Systematic account of animal poisonings in Germany, 2012-2015.

A systematic retrospective study on animal poisonings in Germany (wildlife excluded) between January 2012 and December 2015 was conducted. Data were collected on animal exposure calls to German poison centres, poisoning cases presenting to the University of Veterinary Medicine, Hannover Small Animal and Equine Clinics, cases involving off-label use of veterinary medicinal products reported to the Federal Office of Consumer Protection and Food Safety and toxicological submissions to the Institute of Pharmacology, Toxicology, and Pharmacy, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munich. Descriptive statistics were used to characterise animal type, exposure reason, type and substance, year/month of exposure, case severity and outcome. An evaluation of the data and data sources was also carried out. Variation in poisoning patterns was seen. However, dogs and cats were the most frequently reported species and medicinal products, pesticides and plants were consistently implicated as top causes of poisoning. Advantages and disadvantages were associated with each data source; bias was found to be an important consideration when evaluating poisoning data. This study provided useful information on animal poisonings in Germany and highlights the need for standardised approaches for the collection, evaluation and integration of poisoning data from multiple sources.

[Mass poisoning events]. / Massenvergiftungen.

BACKGROUND: Mass poisoning events are rare and different in some respects from other mass casualties, especially with regard to diagnosis and triage. OBJECTIVES: Based on the description of important historical events and experiences of poison control centers, an overview is provided for different types of mass poisoning events as well as guidelines for specific medical management. MATERIALS AND METHODS: The review is based on a literature search and case reports notified to the Giftinformationszentrum-Nord Poisons Center. RESULTS: Toxicological risk assessment is based on identification of all relevant agents, evaluation of their toxic hazards (toxicity), and evaluation of the exposure (dose and pathway) for all persons exposed. This risk assessment constitutes the basis of medical diagnosis and management. In cases of suspicion of poisoning or poisonings caused by illegal drugs, risk assessment may be difficult due to the lack of important data needed for risk assessment. Mass poisonings caused by ethanol or contaminated food are well understood, with therapy being mainly symptomatic. However, in rare poisonings by other agents, a specific antidote treatment may be important. Thus, adequate antidote supplies must be available for these events. CONCLUSION: As hardly any medical professional has personal practical knowledge of mass poisoning casualties, such events are unique experiences. Thorough preparation and intensive cooperation with poison control centers and-if applicable-public health authorities may be important for best practice event management.

Entry of tromethamine into the cerebrospinal fluid of humans after cerebrovascular events.

OBJECTIVE: The intravenous administration of tromethamine (INN, trometamol) lowers the intracranial pressure in patients with brain edema. One postulated mechanism of action is the increase of the pH of the cerebrospinal fluid. METHODS: To study tromethamine kinetics in serum and cerebrospinal fluid, nine patients with external ventriculostomies and normal serum creatinine values received 60 mmol intravenous tromethamine (Tris 36.34%, pH 11) over 30 minutes. Serum and cerebrospinal fluid were drawn repeatedly, and concentrations were determined by HPLC. RESULTS: Maximum serum concentrations (Cmax) ranged from 211 to 426 mg/L (median, 302 mg/L). The volume of distribution was 0.34 to 0.86 L/kg body weight (median, 0.53 L/kg), and the elimination half-life in serum (t1/2beta) 3.22 to 8.44 hours (median, 4.53 hours). Cerebrospinal fluid Cmax values ranging from 0.68 to 34.14 mg/L (median, 3.88 mg/L) were observed 1 to 12 hours after the end of the tromethamine infusion (median, 2 hours). AUC(CSF)/AUC(S) as a measure of overall cerebrospinal fluid penetration was 0.015 to 0.46 (median, 0.068). Cerebrospinal fluid Cmax and AUC(CSF)/AUC(S) depended on the function of the blood-cerebrospinal fluid barrier. Cerebrospinal fluid t1/2 (8.52 to 14.2 hours; median, 11.2 hours) was substantially longer than the t1/2beta in serum. In vitro, cerebrospinal fluid concentrations < or =30 mg/L did not influence cerebrospinal fluid pH. CONCLUSION: Tromethamine cerebrospinal fluid concentrations will be high enough to increase the pH of the cerebrospinal fluid only at large doses and in patients with a pronounced disruption of the blood-cerebrospinal fluid barrier.

Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures.

