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The Journal of Emergency Medicine Mar 2019Mercury poisoning is an uncommon diagnosis in the United States, but it is a differential diagnosis that physicians should consider because it can lead to potentially...
BACKGROUND
Mercury poisoning is an uncommon diagnosis in the United States, but it is a differential diagnosis that physicians should consider because it can lead to potentially fatal complications if untreated. Due to the nonspecific presentation of mercury poisoning, which includes symptoms such as fever, nausea, vomiting, and abdominal pain, misdiagnosis may occur unless a proper history is taken.
CASE REPORT
In the present case, a white female patient was misdiagnosed repeatedly with a viral illness and sent home from the local hospital. The patient presented with a diffuse full-body rash, fever, myalgias, headache, peripheral neuropathy, oral paresthesias, and tender cervical posterior lymphadenopathy. After obtaining a thorough history, it was discovered that the patient and her family were exposed to mercury through a spill of elemental mercury in their home. Blood mercury levels in the patient were 170 ng/mL. The patient was treated with a course of dimercaprol. Her symptoms improved and she was discharged on hospital day 5. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ultimately, mercury poisoning is a treatable condition, but if exposure continues and the patient is not treated, it may lead to complications such as severe pneumonitis, renal tubular necrosis, and neurological dysfunction. In some instances, neurological symptoms may persist even if the source of exposure is removed. For these reasons, recognition and prompt treatment after a suspected exposure is important.
Topics: Adult; Chelating Agents; Chelation Therapy; Emergency Service, Hospital; Environmental Exposure; Exanthema; Female; Fever; Humans; Mercury; Mercury Poisoning; Myalgia; Succimer
PubMed: 30718027
DOI: 10.1016/j.jemermed.2018.12.039 -
Bioorganic & Medicinal Chemistry Letters Jan 2019Reported herein is a fluorescence assay for the rapid screening of metallo-β-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate...
Reported herein is a fluorescence assay for the rapid screening of metallo-β-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.
Topics: Carbapenems; Dose-Response Relationship, Drug; Fluorescence; Fluorescent Dyes; Humans; Molecular Structure; Structure-Activity Relationship; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 30470495
DOI: 10.1016/j.bmcl.2018.11.025 -
Acta Pharmaceutica Sinica. B Oct 2020Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we...
Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from , , and were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments.
PubMed: 33163338
DOI: 10.1016/j.apsb.2020.09.005 -
Journal of Applied Microbiology Jun 2023To perform a prospective diagnostic study exploring the clinical utility of metagenomic next-generation sequencing (mNGS) in diagnosing community-acquired pneumonia...
Application of metagenomic next-generation sequencing in the diagnosis and resistome analysis of community-acquired pneumonia pathogens from bronchoalveolar lavage samples.
AIMS
To perform a prospective diagnostic study exploring the clinical utility of metagenomic next-generation sequencing (mNGS) in diagnosing community-acquired pneumonia (CAP), and revealing resistome differences in bronchoalveolar lavage fluid (BALF) from CAP patients with varying severity of admission base on Pneumonia Patient Outcomes Research Team (PORT) risk classes.
METHODS AND RESULTS
We compared the diagnostic performances of mNGS and conventional testing for the detection of pathogens in BALF from 59 CAP patients, and performed resistome differences analysis of metagenomic data from 59 BALF samples, namely, 25 from CAP patients with PORT score I (I group), 14 from CAP patients with PORT score II (II group), 12 from CAP patients with PORT score III (III group), and 8 from CAP patients with PORT score IV (IV group). The diagnostic sensitivities of mNGS and conventional testing for the detection of pathogens in BALF in patients with CAP were 96.6% (57/59) and 30.5% (18/59), respectively. There was a significant difference in the overall relative abundance of resistance genes between the four groups (P = 0.014). The results of principal coordinate analysis based on Bray-Curtis dissimilarities showed that there were significant differences in the composition of resistance genes among the I, II, III, and IV groups (P = 0.007). A large number of antibiotic resistance genes, such as those affiliated with multidrug, tetracycline, aminoglycoside, and fosfomycin resistance, were enriched in the IV group.
CONCLUSIONS
In conclusion, mNGS has a high diagnostic value in CAP. There were significant differences present in microbiota resistance to antibiotics in BALF from CAP patients in different PORT risk classes, which should attract enough attention.
