Low dose isoflurane exerts opposing effects on neuronal network excitability in neocortex and hippocampus.

The anesthetic excitement phase occurring during induction of anesthesia with volatile anesthetics is a well-known phenomenon in clinical practice. However, the physiological mechanisms underlying anesthetic-induced excitation are still unclear. Here we provide evidence from in vitro experiments performed on rat brain slices that the general anesthetic isoflurane at a concentration of about 0.1 mM can enhance neuronal network excitability in the hippocampus, while simultaneously reducing it in the neocortex. In contrast, isoflurane tissue concentrations above 0.3 mM expectedly caused a pronounced reduction in both brain regions. Neuronal network excitability was assessed by combining simultaneous multisite stimulation via a multielectrode array with recording intrinsic optical signals as a measure of neuronal population activity.

Relationship between blood alcohol concentration on admission and outcome in dimethoate organophosphorus self-poisoning.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Acute alcohol intoxication often complicates acute organophosphorus pesticide poisoning. * No data are available on how alcohol intoxication affects outcome in acute organophosphorus pesticide poisoning. * In particular, the relationships between plasma alcohol concentration and plasma organophosphorus concentration or outcome are unclear. WHAT THIS STUDY ADDS: * Alcohol co-ingestion is associated with higher concentrations of the organophosphorus insecticide dimethoate, probably due to larger ingestions. * The higher concentrations of dimethoate found with alcohol co-ingestion increase the risk of death in dimethoate poisoning. There was no detectable effect of the alcohol itself on outcome. * Efforts to reduce deaths from insecticide self-poisoning may benefit from concurrent efforts to reduce alcohol consumption. AIMS: Many patients acutely poisoned with organophosphorus insecticides have co-ingested alcohol. Although clinical experience suggests that this makes management more difficult, the relationship between plasma concentration of alcohol and insecticide is unknown. We aimed to determine whether acute intoxication results in ingestion of larger quantities of insecticide in dimethoate self-poisoning and a worse clinical outcome. METHODS: We set up a prospective study of acute dimethoate self-poisoning in Sri Lankan district hospitals. An admission plasma sample was analysed to identify the ingested insecticide; in patients with detectable dimethoate, plasma alcohol was measured. RESULTS: Plasma from 37 of 72 (51.4%) dimethoate-poisoned patients had detectable alcohol [median concentration 1.10 g l(-1)[110 mg dl(-1)][interquartile range (IQR) 0.78-1.65]] a median of 3 h post ingestion. The median plasma dimethoate concentration was higher in patients who had ingested alcohol [479 micromol l(-1) (IQR 268-701) vs. 145 micromol l(-1) (IQR 25-337); P < 0.001]. Plasma dimethoate concentration was positively correlated with plasma alcohol (Spearman's rho= 0.34; P= 0.0032). The median alcohol concentration was higher in the 21 patients who died compared with survivors (0.94 vs. 0.0 g l(-1), P= 0.018). Risk of death was greater amongst individuals who consumed alcohol [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.2, 16.4]; this risk was abolished by controlling for dimethoate concentration (OR 0.3, 95% CI 0.0, 8.8), indicating that deaths were not due to the direct toxic effects of alcohol. CONCLUSIONS: Alcohol co-ingestion is associated with higher plasma concentrations of dimethoate and increased risk of death. Larger studies are required to assess this finding's generalizability, since efforts to reduce deaths from self-poisoning may benefit from concurrent efforts to reduce alcohol consumption.

Isoflurane and sevoflurane dose-dependently impair hippocampal long-term potentiation.

Isoflurane and sevoflurane are commonly used volatile anaesthetics. Although acting via similar cellular mechanisms, the effect of different volatile anaesthetics on synaptic plasticity might differ. In the present study, using acute murine brain slice preparations, we compared the effects of isoflurane and sevoflurane on synaptic transmission and synaptic plasticity (long-term potentiation, LTP) in the CA1 stratum radiatum of the hippocampus. Isoflurane and sevoflurane dose-dependently diminished excitatory postsynaptic field potentials. In the presence of isoflurane (sevoflurane) at concentrations of 0.19, 0.28 and 0.37mM (0.11, 0.21 and 0.42mM), which correspond to 0.7-, 1.0- and 1.4-fold (0.3-, 0.6- and 1.1-fold) minimum alveolar concentration (MAC), high frequency stimulation reliably induced LTP. When isoflurane (sevoflurane) was applied at concentrations of 0.56 and 0.74mM (0.63 and 0.84mM), which equal 2.1- and 2.7-fold (1.7- and 2.2-fold) MAC, LTP was blocked. Our results indicate, that both anaesthetics influence synaptic strength to a similar degree, with only high concentrations blocking hippocampal CA1 stratum radiatum long-term potentiation.

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.

Determination of botulinum toxins after peptic sample pre-treatment by multidimensional nanoscale liquid chromatography and nano-electrospray ion-trap mass spectrometry.

Botulinum neurotoxin types A to G are produced from different strains of Clostridium botulinum. The complex neurotoxins belong to the most toxic substances known and cause botulism both in humans and animals. Botulinum toxin complexes are produced with molecular weights of 300, 500 and 900 kDa. These large protein complexes contain beside the toxic zinc protease of 150 kDa, additional neurotoxin associated proteins, which are responsible for the extreme pH and protease stability. In this study we present for the first time a rugged detection method of botulinum toxins at femtomole levels in complex culture media after peptic sample pre-treatment and 2D-nano-LC-ESI-MS-MS-technique. In contrast to other studies, we used progenitor toxins directly from culture supernatant of C. botulinum strains A, B, E and F without further purification, to simulate complex, protein-containing sample conditions. We were able to demonstrate, that peptic pre-treatment is a great challenge in reducing ubiquitous proteins as well as proteins from suspicious samples. The study also found that multidimensional chromatography leads to significant better peptide differentiation and identification in protein loaded matrices than one dimensional nano-LC-ESI-MS.

