Acute Organophosphate Poisoning Research Articles

Acute intoxication with diisopropylfluorophosphate promotes cellular senescence in the adult male rat brain.

Acute intoxication with high levels of organophosphate (OP) cholinesterase inhibitors can cause cholinergic crisis, which is associated with acute, life-threatening parasympathomimetic symptoms, respiratory depression and seizures that can rapidly progress to status epilepticus (SE). Clinical and experimental data demonstrate that individuals who survive these acute neurotoxic effects often develop significant chronic morbidity, including behavioral deficits. The pathogenic mechanism(s) that link acute OP intoxication to chronic neurological deficits remain speculative. Cellular senescence has been linked to behavioral deficits associated with aging and neurodegenerative disease, but whether acute OP intoxication triggers cellular senescence in the brain has not been investigated. Here, we test this hypothesis in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats were administered DFP (4mg/kg, s.c.). Control animals were administered an equal volume (300µL) of sterile phosphate-buffered saline (s.c.). Both groups were subsequently injected with atropine sulfate (2mg/kg, i.m.) and 2-pralidoxime (25mg/kg, i.m.). DFP triggered seizure activity within minutes that rapidly progressed to SE, as determined using behavioral seizure criteria. Brains were collected from animals at 1, 3, and 6months post-exposure for immunohistochemical analyses of p16, a biomarker of cellular senescence. While there was no immunohistochemical evidence of cellular senescence at 1-month post-exposure, at 3- and 6-months post-exposure, p16 immunoreactivity was significantly increased in the CA3 and dentate gyrus of the hippocampus, amygdala, piriform cortex and thalamus, but not the CA1 region of the hippocampus or the somatosensory cortex. Co-localization of p16 immunoreactivity with cell-specific biomarkers, specifically, NeuN, GFAP, S100β, IBA1 and CD31, revealed that p16 expression in the brain of DFP animals is neuron-specific. The spatial distribution of p16-immunopositive cells overlapped with expression of senescence associated β-galactosidase and with degenerating neurons identified by FluoroJade-C (FJC) staining. The co-occurrence of p16 and FJC was positively correlated. This study implicates cellular senescence as a novel pathogenic mechanism underlying the chronic neurological deficits observed in individuals who survive OP-induced cholinergic crisis.

Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication

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.

Cardiovascular responses of adult male Sprague–Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone

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.

Comparative Analysis of Outcomes in Acute Organophosphate Poisoning With and Without N-acetyl Cysteine Intervention.

Organophosphorus poisoning (OPP) stands as a significant health concern in numerous regions, especially in developing nations. Despite the rising complexities and case fatalities associated with exposure, the treatment approach has remained unchanged for many years. Based on clinical insights, certain pharmacologic agents have demonstrated utility in enhancing outcomes and reducing complications arising from this type of exposure. The objective of this study is to compare the outcome of N-acetyl cysteine in the treatment of acute organophosphate poisoning cases. In terms of a) its impact on the requirement of atropine, b) Length of hospital stay, and mortality. The study was conducted in the intensive care unit (ICU) of the General Hospital Lahore. Thirty patients with a history and clinical presentation indicative of acute organophosphorus poisoning were randomly divided into two groups in a 1:1 ratio. The treatment group received parenteral administration of atropine, pralidoxime, and N-acetylcysteine (NAC) as an adjuvant, and the control group received standard treatment for acute organophosphate (OP) toxicity. Throughout the study duration, 30 patients suffering acute organophosphate (OP) toxicity (14 men, 16 women) were examined, with an age mean of (25.83±11.59) years. In the interventional group, only four patients required ICU admission, but in the control group, eight patients were admitted to ICU. The correlation result between the dose of atropine and length of hospital stays was not statistically significant between both study groups (<0.005). Plasma Cholinesterase (PChE) level (KU L-1) and total dose of Pralidoxime (g) were statistically significant in the length of hospital stay. The data was not normally distributed, so the non-parametric tests were applied. The Wilcoxon ranked test showed significant improvement in both the controlled and interventional groups because the p-value was (<0.005). Intergroup comparison analyzed by using the Mann-Whitney U test showed a significant reduction in the severity and other associated symptoms in the interventional group because the p-value was (0.001). The outcome demonstrated that the NAC group had a decreased demand for atropine rather than Pralidoxime. In the NAC group, the length of hospital stay and mortality was decreased. The administration of NAC to the present study procedure for acute organophosphate (OP) poisoning is suggested.

