Beware of Neurotoxins in Common Plants: Water Hemlock Poisoning Presenting as Convulsive Status Epilepticus.

BACKGROUND: Pediatric status epilepticus occurs in about 44/100.000 children per year with an unknown cause in about a third of patients. One cause can be the ingestion of plants containing toxins that target the central nervous system. Here we describe an ingestion of water hemlock resulting in a status epilepticus. METHODS: We studied in detail the clinical, laboratory, electrophysiological, and radiological features of a patient with status epilepticus. RESULTS: A 9-year-old boy presented to the pediatric emergency department for sudden onset of nausea, vomiting, and status epilepticus approximately one hour after the patient had bitten into the root of a water plant in an inner-city park. Bilateral tonic-clonic seizures could only be terminated after administration of midazolam, lorazepam, and finally propofol. Cranial MRI, cerebrospinal fluid, and EEG findings were largely unremarkable. The ingested plant was identified as water hemlock through a detailed search with the help of a drawing issued by the patient with the help of the medical team. The specific toxicological analysis for water hemlock verified the presence of cicutoxin and cicudiol in the blood sample. The patient was discharged, levetiracetam was weaned off four weeks later, and he has remained seizure free since. CONCLUSIONS: Given the considerable percentage of cases of unknown etiology in new-onset pediatric status epilepticus, it is important to consider plant intoxication as a possible cause.

Botulinum Toxin: From Poison to Possible Treatment for Spasticity in Spinal Cord Injury.

Botulism has been known for about three centuries, and since its discovery, botulinum toxin has been considered one of the most powerful toxins. However, throughout the 20th century, several medical applications have been discovered, among which the treatment of spasticity stands out. Botulinum toxin is the only pharmacological treatment recommended for spasticity of strokes and cerebral palsy. Although its use as an adjuvant treatment against spasticity in spinal cord injuries is not even approved, botulinum toxin is being used against such injuries. This article describes the advances that have been made throughout history leading to the therapeutic use of botulinum toxin and, in particular, its application to the treatment of spasticity in spinal cord injury.

Awareness on tetrodotoxin of illegal activity: forensic issue from a rare homicide case report and literature review.

The authors describe an extremely rare case of homicide by injecting tetrodotoxin (TTX) as lethal neurotoxin found in puffer fish. After a thorough investigation, the male victim was found to have a broken stalk from syringe needle in the subcutaneous tissue of left buttock and severe asphyxia confirmed by the main pathological findings at autopsy. During tortuous toxicological analysis，TTX was revealed by ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) as well as acute intoxication confirmed from forensic examination. The literature of qualitative and quantitative determination of TTX from human fluids was also reviewed to expect widely acceptable detection strategies. This case highlighted the importance of TTX toxicant with chemical formula name purchased through e-commerce，so as to improve particular emphasis and supervision on harmful substances possibly using hidden information or illegal means. Histopathological and toxicological results demonstrated here provided a reference and other useful information to the challenges of forensic casework. In general, the case report illustrates medico-legal issues of more attention to the possibility of TTX poisoning in rapid death and the need of routine postmortem tox screening in future practice.

Neurotoxic Plants that Poison Livestock.

In the western United States, poisonous plants most often affect grazing livestock, and the related livestock losses are estimated to cost the grazing livestock industry more than $200 million annually. Many of these toxic plants contain neurotoxins that damage or alter the function of neurologic cells in the central and peripheral nervous systems. The objectives of this article are to present common North American neurotoxic plants, including conditions of poisoning, clinical disease, pathologic changes, and available diagnostics, to identify poisoned animals and the potential prognosis for poisoned animals.

Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine.

Snake venom three-finger α-neurotoxins (α-3FNTx) act on postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ) to produce skeletal muscle paralysis. The discovery of the archetypal α-bungarotoxin (α-BgTx), almost six decades ago, exponentially expanded our knowledge of membrane receptors and ion channels. This included the localisation, isolation and characterization of the first receptor (nAChR); and by extension, the pathophysiology and pharmacology of neuromuscular transmission and associated pathologies such as myasthenia gravis, as well as our understanding of the role of α-3FNTxs in snakebite envenomation leading to novel concepts of targeted treatment. Subsequent studies on a variety of animal venoms have yielded a plethora of novel toxins that have revolutionized molecular biomedicine and advanced drug discovery from bench to bedside. This review provides an overview of nAChRs and their subtypes, classification of α-3FNTxs and the challenges of typifying an increasing arsenal of structurally and functionally unique toxins, and the three-finger protein (3FP) fold in the context of the uPAR/Ly6/CD59/snake toxin superfamily. The pharmacology of snake α-3FNTxs including their mechanisms of neuromuscular blockade, variations in reversibility of nAChR interactions, specificity for nAChR subtypes or for distinct ligand-binding interfaces within a subtype and the role of α-3FNTxs in neurotoxic envenomation are also detailed. Lastly, a reconciliation of structure-function relationships between α-3FNTx and nAChRs, derived from historical mutational and biochemical studies and emerging atomic level structures of nAChR models in complex with α-3FNTxs is discussed.