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims.

4-Hydroxy-l-(3-pyridyl)-l-butanone (HPB)-releasing adducts are formed by metabolic activation of N'-nitrosonornicotine and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone and have been proposed as specific biomarkers for exposure to tobacco smoke. However, in several studies hemoglobin adducts releasing HPB were on average less than threefold higher in smokers compared to nonsmokers. Using an improved analytical method we have recently found a sevenfold difference in DNA adduct levels in the lung from smoking and nonsmoking lung cancer patients. In the present study we extended the determination of HPB-releasing DNA adducts by gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NICI-MS) to samples of peripheral lung, lower esophagus and cardia from tumor-free sudden death victims (primarily road traffic accidents, suicide and sudden cardiac arrest). The donors were classified as either current smokers or nonsmokers based on cotinine in either blood or urine (cut-off values for active smoking: >15 ng cotinine/ml blood or >100 ng cotinine/ml urine). Contrary to our expectation, DNA adduct levels (fmol HPB/mg DNA) in lung tissue from tumor-free smokers (N=32, 92+/-148) were not significantly different from values in nonsmokers (N=56, 61+/-66). The values in tumor-free smokers were on average more than fourfold lower compared to smoking lung cancer patients in our previous study. Adduct levels in the mucosa of esophagus (N=82; 133+/-160) and cardia (N=30; 108+/-102) of sudden death victims did not show any difference according to the current smoking status. HPB-releasing DNA adduct levels in cardia and esophagus were significantly correlated (N=29; Spearman r=0.609; p<0.001). In contrast, adduct levels in lung did not correlate with either esophagus (77 cases) or cardia (28 cases). Further studies are necessary to elucidate the discrepancies in lung DNA adduct levels in smokers with or without lung cancer and to identify obvious additional sources other than tobacco for these adducts.

Frequency of different anti-depressants associated with suicides and drug deaths.

From each case of suicide and drug-related death autopsied in the Institute of Forensic Medicine, Munich during the years 2001--2005, a toxicological investigation on anti-depressants (AD) was performed. In 180 suicides and 72 narcotic drug death cases, ADs were detected: 4 different classic tricyclic anti-depressants (TCAs), 6 other non-selective monoamine re-uptake inhibitors (NSMRIs), 5 selective serotonin re-uptake inhibitors (SSRIs) and 3 other ADs. The suicides were grouped further according to the type of suicide (violent or non-violent). The prescription frequency of the ADs in Germany, expressed as the defined daily dosages (DDDs), during the investigated years served for comparison. There were serious differences in the frequency of different ADs regarding to the manner of suicide. In cases associated with doxepin and trimipramine, non-violent suicides were distinctly over-represented, as in cases in which the drug itself was responsible for the death as in cases of non-violent suicides in other manners. In contrast, in cases with citalopram or opipramol, violent forms of suicides were significantly over-represented. For amitriptyline, the ratio was approximately balanced. For the remainder of the ADs, the case numbers were too low for a valid evaluation. The different frequency distributions of the ADs, associated with violent and non-violent suicides may be explained by their different pharmacological active profiles and the different lethality of overdoses of the different ADs. There was no indication at all for a special suicidal problem of SSRIs in juveniles. Amongst 1,127 suicides within 5 years, in an area with approximately 5 million people, the youngest suicide victim with SSRIs was 28 years old. In drug death cases, citalopram was obviously over-represented.

Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study.

BACKGROUND: Although more than 100 organophosphorus insecticides exist, organophosphorus poisoning is usually regarded as a single entity, distinguished only by the compound's lethal dose in animals. We aimed to determine whether the three most common organophosphorus insecticides used for self-poisoning in Sri Lanka differ in the clinical features and severity of poisoning they cause. METHODS: We prospectively studied 802 patients with chlorpyrifos, dimethoate, or fenthion self-poisoning admitted to three hospitals. Blood cholinesterase activity and insecticide concentration were measured to determine the compound and the patients' response to insecticide and therapy. We recorded clinical outcomes for each patient. FINDINGS: Compared with chlorpyrifos (35 of 439, 8.0%), the proportion dying was significantly higher with dimethoate (61 of 264, 23.1%, odds ratio [OR] 3.5, 95% CI 2.2-5.4) or fenthion (16 of 99, 16.2%, OR 2.2, 1.2-4.2), as was the proportion requiring endotracheal intubation (66 of 439 for chlorpyrifos, 15.0%; 93 of 264 for dimethoate, 35.2%, OR 3.1, 2.1-4.4; 31 of 99 for fenthion, 31.3%, 2.6, 1.6-4.2). Dimethoate-poisoned patients died sooner than those ingesting other pesticides and often from hypotensive shock. Fenthion poisoning initially caused few symptoms but many patients subsequently required intubation. Acetylcholinesterase inhibited by fenthion or dimethoate responded poorly to pralidoxime treatment compared with chlorpyrifos-inhibited acetylcholinesterase. INTERPRETATION: Organophosphorus insecticide poisoning is not a single entity, with substantial variability in clinical course, response to oximes, and outcome. Animal toxicity does not predict human toxicity since, although chlorpyrifos is generally the most toxic in rats, it is least toxic in people. Each organophosphorus insecticide should be considered as an individual poison and, consequently, patients might benefit from management protocols developed for particular organophosphorus insecticides.