High-dose immunosuppression to prevent death after paraquat self-poisoning – a randomised controlled trial

Context: Intentional self-poisoning with the herbicide paraquat has a very high case-fatality and is a major problem in rural Asia and Pacific.

Objectives: We aimed to determine whether the addition of immunosuppression to supportive care offers benefit in resource poor Asian district hospitals.

Materials and methods: We performed a randomised placebo-controlled trial comparing immunosuppression (intravenous cyclophosphamide up to 1?g/day for two days and methylprednisolone 1?g/day for three days, and then oral dexamethasone 8?mg three-times-a-day for 14 days) with saline and placebo tablets, in addition to standard care, in patients with acute paraquat self-poisoning admitted to six Sri Lankan hospitals between 1st March 2007 and 15th November 2010. The primary outcome was in-hospital mortality.

Results: 299 patients were randomised to receive immunosuppression (147) or saline/placebo (152). There was no significant difference in in-hospital mortality rates between the groups (immunosuppression 78 [53%] vs. placebo 94 [62%] (Chi squared test 2.4, p?=?.12). There was no difference in mortality at three months between the immunosuppression (101/147 [69%]) and placebo groups (108/152 [71%]); (mortality reduction 2%, 95% CI: ?8 to +12%). A Cox model did not support benefit from high-dose immunosuppression but suggested potential benefit from the subsequent two weeks of dexamethasone.

Conclusions: We found no evidence that high dose immunosuppression improves survival in paraquat-poisoned patients. The continuing high mortality means further research on the use of dexamethasone and other potential treatments is urgently needed.     

AMEE Education Guide no. 28: the development and role of departments of medical education

A department of medical education is becoming an essential requirement for a medical school. This publication is intended for those wishing to establish or develop a medical education department. It may also prove useful to teachers in medicine by providing information on how such a department can support their activities. This will vary with the local context but the principles are generalizable. Medical education departments are established in response to increased public expectations relating to healthcare, societal trends towards increased accountability, educational developments, increased interest in what to teach and how to educate doctors and the need to train more doctors. The functions of a department of medical education include research, teaching, service provision and career development of the staff. The scope of its activities includes undergraduate and postgraduate education, continuing professional development and continuing medical education. These activities may be extended to other healthcare professions. Flexibility is the key to staffing a department of medical education. Various contractual arrangements, affiliations and support from non-affiliated personnel are needed to provide a multi-professional team with a range of expertise. The precise structure of the department will depend on the individual institution. The name of the department may suggest its position within the university structure. The director provides academic leadership for the department and his/her responsibilities include promotion of staff collaboration, fostering career development of the staff and establishing local, regional and international links. Financial support may come from external funding agencies, government or university sources. Some departments of medical education are financially self-supporting. The department should be closely integrated with the medical school. Support for the department from the dean is an essential factor for sustainability. Several case studies of medical education departments throughout the world are included as examples of the different roles and functions of a department of medical education.     

Survival pattern in patients with acute organophosphate poisoning receiving intensive care

BACKGROUND: Approximately 35% of patients acutely poisoned with organophosphates (OP) in developing countries like Sri Lanka require intensive care and mechanical ventilation. However, death rates remain high. OBJECTIVE: To study the outcomes and predictors of mortality in patients with acute OP poisoning requiring intensive therapy at a regional center in Sri Lanka over a period of 40 months. METHODS: Retrospective analysis of all intensive care records of patients with acute OP poisoning admitted to the Intensive Care Unit (ICU) between March 1998 and July 2001. RESULTS: During the study period, 126 subjects were admitted to the ICU with acute OP poisoning. Records of 10 patients were lost and those of 37 were incomplete and hence were excluded. All the remaining 71 patients (59 male) had required endotracheal intubation and mechanical ventilation for a period of four (median) days (range 1-27) in addition to gastric lavage and standard therapy with atropine and oximes and adequate hydration. Of these 71 patients, 36 (28 male) had died. Life table analysis demonstrated a steep decline in the cumulative survival to 67% during the first three days. Systolic blood pressure of < 100 mmHg and FiO2 of >40% to maintain a SpO2 of >92% within the first 24 h were recognized as poor prognostic indicators among mechanically ventilated patients. CONCLUSION: Mortality following OP poisoning remains high despite adequate respiratory support, intensive care, and specific therapy with atropine and oximes. One-third of the subjects needing mechanical ventilation and reaching intensive care units die within the first 72 h of poisoning. Systolic blood pressure of less than 100 mmHg and the necessity of a FiO2>40% to maintain adequate oxygenation are predictors of poor outcome in patients mechanically ventilated in the ICU.     

Health changes in sri lanka: benefits of primary health care and public health

The Democratic Socialist Republic of Sri Lanka is an island in the Indian Ocean that has achieved a unique status in the world with health indicators that are comparable with those of developed countries. This is illustrated, among others, by the reduction in both child and maternal mortality in the country. This achievement is the result of a range of long-term interventions, including providing education and health care free of charge, training of health care workers, developing public health infrastructure in rural areas, and adopting steps to improve sanitation, nutrition, and immunization coverage.     

