Are anticoagulant drugs ecotoxic for meiobenthic nematodes from Saudi Arabia? First data on taxon/functional diversity and computational evidences.

Community-level effects of anticoagulants have little been studied in the laboratory. In the current study, the different effects of Warfarin and Tinzaparin, individually or in combination, on meiofauna were investigated for the first time using two concentrations (5 and 25 mg·l-1) of Warfarin (W1 and W2) and Tinzaparin (T1 and T2) for 30 days. The results obtained highlighted the highest tolerance of nematodes and amphipods toward the two anticoagulants tested. Moreover, nematode abundance and taxonomic diversity decreased directly after exposure to T2 and T2W1 because of the high mortality of diatom feeders and their replacement by non-selective deposit feeders (case of Tinzaparin) or omnivores-carnivores (case of Warfarin). The relative taxon/functional similarity between controls and mixtures T1W1 and T2W2 recommends that the toxicity of Tinzaparin can be attenuated by Warfarin. Finally, the computational study of Warfarin supports its potential ecotoxicity since it satisfactorily bound and interacted with GLD-3 and SDP macromolecules.

Evaluation of anticoagulant rodenticide sensitivity by examining in vivo and in vitro responses in avian species, focusing on raptors.

Anticoagulant rodenticides (ARs) are used to control pest rodent species but can result in secondary poisoning of non-target animals, especially raptors. In the present study, differences in AR sensitivity among avian species were evaluated by comparing in vivo warfarin pharmacokinetics and effects, measuring cytochrome P450s (CYPs) expression involved in AR metabolism, and conducting in vitro inhibition assays of the AR target enzyme Vitamin K 2,3-epoxide reductase (VKOR). Oral administration of warfarin at 4 mg/kg body weight did not prolong prothrombin time in chickens (Gallus gallus), rock pigeons (Columba livia), or Eastern buzzards (Buteo japonicus). Rock pigeons and buzzards exhibited shorter plasma half-life of warfarin compared to chickens. For the metabolite analysis, 4'-hydroxywarfarin was predominantly detected in all birds, while 10-hydroxywarfarin was only found in pigeons and raptors, indicating interspecific differences in AR metabolism among birds likely due to differential expression of CYP enzymes involved in the metabolism of ARs and variation of VKOR activities among these avian species. The present findings, and results of our earlier investigations, demonstrate pronounced differences in AR sensitivity and pharmacokinetics among bird species, and in particular raptors. While ecological risk assessment and mitigation efforts for ARs have been extensive, AR exposure and adverse effects in predatory and scavenging wildlife continues. Toxicokinetic and toxicodynamic data will assist in such risk assessments and mitigation efforts.

An atypical presentation of anticoagulant rodenticide toxicosis in a dog.

A 5-month-old intact female Australian shepherd dog was referred to our clinic for neurologic signs including ataxia, a head tilt, and altered mentation following consumption of an unidentified rodenticide several days prior to developing clinical signs. A provisional diagnosis of bromethalin toxicosis had been made, given the neurologic signs seen and the general increased use of bromethalin-containing rodenticide products. However, on physical examination, the dog was noted to have scleral hemorrhage and bleeding at the venipuncture sites, which was inconsistent with bromethalin toxicosis. Coagulation testing was supportive of anticoagulant rodenticide toxicosis and the rodenticide was later identified as the first-generation anticoagulant rodenticide diphacinone. The neurologic signs seen were attributed to a coagulopathy causing multifocal hemorrhage into the central nervous system. Neurologic signs rapidly resolved following treatment with a frozen plasma transfusion and vitamin K1. This atypical presentation of an anticoagulant rodenticide toxicosis highlights the need for accurate product identification, if available, and thorough patient examination and laboratory testing. An atypical presentation of anticoagulant rodenticide toxicosis should be considered when neurologic signs are present with clinical bleeding, especially if the type of rodenticide is unknown, or even if it was not thought to have an anticoagulant as the active ingredient. Key clinical message: Given the change in commercially available rodenticide products, this case highlights the need for accurate product identification in cases of suspected toxicosis, and the variable clinical signs that can be seen following anticoagulant rodenticide toxicosis.