Acute Poisoning Emergencies at Gulu University Teaching Hospitals in Northern Uganda: Prevalence, Outcomes and Clinical Challenges

Acute poisonings, including envenomation as well as toxicological emergencies stemming from accidental or intentional ingestion of poisonous substances or drug overdose, are significant worldwide causes of morbidity and mortality. The study aimed to characterise acute poisoning emergencies admitted to two major hospitals in Northern Uganda. We conducted a retrospective review of charts of all patients admitted with acute poisoning emergencies between January and December 2021, as well as a structured interview of hospital staff working in these hospitals on challenges faced while managing these emergencies. Of the total 40,653 patient admissions, 416 (1%) were due to acute poisonings. The majority were admitted to SMHL (71.4%), 43.3% were between 20 and 40 years of age, and 59.9% were males. The average length of hospital stay was 1 (0-3). The most frequent diagnoses were acute alcohol intoxications (27.2%, n=113), snake bites (26.0%, n=108), and organophosphate poisonings (21.2%, n=88). Only 29.6% (n=123) of patients received antidotes. Peak admissions were observed in February, May, and July. The majority of poisonings were intentional (61.3%), resulting in a Case Fatality Rate of 6.3%. In the qualitative findings, participants highlighted key challenges in managing these conditions, including the lack of antidotes, patients presenting late at the hospital, economic barriers, staff shortages, and limited community awareness. Acute poisoning, especially acute alcoholic intoxication, snake bites and organophosphate poisoning, are common in northern Uganda, with significant numbers dying from it. The lack of antidotes remains a problem in these hospitals. Restriction of alcohol consumption use of agricultural organophosphates, and training of healthcare workers in managing these emergencies are recommended

Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. SIGNIFICANCE STATEMENT: Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.

Evidence Implicating Blood-Brain Barrier Impairment in the Pathogenesis of Acquired Epilepsy following Acute Organophosphate Intoxication.

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.

Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Organophospate-Induced Pathology: Mechanisms of Development, Principles of Therapy and Features of Experimental Studies

Organophosphates (OP) are one of the most common neurotoxic xenobiotics. In acute OP poisoning, as a result of suppression of synaptic acetylcholinesterase (AChE) activity, a cholinergic syndrome develops, which can transform into status epilepticus. Within a few days after acute poisoning, the so-called an intermediate syndrome can develop, which is associated with prolonged inhibition of AChE, desensitization of nicotinic receptors, and functional degradation of synapses and muscle fibers. In 10–20 days after a single acute or repeated subacute poisoning, OP-induced delayed polyneuropathy (OPIDN) can develop – a neurodegenerative disease, the signs of which are ataxia, loss of function of the distal sensory and motor axons of peripheral nerves. The occurrence of a neuropsychiatric disorder (NPD) caused by chronic exposure to relatively low-toxicity organophosphorus compounds is usually not associated with acute poisoning; symptoms include cognitive impairment, chronic fatigue, and extrapyramidal symptoms. The list of possible diseases or pathological conditions (syndromes) that develop as a result of acute, subacute or chronic effects of OP on the human body has expanded in recent years due a number of known neurodegenerative diseases (Alzheimer’s, Parkinson’s, multiple sclerosis, etc.). The aging of the body in general and the aging of the brain in particular are considered in the review from the point of view of the consequences of OP poisoning, which can serve as a nonspecific trigger of aging and related neurodegenerative diseases. Gulf syndrome is not a consequence of OP intoxication, but is also of interest and is considered in the context of OP-induced pathology, since its etiology and pathogenesis are associated with the exposure to cholinesterase inhibitors. The review presents data indicating the important role of the vascular endothelium in the development of OP-induced pathology; The first suggestions were made by clinicians in the late 1980s, and the first experimental data were obtained in the early 2000s. The principles of therapy for acute poisoning are outlined, taking into account experimental data from recent years. Some methods for studying OP in experiments in vitro, ex vivo and in vivo with laboratory animals, including the use of carboxylesterase inhibitors, are presented. The most important part of in vivo investigations has been and remains the search for new biomarkers to assess the effectiveness of adjuvant and regenerative therapies.

