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Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.

Organophosphate (OP) poisoning can trigger cholinergic crisis, a life-threatening toxidrome that includes seizures and status epilepticus. These acute toxic responses are associated with persistent neuroinflammation and spontaneous recurrent seizures (SRS), also known as acquired epilepsy. Blood-brain barrier (BBB) impairment has recently been proposed as a pathogenic mechanism linking acute OP intoxication to chronic adverse neurologic outcomes. In this review, we briefly describe the cellular and molecular components of the BBB, review evidence of altered BBB integrity following acute OP intoxication, and discuss potential mechanisms by which acute OP intoxication may promote BBB dysfunction. We highlight the complex interplay between neuroinflammation and BBB dysfunction that suggests a positive feedforward interaction. Lastly, we examine research from diverse models and disease states that suggest mechanisms by which loss of BBB integrity may contribute to epileptogenic processes. Collectively, the literature identifies BBB impairment as a convergent mechanism of neurologic disease and justifies further mechanistic research into how acute OP intoxication causes BBB impairment and its role in the pathogenesis of SRS and potentially other long-term neurologic sequelae. Such research is critical for evaluating BBB stabilization as a neuroprotective strategy for mitigating OP-induced epilepsy and possibly seizure disorders of other etiologies. SIGNIFICANCE STATEMENT: Clinical and preclinical studies support a link between blood-brain barrier (BBB) dysfunction and epileptogenesis; however, a causal relationship has been difficult to prove. Mechanistic studies to delineate relationships between BBB dysfunction and epilepsy may provide novel insights into BBB stabilization as a neuroprotective strategy for mitigating epilepsy resulting from acute organophosphate (OP) intoxication and non-OP causes and potentially other adverse neurological conditions associated with acute OP intoxication, such as cognitive impairment.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5 min, even as late as 1 h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration. Rats with an implanted jugular vein cannula were infused with 1,000 µL of the 10% isoflurane-lipid emulsion (ILE) mixture at a rate of 200 µL per minute, which achieved full anesthesia lasting approximately 10 min. When administered 30 min after a highly lethal dose of the organophosphate insecticide paraoxon (POX), the short-duration administration halted convulsions over the course of the study and prevented the great majority of neuronal loss as shown by Fluoro-Jade B staining (FJB). Our results indicate that injectable isoflurane is very effective for treating organophosphate poisoning, negating the need for vaporizer equipment and enabling intravenous therapy. [ABSTRACT FROM AUTHOR]

Introduction: Ethion is an organophosphate used as an acaricide and insecticide, that is restricted worldwide. In Colombia, pesticide poisoning is the third most common cause of chemical intoxication. On 9 October 2022, an outbreak of ethion poisoning occurred in Pereira. The aim of this study was to describe the clinical and epidemiological characteristics of the outbreak. Methods: This is a descriptive study of an outbreak of organophosphate poisoning. The onset of symptoms occurred on 9 October 2022, following the consumption of empanadas. Information was collected on sociodemographic characteristics and clinical manifestations, as well as from paraclinical examinations. Data were obtained from clinical histories, field epidemiological investigations, and inspection visits. Food samples were collected for analysis by gas chromatography-mass spectrometry. Attack rates, proportions, and measures of central tendency, dispersion, and position were calculated. Results: The case definition was met by 37 individuals with a median age of 30 years; all presented with muscarinic symptoms, 29 patients presented with nicotinic symptoms, and 20 patients presented with neurological symptoms. Males were the most affected (57%), and the most common time of symptom onset was 10:00 am. Twenty-three patients (62%) required intensive care unit admission, of whom 14 (38%) required mechanical ventilation. No deaths were reported. Erythrocyte acetylcholinesterase activity was reduced in all patients. Ethion was detected in mass-prepared maize and empanadas at concentrations greater than 0.1 mg/kg. The consumption of empanadas was identified as the common source. Discussion: In Colombia, pesticide poisonings are the third most common type of poisoning caused by chemical substances reported to the National Health Institute through the National Public Health Surveillance System. In the present outbreak, ethion was in empanadas, likely due to contamination of cooking oil. Conclusions: We describe a large ethion-contaminated food poisoning outbreak reported in Colombia. The main symptoms were muscarinic, and the main treatment measures employed were atropine and respiratory support. Increased awareness of pesticide poisoning and training for food handlers are needed. [ABSTRACT FROM AUTHOR]