Investigating the gene expression profiles of rehabilitated Florida manatees (Trichechus manatus latirostris) following red tide exposure.

To investigate a Florida manatee (Trichechus manatus latirostris) mortality event following a red tide bloom in Southwest Florida, an RNA sequencing experiment was conducted. Gene expression changes in white blood cells were assessed in manatees rescued from a red tide affected area (n = 4) and a control group (n = 7) using RNA sequencing. The genes with the largest fold changes were compared between the two groups to identify molecular pathways related to cellular and disease processes. In total, 591 genes (false discovery rate <0.05) were differentially expressed in the red tide group. Of these, 158 were upregulated and 433 were downregulated. This suggests major changes in white blood cell composition following an exposure to red tide. The most highly upregulated gene, Osteoclast associated 2C immunoglobulin-like receptor (OSCAR), was upregulated 12-fold. This gene is involved in initiating the immune response and maintaining a role in adaptive and innate immunity. The most highly downregulated gene, Piccolo presynaptic cytomatrix protein (PCLO), was downregulated by a factor of 977-fold. This gene is associated with cognitive functioning and neurotransmitter release. Downregulation of this gene in other studies was associated with neuronal loss and neuron synapse dysfunction. Among the cellular pathways that were most affected, immune response, including inflammation, wounds and injuries, cell proliferation, and apoptosis were the most predominant. The pathway with the most differentially expressed genes was the immune response pathway with 98 genes involved, many of them downregulated. Assessing the changes in gene expression associated with red tide exposure enhances our understanding of manatee immune response to the red tide toxins and will aid in the development of red tide biomarkers.

[Foodbourne Botulism: A Forgotten Disease]. / Botulismo Alimentar: Uma Doença Esquecida.

Botulism is a serious illness caused by exposure to botulinum toxin. It is manifested by flaccid, paralysis, symmetric and in descending pattern affecting cranial and peripheral nerves. Given the frequent need for invasive mechanical ventilation, these patients should be approached in an intensive care setting. Treatment with anti-botulinum toxin is the only effective treatment. The authors present the case of a 64-year-old patient, with vomiting and vertigo, evolution to diplopia, dysphagia and flaccid, muscle paralysis, installation after ingestion of canning homemade. From the etiologica, we highlight the electroneuromyogram study with a pre-synaptic lesion compatible with the botulism hypothesis. Progressive improvement of the deficits after administration of anti-botulinum toxin. A brief theoretical review is made of a serious, potentially fatal and infrequent pathology in our country.

O botulismo é uma doença grave causada pela exposição a toxina botulínica. Manifesta-se por paralisia flácida, simétrica e em padrão descendente que afeta nervos cranianos e periféricos. Dada a frequente necessidade de ventilação mecânica invasiva, estes doentes devem ser abordados em ambiente de cuidados intensivos. O tratamento com soro anti-toxina botulínica é o único eficaz. Os autores apresentam o caso de uma doente de 64 anos, com quadro de vómitos e vertigem, com evolução para diplopia, disfagia e parésia muscular flácida, simétrica e descendente, com instalação após ingestão de conserva alimentar de fabrico caseiro. Do estudo etiológico salienta-se eletroneuromiograma com lesão pré sináptica compatível com hipótese de botulismo. Melhoria progressiva dos défices após administração de soro anti-toxina botulínica. Faz-se uma breve revisão teórica de uma patologia grave, potencialmente fatal e pouco frequente no nosso país.

Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans.

Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve-muscle preparations, supporting its effectiveness in human post-synaptic paralysis.

Neurotoxicity of Prosopis juliflora: from Natural Poisoning to Mechanism of Action of Its Piperidine Alkaloids.

Prosopis juliflora was introduced in northeastern Brazil in the 1940s, and since then, it has been available as an alternative for animal nutrition. However, the consumption of P. juliflora as main or sole source of food causes an illness in animals known locally as "cara torta" disease. Cattle and goats experimentally intoxicated presents neurotoxic damage in the central nervous system. Histologic lesions were mainly characterized by vacuolation and loss of neurons in trigeminal motor nuclei. Furthermore, mitochondrial damage in neurons and gliosis was reported in trigeminal nuclei of intoxicated cattle. Studies, using neural cell cultures, have reproduced the main cellular alterations visualized in cara torta disease and contributed to understanding the mechanism of action piperidine alkaloids, the main neurotoxic compound in P. juliflora leaves and pods. Here, we will present aspects of the biological and toxicological properties of P. juliflora and its pharmacologically active compounds.