Présentation atypique d'une toxicose aux rodenticides anticoagulants chez un chien. Une chienne berger australien intacte âgée de 5 mois a été référée à notre clinique pour des signes neurologiques, notamment de l'ataxie, une inclinaison de la tête et une altération de l'état mental à la suite de la consommation d'un rodenticide non identifié plusieurs jours avant l'apparition des signes cliniques. Un diagnostic provisoire de toxicose à la brométhaline avait été posé, compte tenu des signes neurologiques observés et d'une utilisation historique accrue de produits rodenticides contenant de la brométhaline. Cependant, lors de l'examen physique, il a été constaté que le chien présentait une hémorragie sclérale et des saignements au niveau des sites de ponction veineuse, ce qui n'était pas cohérent avec une toxicose à la brométhaline. Les tests de coagulation ont confirmé la toxicose au rodenticide anticoagulant et le rodenticide a ensuite été identifié comme étant le rodenticide anticoagulant de première génération diphacinone. Les signes neurologiques observés ont été attribués à une coagulopathie provoquant une hémorragie multifocale du système nerveux central. Les signes neurologiques ont rapidement disparu après un traitement par transfusion de plasma congelé et de vitamine K1. Cette présentation atypique d'une toxicose aux rodenticides anticoagulants met en évidence la nécessité d'une identification précise du produit, si disponible, ainsi que d'un examen approfondi du patient et de tests de laboratoire. Une présentation atypique de toxicose des rodenticides anticoagulants doit être envisagée lorsque des signes neurologiques sont présents avec saignement clinique, en particulier si le type de rodenticide est inconnu, ou même si l'on ne pense pas qu'un anticoagulant soit l'ingrédient actif.Message clinique clé :Compte tenu de l'évolution des produits rodenticides disponibles dans le commerce, ce cas met en évidence la nécessité d'une identification précise du produit en cas de suspicion de toxicose et les signes cliniques variables qui peuvent être observés à la suite d'une toxicose au rodenticide anticoagulant.(Traduit par Dr Serge Messier).

Silent killers? The widespread exposure of predatory nocturnal birds to anticoagulant rodenticides.

Anticoagulant rodenticides (ARs) influence predator populations and threaten the stability of ecosystems. Understanding the prevalence and impact of rodenticides in predators is crucial to inform conservation planning and policy. We collected dead birds of four nocturnal predatory species across differing landscapes: forests, agricultural, urban. Liver samples were analysed for eight ARs: three First Generation ARs (FGARs) and five SGARs (Second Generation ARs). We investigated interspecific differences in liver concentrations and whether landscape composition influenced this. FGARs were rarely detected, except pindone at low concentrations in powerful owls Ninox strenua. SGARs, however, were detected in every species and 92 % of birds analysed. Concentrations of SGARs were at levels where potential toxicological or lethal impacts would have occurred in 33 % of powerful owls, 68 % of tawny frogmouths Podargus strigoides, 42 % of southern boobooks N. bookbook and 80 % of barn owls Tyto javanica. When multiple SGARs were detected, the likelihood of potentially lethal concentrations of rodenticides increased. There was no association between landscape composition and SGAR exposure, or the presence of multiple SGARs, suggesting rodenticide poisoning is ubiquitous across all landscapes sampled. This widespread human-driven contamination in wildlife is a major threat to wildlife health. Given the high prevalence and concentrations of SGARs in these birds across all landscape types, we support the formal consideration of SGARs as a threatening process. Furthermore, given species that do not primarily eat rodents (tawny frogmouths, powerful owls) have comparable liver rodenticide concentrations to rodent predators (southern boobook, eastern barn owl), it appears there is broader contamination of the food-web than anticipated. We provide evidence that SGARs have the potential to pose a threat to the survival of avian predator populations. Given the functional importance of predators in ecosystems, combined with the animal welfare impacts of these chemicals, we propose governments should regulate the use of SGARs.