Background and Aim: Organophosphate compounds, including nerve agents, pesticides, chemical agent analogs, and Novichok, pose a serious health hazard to humans. Their use against humans was banned by 192 countries in 1993 under the Chemical Weapons Convention. The toxic effects of these compounds involve the phosphorylation and subsequent inhibition of the enzyme acetylcholinesterase, leading to the accumulation of acetylcholine in the synapses of the central and peripheral nervous systems, resulting in neurotoxic poisoning symptoms. The drugs used to treat this poisoning are compounds that can cross the blood-brain barrier by a maximum of 10% and therefore do not effectively detoxify the central nervous system. This research aims to design and synthesize a superparamagnetic nano-reactivator to activate the inhibited enzyme in the central nervous system. Methods: In this study, iron oxide nanoparticles conjugated with 2-pyridinium aldoxime were designed and synthesized in four steps. The characteristics of the nanoparticles were determined by infrared spectroscopy, energy-dispersive X-ray spectroscopy (EDS), elemental analysis, dynamic light scattering (DLS), and electron microscopy (SEM). Their activation effect was compared with pralidoxime, a commercially available drug, using the Ellman method in vitro. Results: The results of the Ellman method showed that the percentage of activation of the paraoxon-inhibited enzyme by pralidoxime as a commercially available antidote and the synthesized nanoparticles at a concentration of 5 mM over 30 minutes was 88.6% and 39.3%, respectively. Conclusion: This study demonstrated that the designed iron oxide nanoparticles conjugated with 2-pyridinium aldoxime can be synthesized and activate acetylcholinesterase inhibited by paraoxon. Therefore, future studies should investigate the effect of other groups such as 4-pyridinium aldoxime, 2,4-pyridinium aldoxime, etc., on the enzyme activation performance and the ability of these nanoparticles to cross the blood-brain barrier. [ABSTRACT FROM AUTHOR]

Paraquat is a widely used non-selective herbicide in Indian agriculture. It has gained popularity for its misuse in suicidal poisoning, primarily because it lacks an antidote, and ingestion often leads to death. When examining the historical trends of pesticide-related suicidal poisonings in India, there is a noticeable transition from endrin, organophosphates and rodenticides to the current prevalent use of paraquat. This review delves into globally reported cases of homicidal paraquat poisonings, which are sporadically reported in India as well, although not published in mainstream academia. Clinicians must remain vigilant in homicidal paraquat poisoning situations as there is often improper history at the time of presentation. Such cases typically present with some non-specific symptoms such as oral and pharyngeal burns and appear like any other typical acute gastroenteritis or a flu-like illness which ultimately leads to death as a result of pulmonary complications. At the same time, forensic pathologists need to be well versed in the characteristic autopsy findings and analytical toxicology considerations of paraquat-induced criminal poisoning, given the occasional incidents in India. The use of paraquat as a weapon in poisoning cases is a significant public health concern that underscores the need for a ban on paraquat in India.

