Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Mechanism-specific injury biomarkers predict nephrotoxicity early following glyphosate surfactant herbicide (GPSH) poisoning(Elsevier, 2016) Mohamed, F.; Endre, Z.H.; Pickering, J.W.; Jayamanne, S.; Palangasinghe, C.; Shahmy, S.; Chathuranga, U.; Wijerathne, T.; Shihana, F.; Gawarammana, I.; Buckley, N.A.Acute kidney injury (AKI) is common following glyphosate surfactant herbicide (GPSH) self-poisoning. Serum creatinine (sCr) is the most widely used renal biomarker for diagnosis of AKI although a recent study in rats suggested that urinary kidney injury molecule-1 predicted AKI earlier and better after GPSH-induced nephrotoxicity. We explored the utility of a panel of biomarkers to diagnose GPSH-induced nephrotoxicity in humans. In a prospective multi-centre observational study, serial urine and blood samples were collected until discharge and at follow-up. The diagnostic performance of each biomarker at various time points was assessed. AKI was diagnosed using the Acute Kidney Injury Network (AKIN) definitions. The added value of each biomarker to sCr to diagnose AKI was assessed by the integrated discrimination improvement (IDI) metric. Of 90 symptomatic patients, 51% developed AKI and 5 patients who developed AKIN ≥ 2 died. Increased sCr at 8 and 16 hours predicted moderate to severe AKI and death. None of the 10 urinary biomarkers tested increased above normal range in patients who did not develop AKI or had mild AKI (AKIN1); most of these patients also had only minor clinical toxicity. Absolute concentrations of serum and urinary cystatin C, urinary interleukin-18 (IL-18), Cytochrome C (CytoC) and NGAL increased many fold within 8 hours in patients who developed AKIN ≥ 2. Maximum 8 and 16 hour concentrations of these biomarkers showed an excellent diagnostic performance (AUC-ROC ≥0.8) to diagnose AKIN ≥ 2. However, of these biomarkers only uCytoC added value to sCr to diagnose AKI when assessed by IDI metrics. GPSH-induced nephrotoxicity can be diagnosed within 24 hours by sCr. Increases in uCytoC and uIL-18 confirm GPSH-induces apoptosis and causes mitochondrial toxicity. Use of these biomarkers may help to identify mechanism specific targeted therapies for GPSH nephrotoxicity in clinical trials.Item Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion(Amsterdam, Elsevier/North Holland, 2015) Mohamed, F.; Buckley, N.A.; Jayamanne, S.; Pickering, J.W.; Peake, P.; Palangasinghe, C.; Wijerathna, T.; Ratnayake, I.; Shihana, F.; Endre, Z.H.Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning.Item Snake antivenom for snake venom induced consumption coagulopathy(Update Software, 2015) Maduwage, K.; Buckley, N.A.; de Silva, H.J.; Lalloo, D.G.; Isbister, G.K.BACKGROUND : Snake venom induced consumption coagulopathy is a major systemic effect of envenoming. Observational studies suggest that antivenom improves outcomes for venom induced consumption coagulopathy in some snakebites and not others. However, the effectiveness of snake antivenom in all cases of venom induced consumption coagulopathy is controversial. OBJECTIVES: To assess the effect of snake antivenom as a treatment for venom induced consumption coagulopathy in people with snake bite. SEARCH METHODS The search was done on 30 January 2015. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), three other sources, clinical trials registers, and we also screened reference lists.SELECTION CRITERIA : All completed, published or unpublished, randomised, controlled trials with a placebo or no treatment arm, where snake antivenom was administered for venom induced consumption coagulopathy in humans with snake bites. DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified trials and independently applied the selection criteria. MAIN RESULTS No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS Randomised placebo-controlled trials are required to investigate the effectiveness of snake antivenom for clinically relevant outcomes in patients with venom induced consumption coagulopathy resulting from snake bite. Although ethically difficult, the routine administration of a treatment that has a significant risk of anaphylaxis cannot continue without strong evidence of benefit.Item Formulation changes and time trends in outcome following paraquat ingestion in Sri Lanka(Informa Healthcare, 2011) Wilks, M.F.; Tomenson, J.A.; Fernando, R.; Ariyananda, P.L.; Berry, D.J.; Buckley, N.A.; Gawarammana, I.B.; Jayamanne, S.; Gunnell, D.; Dawson, A.INTRODUCTION: Deliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following the introduction of a new formulation with an increased emetic concentration, an alginate and a purgative in Sri Lanka. Further, formulation changes were introduced in October 2006; this study was designed to assess the impact of these changes on 6-week mortality following paraquat ingestion. METHODS: Prospective, cohort study of patients admitted with paraquat poisoning to 10 hospitals across Sri Lanka between September 2006 and September 2008. RESULTS: Overall, there was a significant (p < 0.001) increase in survival in the 533 patients included in this study compared to previous data (44.5 vs. 35.2% before September 2006 and 27.1% before October 2004). Patients ingesting the new INTEON formulation had a higher survival rate than those ingesting standard formulation (40.2 vs. 31.0%), but this effect was not statistically significant in Cox's proportional hazards model (hazard ratio 0.81, 95% CI 