Involvement of alcohol in injury cases in rural Sri Lanka: prevalence and associated factors among in-patients in three primary care hospitals.

BACKGROUND: Injuries account for a major proportion of global morbidity and mortality related to alcohol use. Information on the prevalence of alcohol-related injury in rural Sri Lanka is limited. The aims of this study were to determine the burden of alcohol-related injury in a hospital-based sample in rural Sri Lanka and explore factors associated with an increased risk of alcohol-related injury. METHODS: Involvement of alcohol in injury amongst in-patients was assessed in three hospitals in the North Central Province of Sri Lanka over 6 months. Adult (≥ 18 years) patients were eligible. Patients were assessed for: injury characteristics, current alcohol use (in the past year) using the Alcohol Use Disorder Identification Test (AUDIT), and acute intoxication. Patients with a blood alcohol concentration (BAC) reading equivalent of 10 mg/dL (2.17 mmol/L) were considered as having an alcohol-related injury. Binary logistic regression was used to explore association between alcohol-related injury and demographic and injury characteristics. RESULTS: A total of 883 injured patients were eligible and consented to the study. No alcohol use was reported by 487 (55.2%) of patients (35.6% of men, 95.2% of women). Prevalence of alcohol-related injuries was 14.8% overall and 32.8% among current alcohol users. Almost all patients with an alcohol-related injury were male (122/123; 99.2%); 24 (18.8%) of these patients scored positive for possible alcohol dependence. Patients with an alcohol-related injury had significantly higher AUDIT scores (median = 15 vs 6, p < 0.001), were significantly more likely to be aged 26-40 (OR 2.29, 95% CI:1.11, 4.72) or 41-55 years (OR 2.76, 95% CI: 1.29, 5.90) (compared to 18-25 years), to have a transport-related injury (OR 5.14, 95% CI: 2.30, 11.49) (compared to animal/plant sting/bite), and have intentional injuries (OR 3.47, 95% CI: 1.01, 11.87). CONCLUSIONS: One in three injuries among people who drank alcohol in this sample were alcohol-related. In addition, problematic alcohol use was higher among those with alcohol-related injury. Further work is needed to explore whether this prevalence of alcohol-related injury is reflected in other rural settings in Sri Lanka.

Socioeconomic position and suicidal behaviour in rural Sri Lanka: a prospective cohort study of 168,000+ people.

PURPOSE: Lower socioeconomic position (SEP) is associated with an increased risk of suicidal behaviour in high income countries, but this association is not established in low- and middle-income countries (LMIC). METHODS: We investigated the association of SEP with suicidal behaviour in a prospective cohort study of 168,771 Sri Lankans followed up for episodes of attempted suicide and suicide. SEP data were collected at baseline at the household and individual level at the start of the follow-up period. We used multilevel Poisson regression models to investigate the association of SEP at community, household and individual levels with attempted suicide/suicide. RESULTS: Lower levels of asset ownership [IRR (95% CI) suicide 1.74 (0.92, 3.28); attempted suicide 1.67 (1.40, 2.00)] and education [suicide 3.16 (1.06, 9.45); attempted suicide 2.51 (1.70, 3.72)] were associated with an increased risk of suicidal behaviour. The association of these measures of SEP and attempted suicide was stronger in men than women. Individuals living in deprived areas [1.42 (1.16, 1.73)] and in households with a young female head of household [1.41 (1.04, 1.93)] or a temporary foreign migrant [1.47 (1.28, 1.68)] had an elevated risk of attempted suicide. Farmers and daily wage labourers had nearly a doubling in risk of attempted suicide compared to other occupations. CONCLUSIONS: Improved employment opportunities, welfare and mental health support services, as well as problem-solving skills development, may help support individuals with poorer education, farmers, daily wage labourers, individuals in young female-headed households and temporary foreign migrant households.

Pain management in pigs undergoing experimental surgery; a literature review (2012-4).