Topics: Humans; Prospective Studies; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; High-Throughput Nucleotide Sequencing; Anti-Bacterial Agents; Dimercaprol; Metagenomics; Pneumonia; Sensitivity and Specificity
PubMed: 37188649
DOI: 10.1093/jambio/lxad102 -
Pharmaceutics Feb 2023Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines....
Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines. Ionizable cationic lipids are the most important component in LNPs. Herein, we developed a series of new ionizable lipids featuring bioreducible disulfide bonds, and constructed a library of lipids derived from dimercaprol. LNPs prepared from these ionizable lipids could be stored at 4 °C for a long term and are non-toxic toward HepG2 and 293T cells. In vivo experiments demonstrated that the best C4S18A formulations, which embody linoleoyl tails, show strong firefly luciferase (Fluc) mRNA expression in the liver and spleen via intravenous (IV) injection, or at the local injection site via intramuscular injection (IM). The newly designed ionizable lipids can be potentially safe and high-efficiency nanomaterials for mRNA therapy.
PubMed: 36839799
DOI: 10.3390/pharmaceutics15020477 -
Redox Biology Jul 2024Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory...
Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP's ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.
Topics: Animals; Rats; Glutathione; Status Epilepticus; Oxidative Stress; Neuroinflammatory Diseases; Male; Disease Models, Animal; Hippocampus; Cysteamine; Antioxidants; Glutamate-Cysteine Ligase; Liver
PubMed: 38714094
DOI: 10.1016/j.redox.2024.103168 -
Science Translational Medicine May 2020Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to...
Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to systemic hemorrhage and coagulopathy and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity and low affordability and must be administered in clinical settings because of its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially affects patient outcomes after envenoming. Here, we investigated the value of metal ion chelators as prehospital therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS) were found to potently antagonize the activity of Zn-dependent snake venom metalloproteinases in vitro. Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also considerably extended survival in a "challenge and treat" model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming. Last, the potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that the safe and affordable repurposed metal chelator DMPS can effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the promise of this drug as an early, prehospital, therapeutic intervention for hemotoxic snakebite envenoming.
Topics: Africa; Animals; Asia; Chelating Agents; Humans; Mice; Snake Bites; Viper Venoms
PubMed: 32376771
DOI: 10.1126/scitranslmed.aay8314 -
Probing the mechanisms of inhibition for various inhibitors of metallo-β-lactamases VIM-2 and NDM-1.Journal of Inorganic Biochemistry Sep 2020To probe the mechanism of inhibition of several previously-published metallo-β-lactamase (MBL) inhibitors for the clinically-important MBL Verona integron-encoded...
To probe the mechanism of inhibition of several previously-published metallo-β-lactamase (MBL) inhibitors for the clinically-important MBL Verona integron-encoded metallo-β-lactamase 2 (VIM-2), equilibrium dialyses with metal analyses, native state electrospray ionization mass spectrometry (ESI-MS), and UV-Vis spectrophotometry were utilized. The mechanisms of inhibition were analyzed for ethylenediaminetetraacetic acid (EDTA); dipicolinic acid (DPA) and DPA analogs 6-(1H-tetrazol-5-yl)picolinic acid (1T5PA) and 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid (3AP-DPA); thiol-containing compounds, 2,3-dimercaprol, thiorphan, captopril, and tiopronin; and 5-(pyridine-3-sulfonamido)-1,3-thiazole-4-carboxylic acid (ANT-431). UV-Vis spectroscopy and native-state ESI-MS results showed the formation of ternary complexes between VIM-2 and 1T5PA, ANT-431, thiorphan, captopril, and tiopronin, while a metal stripping mechanism was shown with VIM-2 and EDTA and DPA. The same approaches were used to show the formation of a ternary complex between New Delhi Metallo-β-lactamase (NDM-1) and ANT-431. The studies presented herein show that most of the inhibitors utilize a similar mechanism of inhibition as previously reported for NDM-1. These studies also demonstrate that native mass spectrometry can be used to probe the mechanism of inhibition at lower enzyme/inhibitor concentrations than has previously been achieved.
Topics: Protein Binding; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Zinc; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 32622213
DOI: 10.1016/j.jinorgbio.2020.111123 -
Journal of Veterinary Internal Medicine 2023Nonbronchoscopic bronchoalveolar lavage (nBAL) is routinely performed in calves, and airway cytology has great potential in airway disease diagnostics. A good reference...
