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Developmental Neuroscience 2021Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with... (Review)
Review
Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic SCN1A variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.
Topics: Animals; Autism Spectrum Disorder; Brain Diseases; Exons; Humans; Mutation; Poisons
PubMed: 33971653
DOI: 10.1159/000516143 -
ALTEX 2021Handling of chemicals is an often-neglected area of test descriptions. Some important aspects are highlighted here, using methyl-phenyl-tetrahydropyridine (MPTP),...
Handling of chemicals is an often-neglected area of test descriptions. Some important aspects are highlighted here, using methyl-phenyl-tetrahydropyridine (MPTP), ferrous sulfate (FeSO4·xH2O) and ciguatoxin as example compounds. These are used to provide some background on aspects of acid-base equilibria, redox state, crystal water, natural compound mixtures, and chemical naming systems. Also, solvents and impurities are addressed, for instance concerning their often high (millimolar range) concentrations in assay buffers and cell culture media. The discussion of these aspects calls for a more standardized preparation of test solutions and a more extensive disclosure of the procedure in publications; it also suggests more flexibility in data mining, as compounds with clearly different identifiers may have been used to produce highly similar or fully identical test conditions. While this short overview is not intended as definitive guidance, it does demand more active involvement of all test developers and performers with these issues, and it calls for more transparent information disclosure concerning the preparation and use of test and control chemical solutions.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Ciguatoxins; Drug Contamination; Ferrous Compounds; Poisons; Quality Control; Reproducibility of Results
PubMed: 33452536
DOI: 10.14573/altex.2012311 -
Basic & Clinical Pharmacology &... Jun 2023Cyclopeptide mushroom poisoning is responsible for 90%-95% of deaths from macrofungi ingestion. The main objectives of this study are to describe cases of cyclopeptide...
Cyclopeptide mushroom poisoning is responsible for 90%-95% of deaths from macrofungi ingestion. The main objectives of this study are to describe cases of cyclopeptide mushroom poisoning and to determine risk factors that may influence the severity/mortality of poisoned patients. We included all cases of amatoxin toxicity reported to two French Poison Centers from 2013 through 2019. We compared the severity with the Poison Severity Score (PSS) and the outcomes of patients using simple logistic regression and multinomial logistic regression. We included 204 cases of amatoxin toxicity. More than three-quarters developed an increase in AST and/or ALT (78.1%), and over half developed a decrease in prothrombin ratio (<70%: 53%) and/or Factor V (<70%: 54%). One-third developed an acute renal injury (AKI). Twelve patients (5.9%) developed post-poisoning sequelae (persistent kidney injury more than 1 month after ingestion and liver transplant). Five patients (2.5%) received a liver transplant, and nine died (4.4%). The mean time to onset of digestive disorders was shorter in PSS2 and PSS3-4 patients (10.9 ± 3.9/11.3 ± 6.3 h) than in PSS1 patients (14 ± 6.5 h; p < 0.05). Patients who died or developed post-poisoning sequelae had more frequent cardiovascular comorbidities compared with recovered patients (60.0% versus 29.5%; p < 0.01).
Topics: Humans; Mushroom Poisoning; Peptides, Cyclic; Retrospective Studies; Liver Failure, Acute; Disease Progression; Poisons
PubMed: 36908014
DOI: 10.1111/bcpt.13858 -
The Veterinary Clinics of North... Nov 2020Whether poisoned by grazing toxic plants or by eating feeds that are contaminated by toxic plants, affected livestock often have compromised reproductive function... (Review)
Review
Whether poisoned by grazing toxic plants or by eating feeds that are contaminated by toxic plants, affected livestock often have compromised reproductive function including infertility, abortion, and fetal deformities. Certainly all diagnostic tools-field studies, clinical signs, gross and microscopic pathology as well as chemical identification of plant and plant toxins in animal samples-are essential to make an accurate diagnosis, to develop intervening management strategies and to improve the reproductive performance. The objectives of this review are to briefly introduce toxic plants that are reproductive toxins, abortifacients, or teratogens.
