Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

BACKGROUND: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. METHODS: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood-brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. RESULTS: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. CONCLUSION: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders.

Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication.

Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.

Portal vein gas and pneumatosis intestinalis: A case of intestinal necrosis caused by acute organophosphorus pesticide poisoning?

Acute organophosphorus pesticide poisoning (AOPP) is fairly common in rural areas of Asia. The symptoms of AOPP are mainly caused by acetylcholine accumulation. According to the clinical characteristics, AOPP symptoms can fall into the following three categories: muscarinic, nicotinic, and central. Death from fatal poisoning is caused by respiratory paralysis, and neurological complications are common. However, no case of intestinal necrosis caused by AOPP has been reported. Hepatic portal vein gas and pneumatosis intestinalis are considered typical and early imaging manifestations of intestinal necrosis. In this article, we describe a very rare case of computed tomography imaging-proven intestinal necrosis caused by AOPP.

Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication.

Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are potentially lethal and carry long-term neurological morbidity. Current antidotes for organophosphate (OP) intoxication include atropine, 2-PAM and diazepam (a benzodiazepine for treating seizures and SE). There is some evidence for partial or complete loss of diazepam anticonvulsant efficacy when given 30 min or later after exposure to an OP; this condition is known as refractory SE. Effective therapies for OP-induced SE are lacking and it is unclear why current therapies do not work. In this study, we investigated the time-dependent efficacy of diazepam in the nerve agent surrogate DFP model of OP intoxication on seizure suppression and neuroprotection in rats, following an early and late therapy. Diazepam (5 mg/kg, IM) controlled seizures when given 10 min after DFP exposure ("early"), but it was completely ineffective at 60 or 120 min ("late") after DFP. DFP-induced neuronal injury, neuroinflammation, and neurodegeneration of principal cells and GABAergic interneurons were significantly reduced by early but not late therapy. These findings demonstrate that diazepam failed to control seizures, SE and neuronal injury when given 60 min or later after DFP exposure, confirming the benzodiazepine-refractory SE and brain damage after OP intoxication. In addition, this study indicates that degeneration of inhibitory interneurons and inflammatory glial activation are potential mechanisms underlying these morbid outcomes of OP intoxication. Therefore, novel anticonvulsant and neuroprotectant antidotes, superior to benzodiazepines, are desperately needed for controlling nerve agent-induced SE and brain injury.

Acute renal involvement in organophosphate poisoning: histological and immunochemical investigations.

PURPOSE: Today, the long-term effects of partial exposure of cholinesterase on the kidney continue to be a research topic. In this study, we aimed to histopathologically investigate the possible effect of acute toxicity due to fenthion, an organophosphate (OP) compound, on the kidneys. METHODS: In all, 21 rats were randomly divided into three groups. Experimental group was each administered intraperitoneal 0.8 g/kg fenthion within physiologic serum. Sham group was only administered intraperitoneal physiologic serum. The control group continued normal nutrition with no procedure performed. After 24 h, all rats were sacrificed by cervical dislocation. Half of the recipient kidney tissues were examined histopathologically and the other half biochemically. RESULTS: No histopathological findings were found in the control group. Rats in the experimental group were observed to have epithelial cell disorganization in tubules, moderate epithelial cell loss, and degeneration. Again, expansion of tubules, vacuolization of tubular epithelial cells, and tubular structure approaching atrophy were observed, with cells approaching apoptosis and common hemorrhage noted although rats in the sham group were observed to have mild tubular degeneration. CONCLUSIONS: It should not be forgotten that one of the causes of systemic complaints linked to acute toxicity exposed to the OP compound of fenthion may be cellular injury to glomerular and tubular structures in the kidneys.

In vivo effects of intravenous lipid emulsion on lung tissue in an experimental model of acute malathion intoxication.

