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Scientific Reports May 2020Two unique housefly strains, PSS and N-PRS (near-isogenic line with the PSS), were used to clarify the mechanisms associated with propoxur resistance in the housefly,...
Two unique housefly strains, PSS and N-PRS (near-isogenic line with the PSS), were used to clarify the mechanisms associated with propoxur resistance in the housefly, Musca domestica. The propoxur-selected resistant (N-PRS) strain exhibited >1035-fold resistance to propoxur and 1.70-, 12.06-, 4.28-, 57.76-, and 57.54-fold cross-resistance to beta-cypermethrin, deltamethrin, bifenthrin, phoxim, and azamethiphos, respectively, compared to the susceptible (PSS) strain. We purified acetylcholinesterase (AChE) from the N-PRS and PSS strains using a procainamide affinity column and characterized the AChE. The sensitivity of AChE to propoxur based on the bimolecular rate constant (K) was approximately 100-fold higher in the PSS strain compared to the N-PRS strain. The cDNA encoding Mdace from both the N-PRS strain and the PSS strain were cloned and sequenced using RT-PCR. The cDNA was 2073 nucleotides long and encoded a protein of 691 amino acids. A total of four single nucleotide polymorphisms (SNPs), I162M, V260L, G342A, and F407Y, were present in the region of the active site of AChE from the N-PRS strain. The transcription level and DNA copy number of Mdace were significantly higher in the resistant strain than in the susceptible strain. These results indicated that mutations combined with the up-regulation of Mdace might be essential in the housefly resistance to propoxur.
Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Gene Expression Regulation, Enzymologic; Houseflies; Insect Proteins; Insecticide Resistance; Insecticides; Mutation; Polymorphism, Single Nucleotide; Propoxur
PubMed: 32439946
DOI: 10.1038/s41598-020-65242-3 -
Molecular Omics Aug 2020Small molecule monosaccharide analogs (e.g. 4F-GlcNAc, 4F-GalNAc) and acceptor decoys (e.g. ONAP, SNAP) are commonly used as metabolic glycoengineering tools to perturb...
Robustness in glycosylation systems: effect of modified monosaccharides, acceptor decoys and azido sugars on cellular nucleotide-sugar levels and pattern of N-linked glycosylation.
Small molecule monosaccharide analogs (e.g. 4F-GlcNAc, 4F-GalNAc) and acceptor decoys (e.g. ONAP, SNAP) are commonly used as metabolic glycoengineering tools to perturb molecular and cellular recognition processes. Azido-derivatized sugars (e.g. ManNAz, GlcNAz, GalNAz) are also used as bioorthogonal probes to assay the glycosylation status of cells and tissue. With the goal of obtaining a systems-level understanding of how these compounds work, we cultured cells with these molecules and systematically evaluated their impact on: (i) cellular nucleotide-sugar levels, and (ii) N-linked glycosylation. To this end, we developed a streamlined, simple workflow to quantify nucleotide-sugar levels using amide-based hydrophilic interaction liquid chromatography (HILIC) separation followed by negative-mode electrospray ionization mass spectrometry (ESI-MS/MS) using an Orbitrap detector. N-Glycans released from cells were also procainamide functionalized and quantified using positive-mode ESI-MS/MS. Results show that all tested compounds changed the baseline nucleotide-sugar levels, with the effect being most pronounced for the fluoro-HexNAc compounds. These molecules depressed UDP-HexNAc levels in cells by up to 80%, while concomitantly elevating UDP-4F-GalNAc and UDP-4F-GlcNAc. While the measured changes in nucleotide-sugar concentration were substantial in many cases, their impact on N-linked glycosylation was relatively small. This may be due to the high nucleotide-sugar concentrations in the Golgi, which far exceed the K values of the glycosylating enzymes. Thus, the glycosylation system output exhibits 'robustness' even in the face of significant changes in cellular nucleotide-sugar concentrations.
