Pralidoxime in Acute Organophosphorus Insecticide Poisoning-A Randomised Controlled Trial

Background: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. Methods and Findings: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio HR] 1.69, 95% confidence interval CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 21.5%], placebo 24/114 21.1%], adjusted HR 1.27 95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Conclusions: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required

Comparative Economic Evaluation of Haemophilus influenzae Type b Vaccination in Belarus and Uzbekistan

BACKGROUND: Hib vaccine has gradually been introduced into more and more countries during the past two decades, partly due to GAVI Alliance support to low-income countries. However, since Hib disease burden is difficult to establish in settings with limited diagnostic capacities and since the vaccine continues to be relatively expensive, some Governments remain doubtful about its value leading to concerns about financial sustainability. Similarly, several middle-income countries have not introduced the vaccine. The aim of this study is to estimate and compare the cost-effectiveness of Hib vaccination in a country relying on self-financing (Belarus) and a country eligible for GAVI Alliance support (Uzbekistan). METHODS AND FINDINGS: A decision analytic model was used to estimate morbidity and mortality from Hib meningitis, Hib pneumonia and other types of Hib disease with and without the vaccine. Treatment costs were attached to each disease event. Data on disease incidence, case fatality ratios and costs were primarily determined from national sources. For the Belarus 2009 birth cohort, Hib vaccine is estimated to prevent 467 invasive disease cases, 4 cases of meningitis sequelae, and 3 deaths, while in Uzbekistan 3,069 invasive cases, 34 sequelae cases and 341 deaths are prevented. Estimated costs per discounted DALY averted are US$9,323 in Belarus and US$ 267 in Uzbekistan. CONCLUSION: The primary reason why the cost-effectiveness values are more favourable in Uzbekistan than in Belarus is that relatively more deaths are averted in Uzbekistan due to higher baseline mortality burden. Two other explanations are that the vaccine price is lower in Uzbekistan and that Uzbekistan uses a three dose schedule compared to four doses in Belarus. However, when seen in the context of the relative ability to pay for public health, the vaccine can be considered cost-effective in both countries

Coenzyme Q10 Reduces Ethanol-Induced Apoptosis in Corneal Fibroblasts

Dilute ethanol (EtOH) is a widely used agent to remove the corneal epithelium during the modern refractive surgery. The application of EtOH may cause the underlying corneal fibroblasts to undergo apoptosis. This study was designed to investigate the protective effect and potential mechanism of the respiratory chain coenzyme Q10 (CoQ10), an electron transporter of the mitochondrial respiratory chain and a ubiquitous free radical scavenger, against EtOH-induced apoptosis of corneal fibroblasts. Corneal fibroblasts were pretreated with CoQ10 (10 µM) for 2 h, followed by exposure to different concentrations of EtOH (0.4, 2, 4, and 20%) for 20 s. After indicated incubation period (2–12 h), MTT assay was used to examine cell viability. Treated cells were further assessed by flow cytometry to identify apoptosis. Reactive oxygen species (ROS) and the change in mitochondrial membrane potential were assessed using dichlorodihydrofluorescein diacetate/2′,7′-dichlorofluorescein (DCFH-DA/DCF) assays and flow-cytometric analysis of JC-1 staining, respectively. The activity and expression of caspases 2, 3, 8, and 9 were evaluated with a colorimetric assay and western blot analysis. We found that EtOH treatment significantly decreased the viability of corneal fibroblasts characterized by a higher percentage of apoptotic cells. CoQ10 could antagonize the apoptosis inducing effect of EtOH. The inhibition of cell apoptosis by CoQ10 was significant at 8 and 12 h after EtOH exposure. In EtOH-exposed corneal fibroblasts, CoQ10 pretreatment significantly reduced mitochondrial depolarization and ROS production at 30, 60, 90, and 120 min and inhibited the activation and expression of caspases 2 and 3 at 2 h after EtOH exposure. In summary, pretreatment with CoQ10 can inhibit mitochondrial depolarization, caspase activation, and cell apoptosis. These findings support the proposition that CoQ10 plays an antiapoptotic role in corneal fibroblasts after ethanol exposure

Three dimensional electron microscopy reveals changing axonal and myelin morphology along normal and partially injured optic nerves

Following injury to the central nervous system, axons and myelin distinct from the initial injury site undergo changes associated with compromised function. Quantifying such changes is important to understanding the pathophysiology of neurotrauma; however, most studies to date used 2 dimensional (D) electron microscopy to analyse single sections, thereby failing to capture changes along individual axons. We used serial block face scanning electron microscopy (SBF SEM) to undertake 3D reconstruction of axons and myelin, analysing optic nerves from normal uninjured female rats and following partial optic nerve transection. Measures of axon and myelin dimensions were generated by examining 2D images at 5 µm intervals along the 100 µm segments. In both normal and injured animals, changes in axonal diameter, myelin thickness, fiber diameter, G-ratio and percentage myelin decompaction were apparent along the lengths of axons to varying degrees. The range of values for axon diameter along individual reconstructed axons in 3D was similar to the range from 2D datasets, encompassing reported variation in axonal diameter attributed to retinal ganglion cell diversity. 3D electron microscopy analyses have provided the means to demonstrate substantial variability in ultrastructure along the length of individual axons and to improve understanding of the pathophysiology of neurotrauma

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Case Report - Cardiomediastinal Tamponade and Shock Following Three-Stage Transthoracic Oesophagectomy

Massive gastric tube dilatation causing cardiomediastinal tamponade is an unusual cause of obstructive shock after transthoracic oesophagectomy. A 55-year-old female was operated for total transthoracic oesophagectomy. Twelve hours after the surgery, she developed hypotension and raised central venous pressure unresponsive to fluid infusion and ionotropes. X-ray chest showed a massively dilated stomach, which was causing intrathoracic tamponade. Suction applied to the nasogastric tube led to aspiration of 150-200 ml of fluid and a large volume of air, which led to resolution of the haemodynamic instability. A simple manoeuvre like nasogastric suction in postoperative case of oesophagectomy can serve as a diagnostic as well as therapeutic tool. It must be performed before resorting to invasive and expensive examination or intervention