Arik Eisenkraft

Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities

The 5.5 Mb chromosome 7q21–22 ACHE/PON1 locus harbours the ACHE gene encoding the acetylcholine hydrolyzing, organophosphate (OP)‐inhibitable acetylcholinesterase protein and the paraoxonase gene PON1, yielding the OP‐hydrolyzing PON1 enzyme which also displays arylesterase activity. In search of inherited and acquired ACHE–PON1 interactions we genotyped seven polymorphic sites and determined the hydrolytic activities of the corresponding plasma enzymes and of the AChE‐homologous butyrylcholinesetrase (BChE) in 157 healthy Israelis. AChE, arylesterase, BChE and paraoxonase activities in plasma displayed 5.4‐, 6.5‐, 7.2‐ and 15.5‐fold variability, respectively, with genotype‐specific differences between carriers of distinct compound polymorphisms. AChE, BChE and arylesterase but not paraoxonase activity increased with age, depending on leucine at PON1 position 55. In contrast, carriers of PON1 M55 displayed decreased arylesterase activity independent of the − 108 promoter polymorphism. Predicted structural consequences of the PON1 L55M substitution demonstrated spatial shifts in adjacent residues. Molecular modelling showed substrate interactions with the enzyme variants, explaining the changes in substrate specificity induced by the Q192R substitution. Intriguingly, PON1, but not BChE or arylesterase, activities displayed inverse association with AChE activity. Our findings demonstrate that polymorphism(s) in the adjacent PON1 and ACHE genes affect each others expression, predicting for carriers of biochemically debilitating ACHE/PON1 polymorphisms adverse genome–environment interactions.

Guidelines for Treating Cardiac Manifestations of Organophosphates Poisoning with Special Emphasis on Long QT and Torsades De Pointes

Organophosphate poisoning may precipitate complex ventricular arrhythmias, a frequently overlooked and potentially lethal aspect of this condition. Acute effects consist of electrocardiographic ST-T segment changes and AV conduction disturbances of varying degrees, while long-lasting cardiac changes include QT prolongation, polymorphic tachycardia (“Torsades de Pointes”), and sudden cardiac death. Cardiac monitoring of organophosphate intoxicated patients for relatively long periods after the poisoning and early aggressive treatment of arrhythmias may be the clue to better survival. We present here a review of the literature with a focus on late cardiac arrhythmias (mainly “Torsades de pointes”), possible mechanisms, and treatment modalities, with special emphasis on postpoisoning monitoring for development of arrhythmias.

The Role of Glutamate and the Immune System in Organophosphate-induced CNS Damage

Organophosphate (OP) poisoning is associated with long-lasting neurological damage, which is attributed mainly to the excessive levels of glutamate caused by the intoxication. Glutamate toxicity, however, is not specific to OP poisoning, and is linked to propagation of damage in both acute and chronic neurodegenerative conditions in the central nervous system (CNS). In addition to acute excitotoxic effects of glutamate, there is now a growing amount of evidence of its intricate immunomodulatory effects in the brain, involving both the innate and the adaptive immune systems. Moreover, it was demonstrated that immunomodulatory treatments, aimed at regulating the interaction between the resident immune cells of the brain (microglia) and the peripheral immune system, can support buffering of excessive levels of glutamate and restoration of the homeostasis. In this review, we will discuss the role of glutamate as an excitotoxic agent in the acute phase of OP poisoning, and the possible functions it may have as both a neuroprotectant and an immunomodulator in the sub-acute and chronic phases of OP poisoning. In addition, we will describe the novel immune-based neuroprotective strategies aimed at counteracting the long-term neurodegenerative effects of glutamate in the CNS.

sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats

Organophosphates (OPs) are commonly used insecticides for agriculture and domestic purposes, but may also serve as nerve agents. Exposure to OPs result in overstimulation of the cholinergic system and lead to status epilepticus (SE), a life‐threatening condition that is often resistant to treatment. SE is associated with significant neuronal damage, neurocognitive dysfunction, and the development of lifelong epilepsy. Therefore, rapid termination of SE and prevention of brain damage is of high interest. Here we tested the efficacy of sec‐butyl‐propylacetamide (SPD) and two of its individual stereoisomers, (2S,3S)‐SPD and (2R,3R)‐SPD, in discontinuing OP‐induced seizures. SPD is a one carbon homolog of valnoctamide, a central nervous system (CNS)–active constitutional isomer of valproic acid (VPA) corresponding amide valpromide.