Active metabolite of the neurotoxic rodenticide bromethalin along with anticoagulant rodenticides detected in birds of prey in the northeastern United States.

Little is known about the ecologic fate of the neurotoxic rodenticide bromethalin, which is currently registered for use in the United States, Canada, and other countries including Australia. There is minimal research on bromethalin's potential to cause secondary toxicosis in nontarget wildlife. The aim of this study was to evaluate adipose tissue in four species of birds of prey presented to a wildlife clinic in Massachusetts, USA, for desmethylbromethalin (DMB), the active metabolite of bromethalin. Birds were also screened for anticoagulant rodenticides (ARs) in liver tissue to present a more complete picture of rodenticide exposures in this geographic area and to evaluate the impact of current mitigation measures in place during the time of sampling, 2021-2022. A total of 44 hawks and owls were included; DMB was found in 29.5% of birds and ARs were present in 95.5%. All birds with DMB detections also had residues of ARs. Among birds positive for ARs, 81% had two or more compounds. To the authors' knowledge the data presented here represent the first published monitoring study to document bromethalin/DMB bioaccumulation in obligate carnivores. As DMB is a more potent neurotoxicant than its parent compound, these results are cause for concern and an indication that further monitoring and study of the potential risk of bromethalin to wildlife species is needed. These findings have global implications as increasing concern regarding exposure to and toxicosis from ARs in nontarget wildlife worldwide leads to a search for alternatives and effective mitigation approaches.

Interest of the faecal and plasma matrix for monitoring the exposure of wildlife or domestic animals to anticoagulant rodenticides.

Anticoagulant rodenticides (ARs), particularly second-generation compounds (SGAR), are known to be a potential threat to unintended species due to their tissue persistence. The liver is the storage tissue of ARs and is a matrix of choice in diagnosing exposure and intoxication of non-target fauna. However, it is only available on dead animals. Blood and faeces can be used on living animals. These two biological matrices were compared in terms of their relevance to exposure to ARs. In addressing this question, we compared the faecal, plasma and liver concentrations of bromadiolone, one of the SGAR frequently implicated in wildlife exposure. We studied this comparison at the individual level and at the population level, considering three influencing factors: dose, sex and time. Our findings demonstrate that faecal analyses are more valuable than plasma analyses for monitoring AR exposure of domestic and wild animals, even if faecal concentrations cannot be correlated with liver concentrations.

A Combined Bioassay and Nanofractionation Approach to Investigate the Anticoagulant Toxins of Mamba and Cobra Venoms and Their Inhibition by Varespladib.

Envenomation by elapid snakes primarily results in neurotoxic symptoms and, consequently, are the primary focus of therapeutic research concerning such venoms. However, mounting evidence suggests these venoms can additionally cause coagulopathic symptoms, as demonstrated by some Asian elapids and African spitting cobras. This study sought to investigate the coagulopathic potential of venoms from medically important elapids of the genera Naja (true cobras), Hemachatus (rinkhals), and Dendroaspis (mambas). Crude venoms were bioassayed for coagulant effects using a plasma coagulation assay before RPLC/MS was used to separate and identify venom toxins in parallel with a nanofractionation module. Subsequently, coagulation bioassays were performed on the nanofractionated toxins, along with in-solution tryptic digestion and proteomics analysis. These experiments were then repeated on both crude venoms and on the nanofractionated venom toxins with the addition of either the phospholipase A2 (PLA2) inhibitor varespladib or the snake venom metalloproteinase (SVMP) inhibitor marimastat. Our results demonstrate that various African elapid venoms have an anticoagulant effect, and that this activity is significantly reduced for cobra venoms by the addition of varespladib, though this inhibitor had no effect against anticoagulation caused by mamba venoms. Marimastat showed limited capacity to reduce anticoagulation in elapids, affecting only N. haje and H. haemachatus venom at higher doses. Proteomic analysis of nanofractionated toxins revealed that the anticoagulant toxins in cobra venoms were both acidic and basic PLA2s, while the causative toxins in mamba venoms remain uncertain. This implies that while PLA2 inhibitors such as varespladib and metalloproteinase inhibitors such as marimastat are viable candidates for novel snakebite treatments, they are not likely to be effective against mamba envenomings.