Subcellular Distribution of HDAC1 in Neurotoxic Conditions Is Dependent on Serine Phosphorylation.

Calcium-dependent nuclear export of histone deacetylase 1 (HDAC1) was shown previously to precede axonal damage in culture, but the in vivo relevance of these findings and the potential posttranslational modifications of HDAC1 remained elusive. Using acute hippocampal slices from mice of either sex with genetic conditional ablation of Hdac1 in CA1 hippocampal neurons (i.e., Camk2a-cre;Hdac1fl/fl), we show significantly diminished axonal damage in response to neurotoxic stimuli. The protective effect of Hdac1 ablation was detected also in CA3 neurons in Grik4-cre;Hdac1fl/f mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid. The amino acid residues modulating HDAC1 subcellular localization were identified by site-directed mutagenesis, which identified serine residues 421 and 423 as critical for its nuclear localization. The physiological phosphorylation of HDAC1 was decreased by neurotoxic stimuli, which stimulated the phosphatase enzymatic activity of calcineurin. Treatment of neurons with the calcineurin inhibitors FK506 or cyclosporin A resulted in nuclear accumulation of phospho-HDAC1 and was neuroprotective. Together, our data identify HDAC1 and the phosphorylation of specific serine residues in the molecule as potential targets for neuroprotection.SIGNIFICANCE STATEMENT The importance of histone deacetylation in normal brain functions and pathological conditions is unquestionable, yet the molecular mechanisms responsible for the neurotoxic potential of histone deacetylase 1 (HDAC1) and its subcellular localization are not fully understood. Here, we use transgenic lines to define the in vivo relevance of HDAC1 and identify calcineurin-dependent serine dephosphorylation as the signal modulating the neurotoxic role of HDAC1 in response to neurotoxic stimuli.

Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior.

Domoic acid (DA) is a neurotoxin that is naturally produced by phytoplankton and accumulates in seafood during harmful algal blooms. As the prevalence of DA increases in the marine environment, there is a critical need to identify seafood consumers at risk of DA poisoning. DA exposure was estimated in recreational razor clam (Siliqua patula) harvesters to determine if exposures above current regulatory guidelines occur and/or if harvesters are chronically exposed to low levels of DA. Human consumption rates of razor clams were determined by distributing 1523 surveys to recreational razor clam harvesters in spring 2015 and winter 2016, in Washington, USA. These consumption rate data were combined with DA measurements in razor clams, collected by a state monitoring program, to estimate human DA exposure. Approximately 7% of total acute exposures calculated (including the same individuals at different times) exceeded the current regulatory reference dose (0.075mgDA·kgbodyweight-1·d-1) due to higher than previously reported consumption rates, lower bodyweights, and/or by consumption of clams at the upper range of legal DA levels (maximum 20mg·kg-1 wet weight for whole tissue). Three percent of survey respondents were potentially at risk of chronic DA exposure by consuming a minimum of 15 clams per month for at 12 consecutive months. These insights into DA consumption will provide an additional tool for razor clam fishery management.

[Cholinesterase activity assays and their use in the diagnosis of various pathological states including poisoning by neurotoxic agents]. / Stanovení aktivity cholinesteras a jejich vyuzití pro diagnostiku patologických stavu.

Cholinesterases are enzymes important for some nerve transmissions where the enzyme acetylcholinesterase plays a crucial role. The second enzyme, butyrylcholinesterase, is not necessary for the neurotransmission but it is involved in some detoxification reactions. A survey of literature, a discussion of diagnostic importance and the methods for an activity assay are presented in this review article. Liver failures, exposure to neurotoxic compounds, genetic dispositions are outlined here. In the field of assays, spectrophotometric, colorimetric and electrochemical tests are discussed.Key words: acetylcholinesterase butyrylcholinesterase poisoning liver function test pesticide nerve agent Alzheimer disease pathological state.

¿Fueron los aztecas quienes primero representaron la enfermedad de Parkinson? / Were the Aztecs the first to represent Parkinson's disease?

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Risk to human health associated with the environmental occurrence of cyanobacterial neurotoxic alkaloids anatoxins and saxitoxins.

Cyanobacteria are ubiquitous photosynthetic micro-organisms forming blooms and scums in surface water; among them some species can produce cyanotoxins giving rise to some concern for human health and animal life. To date, more than 65 cyanobacterial neurotoxins have been described, of which the most studied are the groups of anatoxins and saxitoxins (STXs), comprising many different variants. In freshwaters, the hepatotoxic microcystins represent the most frequently detected cyanotoxin: on this basis, it could appear that neurotoxins are less relevant, but the low frequency of detection may partially reflect an a priori choice of target analytes, the low method sensitivity and the lack of certified standards. Cyanobacterial neurotoxins target cholinergic synapses or voltage-gated ion channels, blocking skeletal and respiratory muscles, thus leading to death by respiratory failure. This review reports and analyzes the available literature data on environmental occurrence of cyanobacterial neurotoxic alkaloids, namely anatoxins and STXs, their biosynthesis, toxicology and epidemiology, derivation of guidance values and action limits. These data are used as the basis to assess the risk posed to human health, identify critical exposure scenarios and highlight the major data gaps and research needs.