Numerous xenobiotics are capable of inducing their own metabolism and by enzyme induction can also lead to enhanced biotransformation of other xenobiotics. In this project, we examined the influence of pyrethroids (permethrin, cypermethrin, and fenvalerate) on the expression and activity of the phenobarbital (PB)-inducible cytochrome P450 2B1 isoform (CYP2B1) in primary rat hepatocyte cultures. Incubation of hepatocyte cultures with pyrethroids resulted in a marked CYP2B1 induction. Among the tested pyrethroids, permethrin elicited the most pronounced induction of CYP2B1 mRNA, which exceeded maximal induction achieved by PB at concentrations approximately 10-fold higher. Furthermore, permethrin induced CYP3A1 mRNA expression, while the expression of the CYP1A1 isoform, which in vivo is not responsive to PB treatment, was not significantly affected by pyrethroids. Permethrin-dependent enhancement of CYP2B1 and CYP3A1 mRNA expression was repressed by the hepatotrophic cytokine epidermal growth factor, which is known to also inhibit PB-dependent induction of CYP2B1. Several metabolites of permethrin formed by hepatocytes (3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid) were ineffective in inducing CYP2B1 mRNA. Furthermore, permethrin stimulated the expression of the luciferase reporter gene under control of the CYP2B1 promoter (comprising the PB-responsive enhancer module) in transiently transfected primary hepatocyte cultures. Thus, permethrin-stimulated gene expression occurred on the transcriptional level. Taken together, these results indicate that the pyrethroid permethrin is a PB-like inducer. Due to its superior potency in induction, permethrin appears as a useful substance for mechanistic studies to elucidate the mechanism of enzyme induction by phenobarbital.

Separation and characterisation of light scattering transients from rod outer segments of vertebrate photoreceptors: design and performance of a Multi Angle Flash Photolysis Apparatus (MAFPA).

A device was built for the simple computer-controlled routine determination of the angular dependence of light scattering transients obtained from biological material. It was called Multi Angle Flash Photolysis Apparatus (MAFPA). The MAFPA allows the simultaneous registration of rapid, light-induced light scattering transients at eight scattering angles between 0 degree and 28 degrees. In typical applications changes in scattered light intensity as small as delta I/I = 4 X 10(-5) can be resolved at scattering angles less than 24 degrees, while at 28 degrees the resolution drops to delta I/I = 2 X 10(-4). The time resolution is 32 microseconds. The MAFPA was designed for high accuracy, ease of use and ruggedness. It is made from relatively inexpensive parts and can be copied fairly easily by a good machine/electronics shop. In this communication we describe the design of the MAFPA and how it was used for the characterisation of four structurally distinct light-induced light scattering signals from photoreceptor rod outer segments. These signals are known as P (or binding) signal, G- (or dissociation) signal, N (or rhodopsin) signal and as the ATP-dependent signal AL. The signals have been separated by means of their different angular dependence, their different saturation behavior and nucleotide requirement. A great number of detailed studies will have to be carried out before one can fully understand the physical and biochemical origin of these signals. At this point, however, it can be stated that the so-called 'dissociation signal', showing an angular dependence indicative of a change in refractive index or scattering mass, is not merely an inversion of the preceding 'binding signal', the latter clearly reflecting a gross structural change, i.e. a shrinkage of the disks. Moreover, there are conditions where P signals are observed to persist even after the completion of the subsequent dissociation signals. The two remaining signals N and AL show a pronounced angular dependence which is not easily interpreted. The fact that both exhibit a maximal amplitude at relatively small angles seems to indicate the participation of rather large structural domains.

A polychromatic flash photolysis apparatus (PFPA).

A wide variety of biologically relevant chemical intermediates have been identified and characterised by their spectral properties. When rapid kinetics, i.e. rapid changes in these spectral properties are studied, the equipment designed for these studies (flash photolysis-, T-jump apparatus) usually allows only the registration of intensity changes of the monitoring light beam at one particular wavelength. Quite frequently, however, particularly in biological systems, the reactions of interest are too complex to be fully understood using single wavelength techniques. We have therefore designed and built a flash photolysis apparatus which permits the simultaneous recording of absorbance changes at 32 wavelengths, freely selectable between 300 and 1000 nm, as well as changes in fluorescence, luminescence, birefringence and light scattering. The apparatus, which we have called Polychromatic Flash Photolysis Apparatus (PFPA), acquires up to 8000 difference spectra per second with an amplitude resolution of better than 0.0001 absorbance unit. Data acquisition and activation of an actinic xenon flash unit occurs under computer control. The same computer is responsible for data storage, handling and graphic display. This communication describes the PFPA, its performance, and, as a demonstration of its potential usefulness, its application to the measurement of the light driven photocycle of bacterial rhodopsin, the proton pumping protein of Halobacterium halobium.

A simple and rapid procedure for the isolation of intact bovine rod outer segments (ROS).