Failure to provide effective analgesia to animals in noxious studies contravenes the obligation to refine animal experimentation and, by increasing 'noise' in physiological data sets, may decrease the scientific validity of results. Pig models of surgical conditions are becoming increasingly important and used for translational work. This review aimed to determine the extent to which the recent biomedical literature describes pain assessment and alleviation in pigs recovering from experimental surgery. Three databases (Medline, Web of Knowledge, and Google Scholar) were searched to find relevant studies published from January 2012 to March 2014. Information on pain assessment and peri- and postoperative analgesia was extracted. The review identified 233 papers meeting selection criteria. Most articles (193/233, 83%) described use of drugs with analgesic properties, but only 87/233 (37%) described postoperative analgesia. No article provided justification for the analgesic chosen, despite the lack of guidelines for analgesia in porcine surgical models and the lack of formal studies on this subject. Postoperative pain assessment was reported in only 23/233 (10%) articles. It was found that the reporting of postoperative pain management in the studies was remarkably low, reflecting either under-reporting or under-use. Analgesic description, when given, was frequently too limited to enable reproducibility. Development of a pain-scoring system in pigs, together with the mandatory description of pain management in submitted articles, would contribute to improved laboratory pig welfare.

Translational toxicological research: investigating and preventing acute lung injury in organophosphorus insecticide poisoning.

Poisoning through ingestion of organophosphorus (OP) insecticide is a leading cause of suicide globally. Severe poisoning with OP compounds creates an unconscious, paralysed patient with respiratory failure. These symptoms make pulmonary aspiration of stomach contents highly likely, potentially causing an acute lung injury. To explore this hypothesis, we created a Gottingen minipig pulmonary aspiration model (n=26) to investigate the mechanism and severity of lung injury created through pulmonary instillation of 0.5 mL/kg mixtures of porcine gastric juice (GJ), OP and/or its solvent. Early results show that aspiration of OP and GJ causes pulmonary neutrophil sequestration, alveolar haemorrhage and interstitial oedema, with disruption of the alveolar-capillary membrane. Further measurements will include quantitative CT imaging, histopathology scoring, acute lung injury biomarkers and respiratory function. In order to test the validity of the minipig model, a pilot study in Sri Lanka has been devised to observe signs of lung injury in human patients who have ingested OP insecticide with or without clinical evidence of pulmonary aspiration. Lung injury will be assessed with PaO2/FIO2 ratios and physiological dead space measurement. Blood, bronchoalveolar lavage and urine will be taken at 24 and 48 h after poisoning and at 3-4 h in surgical control patients to measure acute lung injury biomarkers. An unpublished toxicology study from Sri Lanka, 2011-2012, showed that over 40% of unconscious poisoned patients with a GCS <9 were not intubated for ambulance transfer between rural and district hospitals. Delay in intubation leads to aspiration pneumonitis and pneumonia in 38%-45% of unconscious poisoned patients. We hypothesise that non-drug assisted placement of supraglottic airways may be a good tool for use in unconscious poisoned patients requiring transfer from small rural hospitals in Asia. They could confer better airway protection than no airway intervention and reduce both morbidity and mortality.

The cost-effectiveness of banning highly hazardous pesticides to prevent suicides due to pesticide self-ingestion across 14 countries: an economic modelling study.

