Yoav Yehezkelli

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.

Clinical and Immune Responses after Revaccination of Israeli Adults with the Lister Strain of Vaccinia Virus

BACKGROUND During the winter of 2002-2003, the Israeli health authorities launched a campaign to vaccinate first responders against smallpox. METHODS In an open study, 159 healthy, preimmunized adults, 24-52 years old, who participated in the campaign were vaccinated with the Lister strain of vaccinia virus by the multipuncture technique. The safety, immunogenicity, and reactogenicity of the vaccine were assessed. RESULTS Successful vaccination rates were 61% and 56%, on the basis of clinical take and seroconversion, respectively. Adverse events among the vaccinees were minor. Seventy-nine (88%) of the 90 vaccinees with clinical take also seroconverted ( kappa =0.779). The level of preexisting antibodies inversely correlated with the rates of clinical take and seroconversion (P</=.0098). In the group of vaccinees with the lowest preexisting levels of antibodies, 89% and 86% developed clinical take or seroconverted, respectively. The time since last vaccination was significantly associated with the rates of clinical take and seroconversion (P</=0.001). CONCLUSIONS These rates of successful vaccination in previously immunized individuals are consistent with the historical experience of use of this vaccine in Israel. The rate of occurrence and the severity of local and other reactions in the vaccinees were within the expected range. Levels of preexisting antibodies and the time since last vaccination played a major role in determining success rates.

OP or not OP: the medical challenge at the chemical terrorism scene.

Since the 1995 Tokyo subway sarin attack, terrorist attacks involving weapons of mass destruction or other industrial chemicals present worldwide security and health concerns. On-scene medical triage and treatment in such events is crucial to save as many lives as possible and minimize the deleterious effects of the toxic agent involved. Since there are many chemicals that can be used as potential terrorist weapons, the medical challenge for the emergency medical services (EMS) is a combination of: (1) recognizing that a chemical terrorist attack (non-conventional) has occurred; and (2) identifying the toxic agent followed by proper antidotal treatment. The latter must be done as quickly as possible, preferably on-scene. The most valuable decision at this stage should be whether the agent is organophosphate (OP) or not OP, based on clinical findings observed by pre-trained, first responders. This decision is crucial, since only OP intoxication has readily available, rapidly acting, onscene, specific agents such as atropine and one of the oximes, preferably administered using autoinjectors. Due to the lack of a specific antidote, exposure to other agents (such as industrial chemicals, e.g., chlorine, bromide, or ammonia) should be treated on-scene symptomatically with non-specific measures, such as decontamination and supportive treatment. This paper proposes an algorithm as a cognitive framework for the medical teams on-scene. This algorithm should be part of the medical teams training for preparedness for chemical terrorist attacks, and the team should be trained to use it in drills. Implementing this path of thinking should improve the medical outcome of such an event.

Civilian Adult Self Injections of Atropine – Trimedoxime (TMB4) Auto-Injectors

Introduction. The clinical effects of self injections of atropine–trimedoxime auto-injectors distributed to the civilian population as a field antidote for nerve agent attack were assessed. Methods. Data on self injections by adults (≥18 years) were collected from the Israel Poison Information Center and a hospital Emergency Departments records during a 2-year period. The data included demographics, time interval from injection, type of auto-injector, clinical manifestations and atropinization score. Results. Sixty-five patients, all with unintentional self injections, were reported. Systemic atropine effects were observed in 24 patients, but no severe atropinization. The atropinization score was significantly higher in the 2 mg atropine dose group than in the two lower dose groups, which were in the normal range. No specific adverse effects attributable to trimedoxime were observed. Intravenous fluids and physostigmine were not required. Conclusion. Only mild reactions were observed following self-injection of atropine trimedoxime auto-injectors in adults, attesting to their relative safety under these conditions.

Ricin: A Possible, Noninfectious Biological Weapon

On September 7, 1978, 49-year-old Bulgarian exile named Georgi Markov was hit by an umbrellas tip while waiting in a bus station in London. The next day, he was admitted to a hospital in a severe condition, which rapidly deteriorated, terminating in his death 4 days later. A tiny pellet was removed from his thigh in autopsy. Based on the clinical course and on the pellet dimensions, it was concluded that Markov was assassinated using the poison ricin (Crompton and Gall, 1980; Franz and Jaax, 1997).

Safety of Biological/Chemical Respiratory Protection Filter for Patients in Need of Oxygen Supplementation

BACKGROUND During the 2003 war in Iraq, Israel faced the problem of supplying biological/chemical respiratory protection for a population in need of ventilator support. The devices in use were insufficient in terms of protective value, costs, and availability. An adaptor was developed to allow connection between respirators and the standard biological/chemical filter canister. OBJECTIVE As part of the safety protocol for such a device, an investigation was made to determine the possibility of combustion of the biological/chemical filter canister, because of a possible exothermic reaction between the inspired oxygen-enriched air flow passing through the canister and the activated charcoal component of the filter. METHODS A mechanical ventilator generated airflow with a frequency of 24 breaths per minute and a 500-mL tidal volume, for 90 minutes, through 14 standard filter canisters in a sealed chamber at a temperature of 25 degrees C and through seven canisters at a temperature of 30 degrees C. Incremental levels of oxygen (21-100%) were used for each set of canisters. The temperature of each filter was recorded throughout the examination. RESULTS There was no elevation in the final temperature of the filters after 90 minutes of airflow with high oxygen levels. There were no signs of ignition. CONCLUSION High oxygen levels passing through the activated carbon in the filter canister placed between the mechanical ventilator and the patient do not cause a combustion reaction, making it a safe means for respiratory protection for patients undergoing mechanical ventilation.

Risk Communication to Health-Care Workers as a Risk Reduction Measure in Bioterrorism

A Bioterrorism act is a possibility perhaps more realistic today then ever before. Health-care workers will always be in the forefront of mitigating disease. In case the offending agent is contagious, the outbreak might spread from person to person, medical personnel being in specific jeopardy because of their increased contact with ill people. Spread among medical staff was an important route in propagation of the severe acute respiratory syndrome (SARS) epidemic in 2003. Infection control measures have proved invaluable in halting the progress of the epidemic. Fortunately, medical personnel neither encounter highly contagious illnesses, nor bioterrorism, in their daily practice. One must therefore assume that there will be increased anxiety among health-care workers in the face of an unfamiliar disease. A bioterrorism event can be caused by a vast range of agents, which differ considerably in their contagiousness and risk to the environment. An inappropriate perception of the true risks in case of a bioterrorism event might lead to improper actions being taken