Organophosphate poisoning remains a global health crisis without efficacious treatments to prevent neurotoxicity. We examined whether antidotal tiger nut and coconut dietary intervention could ameliorate neurobehavioral deficits from organophosphate dichlorvos-induced gut-brain axis dysregulation in a mouse model. Mice were divided into groups given control diet, dichlorvos-contaminated diets, or dichlorvos plus nut-enriched diets. They were exposed to a DDVP-contaminated diet for 4 weeks before exposure to the treatment diets for another 8 weeks. This was followed by behavioural assessments for cognitive, motor, anxiety-, and depressive-like behaviours. Faecal samples (pre- and post-treatment), as well as blood, brain, and gut tissues, were collected for biochemical assessments following euthanasia. Dichlorvos-exposed mice displayed impairments in cognition, motor function, and mood along with disrupted inflammatory and antioxidant responses, neurotrophic factor levels, and acetylcholinesterase activity in brain and intestinal tissues. Weight loss and altered short-chain fatty acid levels additionally indicated gut dysfunction. However, intervention with tiger nut and/or coconut- enriched diet after dichlorvos exposure attenuated these neurobehavioral, and biochemical alterations. Our findings demonstrate organophosphate-induced communication disruptions between the gut and brain pathways that manifest in neuropsychiatric disturbances. Overall, incorporating fibre-rich nuts may represent an antidotal dietary strategy to reduce neurotoxicity and prevent brain disorders associated with organophosphate poisoning.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5 min, even as late as 1 h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration. Rats with an implanted jugular vein cannula were infused with 1,000 μL of the 10% isoflurane-lipid emulsion (ILE) mixture at a rate of 200 μL per minute, which achieved full anesthesia lasting approximately 10 min. When administered 30 min after a highly lethal dose of the organophosphate insecticide paraoxon (POX), the short-duration administration halted convulsions over the course of the study and prevented the great majority of neuronal loss as shown by Fluoro-Jade B staining (FJB). Our results indicate that injectable isoflurane is very effective for treating organophosphate poisoning, negating the need for vaporizer equipment and enabling intravenous therapy.

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes. [ABSTRACT FROM AUTHOR]

Dichlorvos, an organophosphate compound, has the potential to cause acute kidney injury (AKI) besides its well-known neuromuscular complications. We report a case of severe-recurrent AKI that progressed to end-stage-renal-disease (ESRD) following accidental exposure to Dichlorvos. A 52-year-old male farmer presented with breathlessness after accidental exposure while spraying in the field. He required mechanical ventilation due to allergic pneumonitis and developed anuric AKI, requiring renal replacement therapy (RRT). Biopsy revealed severe acute tubulointerstitial nephritis (ATIN), which responded to steroids, and the patient became dialysis-independent by 4 weeks. Two weeks later, the patient had recurrent AKI requiring RRT. A repeat biopsy revealed severe ATIN. However, despite steroid treatment, he progressed to ESRD. Organophosphate compounds can cause renal injury with a wide spectrum of presentations, ranging from subclinical AKI to severe dialysis-dependent renal failure, which may eventually progress to end-stage renal disease. [ABSTRACT FROM AUTHOR]

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

Purpose: This case report aims to describe a rare manifestation of isolated hypoglossal nerve palsy (HNP) resulting from organophosphate poisoning (OP), specifically organophosphate- induced delayed neuropathy (OPIDN). The primary objective of this case report is to highlight this unusual manifestation and discuss its potential underlying mechanisms, emphasizing the importance of timely diagnosis and appropriate management., Case Report: A 31-year-old male with a history of consuming a commercial chlorpyrifos formulation presented with acute organophosphate poisoning symptoms that improved with appropriate treatment. However, two weeks later, the patient developed neurological deficits (numbness and weakness spreading from the plantar region to the upper limbs) involving the hypoglossal nerve, manifesting as left-sided tongue deviation, fasciculation, and atrophy, resulting in speech and swallowing difficulties. A comprehensive workup ruled out other potential causes of HNP, supporting the link between OPIDN and isolated HNP. Despite regaining limb strength, the patient's speech and swallowing issues persisted, prompting a follow-up visit to our hospital for further management and rehabilitation., Conclusion: This case report highlights a unique manifestation of OPIDN, resulting in isolated HNP, a rare phenomenon. The correlation between exposure to chlorpyrifos, acute organophosphate poisoning, and delayed onset of HNP suggests a causative relationship. Prompt diagnosis, appropriate treatment, and timely speech and swallowing rehabilitation are vital for optimizing outcomes in such cases. Further research is needed to understand the mechanisms underlying this selective vulnerability of OPIDN and to develop targeted interventions.