BACKGROUND: Reducing suicides is a key Sustainable Development Goal target for improving global health. Highly hazardous pesticides are among the leading causes of death by suicide in low-income and middle-income countries. National bans of acutely toxic highly hazardous pesticides have led to substantial reductions in pesticide-attributable suicides across several countries. This study evaluated the cost-effectiveness of implementing national bans of highly hazardous pesticides to reduce the burden of pesticide suicides. METHODS: A Markov model was developed to examine the costs and health effects of implementing a national ban of highly hazardous pesticides to prevent suicides due to pesticide self-poisoning, compared with a null comparator. We used WHO cost-effectiveness and strategic planning (WHO-CHOICE) methods to estimate pesticide-attributable suicide rates for 100 years from 2017. Country-specific costs were obtained from the WHO-CHOICE database and denominated in 2017 international dollars (I$), discounted at a 3% annual rate, and health effects were measured in healthy life-years gained (HLYGs). We used a demographic projection model beginning with the country population in the baseline year (2017), split by 1-year age group and sex. Country-specific data on overall suicide rates were obtained for 2017 by age and sex from the Global Burden of Disease Study 2017 Data Resources. The analysis involved 14 countries spanning low-income to high-income settings, and cost-effectiveness ratios were analysed at the country-specific level and aggregated according to country income group and the proportion of suicides due to pesticides. FINDINGS: Banning highly hazardous pesticides across the 14 countries studied could result in about 28 000 (95% uncertainty interval [UI] 24 000-32 000) fewer suicide deaths each year at an annual cost of I$0·007 per capita (95% UI 0·006-0·008). In the population-standardised results for the base case analysis, national bans produced cost-effectiveness ratios of $94 per HLYG (95% UI 73-123) across low-income and lower-middle-income countries and $237 per HLYG (95% UI 191-303) across upper-middle-income and high-income countries. Bans were more cost-effective in countries where a high proportion of suicides are attributable to pesticide self-poisoning, reaching a cost-effectiveness ratio of $75 per HLYG (95% UI 58-99) in two countries with proportions of more than 30%. INTERPRETATION: National bans of highly hazardous pesticides are a potentially cost-effective and affordable intervention for reducing suicide deaths in countries with a high burden of suicides attributable to pesticides. However, our study findings are limited by imperfect data and assumptions that could be improved upon by future studies. FUNDING: WHO.

Overdose in young children treated with anti-reflux medications: Poisons enquiry evidence of excess 10-fold dosing errors with ranitidine.

BACKGROUND: Accidental drug overdose is a common problem in young children. We examined the influence of formulation and dose in enquiries for different gastro-oesophageal reflux disease treatments in children under 5 years to the UK's National Poisons Information Service. METHODS: Overdose characteristics with ranitidine, omeprazole or domperidone were compared with those of metoclopramide and the H-1 antagonist chlorphenamine, for the period 1 July 2007 to 30 June 2015. RESULTS: There were a total of 1092 ranitidine, 618 domperidone and 1193 omeprazole cases; 669, 281 and 424, respectively, were single agent enquiries; of these 77% (517) of ranitidine, 52% (145) domperidone and 32% (135) omeprazole cases occurred in children <5 years. In comparison, 17% (34/424) of metoclopramide and 53% (533/1013) of chlorphenamine were <5 years; 79% (410/517) of ranitidine overdose enquiries in children <5 years were under 6 months of age, higher than domperidone (68/145, 47%; p < 0.05), omeprazole (8/135, 6%), chlorphenamine (13/553, 2%) or metoclopramide (1/34, 3%) (all p < 0.01). In children aged <6 months, 101 were 10-fold overdoses, 86 with ranitidine. CONCLUSIONS: Tenfold overdoses in children (<5 years) were a feature of ranitidine enquiries, likely due to the high concentration of the syrup. This has relevance to other liquid formulations used for non-licenced indications in young children. Such therapeutic errors cause significant carer anxiety and healthcare utilization. Assistance is needed from manufacturers and legislators in modifying formulation so that drugs can be safely used in young children. Education of prescribers and carers is also needed to reduce the incidence of such errors that cause significant carer anxiety and healthcare utilization.

Attempted suicide in Sri Lanka - An epidemiological study of household and community factors.