A method is described which allows the rapid isolation and purification of intact rod outer segments (ROS) from cattle eyes. It requires very fresh retinal material and can be completed within less than 2 h of the death of the animals. Cattle eyes are dissected in the usual manner, the retinae are isolated and the ROS are separated from the rest of the retina by gentle vortexing and filtration through a nylon mesh. The resulting crude ROS suspension is purified on a discontinuous sucrose density gradient. Two fractions are obtained, the major one consisting of mostly intact ROS, the minor one of RIS-ROS, i.e. of ROS which are still connected to part of their inner segment. The ROS are washed once and can be stored on ice for several days without loosing their intact plasma membrane. They can be transformed to leaky ROS by a quick freeze/thawing cycle or, if one wants unobstructed access to the interdiskal space, they can be subjected to a mild lysis treatment. The resulting ROS material is characterised using light microscopy, electron microscopy, light scattering, gel electrophoresis and absorption spectroscopy. It contains unusually low levels of 48k-protein and very high levels of G-protein. The latter cannot be washed out in the presence of GTP-gamma-S, even in the case of leaky ROS.

Optical probes of intradiskal processes in rod photoreceptors. II: Light-scattering study of ATP-dependent light reactions.

Rod outer segment (ROS) disks, either stacked or freely floating, respond to flash illumination to yield a specific, ATP-dependent, light-scattering signal AL. In broken ROS AL signals occur only when AD signals have preceded them. The degree to which the preceding AD signal has been completed determines the amplitude of the following AL signal. However, in freshly detached ROS from dark-adapted frogs Al signals with maximal size can be obtained without pre-incubation with exogenous ATP. The energized state, which is restored in broken ROS with the help of ATP, appears to prevail in the living retina and must therefore be considered to be "physiological". AL signals require structurally intact disks. Neither peripheral ROS proteins nor connecting filaments between adjacent disks are necessary. Their structural origin is the same as that of the preceding AD signal, i.e. osmotic disk swelling. AL signals consist of a single slow kinetic component (half-life 10 s at room temperature) and multiphase fast kinetic component (70 ms). The slow phase corresponds to a light-stimulated resumption of ATPase activity (this has been dealt with in a previous paper) whereas the fast component reflects an immediate response of the energized disk to the metarhodopsin I to metarhodopsin II transition. The latter effect is the subject of this paper. A variety of experiments, using different ATPase inhibitors, ionophores and membrane-permeable salts, have been carried out; they are all consistent with notion that AL originates in the disk interior and probes the existence of a proton electrochemical potential difference delta mu (H+) across the disk membrane. A model is presented which can explain all given properties of AL satisfactorily. According to this model the photolysis of rhodopsin causes a proton release in the disk lumen. This, in turn, results in osmotic swelling of the disks, provided that the internal buffer sites have been (at least partially) titrated with protons prior to the flash. Such conditions, i.e. a low internal pH, are provided by the proton transport across the disk membrane, which presumably takes place during the course of the preceding AD signal.

Optical probes of intradiskal processes in rod photoreceptors. I: Light-scattering study of ATP-dependent dark reactions.

ATP can cause dramatic structural changes in the outer segment of rod photoreceptors. These changes can be visualized by means of a concomitant light-scattering signal AD, a decrease in scattered light intensity of over 20%. The large size of the signal suggests that major structural changes occur. The underlying molecular events may reflect an important, yet still unknown, part of the photoreceptor machinery. AD signals reflect ATPase-driven transmembrane events which occur in and at the disk membrane. Their only structural prerequisite is the structural integrity of the disk compartment. The angular dependence of AD, which can be mimicked by an osmotically-induced disk-swelling, suggests that the disk compartment swells during the production of the AD signal. AD signals proceed with first-order kinetics (half-life = 1 min at 20 degrees C and ATP concentrations of greater than 100 microM) and are accompanied by the hydrolysis of approximately 4 mol ATP (mol rhodopsin)-1. The AD signal is inhibited by a number of transport ATPase inhibitors (quercetin, NBD.Cl, vanadate, DCCD), but not by oligomycin, azide and ouabain. The sensitivity to DCCD, together with the fact that except magnesium no other cation has to be present, points to a proton translocation. This proton transport appears to be electrogenic, since AD signals require the presence of a permeant anion. In physiological saline this is chloride, and the chloride flux is facilitated by a DIDS-sensitive anion transport unit in the disk membrane.

Determination of 2-hydroxyphenylacetic acid (2HPAA) in urine after oral and parenteral administration of coumarin by gas-liquid chromatography with flame-ionization detection.

