1% trifluoperazine, 2% thioridazine) and anaesthetics (20% lidocaine and 3% benoxinate) were dissolved in pluronic F-127 base according to Kim et al. (Eur. J. Pharmacol. 1996; 313: 107-114) or in saline, and were applied either topically as ointments or by intradermal injection, as early as 5 min post-exposure (twice a day for at least 3 days). The results demonstrated that topically applied pluronic base ointments containing lidocaine or pentamide produce beneficial effects when applied immediately after short-term HD exposure to pig skin.

Administration, Topical↗

PubMed2000

Beneficial effects of topical anti-inflammatory drugs against sulfur mustard-induced ocular lesions in rabbits.

Ocular injuries following sulfur mustard (HD) exposure are characterized by an inflammatory response, observed as eyelid swelling, conjunctivitis, corneal oedema and cellular infiltration starting 1-4 h after exposure, depending on dose. These effects heal partially during the first 1-2 weeks after exposure, with the later appearance of neovascularization, recurrent erosions and recurrent oedema of the cornea (delayed response). We have shown previously that topically applied steroid treatment, administered after HD exposure, attenuated the extent of neovascularization, one of the characteristics of delayed ocular pathology in rabbits. The present study was designed to characterize further the initial inflammatory response and to elucidate the role of anti-inflammatory (AI) drugs as a potential therapy. Rabbit eyes were exposed to HD vapour (390 microg l(-1) for 2 min) and were treated with a topical commercial ophthalmic solution of dexamethasone or diclofenac, starting 1 h post-exposure (four times a day). Inflammation was evaluated by clinical observations, biochemical analysis of aqueous humour and by histology. Sulfur mustard exposure initiated typical clinical ocular symptoms within 4-6 h after exposure. Biochemical analysis of aqueous humour showed that protein content and prostaglandin E (PGE) increased significantly at 6 h and were still high 48 h after HD exposure. Light microscopy evaluation revealed severe damage to the cornea, characterized by epithelial denudation, oedema and cellular infiltration (mostly eosinophiles) in the stroma. Both treatments were effective in alleviating the clinical symptoms and in preventing the HD-induced increase in protein and PGE in the anterior chamber, as well as the cellular infiltration, in the corneal stroma. However, the AI treatments had no therapeutic effect on corneal erosions, and a short delay in epithelial regeneration was noted. It is concluded that AI drugs are potential candidates for the treatment of ocular lesions following HD exposure.

Animals↗

PubMed2000

Sulfur mustard toxicity in macrophages: effect of dexamethasone.

Cells from the murine macrophage-like cell line J774A.1 (J774) and cultures of primary alveolar macrophages (PAM) obtained from guinea pigs were exposed to sulfur mustard (HD, 50-200 microM) and treated with dexamethasone (2.5 microM) 10 min after HD exposure. Cell cultures were studied at 3 and 24 h after exposure by the cleavage of Thiazolyl blue reaction (MTT) reaction and crystal violet staining (viability assays), by morphological observation and by [3H]thymidine incorporation. Exposure of J774 cells to HD caused a dose-dependent decrease in viability that was evident at 24 h. Although no significant change in viability was observed at 3-4 h after HD exposure, a dose-dependent decrease in [3H]thymidine incorporation was observed. Treatment with dexamethasone caused a dose-dependent decrease in viability. However, the combined exposure to HD and dexamethasone had a synergistic effect on the decrease of cell viability. This synergistic effect is not due to a change in DNA synthesis rate because [3H]thymidine incorporation was not affected by dexamethasone. In PAM cultures, HD caused some 'activating' effect on [3H]thymidine incorporation and an increase in cell number at the lower dose (100 microM) but this was less at 200 microM. Both effects were reduced by dexamethasone treatment. We conclude that macrophages derived from different sources exhibit a different responsiveness to immunomodulators (HD and dexamethasone) and that dexamethasone can reduce the 'inflammatory' effect of HD in PAM.

Animals↗

PubMed2000

The inertia of self-regulation: a game-theoretic approach to reducing passive smoking in restaurants.

Two alternate regulatory approaches can be used to reduce exposure to environmental tobacco smoke in workplaces. The first is voluntary, self-regulation introduced by management, which is supported by common law and occupational health legislation that emphasises the employers' 'duty of care'. The second is public health legislation that bans smoking outright in enclosed places. In Australia, self-regulation has succeeded in restricting tobacco smoking in most indoor workplaces but has been a relative failure in the hospitality industry. Claims that this reflects consumer preference by diners, club and hotel patrons are not backed by survey evidence, typically showing large majority support for non-smoking establishments. Insights from game theory show why reliance on the duty of care is unlikely to succeed even when establishment operators collectively support a non-smoking policy. Using plausible assumptions about the net costs of unilaterally introducing smoking restrictions, what makes good sense for society as a whole is likely to be the least profitable option for an individual operator acting alone. Operators find themselves in the classic prisoner's dilemma. If the aim of policy is to restrict smoking in public places in order to protect the health of employees then game-theory predicts that public health legislation banning smoking in enclosed places will be more effective than self-regulation and reliance on the duty of care.

Australia↗

PubMed2000

Reversal of presynaptic deficits of apolipoprotein E-deficient mice in human apolipoprotein E transgenic mice.