BACKGROUND: An individual's suicide risk is determined by personal characteristics, but is also influenced by their environment. Previous studies indicate a role of contextual effects on suicidal behaviour, but there is a dearth of quantitative evidence from Asia. METHODS: Individual and community level data were collected on 165,233 people from 47,919 households in 171 communities in rural Sri Lanka. Data were collected on individual (age, sex, past suicide attempts and individual socioeconomic position (SEP)) and household (household SEP, pesticide access, alcohol use and multigenerational households) level factors. We used 3-level logit models to investigate compositional (individual) and contextual (household/community) effects. RESULTS: We found significant variation between households 21% (95% CI 18%, 24%) and communities 4% (95% CI 3%, 5%) in the risk of a suicide attempt. Contextual factors as measured by low household SEP (OR 2.37 95% CI 2.10, 2.67), low community SEP (OR 1.45 95% CI 1.21, 1.74), and community 'problem' alcohol use (OR 1.44 95% CI 1.19, 1.75) were associated with an increased risk of suicide attempt. Women living in households with alcohol misuse were at higher risk of attempted suicide. We observed a protective effect of living in multigenerational households (OR 0.53 95% CI 0.42, 0.65). LIMITATIONS: The outcome was respondent-reported and refers to lifetime reports of attempted suicide, therefore this study might be affected by socially desirable responding. CONCLUSIONS: Our study finds that contextual factors are associated with an individual's risk of attempted suicide in Sri Lanka, independent of an individual's personal characteristics.

Hospital usage of TOXBASE in Great Britain: Temporal trends in accesses 2008 to 2015.

AIM: To examine temporal trends in accesses to the UK's National Poison Information Service's TOXBASE database in Britain. METHODS: Generalized additive models were used to examine trends in daily numbers of accesses to TOXBASE from British emergency departments between January 2008 and December 2015. Day-of-the-week, seasonality and long-term trends were analysed at national and regional levels (Wales, Scotland and the nine English Government Office Regions). RESULTS: The long-term trend in daily accesses increases from 2.8 (95% confidence interval (CI): 2.6-3.0) per user on 1 January 2008 to 4.6 (95% CI: 4.3-4.9) on 31 December 2015, with small but significant differences in population-corrected accesses by region ( p < 0.001). There are statistically significant seasonal and day of the week patterns ( p < 0.001) across all regions. Accesses are 18% (95% CI: 14-22%) higher in summer than in January and at the weekend compared to weekdays in all regions; there is a 7.5% (95% CI: 6.1-8.9%) increase between Friday and Sunday. CONCLUSIONS: There are consistent in-year patterns in access to TOXBASE indicating potential seasonal patterns in poisonings in Britain, with location-dependent rates of usage. This novel descriptive work lays the basis for future work on the interaction of TOXBASE use with emergency admission of patients into hospital.

Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis.

Hemostasis in the brain is of paramount importance because bleeding into the neural parenchyma can result in paralysis, coma, and death. Consistent with this sensitivity to hemorrhage, the brain contains large amounts of tissue factor (TF), the major cellular initiator of the coagulation protease cascades. However, to date, the cellular source for TF in the central nervous system has not been identified. In this study, analysis of murine brain sections by in situ hybridization demonstrated high levels of TF mRNA in cells that expressed glial fibrillary acidic protein, a specific marker for astrocytes. Furthermore, primary mouse astrocyte cultures and astrocyte cell lines from mouse, rat, and human constitutively expressed TF mRNA and functional protein. These data indicated that astrocytes are the primary source of TF in the central nervous system. We propose that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain. Finally, we observed an increase in TF mRNA expression in the brains of scrapie-infected mice. This modulation of TF expression in the absence of hemorrhage suggested that TF may function in processes other than hemostasis by altering protease generation in normal and diseased brain.

The impact of pesticide regulations on suicide in Sri Lanka.