Massive warfarin overdose management in an adolescent patient.

INTRODUCTION: Warfarin is a widely used oral anticoagulant with established reversal guidelines in the setting of a supratherapeutic international normalized ratio (INR). Limited literature exists on managing acute warfarin overdoses in patients who are not chronically anticoagulated. CASE: A 15-year-old male, with no indication for anticoagulation, presented to a pediatric emergency department after an acute 1,000 mg warfarin ingestion. He had no significant complaints upon presentation aside from a mild intermittent headache. His past medical history was significant for anxiety, depression, Tourette syndrome, attention deficit hyperactivity disorder, and polysubstance misuse. Computed tomography of his head was unremarkable and serum acetaminophen, salicylate, and ethanol concentrations were negative. Approximately 16 h post-ingestion, his INR was 1.9 with an increase to 3.3 by 26 h. The regional poison center was consulted and recommended, consistent with the CHEST guidelines, holding treatment with vitamin K until INR was >10 or if signs or symptoms of bleeding occurred. The patient was admitted for monitoring and by hospital day (HD) #4, his INR had risen to >11.8 at which point oral vitamin K 10 mg was administered. On HD #7, the patient was deemed stable for transfer to inpatient psychiatry after repeat INRs of 2.9 and 3.4. DISCUSSION: Case reports have demonstrated early administration of vitamin K can temporarily lower INR and prevent detection of rebound. The CHEST warfarin reversal guidelines describe the risks and benefits with respect to bleeding and thrombosis in the non-intentional overdose patient. Application and extrapolation of these guidelines to acute overdose in patients who lack an indication for anticoagulation may or may not be warranted. CONCLUSION: While established clinical guidance exists on reversing a supratherapeutic INR in patients chronically anticoagulated with warfarin, the risks and benefits of extrapolating this approach are unclear in those who lack an indication for anticoagulation.

Toxicokinetic analysis of the anticoagulant rodenticides warfarin & diphacinone in Egyptian fruit bats (Rousettus aegyptiacus) as a comparative sensitivity assessment for Bonin fruit bats (Pteropus pselaphon).

Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals and birds to the poisons to ensure the rodenticides are used effectively. The Bonin Islands are an archipelago located 1000 km southeast of the Japanese mainland and are famous for the unique ecosystems. Here the first-generation anticoagulant rodenticide diphacinone has been used against introduced black rats (Rattus rattus). The only land mammal native to the archipelago is the Bonin fruit bat (Pteropus pselaphon), but little is known regarding its sensitivity to rodenticides. In this study, the Egyptian fruit bats (Rousettus aegyptiacus) was used as a model animal for in vivo pharmacokinetics and pharmacodynamics analysis and in vitro enzyme kinetics using their hepatic microsomal fractions. The structure of vitamin K epoxide reductase (VKORC1), the target protein of the rodenticide in the Bonin fruit bat, was predicted from its genome and its binding affinity to rodenticides was evaluated. The Egyptian fruit bats excreted diphacinone slowly and showed similar sensitivity to rats. In contrast, they excreted warfarin, another first-generation rodenticide, faster than rats and recovered from the toxic effect faster. An in silico binding study also indicated that the VKORC1 of fruit bats is relatively tolerant to warfarin, but binds strongly to diphacinone. These results suggest that even chemicals with the same mode of action display different sensitivities in different species: fruit bat species are relatively resistant to warfarin, but vulnerable to diphacinone.