0.61?1.08 (unadjusted) and 1.17, 95% CI 0.82?1.68 (fully adjusted), respectively). CONCLUSIONS: This study has confirmed a continued improvement in survival of patients following self-harm with paraquat in Sri Lanka in recent years; however, in contrast to previous investigations, a beneficial effect associated with the INTEON formulation could not be substantiated. This may be partly due to the large number of patients in whom paraquat concentrations were too low for analytical confirmation of the formulation (n = 105) and who had a very high survival rate (86.7%).Item Delayed psychological morbidity associated with snakebite envenoming(Public Library of Science, 2011) Williams, S.S.; Wijesinghe, C.A.; Jayamanne, S.F.; Buckley, N.A.; Dawson, A.H.; Lalloo, D.G.; de Silva, H.J.INTRODUCTION: The psychological impact of snakebite on its victims, especially possible late effects, has not been systematically studied. OBJECTIVES: To assess delayed somatic symptoms, depressive disorder, post-traumatic stress disorder (PTSD), and impairment in functioning, among snakebite victims. METHODS: The study had qualitative and quantitative arms. In the quantitative arm, 88 persons who had systemic envenoming following snakebite from the North Central Province of Sri Lanka were randomly identified from an established research database and interviewed 12 to 48 months (mean 30) after the incident. Persons with no history of snakebite, matched for age, sex, geograpical location and occupation, acted as controls. A modified version of the Beck Depression Inventory, Post-Traumatic Stress Symptom Scale, Hopkins Somatic Symptoms Checklist, Sheehan Disability Inventory and a structured questionnaire were administered. In the qualitative arm, focus group discussions among snakebite victims explored common somatic symptoms attributed to envenoming. RESULTS: Previous snakebite victims (cases) had more symptoms than controls as measured by the modified Beck Depression Scale (mean 19.1 Vs 14.4; p<0.001) and Hopkins Symptoms Checklist (38.9 vs. 28.2; p<0.001). 48 (54%) cases met criteria for depressive disorder compared to 13 (15%) controls. 19 (21.6%) cases also met criteria for PTSD. 24 (27%) claimed that the snakebite caused a negative change in their employment; nine (10.2%) had stopped working and 15 (17%) claimed residual physical disability. The themes identified in the qualitative arm included blindness, tooth decay, body aches, headaches, tiredness and weakness. CONCLUSIONS: Snakebite causes significant ongoing psychological morbidity, a complication not previously documented. The economic and social impacts of this problem need further investigationItem Community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol(BioMed Central, 2011) Pearson, M.; Konradsen, F.; Gunnell, D.; Dawson, A.H.; Pieris, R.; Weerasinghe, M.; Knipe, D.W.; Jayamanne, S.; Metcalfe, C.; Hawton, K.; Wickremasinghe, A.R.; Atapattu, W.; Bandara, P.; de Silva, D.; Ranasinghe, A.; Mohamed, F.; Buckley, N.A.; Gawarammana, I.; Eddleston, M.A.BACKGROUND: The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. METHODS/DESIGN: A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. DISCUSSION: This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.Item Fetal effects of environmental exposure of pregnant women to organophosphorus compounds in a rural farming community in Sri Lanka(Informa Healthcare, 2008) Samarawickrema, N.; Pathmeswaran, A.; Wickremasinghe, R.; Peiris-John, R.; Karunaratna, M.; Buckley, N.A.; Dawson, A.; de Silva, J.BACKGROUND: The possible deleterious effects of low-grade, chronic environmental and occupational exposure to organophosphorus compounds (OPCs) are not well documented. OBJECTIVE: To investigate the possible effects of low-level, chronic exposure of pregnant mothers to OPCs on the fetus by measuring OPC levels, and using markers of OPC exposure, oxidative stress and oxidative tissue damage. METHODS: Toxicity was assessed by measuring (i) OPC levels in breast milk and plasma from maternal and cord blood using gas chromatography, (ii) maternal and fetal butyrylcholinesterase (BChE) activity using inhibition assays, (iii) antioxidant status of the fetus using superoxide dismutase activity assays, (iv) oxidative stress in the fetus by determining malondialdehyde (MDA) concentrations, and (v) examining for fetal DNA fragmentation using electrophoresis. Samples were obtained from consenting mothers living in a farming community in southern Sri Lanka at the end of the pesticide spray season (study group) and just before the commencement of the spray season (in-between spray season; control group). RESULTS: Organophosphate residues were detected in only two subjects (chlorpyrifos in maternal and cord blood of one during the spray season and dimethoate in breast milk of another during the in between spray season), but the test employed was capable of only detecting concentrations above 0.05 mg/l. However, cord blood obtained during the spray season showed significant inhibition of BChE activity, increased oxidative stress and more DNA fragmentation when compared with cord blood obtained during the in-between spray season. CONCLUSIONS: Inhibition of cord blood BChE activity indicates fetal exposure to organophosphorus compounds during times when there is a high probability of environmental drift. This provides a plausible explanation for the increased oxidative stress and high DNA fragmentation in the fetus. Long-term outcomes of such exposures are unknown.