Topics: Azides; Chromatography, Liquid; Glycomics; Glycosylation; HL-60 Cells; Humans; Intracellular Space; Monosaccharides; Nucleotides; Polysaccharides; Sugars; Tandem Mass Spectrometry
PubMed: 32352119
DOI: 10.1039/d0mo00023j -
Experimental Physiology May 2020What is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined...
NEW FINDINGS
What is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency? What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy.
ABSTRACT
Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S -S [basic drive cycle length] = 550 ms) and short (S -S = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S -S = 550 ms were significantly attenuated at S -S = 200 ms, in both the regular (S ) and the premature (S ) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S -S pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S and S beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S -S intervals, it was invariably reduced by these agents at the short S -S intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Electrophysiological Phenomena; Female; Flecainide; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Phenethylamines; Procainamide; Quinidine; Sulfonamides
PubMed: 32175633
DOI: 10.1113/EP088165 -
Drug Safety - Case Reports Sep 2019Systemic lupus erythematosus (SLE) can be induced by various medications, such as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, and...
Systemic lupus erythematosus (SLE) can be induced by various medications, such as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, and minocycline. A patient was admitted complaining of fever with chills and rigor. After being diagnosed with tuberculous meningitis, the patient was given antituberculosis treatment. As the patient did not improve, detailed investigations were conducted, and elevated antinuclear antibody levels were found. The consulting physician diagnosed that the patient was suffering from SLE. As isoniazid is associated with an increased risk of developing SLE, it was suspected as the culprit drug. After withdrawing isoniazid from the antituberculosis treatment regimen, the patient improved and was discharged. Based on the WHO-UMC and Naranjo's causality assessment criteria, an association between the reaction and isoniazid was deemed probable. The reaction was moderately severe (level 4b) according to the modified Hartwig and Siegel scale.
PubMed: 31541371
DOI: 10.1007/s40800-019-0102-y -
Academic Emergency Medicine : Official... Sep 2019Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both chemical-first and electrical-first strategies have been advocated, there are no comparative effectiveness data to guide clinicians.
METHODS
At six urban Canadian centers, ED patients ages 18 to 75 with uncomplicated symptomatic AF of less than 48 hours and CHADS score of 0 or 1 were randomized using concealed allocation in a 1:1 ratio to one of the following strategies: 1) chemical cardioversion with procainamide infusion, followed by electrical countershock if unsuccessful; or 2) electrical cardioversion, followed by procainamide infusion if unsuccessful. The primary outcome was the proportion of patients discharged within 4 hours of arrival. Secondary outcomes included ED length-of-stay (LOS); prespecified ED-based adverse events; and 30-day ED revisits, hospitalizations, strokes, deaths, and quality of life (QoL).
RESULTS
Eighty-four patients were analyzed: 41 in the chemical-first group and 43 in the electrical-first group. Groups were balanced in terms of age, sex, vital signs, and CHADS scores. All patients were discharged home, with 83 (99%) in sinus rhythm. In the chemical-first group, 13 of 41 patients (32%) were discharged within 4 hours compared to 29 of 43 patients (67%) in the electrical-first group (p = 0.001). In the chemical-first group, the median ED LOS was 5.1 hours (interquartile range [IQR] = 3.5 to 5.9 hours) compared to 3.5 hours (IQR = 2.4 to 4.6 hours) in the electrical-first group, for a median difference of 1.2 hours (95% confidence interval = 0.4 to 2.0 hours, p < 0.001). No patients experienced stroke or death. All other outcomes, including adverse events, ED revisits, and QoL, were similar.
CONCLUSION
In uncomplicated ED AF patients managed with rhythm control, chemical-first and electrical-first strategies both appear to be successful and well tolerated; however, an electrical-first strategy results in a significantly shorter ED LOS.
Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Canada; Electric Countershock; Emergency Service, Hospital; Female; Humans; Length of Stay; Male; Middle Aged; Procainamide; Quality of Life; Young Adult
PubMed: 31423687
DOI: 10.1111/acem.13669 -
Academic Emergency Medicine : Official... Sep 2019
PubMed: 31002448
DOI: 10.1111/acem.13767