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment.

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.

Hospital-based surveillance for acute pesticide poisoning caused by neurotoxic and other pesticides in Tanzania.

BACKGROUND AND AIM: Acute pesticide poisoning (APP), particularly with neurotoxic agents, is often under-reported in developing countries. This study aimed to estimate the burden of APP in Tanzania due to neurotoxic and other pesticides in order to propose a surveillance system. METHODS: The study reviewed hospital admission data for APP retrospectively (2000-2005) in 30 facilities in four regions of Tanzania. A prospective follow-up over 12 months in 2006 focused on 10 facilities with the highest reporting of APP. RESULTS: The majority of known poisoning agents were organophosphates or WHO class I and II pesticides. APP involving suicide was significantly more likely to be fatal in both retrospective (PRR fatal/non-fatal=3.8; 95% CI=1.8-8.0) and in prospective (PRR=8.7; 95% CI=1.1-65) studies. There was a significant association between suicide and gender (PRR female/male=1.5; 95% CI=1.1-2.0) in the prospective study. Occupational circumstances as a cause of APP, which was relatively small in both studies (8.5% in the retrospective and 10.2% in the prospective study) was less common amongst men compared to women (6.1% for males versus 12.0% for females) in the retrospective study but almost equal in prospective study (10.2% for males versus 10.1% for females). Contrasting retrospective to prospective studies, the annual incidence rate almost tripled (from 1.43 to 4.05 per 100,000) and mortality rate doubled (from 0.11 to 0.22 per 100,000). Case fatality declined accordingly from 7.8% to 5.6% in prospective study. The study revealed a substantial improvement in the completeness of data with prospective data collection. Missing data for circumstances and agents declined by 24.1% and 9.9%, respectively. Despite this improvement, routine reporting could only generate 33-50% of the information needed for a notification of banned or severely restricted chemicals under the Prior Informed Consent (PIC) convention. CONCLUSION: The two to threefold increase in rates with prospective data collection suggests significant under-reporting of APP by neurotoxic and other pesticides. Routine reporting is likely to under-estimate the burden from pesticides, particularly for women in occupational settings. The burden of APP and the specific pesticides causing serious problems in Tanzania would continue to be missed without improved surveillance systems.

Perspectives on neuroinflammation and excitotoxicity: a neurotoxic conspiracy?

Emerging evidences underline the ability of several environmental contaminants to induce an inflammatory response within the central nervous system, named neuroinflammation. This can occur as a consequence of a direct action of the neurotoxicant to the CNS and/or as a response secondary to the activation of the peripheral inflammatory response. In both cases, neuroinflammation is driven by the release of several soluble factors among which pro-inflammatory cytokines. IL-1ß and TNF-α have been extensively studied for their effects within the CNS and emerged for their role in the modulation of the neuronal response, which allow the immune response to integrate with specific neuronal functions, as neurotransmission and synaptic plasticity. In particular, it has been evidenced a potential detrimental link between these cytokines and the glutamatergic system that seems to be part of increased brain excitability and excitotoxicity occurring in different pathological conditions. Aim of this mini-review will be to present experimental evidence on the way IL-1ß and TNF-α impact neurons, focusing on the glutamatergic signalling, to provide a perspective on novel pathways possibly involved in environmental contaminants neurotoxicity.

Domoic acid epileptic disease.

Domoic acid epileptic disease is characterized by spontaneous recurrent seizures weeks to months after domoic acid exposure. The potential for this disease was first recognized in a human case study of temporal lobe epilepsy after the 1987 amnesic shellfish-poisoning event in Quebec, and was characterized as a chronic epileptic syndrome in California sea lions through investigation of a series of domoic acid poisoning cases between 1998 and 2006. The sea lion study provided a breadth of insight into clinical presentations, unusual behaviors, brain pathology, and epidemiology. A rat model that replicates key observations of the chronic epileptic syndrome in sea lions has been applied to identify the progression of the epileptic disease state, its relationship to behavioral manifestations, and to define the neural systems involved in these behavioral disorders. Here, we present the concept of domoic acid epileptic disease as a delayed manifestation of domoic acid poisoning and review the state of knowledge for this disease state in affected humans and sea lions. We discuss causative mechanisms and neural underpinnings of disease maturation revealed by the rat model to present the concept for olfactory origin of an epileptic disease; triggered in dendodendritic synapases of the olfactory bulb and maturing in the olfactory cortex. We conclude with updated information on populations at risk, medical diagnosis, treatment, and prognosis.