Topics: Abortifacient Agents; Animals; Congenital Abnormalities; Female; Genital Diseases, Female; Genital Diseases, Male; Infertility; Livestock; Male; Plant Poisoning; Plants, Toxic
PubMed: 33032703
DOI: 10.1016/j.cvfa.2020.08.004 -
Toxicon : Official Journal of the... Dec 2020Baccharis coridifolia is one of the most common poisonous plants affecting livestock in Uruguay. Poisoning occurs when animals raised in areas free of B. coridifolia are...
Baccharis coridifolia is one of the most common poisonous plants affecting livestock in Uruguay. Poisoning occurs when animals raised in areas free of B. coridifolia are transported to pastures containing the plant. Young stock become spontaneously averted to it after ingesting non-toxic amounts of the plant. As B. coridifolia is widespread in the country, farmers selling livestock report when animals have been raised in areas with the plant, meaning that they are naturally averted and will not ingest it if introduced in B. coridifolia-containing paddocks. Of 2456 farmers from 18 departments of Uruguay selling cattle through online auctions between June 2019 and May 2020, 78% mentioned that the animals they were selling were raised in grasslands containing B. coridifolia. However, only 35.8% of the farmers from three departments of Eastern Uruguay mentioned that their cattle were raised in grasslands with B. coridifolia. Herds from these departments presented 16.7 times (95% CI: 13.1-21.3; p < 0.001) more risk of not being naturally averted to B. coridifolia ingestion than the herds of the other 15 departments of the country. In this paper we review all outbreaks of B. coridifolia poisoning reported in livestock in Uruguay from 1911 to present. We also describe three outbreaks of poisoning, one in cattle and two in sheep that were poisoned in the same farms in which the animals were raised. Intoxication occurred when the animals raised indoors and/or in cultivated pastures without B. coridifolia were introduced into grasslands of the same farms containing B. coridifolia. Typical gastrointestinal lesions were observed in pathological examinations. Furthermore, two of three necropsied heifers showed severe acute nephrosis, which had not been reported previously in this poisoning.
Topics: Animals; Baccharis; Cattle; Cattle Diseases; Disease Outbreaks; Livestock; Plant Poisoning; Plants, Toxic; Sheep; Uruguay
PubMed: 33049244
DOI: 10.1016/j.toxicon.2020.10.006 -
Journal of Primary Health Care Sep 2021
Topics: Borago; Humans; Poisons
PubMed: 34588114
DOI: 10.1071/HC19564 -
Anti-cancer Agents in Medicinal... 2022Regardless of the growing discovery of anticancer treatments targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance... (Review)
Review
Regardless of the growing discovery of anticancer treatments targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance because tumours harbor a greater population of actively dividing cells than normal tissues. Conventional anti-mitotic agents or microtubule poisons acting on the major mitotic spindle protein tubulin have been effectively used in clinical settings for cancer chemotherapy over the last three decades. However, the use of these drugs is associated with limited clinical utility due to serious side effects such as debilitating and dose-limiting peripheral neuropathy, myelosuppression, drug resistance, and allergic reactions. Therefore, research initiatives have been undertaken to develop novel microtubule motor proteins inhibitors that can potentially circumvent the limitations associated with conventional microtubule poisons. Kinesin spindle proteins (KSP) belonging to the kinesin-5 family play a crucial role during mitosis and unregulated cell proliferation. Evidence from preclinical studies and different phases of clinical trials have presented kinesin spindle protein as a promising target for cancer therapeutics. Kinesin spindle protein inhibitors causing mitosis disruption without interfering with microtubule dynamics in non-dividing cells offer a potential therapeutic alternative for the management of several major cancer types and are devoid of side effects associated with classical anti-mitotic drugs. This review summarizes recent data highlighting progress in the discovery of targeted KSP inhibitors and presents the development of scaffolds, structure-activity relationships, and outcomes of biological and enzyme inhibition studies. We reviewed the recent literature reports published over the last decade, using various electronic database searches such as PubMed, Embase, Medline, Web of Science, and Google Scholar. Clinical trial data till 2021 was retrieved from ClinicalTrial.gov. Major chemical classes developed as selective KSP inhibitors include dihydropyrimidines, β-carbolines, carbazoles, benzimidazoles, fused aryl derivatives, pyrimidines, fused pyrimidines, quinazolines, quinolones, thiadiazolines, spiropyran, and azobenzenes. Drugs such as filanesib, litronesib, ispinesib have entered clinical trials; the most advanced phase explored is Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.