Organophosphate (OP) poisoning is a critical public health issue, particularly in agricultural regions where these compounds are extensively used as pesticides. The toxic effects of OP compounds arise from their inhibition of acetylcholinesterase, leading to an accumulation of acetylcholine and a subsequent cholinergic crisis, which can be fatal if not promptly treated. Traditional management of OP poisoning includes the administration of atropine and pralidoxime; however, these treatments often fall short of reducing the high morbidity and mortality associated with severe cases. Recent research has highlighted the potential of magnesium sulfate as an adjunctive treatment for OP poisoning. Magnesium sulfate exerts its beneficial effects through mechanisms such as calcium channel blockade and stabilization of neuromuscular junctions, which help mitigate the cholinergic hyperactivity induced by OP compounds. Clinical studies have shown that magnesium sulfate can significantly reduce the duration of intensive care unit (ICU) stays and improve overall patient outcomes. This narrative review aims to comprehensively analyze current insights into using magnesium sulfate to manage OP poisoning. It discusses the pathophysiology of OP poisoning, the pharmacological action of magnesium sulfate, and the clinical evidence supporting its use. Furthermore, the review will address the safety profile of magnesium sulfate and its potential role in current treatment guidelines. By synthesizing available evidence, this review seeks to establish magnesium sulfate as a game-changer in the management of OP poisoning, ultimately contributing to better clinical practices and patient outcomes., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nelakuditi et al.)

Organophosphate poisoning (OPP) remains a significant public health issue globally, particularly in middle- and low-income countries. This study aimed to assess the effectiveness of physiotherapy interventions in managing patients with OPP, focusing on reducing the severity of intermediate syndrome symptoms and associated complications such as respiratory muscle weakness and bilateral loculated pleural effusions. A 48-year-old male with a history of alcohol consumption was transferred to the medicine intensive care unit due to poison ingestion. The patient exhibited symptoms of respiratory distress and decreased consciousness, necessitating intubation and mechanical ventilation. Physiotherapy interventions included patient education, secretion mobilization, vital capacity improvement, secondary complication prevention, chest expansion exercises, dyspnea-relieving positions, and mobilization. The patient's progress was monitored using various scales, including the Functional Independence Measure Scale, ICU Mobility Scale, and Chelsea Critical Care Physical Assessment Tool. Significant improvements in functional independence, mobility, and psychological well-being were observed throughout the intervention period. This study highlights the importance of physiotherapy in the comprehensive management of OPP, emphasizing its role in mitigating respiratory complications and improving overall functional outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vikhe et al.)

While accidental poisoning is fairly common in children, the data are sparse when organophosphate (OP) is considered the culprit toxin. Only case reports of such patients from the Southeast Asian Region have been documented, despite it contributing largely to the global burden of organophosphorus poisoning in the adult population. This can be attributed to difficulty in diagnosing children because of varied presentations in the pediatric population and unreliable or unavailable exposure history. We present a case of a 19-month-old toddler who presented to the ED with OP poisoning, which proved to be a diagnostic and management challenge because of more common differentials and the unavailability of a clear history., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

Fenitrothion is one of the most globally used organophosphorus pesticides, which can cause neurological symptoms, including involuntary movements. However, due to the limited number of case report, information on its treatment is also scarce. Here we presented a 74-year-old Japanese woman who was admitted to our hospital due to a persistent nausea and vomiting after ingesting 200 mL of 50% fenitrothion for a suicidal attempt. She received continuous intravenous infusion of atropine and 2-pyridine aldoxime methiodide under mechanical ventilation and continuous hemodiafiltration. However, she developed fasciculations of the face and right arm on day 11, which raised suspicions of delayed neuropathy associated with organophosphorus poisoning. To reduce the risk of respiratory depression, she received intravenous levetiracetam at a dosage of 1,000 mg/day. However, as her fasciculations persisted, the levetiracetam dosage was adjusted to 2,000 mg/day on day 14. On the following day, her fasciculations subsided. Neurologic symptoms of lipid-soluble organophosphorus poisoning, including fenitrothion, can sometimes delay following ingestion. Temporary administration of levetiracetam may prove effective in alleviating fasciculations.