The possible role of intravenous lipid emulsion in the treatment of chemical warfare agent poisoning

Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, without proper and early antidotal treatment, death. Most of these compounds are highly lipophilic. Sulfur mustard is a toxic lipophilic alkylating agent, exerting its damage through alkylation of cellular macromolecules (e.g., DNA, proteins) and intense activation of pro-inflammatory pathways. Currently approved antidotes against OPs include the peripheral anticholinergic drug atropine and an oxime that reactivates the inhibited cholinesterase. Benzodiazepines are used to stop organophosphate-induced seizures. Despite these approved drugs, efforts have been made to introduce other medical countermeasures in order to attenuate both the short-term and long-term clinical effects following exposure. Currently, there is no antidote against sulfur mustard poisoning. Intravenous lipid emulsions are used as a source of calories in parenteral nutrition. In recent years, efficacy of lipid emulsions has been shown in the treatment of poisoning by fat-soluble compounds in animal models as well as clinically in humans. In this review we discuss the usefulness of intravenous lipid emulsions as an adjunct to the in-hospital treatment of chemical warfare agent poisoning.

Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase

The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec-butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec-butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy.

The association between self-perceived proficiency of personal protective equipment and objective performance: An observational study during a bioterrorism simulation drill

Highlights:We compared between self‐perceived proficiency of PPE use and objective performance.• There was no correlation between comfort and objective performance scores.• Clinics personnel performed better than hospital personnel.• Self‐perceived proficiency is a poor predictor of appropriate PPE use. Background The recent Ebola virus disease outbreak emphasized the potential misuse of personal protective equipment (PPE) by health care workers (HCWs) during such an event. We aimed to compare self‐perceived proficiency of PPE use and objective performance, and identify predictors of low compliance and PPE misuse. Methods: An observational study combined with subjective questionnaires were carried out during a bioterror simulation drill. Forty‐two observers evaluated performance under PPE. Mistakes were recorded and graded using a structured observational format and were correlated with the subjective questionnaires and with demographic parameters. Results: One hundred seventy‐eight HCWs from community clinics and hospitals were included. The mean self‐perceived proficiency was high (6.1 out of 7), mean level of comfort was moderate (4.0 out of 7), and mean objective performance was intermediate (9.5 out of 13). There was no correlation between comfort and objective performance scores. Self‐perceived proficiency was in correlation with donning and continuous performance with PPE but not with doffing. Clinic personnel performed better than personnel in hospitals (40.3% vs 67.8% with 3 or more mistakes, respectively; P = .001). Demographic characteristics had no correlation with objective or self‐perceived performance. Conclusions: Self‐perceived proficiency is a poor predictor of appropriate PPE use. The results suggest poor awareness of the possibility of PPE misuse.

Toxins as biological weapons for terror—characteristics, challenges and medical countermeasures: a mini-review

Toxins are hazardous biochemical compounds derived from bacteria, fungi, or plants. Some have mechanisms of action and physical properties that make them amenable for use as potential warfare agents. Currently, some toxins are classified as potential biological weapons, although they have several differences from classic living bio-terror pathogens and some similarities to manmade chemical warfare agents. This review focuses on category A and B bio-terror toxins recognized by the Centers for Disease Control and Prevention: Botulinum neurotoxin, staphylococcal enterotoxin B, Clostridium perfringens epsilon toxin, and ricin. Their derivation, pathogenesis, mechanism of action, associated clinical signs and symptoms, diagnosis, and treatment are discussed in detail. Given their expected covert use, the primary diagnostic challenge in toxin exposure is the early detection of morbidity clusters, apart from background morbidity, after a relatively short incubation period. For this reason, it is important that clinicians be familiar with the clinical manifestations of toxins and the appropriate methods of management and countermeasures.