The urinary excretion of 2-hydroxyphenylacetic acid (2HPAA) was studied in human volunteers after oral and parenteral doses of coumarin. The presence of 2HPAA in the urine was confirmed by gas chromatography mass spectroscopy (GC MS). Mass spectra of reference material and samples are presented. The determination of 2HPAA was carried out by GC with flame-ionization detection. Prior to analysis samples were extracted into ethyl ether and the analytes were derivatized with trimethlyphenylammonium hydroxide. A calibration range from 0.3 to 150 micrograms ml-1 was established using 3-hydroxyphenyl acetic acid (3HPAA) as an internal standard. On average less than 10% of the coumarin administered were excreted into the urine in the form of 2HPAA.

[Cocaine-body-packing. Infrequent indication for laparotomy]. / Kokain-body-packing. Seltene Indikation zur Laparotomie.

INTRODUCTION: Body-packers or "mules" are drug smugglers who swallow cocaine-filled condoms in order to conceal them during air travel. Body pushers hide drug packages in the rectum or vagina. In a cooperative effort between the Frankfurt Airport Clinic and the GIZ-Nord (Goettingen University poison control center), we performed a retrospective study and developed an algorithm for the problem of "rupture of a cocaine-filled condom in a body-packer." METHODS: In a retrospective analysis, the data of all cocaine body-packers and body pushers who were identified at Frankfurt International Airport from 1985 to 2001 were evaluated.Temporal development, demographic data, and surgical aspects were of special interest. RESULTS: From 1985 to 2001 a total of 280 body pushers and 2880 body-packers were identified: 63 "mules" (2.2%) developed symptoms of severe cocaine intoxication following rupture of a condom. Emergency laparotomy was performed on 20 patients (i.e., 32% of all symptomatic body-packers) and the condoms were removed, while 43 body-packers (68%) died before surgical therapy could be initiated. All operated patients survived. CONCLUSION: Severe cocaine intoxication is life threatening. Patients die from complications caused by generalized vasoconstriction. If the reason for severe cocaine intoxication is the rupture of a cocaine-filled condom,the only possible therapy consists of immediate laparotomy for removal of the condoms.

[Ethanol ingestion following Antabus overdose: acetaldehyde-induced cardiological emergency]. / Ethanolaufnahme nach Antabus-Uberdosierung: Acetaldehyd-induzierter kardiologischer Notfall.

The differential diagnosis of chest pain is challenging, when the clinical presentation appears pathognomonic, yet conventional diagnostic tests fail to reveal the suspected cause. We report the case of a 38-year-old patient who had an acetaldehyde intoxication (antabuse syndrome) in the setting of disulfiram overdose and ethanol ingestion. The patient presented with severe angina pectoris. Coronary artery disease was suspected, because the patient had risk factors and electrocardiographic repolarization changes were present. During the further investigation it became evident that symptoms were solely caused by acetaldehyde intoxication following disulfiram and alcohol ingestion. Toxic levels of acetaldehyde were found in the patient's serum. Coronary artery disease was ruled out by cardiac catheterization.

[Toxicological analysis. Methodology, indication, and evaluation]. / Toxikologische Analytik. Methodik, Indikation und Bewertung.

Clinical toxicological analysis can significantly contribute toward the confirmation or exclusion of poisoning, especially if clinical signs and symptoms of unknown origin have to be explained. It may be of help when planning specific, but risky, poisoning therapies. Besides frequently used immunoassays for the detection of drugs of abuse, of a small number of medical drugs, and of amatoxins. Chromatographic methods with mass-selective detectors are available in specialized toxicology laboratories. The results of toxicological analyses have to be evaluated and interpreted carefully. Poison control centers can offer support for all medical aspects of poisoning including lab investigations.

Harmonisation of product notification to Poisons Centres in EU Member States.

INTRODUCTION: In the European Union (EU), notification of product information by industry to poisons centres and/or competent authorities is a legal obligation for mixtures classified as hazardous. However, EU legislation does not specify the precise information needed for this product notification. As a consequence, varying requirements have been developed in different EU Member States. The European Commission (EC) carried out an assessment of whether harmonisation of product notification can be achieved. This manuscript provides an overview of the most important (discussion) points to reach harmonisation. COMPOSITION AND CONCENTRATION OF INGREDIENTS: Discussions have focused mainly on whether non-classified ingredients should be notified only above a concentration threshold and on the use of defined, narrow concentration ranges instead of exact concentrations for hazardous ingredients. ELECTRONIC DATA EXCHANGE FORMAT: All stakeholders agree to the development of an electronic data exchange format for product notification and identify the eXtensible Markup Language (XML) as the most appropriate format. EUROPEAN PRODUCT DATABASE: Instead of multiple notifications to national databases, the EC will analyse the benefits, feasibility and costs of a European product database to provide a centralised portal for companies to upload their product information. Poisons centres and competent authorities need to have access to this information. UNIQUE PRODUCT IDENTIFIER: A Unique Product Identifier (UPI) on the product label can unambiguously identify the product and its formula and links it to the corresponding notified product information. A procedure for the creation of a UPI by companies has already been proposed. PRODUCT CATEGORY SYSTEM: There is broad support for the development of a hierarchical product category system to facilitate statistical analyses and comparability of poisoning incidents in EU Member States. OUTLOOK: Following a 3-year assessment period, the EC concluded that harmonisation of product notification is an achievable goal. In order to draft an Annex to the CLP Regulation concerning this topic, a new working group with representatives of EU Member States, European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) and other stakeholders will attempt to find consensus on harmonisation of product notification.