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD 50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

Introduction: Background: Childhood poisoning, characterised by exposure to toxic substances, poses a global health concern with variations across regions. Despite the importance of having current information about childhood acute poisoning in our region, there is a noticeable gap in such research in our local context. Regularly reviewing the agents responsible for poisoning in our locale is essential for devising prevention strategies and treatment approaches. This study aimed to examine the patterns and outcomes of childhood poisoning at the Children's Emergency Department of the Federal Medical Centre, Yenagoa, Bayelsa State, Nigeria., Methods: A retrospective cross-sectional study was conducted, analysing cases of childhood poisoning in the Children's Emergency Ward, presenting from January 2013 to December 2022. Sociodemographic data, types of poisoning agents, home interventions, clinical features and outcomes were extracted from medical records., Results: Of 9389 admissions, 81 (0.8%) cases were admitted for childhood poisoning, but only 69 cases were analysed (total n=69). Children aged under 5 years (52.2%) and who were males (59.4%) were mostly involved. Organophosphates (21.7%) and kerosene (20.3%) were common poisoning agents, often accidental (72.5%) and occurring at home (94.2%). Delayed hospital presentation (>2 hours) was common (68.1%). Vomiting (72.5%) and drooling saliva (56.5%) were prevalent symptoms. Hydration (60.9%) was the main hospital intervention, while antidotes were infrequently used (15.9%). Mortality was 8.7%, predominantly due to kerosene ingestion in young children., Conclusion: Organophosphate and kerosene poisoning are the most common in this facility. Enforcement challenges persist, emphasising the importance of safe storage practices and improved poison control measures. Addressing resource constraints for antidote availability and increasing awareness are vital for effective management and prevention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro , achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 μM, a 4-fold increase from our 2018 report. The best QMP ( 1b ), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

Organophosphorus agents are easily absorbed via respiratory, gastrointestinal, and dermal routes, and inhibit the acetylcholine transferase enzyme (AChE), which is responsible for the majority of toxicity caused by organophosphates in the body. A comprehensive search was conducted across three prominent databases, namely Google Scholar, PubMed, and Science Direct, to identify relevant articles published. The search focused on the keywords "MgSO4" or "magnesium sulfate" in conjunction with "organophosphate" or "organophosphate poisoning." Inhibition of AChE results in the accumulation of acetylcholine (ACh) in synapses and stimulation of cholinergic receptors. Considering that several studies have shown the use of magnesium sulfate (MgSO4) in inhibiting the release of ACh in the central and peripheral sympathetic and parasympathetic synapses, this study was conducted to review the role of MgSO4 in the treatment of OP. The intravenous administration of MgSO4 exhibits favorable tolerability and clinical efficacy in alleviating cardiac toxicity associated with OP exposure.