BACKGROUND: Between 1950 and 1995 suicide rates in Sri Lanka increased 8-fold to a peak of 47 per 100,000 in 1995. By 2005, rates had halved. We investigated whether Sri Lanka's regulatory controls on the import and sale of pesticides that are particularly toxic to humans were responsible for these changes in the incidence of suicide. METHODS: Ecological analysis using graphical and descriptive approaches to identify time trends in suicide and risk factors for suicide in Sri Lanka, 1975-2005. RESULTS: Restrictions on the import and sales of WHO Class I toxicity pesticides in 1995 and endosulfan in 1998, coincided with reductions in suicide in both men and women of all ages. 19,769 fewer suicides occurred in 1996-2005 as compared with 1986-95. Secular trends in unemployment, alcohol misuse, divorce, pesticide use and the years associated with Sri Lanka's Civil war did not appear to be associated with these declines. CONCLUSION: These data indicate that in countries where pesticides are commonly used in acts of self-poisoning, import controls on the most toxic pesticides may have a favourable impact on suicide. In Asia, there are an estimated 300,000 deaths from pesticide self-poisoning annually. National and international policies restricting the sale of pesticides that are most toxic to humans may have a major impact on suicides in the region.

Is socioeconomic position associated with risk of attempted suicide in rural Sri Lanka? A cross-sectional study of 165†000 individuals.

BACKGROUND: Lower socioeconomic position (SEP) is associated with an increased risk of suicidal behaviour in high-income countries, but this association is unclear in low-income and middle-income countries. METHODS: We investigated the association of SEP with attempted suicide in a cross-sectional survey of 165 233 Sri Lankans. SEP data were collected at the household (assets, social standing (highest occupation of a household member), foreign employment and young (≤40 years) female-headed households) and individual level (education and occupation). Respondent-reported data on suicide attempts in the past year were recorded. Random-effects logistic regression models, accounting for clustering, were used to investigate the association of SEP with attempted suicide. RESULTS: Households reported 398 attempted suicides in the preceding year (239 per 100 000). Fewer assets (OR 3.2, 95% CI 2.4 to 4.4) and having a daily wage labourer (ie, insecure/low-income job; OR 2.3, 95% CI 1.6 to 3.2) as the highest occupation increased the risk of an attempted suicide within households. At an individual level, daily wage labourers were at an increased risk of attempted suicide compared with farmers. The strongest associations were with low levels of education (OR 4.6, 95% CI 2.5 to 8.4), with a stronger association in men than women. CONCLUSIONS: We found that indicators of lower SEP are associated with increased risk of attempted suicide in rural Sri Lanka. Longitudinal studies with objective measures of suicide attempts are needed to confirm this association. TRIAL REGISTRATION NUMBER: NCT01146496; Pre-results.

Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.

Respiratory failure in acute organophosphorus pesticide self-poisoning.

BACKGROUND: Acute organophosphorus (OP) pesticide poisoning is a major clinical problem in the developing world. Textbooks ascribe most deaths to respiratory failure occurring in one of two distinct clinical syndromes: acute cholinergic respiratory failure or the intermediate syndrome. Delayed failure appears to be due to respiratory muscle weakness, but its pathophysiology is unclear. AIM: To describe the clinical patterns of OP-induced respiratory failure, and to determine whether the two syndromes are clinically distinct. DESIGN: Prospective study of 376 patients with confirmed OP poisoning. METHODS: Patients were observed throughout their admission to three Sri Lankan hospitals. Exposure was confirmed by butyrylcholinesterase and blood OP assays. RESULTS: Ninety of 376 patients (24%) required intubation: 52 (58%) within 2 h of admission while unconscious with cholinergic features. Twenty-nine (32%) were well on admission but then required intubation after 24 h while conscious and without cholinergic features. These two syndromes were not clinically distinct and had much overlap. In particular, some patients who required intubation on arrival subsequently recovered consciousness but could not be extubated, requiring ventilation for up to 6 days. DISCUSSION: Respiratory failure did not occur as two discrete clinical syndromes within distinct time frames. Instead, the pattern of failure was variable and overlapped in some patients. There seemed to be two underlying mechanisms (an early acute mixed central and peripheral respiratory failure, and a late peripheral respiratory failure) rather than two distinct clinical syndromes.

Taking stock: UK national antidote availability increasing, but further improvements are required.