Acute pancreatitis, a significant mortality predictor in acute organophosphate poisoning: an observational study in a tertiary care centre in north India

Background: Organophosphate compounds are one of the most common agents used as poison and acts by accumulation of acetylcholine hormone at neuronal synapses resulting in the symptoms like excessive salivation, vomiting, urination, and increased serum amylase and lipase levels. APACHE 2 score along with ultrasound modality can be used to assess the acute pancreatitis. The primary aim of the study is to find correlation of serum amylase and lipase levels with duration of ICU stay and with radio-logical variables like bulky pancreas. Methods: This observational study conducted at GSVM medical college, Kanpur from December 2020 to October 2022 included 58 out of total 94 admitted patients with acute organophosphate intoxicationn on the basis of inclusion and exclusion criteria. Patients were divided in 3 groups as mild, moderate and severe using q SOFA score at the time of admission. Results: Acute organophosphate poisoning was more prevalent among 20-40 years of age group. Mean serum amylase level values in q SOFA category 0, 1, 2, 3 were 65.2, 82.0, 118.4, 329.9 IU/l respectively and that of mean serum lipase levels on day 1 of admission values were 42.0, 44.3, 38.6 and 115.5 IU/l respectively. Serum amylase levels were positively correlated with duration of ICU stay and were better predictor for acute pancreatitis. Conclusions: In this study we concluded that serum amylase is a better predictor of duration of ICU stay and acute pancreatitis in patients admitted with acute organophosphate poisoning.

The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: A randomized controlled trial

BackgroundMortality in acute organophosphate (OP) poisoning remains high despite current standard therapy with atropine and oximes. Due to dose-limiting side effects of atropine, novel therapies are targeting other putative mechanisms of injury, including oxidative damage, to reduce atropine dosage. ObjectivesN-acetylcysteine (NAC) and magnesium sulfate (MgSO4) have different mechanisms of actions and should act synergistically in OP poisoning. In this study, we wanted to evaluate whether this novel combination, used as an adjuvant to standard care, could improve clinical outcomes. MethodsThe study was conducted in the Emergency Department and ICU of AIIMS Bhubaneswar (a tertiary care center and government teaching institute) between July 2019 and July 2021. Eighty-eight adult patients with history and clinical features of acute OP poisoning were randomly allocated (1:1) into two groups. The Study group received 600 mg NAC via nasogastric tube thrice daily for 3 days plus a single dose of 4 g Inj. MgSO4 IV on first day and the Control group received suitably matched placebo (double-blinding) – in addition to standard care in both the groups. The primary outcome measure was to compare the total dose of Inj. Atropine required (cumulative over the entire treatment duration) between the control group and the study group receiving NAC and MgSO4. The secondary outcome measures were lengths of ICU and hospital stays, need and duration of mechanical ventilation, the differences in BuChE activity, oxidative stress biomarkers – MDA and GSH levels, the incidences of adverse effects including delayed sequalae like intermediate syndrome and OPIDN, and comparison of mortality between the two groups. ResultsData from 43 patients in Control and 42 patients in Study group was finally analyzed. The baseline parameters were comparable. Total atropine requirements were lower in the Study group [175.33 ± 81.25 mg (150.01–200.65)] compared to the Control [210.63 ± 102.29 mg (179.15–242.11)] [Mean ± SD (95% CI)], but was not statistically significant. No significant differences in any of the other clinical or biochemical parameters were noted. ConclusionThe N-acetylcysteine and MgSO4 combination as adjuvants failed to significantly reduce atropine requirements, ICU/hospital stay, mechanical ventilatory requirements, mortality and did not offer protection against oxidative damage.

ChatGPT in Clinical Toxicology.

ChatGPT has recently been shown to pass the United States Medical Licensing Examination (USMLE). We tested ChatGPT (Feb 13, 2023 release) using a typical clinical toxicology case of acute organophosphate poisoning. ChatGPT fared well in answering all of our queries regarding it.

STUDY OF SERUM AMYLASE LEVELS IN ORGANOPHOSPHATE POISONING

Organophosphate (OP) insecticides are the most probable common cause of acute poisonings in developing countries. OP intoxication often presents as medical emergencies, and its related morbidity and mortality have not decreased despite major advances in critical care.This study aims to determine the impact of serum amylase level for estimation of prognosis in patients with acute OP poisoning. Method: This prospective observational hospital-based study was performed on 100 patients with acute OP poisoning. Demographics data, clinical profile, serum amylase levels, complications,hospital stay and outcome were determined.Data were analyzed in the form of a frequency distributions using SPSS 26.0 version software.Result: Most patients were young adults with mean age of 29yrs ± 11yrs with slightly male predominance. Mean serum amylase level was significantly higher among patients with morbidity and mortality. Conclusion: Among patients with OP poisoning,higher serum amylase than normal was associated with severe clinical course and increased risk for mortality.Determination of serum amylase can be an effective marker of the prognosis and clinical course among OP poisoning patients.