Countering health threats by chemicals with a potential terrorist background--creating a rapid alert system for Europe.

BACKGROUND: The acronym "ASHT" stands for "Alerting System and Development of a Health Surveillance System for the Deliberate Release of Chemicals by Terrorists". Imagine this scenario: 15 patients with respiratory symptoms following a concert in Rome and 12 patients coughing after lunch in a cafeteria in the Czech Republic; are these events related? Today these events would never be connected as there is no mechanism to allow EU Member States to share this type of information effectively. The main objective of the ASHT project was to improve data sharing between EU Member States. In part, this was achieved by an internet accessible EU-wide alerting system with the aim to detect the deliberate (i.e. criminal or terrorist) or accidental release of chemicals. Nevertheless more information from police, fire brigades and health professionals is needed. METHODS: Description of the design, development, functionality and testing of the relational database system called "RAS-CHEM" (Rapid Alert System for Chemicals). RESULTS: A database structure appropriate for the description of "events" with sophisticated retrieval functions was developed. For evaluation purposes 37 events were entered into the database including 29 scenarios and 8 historical mass intoxications. The alert level was "background information" for 21 events, "suspected mass intoxication" for 6 cases and "confirmed mass intoxication" for 10 events. CONCLUSION: The RAS-CHEM database works and will be integrated into the Health Emergency Operations Facility (HEOF) with other European Rapid Alert Systems. Poisons centres receive a large number of enquiries and could be important sentinels in this field of toxicovigilance.

Barbiturate intoxication in two dogs confirmed by toxicological urinalysis.

Two dogs were presented within 24 hours to the Department of Small Animal Medicine and Surgery at the University of Veterinary Medicine Hannover for investigation of the sudden onset of neurological abnormalities following a walk in the same park. One dog was observed ingesting a piece of meat. Analysis of urine by gas chromatography-mass spectrometry from each of the dogs identified the presence of barbiturates. Both dogs recovered with supportive treatment. This is the first report to describe the use of toxicological urinalysis with gas chromatography-mass spectrometry for the diagnosis of barbiturate intoxication in dogs.

Unintentional household poisoning in children.

Despite the major reduction in fatal paediatric poisonings that has been achieved in industrialised countries over the last few decades, unintentional paediatric poisoning remains a major public health issue worldwide. In this article, we aim to provide clinicians dealing with poisoned children an overview of the problem and specific guidance on the identification and management of significant poisoning. Substances most frequently ingested by children in the developed world include household chemicals, medication, and plants. Although the great majority of such poisonings have no or limited clinical effects, it puts substantial burden on health care systems. Importantly, a few poisons can kill after ingestion of very small amounts. Unintentional poisoning in developing countries can be much more serious, following ingestion of kerosene, caustic agents, herbal remedies, insecticides or herbicides. Management of symptomatic patients involves supportive care, if available the administration of antidotes, and the removal of the offending drug from the body. Recent position papers on gastric decontamination indicate that such interventions are only rarely necessary. To further reduce the number of deaths and disabilities in the industrialised world and to begin to have an effect in the developing world, much more work is required to both identify and implement prevention strategies to reduce the number of cases of paediatric poisoning.

Biosynthesis of the two halobacterial light sensors P480 and sensory rhodopsin and variation in gain of their signal transduction chains.

The two retinal-containing photoreceptors of halobacteria, P480 and sensory rhodopsin, are formed constitutively and inducibly, respectively. Both photoreceptors are synthesized as apoproteins in cells with nicotine-inhibited retinal synthesis and are reconstituted as chromoproteins by the addition of all-trans retinal to cell membrane preparations. The decrease in photoreceptor-mediated photophobic response at the stationary growth phase of cells is not due to photoreceptor degradation but due to a deficiency of the signal transduction chain in the cell.