Collateral damage: Anticoagulant rodenticides pose threats to California condors.

Anticoagulant rodenticides (ARs) are widespread environmental contaminants that pose risks to scavenging birds because they routinely occur within their prey and can cause secondary poisoning. However, little is known about AR exposure in one of the rarest avian scavengers in the world, the California condor (Gymnogyps californianus). We assessed AR exposure in California condors and surrogate turkey vultures (Cathartes aura) to gauge potential hazard to a proposed future condor flock by determining how application rate and environmental factors influence exposure. Additionally, we examined whether ARs might be correlated with prolonged blood clotting time and potential mortality in condors. Only second-generation ARs (SGARs) were detected, and exposure was detected in all condor flocks. Liver AR residues were detected in 42% of the condors (27 of 65) and 93% of the turkey vultures (66 of 71). Although concentrations were generally low (<10 ng/g ww), 48% of the California condors and 64% of the turkey vultures exposed to ARs exceeded the 5% probability of exhibiting signs of toxicosis (>20 ng/g ww), and 10% and 13% exceeded the 20% probability of exhibiting signs toxicosis (>80 ng/g ww). There was evidence of prolonged blood clotting time in 16% of the free-flying condors. For condors, there was a relationship between the interaction of AR exposure index (legal use across regions where condors existed) and precipitation, and the probability of detecting ARs in liver. Exposure to ARs may complicate recovery efforts of condor populations within their current range and in the soon to be established northern California experimental population. Continued monitoring of AR exposure using plasma blood clotting assays and residue analysis would allow for an improved understanding of their hazard to condors, particularly if paired with recent movement data that could elucidate exposure sources on the landscape occupied by this endangered species.

Untangling interactions between Bitis vipers and their prey using coagulotoxicity against diverse vertebrate plasmas.

Venom is a key evolutionary innovation which plays a primary role in prey subjugation by venomous snakes. However, while there is a growing body of literature indicating the composition and activity of snake venoms is under strong natural selection driven by differences in prey physiology, the majority of studies have historically focussed on the activity of snake venoms with regards only towards human or mammalian physiologies. This study aimed to use clotting assays measuring both time and strength of clotting to characterise the coagulotoxic activity of venoms from a taxonomically, morphologically, and ecologically diverse range of Bitis spp. of viperid snakes upon the plasma of model species: amphibian (Cane Toad, Rhinella marina); lizard (Blue-tongue Skink, Tiliqua scincoides); avian (Domestic Chicken, Gallus gallus); and rodent (Brown Rat, Rattus norvegicus). Significant variation in coagulotoxic activity across the different plasmas was observed between species and compared to the known affects upon human plasma. Bitis caudalis was notable in being active on all four plasmas, but in extremely divergent manners: accelerating clotting times and producing strong, stable clots upon amphibian plasma (consistent with true procoagulation); accelerating clotting time but producing weak, unstable clots upon lizard plasma (consistent with pseudo-procoagulation); delaying avian clotting time beyond machine maximum reading time (strong anticoagulation consistent with either inhibition of clotting enzymes or total destruction of fibrinogen, or both); and delaying clotting of rodent plasma (consistent with inhibition of clotting enzymes) and with only weak clots formed (consistent with destruction of fibrinogen). In contrast, the sister species B. peringueyi and B. schneideri displayed activity only upon the lizard plasma, slightly accelerating the clotting times to produce weak, unstable clots (consistent with pseudo-procoagulation). The other dwarf species, B. cornuta, displayed strong anticoagulation upon avian and rodent plasmas, delaying clotting beyond the machine maximum reading time (strong anticoagulation consistent with either inhibition of clotting enzymes or total destruction of fibrinogen, or both). In contrast, the giant species studied (B. gabonica) showed only a very weak pseudo-procoagulant activity upon lizard plasma. The wide range of variation seen within this study highlights the importance of studying venom activity on relevant models when making conclusions about the ecological role of venoms and the extreme limitation in extrapolating animal results to predict potential human clinical effects.