BACKGROUND
Nonbronchoscopic bronchoalveolar lavage (nBAL) is routinely performed in calves, and airway cytology has great potential in airway disease diagnostics. A good reference framework for nBAL cytology is lacking.
OBJECTIVES
To distinguish different cytological profiles in nBAL from grouped housed calves using cluster analysis, and characterize these profiles on individual and herd levels.
ANIMALS
Three hundred thirty-eight group-housed calves from 60 herds (mainly dairy and beef ).
METHODS
Cross-sectional study. Differential counts of white blood cells were determined on nBAL fluid, followed by differentiation of cytological profiles by K-means-based cluster analysis. These profiles were characterized by reference values, decision tree analysis, and associations with clinical, ultrasonographic, bacteriological, and cytological features.
RESULTS
A normal (55.9%), a neutrophilic (41.1%), and an eosinophilic profile (3.0%) were identified. The normal profile was characterized by reference values of 2.3% to 47.4% neutrophils, 35.1% to 95.1% macrophages, 0.4 to 22.9% lymphocytes, and 0.0% to 0.9% eosinophils. The neutrophilic profile was characterized by ≥44.5% neutrophils, <1.6% eosinophils, and <11.5% lymphocytes. This profile was associated with the isolation of Pasteurella multocida, the presence of neutrophils with toxic granulation, and the presence of phagocytosed bacteria in neutrophils. The eosinophilic profile was characterized by eosinophils ≥1.6% (neutrophilia present) or ≥2.4% (neutrophilia absent), and associated with the presence of mast cells. On herd level, the neutrophilic and eosinophilic profiles were present in 85.0% and 15.0% of the herds, respectively.
CONCLUSIONS AND CLINICAL IMPORTANCE
This study provides a first step in the development of cytological guidelines, aiding the assessment of airway health and inflammation in calves through nBAL fluid cytology.
Topics: Animals; Cattle; Bronchoalveolar Lavage Fluid; Cross-Sectional Studies; Bronchoalveolar Lavage; Inflammation; Cluster Analysis; Dimercaprol; Cattle Diseases
PubMed: 37731196
DOI: 10.1111/jvim.16855 -
The American Journal of Case Reports Jul 2023BACKGROUND ThinPrep Cytolyt is a methanol-based cell preservation solution frequently used to fix tissue samples immediately following endobronchial ultrasound-guided...
BACKGROUND ThinPrep Cytolyt is a methanol-based cell preservation solution frequently used to fix tissue samples immediately following endobronchial ultrasound-guided fine-needle aspiration. Currently, no published reports describe an iatrogenic exposure to Cytolyt. We report the only known case of an accidental intraoperative administration of a methanol solution, with corresponding plasma concentrations, and successful treatment with fomepizole. CASE REPORT A 70-year-old woman with a history of stage IIIA rectal adenocarcinoma was referred for evaluation of a newly identified lung mass. During the procedure, a bronchoalveolar lavage (BAL) of the right upper lobe was performed. After BAL, the proceduralist was informed that the syringe used to instill fluid for the BAL contained Cytolyt rather than saline. The Department of Medical Toxicology was contacted immediately, and the patient received a 15 mg/kg dose of fomepizole. The first plasma methanol level, before fomepizole administration, was elevated to 21 mg/dL. The methanol level was 13 mg/dL 3 h after fomepizole treatment and even lower thereafter; therefore, no additional fomepizole was required. The patient did not develop signs of systemic toxicity and was discharged on hospital day 3. CONCLUSIONS Following methanol exposures, patients can exhibit metabolic acidosis, with potential for blindness, hemodynamic instability, and possibly death if untreated. Fomepizole (4-methylpyrazole) inhibits alcohol dehydrogenase and is a mainstay of treatment. Preventing medical errors is key in ensuring optimal patient care and decreasing adverse events. Providers using CytoLyt and any similar products should be aware of this potential error and approach the possibility of methanol toxicity as they would other routes of methanol exposure.
Topics: Female; Humans; Aged; Fomepizole; Methanol; Antidotes; Pyrazoles; Dimercaprol; Iatrogenic Disease
PubMed: 37461205
DOI: 10.12659/AJCR.937247