Determinants of breastfeeding practices: an analysis of the Sri Lanka Demographic and Health Survey 2006-2007

Identification of factors that predict a woman's infant feeding choice is important for breastfeeding promotion programmes. We analysed a subsample of children under 2 years of age from the most recent Sri Lanka Demographic and Health Survey (SLDHS) to assess breastfeeding practices and factors associated with suboptimal practices. SLDHS 2006-2007 used a stratified two-stage cluster sample of ever-married women aged 15-49 years. Breastfeeding indicators were estimated for the last-born children (n = 2735). Selected indicators were examined against independent variables through cross-tabulations and multivariate analyses. Of the sample, 83.3% initiated breastfeeding within 1 h of birth. Continuation rates declined from 92.6% in first year to 83.5% in second year. Exclusive breastfeeding (EBF) rate under 6 months of age was 75.8%, with median duration being 4.8 months. Delayed initiation of breastfeeding was associated with low birthweight [odds ratio (OR) = 2.24] and caesarean delivery (OR = 3.30), but less likely among female infants (OR = 0.75), mothers from 'estate' sector (OR = 0.61) or richer wealth quintile (OR = 0.60). Non-EBF was associated with children from urban areas (OR = 1.72) and estate sector (OR = 4.48) and absence of post-natal visits by a public health midwife (OR = 1.89). A child was at risk for not currently breastfeeding if born in a private hospital (OR = 3.73), delivered by caesarean section (OR = 1.46) or lived in urban areas (OR = 2.80) or estate sector (OR = 3.23). Those living in estates (OR = 11.4) and not receiving post-natal home visits (OR = 2.62) were more likely to discontinue breastfeeding by 1 year. Breastfeeding indicators in Sri Lanka were higher compared with many countries and determined by socio-economic and health care system factors.     

From the Cover: The emergence of lineage-specific chromosomal topologies from coordinate gene regulation

Although the importance of chromosome organization during mitosis is clear, it remains to be determined whether the nucleus assumes other functionally relevant chromosomal topologies. We have previously shown that homologous chromosomes have a tendency to associate during hematopoiesis according to their distribution of coregulated genes, suggesting cell-specific nuclear organization. Here, using the mathematical approaches of distance matrices and coupled oscillators, we model the dynamic relationship between gene expression and chromosomal associations during the differentiation of a multipotential hematopoietic progenitor. Our analysis reveals dramatic changes in total genomic order: Commitment of the progenitor results in an initial increase in entropy at both the level of gene coregulation and chromosomal organization, which we suggest represents a phase transition, followed by a progressive decline in entropy during differentiation. The stabilization of a highly ordered state in the differentiated cell types results in lineage-specific chromosomal topologies and is related to the emergence of coherence—or self-organization—between chromosomal associations and coordinate gene regulation. We discuss how these observations may be generally relevant to cell fate decisions encountered by progenitor/stem cells.     

Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta

The metabolic syndrome, Type II (non-insulin-dependent) diabetes and obesity are associated with endothelial dysfunction and increased plasma concentrations of NEFAs (non-esterified fatty acids; free fatty acids). The present study was undertaken to define the inhibitory effects of saturated NEFAs on EDR (endothelium-dependent relaxation). Experiments were performed in rings of rabbit aorta to establish (i) dose-response relationships, (ii) the effect of chain length, (iii) the effect of the presence of double bonds, (iv) reversibility and time course of inhibition, and (v) the effect on nitric oxide production. Aortic rings were incubated (1 h) with NEFA-albumin complexes derived from lauric (C(12:0)), myristic (C(14:0)), palmitic (C(16:0)), stearic (C(18:0)) and linolenic (C(18:3)) acids. EDR induced by acetylcholine (0.1-10 mumol/l) was measured after pre-contraction with noradrenaline. Inhibition of EDR was dose-dependent (0.5-2 mmol/l NEFA), and the greatest inhibition (51%) was observed with stearic acid (2 mmol/l). Lauric acid had the smallest inhibitory effect. The inhibitory effects were always reversible and were evident after 15 min of incubation. Linolenic acid caused a significantly lower inhibition of EDR than stearic acid. SOD (superoxide dismutase) restored the inhibitory effect caused by NEFAs, suggesting the involvement of ROS (reactive oxygen species) in removing nitric oxide. The nitric oxide concentration measured after exposure of the rings to acetylcholine was lower after incubation with NEFAs than with Krebs buffer alone. This finding is consistent with removal of nitric oxide by ROS. This claim was supported by the demonstration of increased concentrations of nitrated tyrosine in the rings incubated with NEFAs.     

Genetic ablation of NADPH oxidase enhances susceptibility to cigarette smoke-induced lung inflammation and emphysema in mice

Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted ablation of components of NADPH oxidase (p47(phox) and gp91(phox)) would protect lungs against the detrimental effects of CS. To test this hypothesis, we exposed p47(phox-/-) and gp91(phox-/-) mice to CS and examined inflammatory response and injury in the lung. Surprisingly, although CS-induced ROS production was decreased in the lungs of p47(phox-/-) and gp91(phox-/-) mice compared with wild-type mice, the inflammatory response was significantly increased and was accompanied by development of distal airspace enlargement and alveolar destruction. This pathological abnormality was associated with enhanced activation of the TLR4-nuclear factor-kappaB pathway in response to CS exposure in p47(phox-/-) and gp91(phox-/-) mice. This phenomenon was confirmed by in vitro studies in which treatment of peritoneal macrophages with a nuclear factor-kappaB inhibitor reversed the CS-induced release of proinflammatory mediators. Thus, these data suggest that genetic ablation of components of NADPH oxidase enhances susceptibility to the proinflammatory effects of CS leading to airspace enlargement and alveolar damage.