Anticoagulant rodenticide use in oil palm plantations in Southeast Asia and hazard assessment to non-target animals.

Anticoagulant rodenticides (ARs) are used worldwide for the control of rodent pests and are the main method of control of rat pest populations in agricultural areas. The main aim of this review is to discuss the risk of ARs to non-target wildlife in oil palm areas in Southeast Asia, mainly Indonesia and Malaysia. We discussed AR use in oil palm areas and toxicities of ARs on target and non-target animals. We also reviewed published literature on wildlife species reported in oil palm areas in Southeast Asia and utilizing this information, we assessed the hazard risk of ARs to non-target wildlife in oil palm plantations. ARs are a secondary exposure hazard to rodent-consuming mammalian carnivores, such as leopard cats and civets, and rodent-consuming raptors, such as barn owls. Consumption of dead poisoned prey puts scavengers, such as water monitors, at high risk for AR exposure. Domestic livestock and granivorous birds are at high risk for AR exposure via primary exposure to toxic bait, while omnivores such as macaques and wild pigs are at moderate risk for both primary and secondary exposure to ARs. The effects of ARs on barn owls have been well studied in the field and in laboratory secondary toxicity studies. Thus, the nest-box occupancy and reproductive parameters of local barn owl populations can be monitored as an indicator of the AR exposure level in the area. CLINICAL TRIALS REGISTRATION: No clinical trials were involved in this study.

Toxicological responses to sublethal anticoagulant rodenticide exposure in free-flying hawks.

An important component of assessing the hazards of anticoagulant rodenticides to non-target wildlife is observations in exposed free-ranging individuals. The objective of this study was to determine whether environmentally realistic, sublethal first-generation anticoagulant rodenticide (FGAR) exposures via prey can result in direct or indirect adverse effects to free-flying raptors. We offered black-tailed prairie dogs (Cynomys ludovicianus) that had fed on Rozol® Prairie Dog Bait (Rozol, 0.005% active ingredient chlorophacinone, CPN) to six wild-caught red-tailed hawks (RTHA, Buteo jamaicensis), and also offered black-tailed prairie dogs that were not exposed to Rozol to another two wild-caught RTHAs for 7 days. On day 6, blood was collected to determine CPN's effects on blood clotting time. On day 7, seven of the eight RTHAs were fitted with VHF radio telemetry transmitters and the RTHAs were released the following day and were monitored for 33 days. Prothrombin time (PT) and Russell's viper venom time confirmed that the CPN-exposed RTHAs were exposed to and were adversely affected by CPN. Four of the six CPN-exposed RTHAs exhibited ptiloerection, an indication of thermoregulatory dysfunction due to CPN toxicity, but no signs of intoxication were observed in the reference hawk or the remaining two CPN-exposed RTHAs. Of note is that PT values were associated with ptiloerection duration and frequency; therefore, sublethal CPN exposure can directly or indirectly evoke adverse effects in wild birds. Although our sample sizes were small, this study is a first to relate coagulation times to adverse clinical signs in free-ranging birds.

Prevalence of anticoagulant rodenticide exposure in red-tailed hawks (Buteo jamaicensis) and utility of clotting time assays to detect coagulopathy.