Malathion can be ingested, inhaled, or absorbed through the skin, but acute toxicity is maximized when administered orally. Intravenous lipid emulsion (ILE) treatment is used as a new therapeutic method in cases of systemic toxicity caused by some lipid soluble agents. This study aimed to examine the potential treatment effect of ILE on rat lung tissue in a toxicokinetic model of malathion exposure. Twenty-one adult Wistar albino rats were randomly divided into three equal groups. The groups were organized as group I (control), group II (malathion), and group III (malathion + ILE treatment). Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were evaluated in lung tissues. Immunohistochemical and Western blot analyses were performed to determine the bax, bcl-2, and caspase-3 expression levels. Tissue GSH-Px and SOD activities were decreased and MDA levels were increased in the malathion group. ILE administration increased GSH-Px and SOD activity and decreased MDA levels compared to the malathion group. Furthermore, expression of bax, bcl-2, and caspase-3 significantly increased in the malathion group, and ILE infusion reduced these expression levels. The present study revealed that acute oral malathion administration increased oxidative stress and apoptosis in the lung tissue of rats. ILE infusion prevented oxidative stress and decreased the deleterious effects of malathion. Taken together, the findings of our study suggest that lipid emulsion infusion has treatment efficacy on malathion-induced lung toxicity.

Protective effects of dietary omega-3 fatty acid supplementation on organophosphate poisoning.

In this study, we aimed to study the possible preventive effect of docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, on toxicity caused by chlorpyrifos (CPF). Six groups of Sprague Dawley rats (200-250 g) consisting of equal numbers of males and females (n = 8) were assigned to study. The rats were orally given for 5 days. The control group was administered pure olive oil, which was the vehicle for CPF. The CPF challenge groups were administered oral physiological saline, pure olive oil, or DHA (50, 100 and 400 mg/kg dosages) for 5 days. The animals were weighed on the sixth day and then administered CPF (279 mg/kg, subcutaneously). The rats were weighed again 24 h following CPF administration. The body temperatures and locomotor activities of the rats were also measured. Blood samples, brain and liver tissues were collected for biochemical, histopathological and immunohistochemical examinations. A comparison with the control group demonstrated that CPF administration increased malondialdehyde (MDA) levels in blood, brain and liver, while it reduced catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) concentrations ( p < 0.05-0.001). Advanced oxidation protein products (AOPPs) increased only in the brain ( p < 0.001). DHA reduced these changes in MDA and AOPP values ( p < 0.05-0.001), while it increased CAT, SOD and GPx concentrations ( p < 0.05-0.001). Similarly, DHA prevented the decreases in body weight, body temperature and locomotor activities caused by CPF at 100 mg/kg and 400 mg/kg dosages ( p < 0.05-0.001). Similar to the physiological and biochemical changes, the histopathological damage scores, which increased with CPF ( p < 0.05-0.01), decreased at all three dosages of DHA ( p < 0.05-0.01). Our findings suggest that DHA, by supporting the antioxidant mechanism, reduces toxicity caused by CPF.

Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Myasthenia gravis and related disorders: Pathology and molecular pathogenesis.

Disorders affecting the presynaptic, synaptic, and postsynaptic portions of the neuromuscular junction arise from various mechanisms in children and adults, including acquired autoimmune or toxic processes as well as genetic mutations. Disorders include autoimmune myasthenia gravis associated with acetylcholine receptor, muscle specific kinase or Lrp4 antibodies, Lambert-Eaton myasthenic syndrome, nerve terminal hyperexcitability syndromes, Guillain Barré syndrome, botulism, organophosphate poisoning and a number of congenital myasthenic syndromes. This review focuses on the various molecular and pathophysiological mechanisms of these disorders, characterization of which has been crucial to the development of treatment strategies specific for each pathogenic mechanism. In the future, further understanding of the underlying processes may lead to more effective and targeted therapies of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

The influence of organophosphate and carbamate on sperm chromatin and reproductive hormones among pesticide sprayers.