BACKGROUND: A 2010/2011 audit of the Royal College of Emergency Medicine (RCEM) National Poisons Information Service (NPIS) UK guidelines on antidote availability demonstrated variable stocking of antidotes for the management of poisoned patients; the guidelines were updated and republished in 2013. AIM: To assess if antidote stocking has improved since the 2010/2011 audit and introduction of the 2013 guidelines. METHODS: Questionnaires were sent to Chief Pharmacists at all 215 acute hospitals in England, Wales and Northern Ireland in October 2014. Data were collected on the timing of availability (category A antidotes should be available immediately, category B within 1 h and category C can be held supraregionally) and stock levels. RESULTS: 169 (78.6%) responses were received. Atropine, calcium gluconate and flumazenil (category A) were the only antidotes available in all hospitals within the recommended time and stock levels. Forty-one (24.3%) hospitals held every category A antidote; this increased to 81 (47.9%) for those holding at least one cyanide antidote and all other category A antidotes. The proportion of hospitals stocking category A/B antidotes within the recommended time increased for 20 (90.9%) category A/B antidotes. Fomepizole (category B) availability increased to 62.1% of hospitals from 11.4% in 2010/2011. Other than penicillamine (63.3% hospitals), there was poor availability (2.4%-36.1%) of category C antidotes. CONCLUSIONS: Availability of category A and B antidotes has improved since the 2010/2011 audit and 2013 guidelines. However, there remains significant variability particularly for category C antidotes. More work is required to ensure that those treating poisoned patients have timely access to antidotes focusing particularly on category C antidotes.

Oximes for acute organophosphate pesticide poisoning.

BACKGROUND: Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and oxime to counter acetylcholinesterase inhibition at the synapse. The usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world, who have failed to see benefit in their clinical practice. OBJECTIVES: To find the clinical trial evidence for oximes producing clinical benefit in acute organophosphorus pesticide-poisoned patients. SEARCH STRATEGY: We carried out a systematic search to find randomised clinical trials (RCTs) of oximes in acute organophosphorus pesticide poisoning, using MEDLINE, EMBASE and Cochrane databases. All articles with the text words 'organophosphate' or 'oxime' together with 'poisoning' or 'overdose' were examined. (Search last updated November 2003.) SELECTION CRITERIA: Articles that could possibly be randomised clinical trials were retrieved to determine if this was the case. DATA COLLECTION AND ANALYSIS: The published methodology of the possible RCTs located is not clear. One was found in abstract form only and two other published trials also had many gaps in the published methodology. We have attempted to contact the principal authors of all three trials but have been unable to obtain further information. MAIN RESULTS: Two RCTs have been published, involving 182 patients treated with pralidoxime. These trials did not find benefit. However, the studies did not take into account a number of issues important for outcome and the methodology is unclear. Therefore, a generalised statement on effectiveness cannot be supported by the published results. In particular, characteristics at baseline were not evenly balanced, the dose of oxime was much lower than recommended in guidelines, there were substantial delays to treatment, and the type of organophosphate was not taken into account. The abstract of the third trial, a small possible RCT, is uninterpretable without further data. AUTHORS' CONCLUSIONS: Current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of acute organophosphorus pesticide poisoning. A much larger RCT is required to compare the World Health Organization recommended pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/hr infusion) with placebo. There are many theoretical and practical reasons why oximes may not be useful to patients with overwhelming self-poisoning. Such a study will need to be designed with pre-defined sub-group analysis to allow identification of patient sub-groups that may benefit from oximes.

Prophylactic use of antimicrobials in surgical pig models; a literature review (2012-2014).