Performance of new Poisoning Mortality Score in comparison with SOFA and APACHE II scores in acute organophosphate poisoning

Introduction: Organophosphate (OP) poisoning is a serious public health problem in underdeveloped nations. Many cases of severe poisoning and more than 220,000 deaths are recorded every year. Early detection and treatment can save lives because OP poisoning has a significant fatality rate. The new Poisoning Mortality Score (PMS) has been developed for clinical decision-making and therapeutic guidance in patients with acute poisoning. Methods: This is a retrospective study that included 236 patients with acute OP poisoning who got admitted to a tertiary care hospital over two years after obtaining permission from the institutional ethical committee. The PMS, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated based on patient details. Results: The results showed that the mean age of patients was 32.8 ± 13.4 years; 50.8% were men and 49.2% were women. Out of 236 patients, 214 got discharged and 22 died. The mean ± SD of PMS, SOFA score, and APACHE II scores among the discharged patients were 51±7, 1 ± 2, and 5 ± 5, respectively, and those among the expired patients were 70 ± 12, 7 ± 3, and 28 ± 9, respectively. The best cut-off points for predicting mortality in acute OP poisoning patients for PMS, SOFA score, and APACHE II scores were &gt;65, &gt;3, and &gt;15 with sensitivities of 77.27%, 95.45%, and 95.45%, specificities of 96.26%, 91.59%, and 95.79%, and areas under the receiver operating characteristic curve of 0.917, 0.970, and 0.984, respectively. Conclusion: The study showed that the new PMS is significantly associated with the prediction of mortality in acute OP poisoning in comparison with SOFA and APACHE II scores.

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease

The field of cell biology has seen major advances in both cellular imaging modalities and the development of automated image analysis platforms that increase rigor, reproducibility, and throughput for large imaging data sets. However, there remains a need for tools that provide accurate morphometric analysis of single cells with complex, dynamic cytoarchitecture in a high-throughput and unbiased manner. We developed a fully automated image-analysis algorithm to rapidly detect and quantify changes in cellular morphology using microglia cells, an innate immune cell within the central nervous system, as representative of cells that exhibit dynamic and complex cytoarchitectural changes. We used two preclinical animal models that exhibit robust changes in microglia morphology: (1) a rat model of acute organophosphate intoxication, which was used to generate fluorescently labeled images for algorithm development; and (2) a rat model of traumatic brain injury, which was used to validate the algorithm using cells labeled using chromogenic detection methods. All ex vivo brain sections were immunolabeled for IBA-1 using fluorescence or diaminobenzidine (DAB) labeling, images were acquired using a high content imaging system and analyzed using a custom-built algorithm. The exploratory data set revealed eight statistically significant and quantitative morphometric parameters that distinguished between phenotypically distinct groups of microglia. Manual validation of single-cell morphology was strongly correlated with the automated analysis and was further supported by a comparison with traditional stereology methods. Existing image analysis pipelines rely on high-resolution images of individual cells, which limits sample size and is subject to selection bias. However, our fully automated method integrates quantification of morphology and fluorescent/chromogenic signals in images from multiple brain regions acquired using high-content imaging. In summary, our free, customizable image analysis tool provides a high-throughput, unbiased method for accurately detecting and quantifying morphological changes in cells with complex morphologies.

ECG CHANGES AS A MANIFESTATION OF CARDIAC COMPLICATIONS OF ORGANO PHOSPHORUS COMPOUND POISIONING

To study the extent, frequency and pathogenesis of the cardiac and electrocardiographical manifestations of acute organophosphate poisoning. 37 adult patients admitted over a three-year period with a diagnosis of acute organophosphate was studied prospectively. The clinical features and electrocardiographical nding were recorded.Cardiac complications developed in 23 patients (62.2 percent). These were: noncardiogenic pulmonary oedema in eight cases (21.6 percent), electrocardiographical abnormalities including prolonged Q-Tc interval in 14 cases (37.8 percent), ST-T changes in 11 cases (29.7 percent), and conduction defects in two cases (5.4 percent). Sinus tachycardia occurred in 15 patients (40.5 percent) and sinus bradycardia in seven patients (18.9 percent). Hypertension developed in ve patients (13.5 percent) and hypotension in four patients (10.8 percent). Five patients (13.5 percent) needed respiratory support because of respiratory depression of which two patients developed intermediate syndrome. Out of 14 patients with prolonged Q-Tc interval, only one had polymorphic ventricular tachycardia of the torsade de pointes type. Two patients died from noncardiogenic pulmonary oedema and one from ventricular brillation, giving a hospital mortality of 8.1 percent.Cardiac complications usually occur during the rst hour after exposure. Hypoxemia, electrolyte derangements and acidosis are major predisposing factors for the development of these complications. Intensive supportive treatment, meticulous respiratory care and administration of atropine in adequate doses very early in the course of the illness will reduce the mortality