This study is aimed at evaluating the association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality as well as levels of reproductive and thyroid hormones of pesticide sprayers in Malihabad, Lucknow, Uttar Pradesh, India. Thirty-five healthy men (unexposed group) and 64 male pesticide sprayers (exposed group) were recruited for clinical evaluation of fertility status. Fresh semen samples were evaluated for sperm quality and analyzed for DNA fragmentation index (DFI) by flow cytometry. Pesticide exposure was assessed by measuring erythrocyte acetylcholinesterase and plasma butyrylcholinesterase (BuChE) with a Test-mate ChE field kit. Serum levels of total testosterone (Tt), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) were analyzed using enzyme immunoassay kits. Evidence of pesticide exposure was found in 88.5% of sprayers and significant increments were observed in sperm DFI with significant decrease in some semen parameters. DFI was negatively correlated with BuChE, sperm concentration, morphology, and vitality in these pesticide sprayers. The levels of Tt, PRL, FT4, and TSH appeared to be normal; however, there was a tendency for increased LH and FSH levels in exposed workers. The results confirm the potential impact of chronic occupational exposure to OP and CB pesticides on male reproductive function, which may cause damage to sperm chromatin, decrease semen quality, and produce alterations in reproductive hormones, leading to adverse reproductive health outcomes.

Clinical analysis of penehyclidine hydrochloride combined with hemoperfusion in the treatment of acute severe organophosphorus pesticide poisoning.

This study aimed to observe the clinical curative effect of penehyclidine hydrochloride (PHC) combined with hemoperfusion in treating acute severe organophosphorus pesticide poisoning. We randomly divided 61 patients with severe organophosphorus pesticide poisoning into an experimental group (N = 31) and a control group (N = 30), and we compared the coma-recovery time, mechanical ventilation time, healing time, hospital expenses, and mortality between the two groups. The coma-recovery time, mechanical ventilation time, and healing time were lower in the experimental group than in the control group (P < 0.05), while the hospitalization expenses were higher in the experimental group than in the control group (P < 0.01); moreover, no significant difference was observed in the mortality rate between the two groups. Thus, PHC combined with hemoperfusion exerts a better therapeutic effect in acute severe organophosphorus pesticide poisoning than PHC alone.

Acute pulmonary toxicity following inhalation exposure to aerosolized VX in anesthetized rats.

This study evaluated acute toxicity and pulmonary injury in rats at 3, 6 and 24 h after an inhalation exposure to aerosolized O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX). Anesthetized male Sprague-Dawley rats (250-300 g) were incubated with a glass endotracheal tube and exposed to saline or VX (171, 343 and 514 mg×min/m³ or 0.2, 0.5 and 0.8 LCt50, respectively) for 10 min. VX was delivered by a small animal ventilator at a volume of 2.5 ml × 70 breaths/minute. All VX-exposed animals experienced a significant loss in percentage body weight at 3, 6, and 24 h post-exposure. In comparison to controls, animals exposed to 514 mg×min/m³ of VX had significant increases in bronchoalveolar lavage (BAL) protein concentrations at 6 and 24 h post-exposure. Blood acetylcholinesterase (AChE) activity was inhibited dose dependently at each of the times points for all VX-exposed groups. AChE activity in lung homogenates was significantly inhibited in all VX-exposed groups at each time point. All VX-exposed animals assessed at 20 min and 3, 6 and 24 h post-exposure showed increases in lung resistance, which was prominent at 20 min and 3 h post-exposure. Histopathologic evaluation of lung tissue of the 514 mg×min/m³ VX-exposed animals at 3, 6 and 24 h indicated morphological changes, including perivascular inflammation, alveolar exudate and histiocytosis, alveolar septal inflammation and edema, alveolar epithelial necrosis, and bronchiolar inflammatory infiltrates, in comparison to controls. These results suggest that aerosolization of the highly toxic, persistent chemical warfare nerve agent VX results in acute pulmonary toxicity and lung injury in rats.

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.

[Effect of Huperzine A on neural lesion of acute organophosphate poisoning in mice].