Topics: Antineoplastic Agents; Humans; Kinesins; Neoplasms; Poisons; Pyrimidines; Tubulin Modulators
PubMed: 35043768
DOI: 10.2174/1871520622666220119093105 -
Basic & Clinical Pharmacology &... Dec 2022The primary aim of this pilot study was to develop a machine learning algorithm to predict and distinguish eight poisoning agents based on clinical symptoms. Data were...
The primary aim of this pilot study was to develop a machine learning algorithm to predict and distinguish eight poisoning agents based on clinical symptoms. Data were used from the National Poison Data System from 2014 to 2018, for patients 0-89 years old with single-agent exposure to eight drugs or drug classes (acetaminophen, aspirin, benzodiazepines, bupropion, calcium channel blockers, diphenhydramine, lithium and sulfonylureas). Four classifier prediction models were applied to the data: logistic regression, LightGBM, XGBoost, and CatBoost. There were 201 031 cases used to develop and test the algorithms. Among the four models, accuracy ranged 77%-80%, with precision and F1 scores of 76%-80% and recall of 77%-78%. Overall specificity was 92% for all models. Accuracy was highest for identifying sulfonylureas, acetaminophen, benzodiazepines and diphenhydramine poisoning. F1 scores were highest for correctly classifying sulfonylureas, acetaminophen and benzodiazepine poisonings. Recall was highest for sulfonylureas, acetaminophen, and benzodiazepines, and lowest for bupropion. Specificity was >99% for models of sulfonylureas, calcium channel blockers, lithium and aspirin. For single-agent poisoning cases among the eight possible exposures, machine learning models based on clinical signs and symptoms moderately predicted the causal agent. CatBoost and LightGBM classifier models had the highest performance of those tested.
Topics: Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Poison Control Centers; Poisons; Pilot Projects; Acetaminophen; Bupropion; Lithium; Calcium Channel Blockers; Machine Learning; Diphenhydramine; Benzodiazepines; Aspirin; Poisoning
PubMed: 36181236
DOI: 10.1111/bcpt.13800 -
The Veterinary Clinics of North... Nov 2020Whether exposed by grazing toxic range or pasture plants or by eating contaminated feed, there are plant toxins that produce urinary tract disease, gastroenteritis, and... (Review)
Review
Whether exposed by grazing toxic range or pasture plants or by eating contaminated feed, there are plant toxins that produce urinary tract disease, gastroenteritis, and other miscellaneous or multisystemic diseases. Diagnosis can be challenging and requires incorporation of field studies, clinical signs, gross and microscopic pathology, and chemical identification of plants, toxins, and metabolites in animal samples. The objectives of this review are to introduce poisonous plants that commonly poison livestock in North America; describe clinical and pathologic lesions they produce in livestock; and present current technology available to identify poisoning, treat affected animals, and minimize or avoid poisoning additional animals.
Topics: Animals; Gastrointestinal Diseases; Livestock; North America; Oxalates; Plant Poisoning; Plants, Toxic; Urologic Diseases
PubMed: 33032700
DOI: 10.1016/j.cvfa.2020.08.006 -
Emergency Medicine Clinics of North... May 2022
Topics: Emergency Medicine; Emergency Service, Hospital; Humans; Poisoning
PubMed: 35461634
DOI: 10.1016/j.emc.2022.03.002