Introduction: The aim of this study was to determine the clinical predictors of staphylococcal ventilator-associated pneumonia (VAP) and to compare the outcomes of staphylococcal VAP with non-staphylococcal VAP., Methodology: A retrospective observational study was conducted among adult patients admitted to the medical intensive care unit (MICU) in a tertiary care hospital in India from January 2017 to December 2019. The patients were grouped based on their diagnosis into staphylococcal and non-staphylococcal VAP, and the baseline characteristics, clinical parameters, co-morbidities, and outcome parameters were compared., Results: Out of 2129 MICU admissions, 456 patients with microbiologically confirmed VAP were included, of which 69 (15.1%) had staphylococcal VAP, and the remaining 387 (84.9%) had non-staphylococcal VAP. Organophosphorus (OP) poisoning was identified as an independent predictor of staphylococcal VAP (odds ratio: 2.57; 95% CI: 1.4 to 4.73). The median duration of mechanical ventilation before VAP diagnosis was less in the staphylococcal VAP group (4 vs. 5 days; p = 0.004). The staphylococcal group also showed a better in-hospital outcome., Conclusions: OP poisoning was an independent predictor of staphylococcal VAP. Staphylococcal VAP was diagnosed earlier in patients than non-staphylococcal VAP. Screening for nasal carriage for Staphylococcus, especially in patients with OP poisoning at the time of MICU admission, may help guide antibiotic therapy., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Avijit Chauhan, Hariswar Pari, Radha Sugumaran, Venkateswaran Ramanathan.)

Organophosphate poisoning is a significant global health concern with implications for both occupational and environmental settings. This comprehensive review thoroughly explores the biochemical basis, clinical presentation, diagnostic methods, treatment strategies, and long-term effects of organophosphate exposure. The acute phase is characterized by cholinergic crisis, respiratory distress, and neurological manifestations, while delayed complications include the intermediate syndrome and organophosphate-induced delayed neuropathy. Diagnostic approaches involve clinical evaluation, cholinesterase-level assessments, and imaging studies. Treatment strategies encompass decontamination, antidotes such as atropine and pralidoxime, and supportive care. Long-term effects may include cognitive and neurological sequelae, necessitating rehabilitation approaches such as physical and occupational therapy. Prevention strategies include stringent occupational safety guidelines, sustainable agricultural practices, and public awareness initiatives. The implications for clinical practice underscore the importance of a multidisciplinary approach. At the same time, the call to action emphasizes the need for collaborative efforts in prevention and awareness to mitigate the impact of organophosphate poisoning on public health and the environment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Patel et al.)

Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE., (Copyright © 2024 by The Author(s).)

Hypertension is the most important and well-known risk factor for cardiovascular disease (CVD). Recently, acute organophosphate (OP) poisoning has also been pointed as a CVD risk factor. Despite this evidence, no studies have contrasted the acute toxicosis and cardiovascular (CV) effects of OP poisoning under conditions of normotension and hypertension. In this work, adult male normotensive Wistar and Spontaneously Hypertensive rats (SHR) were intraperitoneally injected with saline or chlorpyrifos (CPF), an OP compound, monitored for acute toxicosis signs and 24-h survival. After poisoning, blood pressure, heart rate and ventilation were recorded, the Bezold-Jarisch Reflex (BJR), the Chemoreflex (CR) were chemically activated, as well as the cardiac autonomic tone (AUT) was assessed. Erythrocyte and brainstem acetylcholinesterase and plasmatic butyrylcholinesterase (BuChE) activities were measured as well as lipid peroxidation, advanced oxidation protein products (AOPP), nitrite/nitrate levels, expression of catalase, TNFα and angiotensin-I converting enzyme (ACE-1) within the brainstem. CPF induced a much more pronounced acute toxicosis and 33 % lethality in SHR. CPF poisoning impaired ventilation in SHR, the BJR reflex responses in Wistar rats, and the chemoreflex tachypneic response in both strains. CPF inhibited activity of cholinesterases in both strains, increased AOPP and nitrite/nitrate levels and expression of TNFα and ACE-1 in the brainstem of Wistar rats. Interestingly, SHR presented a reduced intrinsic BuChE activity, an important bioscavenger. Our findings show that, CPF at sublethal doses in normotensive rats lead to lethality and much more pronounced acute toxicity signs in the SHR. We also showed that cardiorespiratory reflexes were differentially impacted after CPF poisoning in both strains and that the cardiorespiratory disfunction seems to be associated with interference in cholinergic transmission, oxidative stress and inflammation. These results points to an increased susceptibility to acute toxicosis in hypertension, which may impose a significant risk to vulnerable populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)