OBJECTIVE: Effects of neurophathologic changes and expression of Glu and 60 nNOS were observed in acute isocarbophos and phoxim poisoning in mice. METHODS: KM male mice were randomly divided into three groups, which were control, non-treated and Huperzine A (HupA)-treated groups. The control group was given tween-80. Nontreated group was given isocarbophos (14.7 mg/kg) or phoxim (1702 mg/kg). HupA-treated group was given HupA 2h before phoxim or isocarbophos. Twenty-four hours after exposure, the whole brain was removed and adjacent coronal sections was obtained. One part of sections were stained with toluidine blue. The part of sections were used to assessed the expression of Glu and nNOS in the cortex and hippocampal of brain by immunohistochemistry. RESULTS: Compared to control group, non-treated group was observed nissal body nembers reduced and dyeing light. The animals of HupA protective group were observed nissal body nembers reduced, but the lesional degree was lighter obviously than non-treated group. The statistically reduced of the expression of Glu (P<0.01), the elevation of nNOS (P<0.01), after Isocarbophos intoxication were observed. Compared to non-treated group, the significant elevation of Glu (P<0.01) and reduced of nNOS (P<0.01) was observed on HupA-treated groups. Whereas for phoxim treatment, no changes were observed. CONCLUSION: HupA have protective effect against glutamatergic systems disorder caused by Isocarbophos poisoning. Administration of HupA have no effects of the neurotransmitter changes induces by acute poisoning of phoxim. It is different for the toxic effect mechanism of the two organophosphate.

Effects of acute organophosphate ingestion on cognitive function, assessed with the mini mental state examination.

BACKGROUND: Chronic damage to the central nervous system resulting in cognitive impairment has been shown with repeated, low doses of organophosphorus (OP) exposure over month or years. AIM: The study aimed to find out whether there is any cognitive impairment following acute OP exposure that could be detected by a simple screening instrument, the Mini Mental State Examination (MMSE), in clinical settings. SETTINGS AND DESIGN: A cohort study. MATERIALS AND METHODS: The study was conducted with matched controls. Consecutive patients admitted to the hospital with acute ingestion of OP were recruited. Cognitive function was assessed with the MMSE, digit span test, test of long-term memory function and concentration. Patients were assessed twice: at 1 and 6 weeks of exposure. STATISTICAL ANALYSIS: Continuous variables were analyzed with the paired and unpaired T-tests. Non-normally distributed data were analyzed with the Mann-Whitney U test and Wilcoxon Signed Rank test. Discrete variables were analyzed with the Chi-square test. RESULTS: There were 60 patients and 61 controls. The mean age (SD) of the patients and controls was 31.5 (11.6) and 31.3 (11.8) years, respectively. Forty-two patients turned up for the second assessment. Significant impairment of cognitive function was seen in the total score of MMSE (95% CI -2.5 to -0.3), orientation (95% CI -1 to -0.2) and language (95% CI -0.9 to -0.1) domains of MMSE, digit span test (95% CI 0.1-1.7) and test of long-term memory function (95% CI 0.3-2.3) in the first assessment compared with the controls. When the results of the second assessment were compared with the controls, no significant differences were seen. CONCLUSION: Although there was a slight transient cognitive impairment detected with the screening tests following acute OP ingestion, no long-term cognitive defects was detected.

[Intranasal dosing of nerve growth factor protects brain from poisoning of organophosphorus compounds in rats].

OBJECTIVE: To explore the protective effects of intranasal (IN) dosing of nerve growth factor (NGF) on brain injury induced by organophosphorus compounds (OP) in rats. METHODS: The OP-treated Sprague-Dawley rats received an intraperitoneal injection of atropine sulphate and pralidoxime at 1 min after intoxication. Then NGF or saline was dosed via the olfactory pathway. All rats were sacrificed 24 hours after OP exposure. Damaged nerve cells were estimated on corpus striatum strained with hematoxylin-eosin (H&E) method. And the activity of acetylcholinesterase (AchE) and the concentrations of malondialdehyde (MDA) and reduced glutathione hormone (GSH) in corpus striatum were measured by colorimetric method. RESULTS: As assessed by H&E staining, a large number of degenerated and necrotic nerve cells were observed in corpus striatum in rats from in IN saline group. But in IN NGF group, the number of degenerated neurons was smaller than in IN NS group. Following OP exposure, the activity of AchE decreased in corpus striatum in both IN saline and IN NGF groups (0.46 ± 0.11 vs 0.35 ± 0.09 U/mg prot). No significant differences existed between two groups. But the concentrations of MDA in corpus striatum of IN NGF group rats reduced markedly by 25.14% (4.02 ± 0.85 vs 5.37 ± 1.33 nmol/mg prot) and the level of GSH increased sharply by 15.73% (52.82 ± 2.80 vs 45.64 ± 4.88 mg/g prot) as compared with IN saline group (P < 0.05). CONCLUSION: Intranasal dosing of NGF may improve neuropathology and protect rats against OP-induced oxidative damage in corpus striatum.