Biphasic cuirass ventilation is better than bag-valve mask ventilation for resuscitation following organophosphate poisoning

Objective Exposure to organophosphates (OP) may lead to a life threatening cholinergic crisis with death attributed to a rapidly progressive respiratory failure. In a toxicological mass casualty event involving organophosphate exposure, many of the victims may depend on immediate short-term ventilation to overcome the respiratory distress which may exhaust life supporting resources. In addition, the mandatory use of personal protective gear by first responders emphasizes the need for a noninvasive, easy-to-operate ventilation device. Our objective was to assess the efficacy of MRTX, a Biphasic Cuirass Ventilation device, in comparison with standard bag-valve mask ventilation following acute organophosphate poisoning. Methods Pigs were exposed to paraoxon poisoning (1.4 LD50), and treated 8 min later with atropine (0.05 mg/kg). The control group received no further support (n = 9), the two experimental groups received ventilation support initiated 15 min post exposure and lasted for 25 min: one group was ventilated with the commonly used bag-valve mask (Mask group, n = 7) and the other was ventilated with the Biphasic Cuirass Ventilation device (Cuirass group, n = 7). Clinical signs and physiological parameters were monitored during the first hour, and mortality up to 24 h post exposure was recorded. Results No mortality was observed in the Cuirass group following OP poisoning, while mortality in the Control and in the Mask groups was high (67% and 71%, respectively). Mouth excretions of the cuirass-ventilated animals were frothy white as in deep suctioning, as opposed to the clear saliva-like appearance of secretions in the other two groups. No further group differences were recorded. Conclusions The noninvasive, easy-to-operate Biphasic Cuirass Ventilation device was effective in reducing OP-induced mortality and might be advantageous in an organophosphate mass casualty event. This finding should be validated in further investigations.

A Chemical-Biological-Radio-Nuclear (CBRN) Filter can be Added to the Air-Outflow Port of a Ventilator to Protect a Home Ventilated Patient From Inhalation of Toxic Industrial Compounds.

Objectives Chemical-biological-radio-nuclear (CBRN) gas masks are the standard means for protecting the general population from inhalation of toxic industrial compounds (TICs), for example after industrial accidents or terrorist attacks. However, such gas masks would not protect patients on home mechanical ventilation, as ventilator airflow would bypass the CBRN filter. We therefore evaluated in vivo the safety of adding a standard-issue CBRN filter to the air-outflow port of a home ventilator, as a method for providing TIC protection to such patients. Methods Eight adult patients were included in the study. All had been on stable, chronic ventilation via a tracheostomy for at least 3 months before the study. Each patient was ventilated for a period of 1 hour with a standard-issue CBRN filter canister attached to the air-outflow port of their ventilator. Physiological and airflow measurements were made before, during, and after using the filter, and the patients reported their subjective sensation of ventilation continuously during the trial. Results For all patients, and throughout the entire study, no deterioration in any of the measured physiological parameters and no changes in measured airflow parameters were detected. All patients felt no subjective difference in the sensation of ventilation with the CBRN filter canister in situ, as compared with ventilation without it. This was true even for those patients who were breathing spontaneously and thus activating the ventilator’s trigger/sensitivity function. No technical malfunctions of the ventilators occurred after addition of the CBRN filter canister to the air-outflow ports of the ventilators. Conclusions A CBRN filter canister can be added to the air-outflow port of chronically ventilated patients, without causing an objective or subjective deterioration in the quality of the patients’ mechanical ventilation. (Disaster Med Public Health Preparedness. 2018;12:739-743)