Anticoagulant rodenticides (ARs) continue to be used across the United States as a method for controlling pest rodent species. As a consequence, wild birds of prey are exposed to these toxicants by eating poisoned prey items. ARs prevent the hepatic recycling of vitamin K and thereby impede the post-translational processing of coagulation factors II, VII, IX, and X that are required for procoagulant complex assembly. Through this mechanism of action, ARs cause hemorrhage and death in their target species. Various studies have documented the persistence of these contaminants in birds of prey but few have attempted to use affordable and accessible diagnostic tests to diagnose coagulopathy in free-ranging birds of prey. In our study free-ranging red-tailed hawks were found to be exposed to difethialone and brodifacoum. Eleven of sixteen (68%) livers tested for AR exposure had detectable residues. Difethialone was found in 1/16 (6%), and brodifacoum was detected in 10/16 (62%) liver samples that were tested for rodenticide residues. Difethialone was found at a concentration of 0.18 ug/g wet weight and brodifacoum concentrations ranged from 0.003-0.234 ug/g wet weight. Two out of 34 (6%) RTHA assessed for blood rodenticide had brodifacoum in serum with measured concentrations of 0.003 and 0.006 ug/g. The range of clotting times in the prothrombin time (PT) and Russell's viper venom time assays for control RTHA were 16.7 to 39.7 s and 11.5 to 91.8 s, respectively. One study bird was diagnosed with clinical AR intoxication with a brodifacoum levels in blood of 0.006 and 0.234 ug/g wet weight in blood and liver respectively, a packed cell volume (PCV) of 19%, and PT and RVVT times of >180 s. No correlation was found between PT and RVVT in the control or free-range RTHA, and there was no relationship found between the presence of liver anticoagulant residues and clotting times in the PT and RVVT.

Short-term exposure of anticoagulant rodenticides leads to the toxin accumulation from prey (Rattus losea) to predator (Elanus caeruleus).

Rodenticides are widely used around the world since the 1950s. In Taiwan, an anti-rodent operation initiated 1977 and became a regular action annually implied by the government until 2014. This anti-rodent operation caused many animals of non-target species being exposed by rodenticides and became an environmental issue. The Black-winged Kite (Elanus caeruleus) is a small-sized diurnal raptor widely distributed in the Old World continent. Since 2000, a newly colonized population of this species occurred in Taiwan. Although the Black-winged Kites may suffer from the threats of rodenticides, the population is still growing and soon became the most abundant raptor in farmlands of Taiwan. Whether the Black-winged Kite accumulates higher anticoagulant rodenticide residues than other raptors are still unclear. In this study, liver samples of Black-winged Kites were collected from 2013 to 2016, when the detected residues of anticoagulant rodenticides increased annually. The concentration of residue rodenticide was above 0.2 ppm among 30% of the detected samples, which is the toxicity threshold concentration of other raptors. In the meanwhile, the lesser ricefield rat (Rattus losea), the most common prey of Black-winged Kites, also extended the survival period after fed on rodenticide. The longer survival days after being poisoned can enhance the predation opportunity of raptors, thus affect the accumulated rodenticides in the raptors. This study demonstrates that the Black-winged Kite has higher concentration of anticoagulant rodenticide than most other raptors, which provide the case that the raptor can quickly accumulate rodenticide residues within a short period of time.

Differential coagulotoxic and neurotoxic venom activity from species of the arboreal viperid snake genus Bothriechis (palm-pitvipers).