Apolipoprotein E genotype is an important risk factor of Alzheimer's disease, which is associated with the degeneration of distinct brain neuronal systems. In the present study we employed apolipoprotein E-deficient mice and human apolipoprotein E3 and apolipoprotein E4 transgenic mice on a null mouse apolipoprotein E background, to examine the extent to which distinct brain neuronal systems are affected by apolipoprotein E and the isoform specificity of this effect. This was pursued by histological and autoradiographic measurements utilizing neuron specific presynaptic markers. The results thus obtained revealed significant reductions in the levels of brain cholinergic and noradrenergic nerve terminals in young apolipoprotein E-deficient mice and no changes in brain dopaminergic nerve terminals. These cholinergic and noradrenergic presynaptic derangements were ameliorated similarly in human apolipoprotein E3 and apolipoprotein E4 transgenic mice. In the case of the cholinergic system, this resulted in complete reversal of the presynaptic deficits, whereas in the case of the noradrenergic neurons the amelioration was partial. These findings suggest that brain cholinergic and noradrenergic neurons are markedly more dependent on brain apolipoprotein E than brain dopaminergic neurons and that the isoform specificity of these effects is not apparent at a young age under non-challenged conditions.

Acetylcholine↗

PubMed2000

Is the quality of asthma prescribing, as measured by the general practice ratio of corticosteroid to bronchodilator, associated with asthma morbidity?

The objective of this study was to determine whether the quality of asthma prescribing in general practice is associated with the severity of asthma patients' symptoms. Cross-sectional survey of asthma-like symptoms in patients prescribed antiasthma therapy was used. The setting was two general practices with contrasting ratios of corticosteroid to bronchodilator (high vs. low). The main outcome measures were: patient symptoms score and patient characteristics (age, gender, diagnosis, smoking, social class, and deprivation status). Patients on antiasthma therapy from the practice with the low corticosteroid to bronchodilator ratio had a higher mean symptom score (20.1, 95% CI 18.6, 21.7) than patients on antiasthma therapy from the practice with the high corticosteroid to bronchodilator ratio (13.2, 95% CI 11.8, 14.5). The mean difference in patient symptom score between the two practices was 7.0 (95% CI 4.9, 9.0); this changed little after adjustment for potential confounders. The quality of prescribing, as measured by the practice ratio of corticosteroid to bronchodilator, appears to be an important factor in the outcome of asthma care. The ratio of corticosteroid to bronchodilator in a general practice is one indicator of the quality of prescribing for asthma.

Adolescent↗

PubMed2000

A comparison of trends in problematic drug misuse from two reporting systems.

BACKGROUND: Regional Drug Misuse Databases (RDMDs) are considered the main source of intelligence on problem drug takers in England. Originally intended to provide trend data on visible drug use, a recent strategic review concluded that their purpose should be to monitor treatment targets for the Government's latest 10 year strategy to tackle drug misuse. The aim of this analysis was to explore whether the General Practice Research Database (GPRD) could supplement RDMDs. METHODS: A retrospective analysis was carried out using the GPRD and the RDMD in the West Midlands from 1993 to 1997. RESULTS: Extrapolation of GPRD data indicates 6,574 drug misusing or dependent diagnosed patients in primary care in 1997 compared with 3,643 clients reported by all agencies including general practitioners (GPs) to the RDMD. From 1993 to 1997, the RDMD notification rate fluctuated whereas the GPRD rate has increased steadily since 1995. Half of all drug misusing or dependent patients recorded on the GPRD had psychiatric co-morbidity and 10 per cent had been referred to hospital for a drug overdose. CONCLUSIONS: As the GPRD has been unaffected by the demise of statutory notification of drug dependence in 1997, interpretation of trends may be more reliable than on the RDMD. There is also considerable potential for analysis of prescribing patterns, co-morbidity and drug-related hospitalization. As the Department of Health's Strategic Review of RDMDs recommends GPs as 'core reporters' for providing data to the national system, there is a need for a strategy to ensure valid and comprehensive reporting from GPs.

Data Collection↗

PubMed2000

The citation index: what it is and what it isn't.

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Australia↗

PubMed2000

Tobacco taxes are no insurance against litigation.

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Humans↗

PubMed2000

'Sending the wrong signal': analysis of print media reportage of the ACT heroin prescription trial proposal, August 1997.

OBJECTIVE: To analyse and compare newspaper coverage about heroin during a period spanning two government policy decisions to approve, then prevent, a trial of heroin prescription to dependent users. METHOD: All articles published about heroin spanning the two policy decisions (1-19 August 1997) were collected from seven major Australian newspapers. Analyses included content and orientation analyses of all articles and discourse analysis of articles (excluding letters) containing value-laden statements about heroin prescription. Comparisons were made of content, orientation and subtextual themes employed by opponents and proponents of heroin prescription. RESULTS: 231 articles with references to heroin were identified from seven newspapers, 28% were published by The Daily Telegraph. This newspaper campaigned against the heroin prescription trial with 66% of news articles and 100% of opinion items negative in orientation, compared to averages of 11% and 16% of news and opinion articles published by comparison newspapers. Seven subtexts were identified in coverage opposing heroin prescription including "surrender in the war on drugs", "government as drug pedlar" and "deserving/undeserving citizens". Six subtexts supportive of heroin prescription were identified including "failure of prohibition" and "time for new approaches". CONCLUSION: The mid-1997 policy reversal on heroin prescription was due, in part, to the higher activity of opponents following approval of the trial and because proponents did not reframe discourses used to denigrate the proposal. IMPLICATIONS: To be successful, advocates of new policy need to recognise and reframe negative discourses to create new dominant themes which address the concerns of the public.

Australia↗

PubMed2000

Public health should not be a popularity contest: a reply to Gavin Mooney.

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Attitude to Health↗

PubMed2000

M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease. Rationale and perspectives.

A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.

Alzheimer Disease↗