Pattern and outcome of acute organophosphate poisoning at health facilities of Harari Region, Eastern Ethiopia

Introduction: Pesticides are frequently used by plant cultivars to control pests that could affect yield. Although many local farmers in Eastern Ethiopia use organophosphate insecticides extensively for the production of khat, the pattern and treatment outcome of acute poisoning of these organophosphates has been poorly quantified and reported in this region. Materials and Method: A cross-sectional study design was employed at two public hospitals found in Harari region, Ethiopia. The data were collected through face-to-face interviews and card review, then analyzed with SPSS version 20. Pearson’s Chi-square test was used to compare independent variables with the treatment outcome. Statistical significance is defined at 95% confidence interval of odds ratio not including 1 or p &lt; 0.05. Results: A total of 135 cases of organophosphate were admitted in the emergency departments of the hospitals during the study period. 42.2% of participants were adolescents (age: 11–20 years) while the mean age of all participants was 18.8 ± 12.9 years with a range of 1–61 years. 73.7% of the study participants were rural residents. The result showed that 47.4% of the cases were exposed to the poison accidentally. Family disharmony was the common reason among cases poisoned intentionally. The mean time elapsed between poisoning and reaching the health facility was 3.1 h. Atropine was administered for 47% of the cases. About 11% of cases expired following the poison. The home remedy given, lag time, and residency were found to be factors significantly related to poor treatment outcomes. Conclusion: Easy availability, low cost, and excessive popularity of organophosphate use as pesticides in Eastern Ethiopia have increased the incidence of ingestion, resulting in increasing intentional and unintentional poisoning. In the present study, accidental exposure accounts for 47.4%.

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning

Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.

The reversed De Ritis ratio for predicting in-hospital mortality among intensive care patients with organophosphate poisoning

Introduction The uncontrolled use of pesticides signifies a substantial health hazard. This study was designed to explore the prognostic role of on-admission hepatic aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the reversed De Ritis ratio (ALT/AST)] in the prediction of in-hospital mortality among patients with acute organophosphate (OP) poisoning. Patients and methods We conducted a retrospective study based on extracting the required information from the specific medical records for acutely OP-intoxicated patients admitted to the intensive care unit. Results A total of 49 acutely malathion-intoxicated patients were enrolled in the study. The in-hospital mortality rate was 32.7%. Patients were stratified into survivors and non-survivors. Compared to the survivors, the non-survivors had significantly lower Glasgow coma scale scores, mean arterial blood pressure, significantly higher reversed De Ritis ratio (ALT/AST), and ALT and AST activities. The reversed De Ritis ratio (ALT/AST) and ALT demonstrated good discrimination between the survivors and the non-survivors with an area under the curve (AUC) of 0.708 vs 0.781, respectively, however, AST showed satisfactory discrimination, AUC of 0.694. Conclusion Hepatic aminotransferases are useful in predicting in-hospital mortality in acute OP poisoning. ALT is the most specific biomarker. However, the reversed De Ritis ratio (ALT/AST) is the most sensitive one.

Investigation of acute organophosphate poisoning in humans based on sociodemographic and role of neurotransmitters with survival study in South India

The aim of this study was to investigate the sociodemographic characteristics of patients based on the poison chosen and different types of organophosphorus compounds. The data were collected to explore the sociodemographic characteristics of organophosphate (OP)-poisoned patients based on the source, site, and route of poisoning, education level, occupational status, and the purpose of poisoning. Furthermore, we estimated the serotonin and dopamine levels in the plasma samples of patients, and survival plots were also described. During the study of OP pesticide poisoning in 116 human subjects and 5 healthy volunteers, we observed, based on the survival plot, that75.9% of the patients were discharged, and the remaining patients died (24.1% of the patients) due to respiratory failure followed by cardiac arrest. Our findings suggest that the serotonin levels significantly (p < 0.01 and p < 0.001) decreased from 12 to 36 h, whereas the dopamine levels slightly increased from 12 to 36 h in the group with OP poisoning compared to the control group. Based on these findings, this study may aid in deciphering the precise mechanism by which pesticides cause behavioural changes that influence serotonin and dopamine levels in OP-poisoned patients. The purpose of this work was to serve as a small reminder of the risk to public health associated with organophosphate pesticides.