Development of a histopathology scoring system for the pulmonary complications of organophosphorus insecticide poisoning in a pig model.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning.

Differences in biological activities between recombinant human paraoxonase 1 (rhPON1) subtype isozemys R/Q as antidotes against organophosphorus poisonings.

Paraoxonase 1 (PON1) is a type of aromatic esterase widely existing in mammals. It can hydrolyze various kinds of compounds effectively in vivo and in vitro. Previous studies have confirmed that PON1 can be used as antidote against organophosphorus poisonings (OPs). In this study, we obtained two subtype isozymes (i.e. rhPON1R192 and rhPON1Q192) by gene recombination and compared their detoxification effects against different OPs in rats. The rhPON1R192 demonstrated better detoxification effect against chlorpyrifos poisoning than the rhPON1Q192, whose detoxification effect against diazinon poisoning was prior to the former. Both of them showed poor detoxification effect against trithion. Therefore, we concluded that, to different OPs, better detoxification effect may be achieved by selecting the PON1 subtype isozyme with higher specific hydrolytic activity.

Increased heart fibrosis and acute infection in a murine Chagas disease model associated with organophosphorus pesticide metabolite exposure.

Some reports suggest that exposure to organophosphorus (OP) pesticides increases the incidence of infections. Ethylated dialkylphosphates (EtDAPs) are metabolites of OP pesticides widely distributed with immunomodulatory potential. Chagas disease is produced by Trypanosoma cruzi parasites, and resolution of this infection requires the activation of inflammatory macrophages (MΦ), which results in cardiac fibrosis. Some reports indicate that EtDAPs increase the amount of the anti-inflammatory alternatively activated MΦ (M2; CD206+F4/80+). Therefore, we analyzed the course of T. cruzi infection, MΦ profiles from peritoneal exudate cells (PECs), inflammatory cell infiltration and fibrosis in the heart of BALB/c mice exposed to diethyldithiophosphate (DEDTP), diethylthiophosphate (DETP) or diethylphosphate (DEP, 0.01 g/kg), common DAPs produced by OP pesticides, 24 h before infection with T. cruzi. We found that DEDTP increased the parasite burden in blood by 99% at the peak of the infection and enhanced the myocardial damage due to an increase in infiltrated inflammatory cells (induced by DEDTP or DETP) and fibrosis (induced by EtDAPs). In the PECs, exposure to EtDAPs increased the proportion of the MΦ subpopulations of M2a, M2b and M2d, which are associated with tissue repair. These results indicate that exposure to EtDAPs can exacerbate the acute phase of a parasitic infection and increase the long-term damage to the heart.

Risk of Seizures in Patients with Organophosphate Poisoning: A Nationwide Population-Based Study.

OBJECTIVE: Previous research has demonstrated that patients with a history of organophosphate poisoning tend to have a higher risk of neurological disorder. However, research on the rate of seizure development in patients after organophosphate poisoning is lacking. This study examined whether individuals with organophosphate poisoning have an increased risk of seizures through several years of follow-up. PATIENTS AND METHODS: We conducted a retrospective study on a cohort of 45,060 individuals (9012 patients with a history of organophosphate poisoning and 36,048 controls) selected from the Taiwan National Health Insurance Research Database. The individuals were observed for a maximum of 12 years to determine the rate of new-onset seizure disorder. We selected a comparison cohort from the general population that was randomly frequency-matched by age, sex, and index year and further analyzed the risk of seizures using a Cox regression model adjusted for sex, age, and comorbidities. RESULTS: During the study period, the risk of seizure development was 3.57 times greater in patients with organophosphate poisoning compared with individuals without, after adjustments for age, sex, and comorbidities. The absolute incidence of seizures was highest in individuals aged 20 to 34 years in both cohorts (adjusted hazard ratio = 13.0, 95% confidence interval = 5.40-31.4). A significantly higher seizure risk was also observed in patients with organophosphate poisoning and comorbidities other than cirrhosis. CONCLUSIONS: This nationwide retrospective cohort study demonstrates that seizure risk is significantly increased in patients with organophosphate poisoning compared with the general population.