The viperid snake genus Bothriechis consists of eleven species distributed among Central and South America, living across low and high-altitude habitats. Despite Bothriechis envenomations being prominent across the Central and South American region, the functional effects of Bothriechis venoms are poorly understood. Thus, the aim of this study was to investigate the coagulotoxic and neurotoxic activities of Bothriechis venoms to fill this knowledge gap. Coagulotoxic investigations revealed Bothriechis nigroviridis and B. schlegelii to have pseudo-procoagulant venom activity, forming weak clots that rapidly break down, thereby depleting fibrinogen levels and thus contributing to a net anticoagulant state. While one sample of B. lateralis also showed weaker pseudo-procoagulant activity, directly clotting fibrinogen, two samples of B. lateralis venom were anticoagulant through the inhibition of thrombin and factor Xa activity. Differential efficacy of PoliVal-ICP antivenom was also observed, with the pseudo-procoagulant effect of B. nigroviridis venom poorly neutralised, despite this same activity in the venom of B. schlegelii being effectively neutralised. Significant specificity of these fibrinogen cleaving toxins was also observed, with no activity upon model amphibian, avian, lizard or rodent plasma observed. However, upon avian plasma the venom of B. nigroviridis exerted a complete anticoagulant effect, in contrast to the pseudo-procoagulant effect seen on human plasma. Neurotoxic investigations revealed B. schlegelii to be unique among the genus in having potent binding to the orthosteric site of the alpha-1 postsynaptic nicotinic acetylcholine receptor (with B. lateralis having a weaker but still discernible effect). This represents the first identification of postsynaptic nAChR neurotoxic activity for Bothriechis. In conclusion this study identifies notable differential activity within the coagulotoxic and postsynaptic neurotoxic activity of Bothriechis venoms, supporting previous research, and highlights the need for further studies with respect to antivenom efficacy as well as coagulotoxin specificity for Bothriechis venoms.

Sanitary measures considerably improve the management of resistant Norway rats on livestock farms.

BACKGROUND: Norway rats (Rattus norvegicus) need to be controlled to prevent transmission of pathogens and damages to stored products and material, leading to considerable economic risks and losses. Given increasing resistance in Norway rats, the most persistent, bio-accumulative and toxic anticoagulant rodenticides are widely used for management, which presents hazards to the environment especially for non-target species. We investigated how sanitary measures improved management of Norway rats on 12 paired livestock farms in a region of Germany with a high population of resistant rats for reducing application of rodenticides. We recorded food intake, and tracked activity and resistance frequency during the pre-treatment, treatment and post-treatment periods. RESULTS: In the post-treatment period, farms using sanitary measures had a higher control success with > 13% more bait boxes without feeding than farms not using sanitary measures. In addition, the reoccurrence of rats was delayed by 85 days. With increasing accessibility to buildings and more precise positioning of the boxes, control success improved, especially when rats could not spread from water-bearing ditches through the sewer system, and when rat-hunting animals were present. Resistant animals were more common indoors than outdoors, and there were more resistant rats recorded before and during treatment than in the post-treatment period. CONCLUSION: The control success was substantially higher and reoccurrence was delayed using sanitary measures on farms. Sanitary measures can reduce resistance indirectly due to delayed re-colonization and establishment of resistant populations inside buildings. Hence, sanitary measures help to reduce economic losses, rodenticides required for rat management and environmental risk especially in the resistance area. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Risk factors associated with warfarin overdose and complications related to warfarin overdose in the emergency department.

The aim of this study was to investigate risk factors of bleeding and mortality in patients with warfarin overdose (WOD). Totally, 783 patients were included, of which, 272 patients (34.7%) with an INR below 5,364 patients (46.5%) with an INR between 5-10, and 147 patients (18.8%) with an INR of 10 or above. Demographic, clinical, and laboratory findings of the patients were obtained from the Real Life Data Provision Center and Hospital Information Management System. Admittance in autumn (OR = 1.75; p = 0.012), INR = 5-10 (OR = 2.65; p < 0.001), INR ≥ 10 (OR = 9.06; p < 0.001), and antiplatelet use alongside warfarin (OR = 1.93; p < 0.001) were found to be independent risk factors for bleeding in this study. The age (OR= 1.03; p = 0.005), bleeding (OR = 1.69; p = 0.020), primary hypertension (OR = 1.72; p = 0.031), and INR ≥ 10 (OR = 2.02; p = 0.025) were found to be independent risk factors for mortality. The cutoff value for INR in predicting bleeding was found to be >6.35 with 74.2% sensitivity and 72.7% specificity. The significant risk factors were determined in WOD development. INR level, autumn, and antiplatelet use were independently associated with bleeding due to WOD. In addition, bleeding, hypertension and INR levels were independently related to in-hospital-mortality due to WOD.

The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.

Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.