There are no guidelines for antimicrobial use in experimental animals even though appropriate selection is required to reduce risk of surgical site infection (SSI) and resistance development. Pigs are used extensively as experimental surgical models for people. This review compares reported antimicrobial prescription in recently published pig surgical studies (retrieved by PubMed, Web of Knowledge and Google Scholar) with human guidelines for prophylactic antimicrobial use (National Institute of Clinical Excellence and the American Society of Health-System Pharmacists). A five-point appropriate antimicrobial use index (AAUI), based on aforementioned guidelines, was used to grade 233 studies. Use of World Health Organization-designated critically important antimicrobials (CIA) was recorded. Antimicrobial use was described in 111 of 233 (48 per cent) papers. AAUI scores of 5 (maximal compliance) and 0 (no compliance) were awarded to 34 (15 per cent) and 101 (43 per cent) articles. Where reported, prophylactic antimicrobials were mostly administered after surgery (62/95, 65 per cent) and intramuscularly (36/72, 50 per cent). CIAs were described in 21 of 111 (19 per cent) papers and SSIs in 21 of 233 (9 per cent). Reported antimicrobial prophylaxis in experimental pig surgery deviates from human clinical guidelines. This has implications for antimicrobial resistance, study quality and animal welfare. Until species-specific guidelines are formulated, experimental surgical studies involving animals would probably benefit from adherence to human guidelines.

Molecular profile of reactive astrocytes--implications for their role in neurologic disease.

The central nervous system responds to diverse neurologic injuries with a vigorous activation of astrocytes. While this phenomenon is found in many different species, its function is obscure. Understanding the molecular profile characteristic of reactive astrocytes should help define their function. The purpose of this review is to provide a summary of molecules whose levels of expression differentiate activated from resting astrocytes and to use the molecular profile of reactive astrocytes as the basis for speculations on the functions of these cells. At present, reactive astrocytosis is defined primarily as an increase in the number and size of cells expressing glial fibrillary acidic protein. In vivo, this increase in glial fibrillary acidic protein-positive cells reflects predominantly phenotypic changes of resident astroglia rather than migration or proliferation of such cells. Upon activation, astrocytes upmodulate the expression of a large number of molecules. From this molecular profile it becomes apparent that reactive astrocytes may benefit the injured nervous system by participating in diverse biological processes. For example, upregulation of proteases and protease inhibitors could help remodel the extracellular matrix, regulate the concentration of different proteins in the neuropil and clear up debris from degenerating cells. Cytokines are key mediators of immunity and inflammation and could play a critical role in the regulation of the blood-central nervous system interface. Neurotrophic factors, transporter molecules and enzymes involved in the metabolism of excitotoxic amino acids or in the antioxidant pathway may help protect neurons and other brain cells by controlling neurotoxin levels and contributing to homeostasis within the central nervous system. Therefore, an impairment of astroglial performance has the potential to exacerbate neuronal dysfunction. Based on the synopsis of studies presented, a number of issues become apparent that deserve a more extensive analysis. Among them are the relative contribution of microglia and astrocytes to early wound repair, the characterization of astroglial subpopulations, the specificity of the astroglial response in different diseases as well as the analysis of reactive astrocytes with techniques that can resolve fast physiologic processes. Differences between reactive astrocytes in vivo and primary astrocytes in culture are discussed and underline the need for the development and exploitation of models that will allow the analysis of reactive astrocytes in the intact organism.

Molecular mimicry accompanying HIV-1 infection: human monoclonal antibodies that bind to gp41 and to astrocytes.

Monoclonal antibodies that bound to HIV gp41 and cross-reacted with astrocytes were recovered from the blood of three patients infected with HIV-1. Mapping of the specificity of these monoclonal antibodies, using synthetic gp41 peptides, located their epitope to amino acids 644-663 and established their conformation dependence. Six other human monoclonal anti-HIV antibodies were found to bind to HIV gp41 or gp120 but not to reactive astrocytes in brain tissue. Sharing of linear or conformational protein determinants between disparate viral and host proteins is termed molecular mimicry. The consequences of such mimicry by anti-viral antibodies interacting with astrocytes may play a role in the dementia of AIDS patients since a major function of astrocytes is to maintain the appropriate milieu for neuronal function. The finding of such cross-reactive antibodies adds to the evidence for a possible autoimmune pathogenesis in some of the disease manifestations accompanying HIV infection.