Lidocaine is a drug that blocks the sodium channel in a pH, frequency and concentration dependent manner. In this work, we have used a mathematical model of lidocaine developed by our group and ...incorporated it into the Luo Rudy model of ventricular action potential. We have studied the action of lidocaine on the sodium current (I Na ), maximum upstroke velocity (dV/dt) and conduction velocity (CV) in ischemic tissue. Additionally, we measured the block window (BW) in different concentrations of drug .Our results show that 100 mumol/L of lidocaine under simulated acute ischemic conditions reduces the I Na , dV/dt and CV a 42%, 41% and 24% in the normal zone (cell 54), respectively while in the border zone (cell 94) the decreased was 37%; 44% and 18% for the same parameters. Finally, we have found that lidocaine diminished the BW, thus the drug tends to eliminate the UDB.
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.
We conducted a ...double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval CI, 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).
The aim of this study was to investigate the pesticide residues in market fruits (oranges, tangerines, nectarines, peaches and khakis) from one Valencian Cooperative (Spain) and to conduct a ...monitoring of 32 organophosphorous, organonitrogen and organohalogenated pesticides and nine dithiocarbamate fungicides (DTCFs) usually applied on cultures of this area.
Extracts were obtained by an official procedure for routine analysis based on ethyl acetate extraction. Residues of pesticides were determined by gas chromatography with nitrogen phosphorous detector (NPD), electron-capture detector (ECD) and mass spectrometry (MS) detectors. Mean recoveries obtained at fortification levels between 0.05 and 5
mg
kg
−1 were in range of 56–97% with relative standard deviations (RSDs) from 5% to 18%. The limits of quantification (LOQs) were in range of 0.1–140
μg
kg
−1 and lower than maximum residue limits (MRL) established by the Spanish legislation. 73% of the samples had no detectable residues. Of the contaminated samples, 13.8% exceeded the maximum residue limits (MRLs). Peaches and oranges showed the lowest contamination rates (13.9% and 21.3%, respectively). The contamination and violation rates were similar than the percentages recorded in previous monitoring studies in the same Community. Estimated daily intakes (EDIs) were calculated for these compounds in basis of European maximum residue limits (MRL) and residues found in the analysed samples and were compared with the acceptable daily intakes (ADIs).
The massive use of petroleum-based polymers and their improper waste treatment has brought on significant global environmental problems due to their non-biodegradable nature. Starch/poly(vinyl ...alcohol) (PVA) bioplastics are suitable substitutes for conventional polymers, such as polyethylene, due to their full biodegradability and excellent mechanical properties. Knowledge of the pollutant emissions during pyrolysis and combustion of starch/PVA films is important because they can arrive at landfills mixed with conventional polymers and be thermally degraded in uncontrolled fires. On the other hand, controlled thermal treatments could result in thermal valorization of the waste. Pyrolysis and combustion experiments were carried out at 650, 750, 850 and 950 °C in a laboratory furnace. The analysis of carbon oxides, light hydrocarbons, and semivolatile compounds, including polycyclic aromatic hydrocarbons (PAHs), is shown. Experiments showed lower pollutant emissions than those found with conventional polymers, such as polyethylene and polyester, in the same equipment. Nevertheless, the pyrolysis run at 950 °C showed the highest light hydrocarbon yield (123013 mg kg−1), but this is considerably lower than the values found for polyethylene. The main semivolatile compounds (not PAHs) emitted, with maximum yields ranging from 1351 to 4694 mg kg−1, were benzaldehyde, phenol, indene, and acetophenone. Specifically, the total semivolatile compounds emitted after pyrolysis and combustion of starch/PVA samples represent only 38 and 50%, respectively, of those emitted with polyethylene. Further, the main PAHs were naphthalene, acenaphthylene, and phenanthrene with maximum values of 4694, 2704 and 1496 mg kg−1, respectively. The PAH yield was considerably higher in experiments with low oxygen content.
•Pollutant emissions from thermal decomposition of starch/PVA films have been studied.•The maximum formation of the 16 PAHs was found in the pyrolysis run at 950 °C.•TEQ values increase with temperature and decrease when the oxygen content increases.•Emissions of PAHs from starch/PVA films were considerably lower than with PE.
Lidocaine is used as an antiarrhythmic drug, its effectiveness is based on its ability to induce use- dependent block of cardiac sodium channels. This drug has an effect on conduction velocity (CV) ...and effective refractory period (ERP). Changes in CV and ERP could have an important role in the induction or suppression of reentrant circuits. We have studied the effect of lidocaine on CV, ERP and the characteristics of reentry conduction induced in regional ischemic tissue by computer simulations. The bi-dimensional tissue includes an ischemic zone that corresponds to 9 minutes of ischemia. This study demonstrates that the lidocaine reduces the CV 40% and 50% and prolongs of ERP 5% and 14% for 50 and 100 muM of lidocaine respectively. As well as, lidocaine can depress 20% and 60% the window vulnerable respectively.
Antibiotic resistance is a growing threat to human health, caused in part by pathogens accumulating antibiotic resistance genes (ARGs) through horizontal gene transfer. New ARGs are typically not ...recognized until they have become widely disseminated, which limits our ability to reduce their spread. In this study, we use large-scale computational screening of bacterial genomes to identify previously undiscovered mobile ARGs in pathogens. From ~1 million genomes, we predict 1,071,815 genes encoding 34,053 unique aminoglycoside-modifying enzymes (AMEs). These cluster into 7,612 families (<70% amino acid identity) of which 88 are previously described. Fifty new AME families are associated with mobile genetic elements and pathogenic hosts. From these, 24 of 28 experimentally tested AMEs confer resistance to aminoglycoside(s) in Escherichia coli, with 17 providing resistance above clinical breakpoints. This study greatly expands the range of clinically relevant aminoglycoside resistance determinants and demonstrates that computational methods enable early discovery of potentially emerging ARGs.
Atrial fibrillation (AF) is the most common atrial tachyarrhythmia. Recently, pulmonary vein ectopic focus has been demonstrated that it can trigger reentry in the presence of a vulnerable substrate ...and lead to AF. We examined the effects of ectopic focus frequency on the generation of AF. In this study, the effects of remodelling on ionic currents were incorporated in a two-dimensional anisotropic model of human left atrial tissue. Ectopic activity initiated a stable reentry around the right pulmonary veins. The interaction of this ectopic activity with a rapid sinus rhythm generated fibrillatory conduction. This fibrillatory rhythm was maintained only at high rates of ectopic focus. Our study suggests that the interaction of high frequency ectopic activity and rapid sinus rhythm facilitates the progress from a stable reentrant mechanism to fibrillatory conduction in remodelling atrial tissue.
Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for ...HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control.
Atrial arrhythmias are characterised by rapid and irregular activation of atrium. In this study, the effects of remodelling on ionic currents were incorporated in a model of human atrial action ...potential and were integrated in a two-dimensional (2D) model of human left atrium tissue including orifices for right pulmonary veins. We examined the effects of atrial remodelling on atrial arrhythmias when ectopic beats between pulmonary veins were applied. Under normal tissue conditions, no re-entry phenomenon was induced. In atrial remodelling, action potential duration (APD), effective refractory period (ERP) and conduction velocity (CV) were decremented and stable re-entries around the right pulmonary veins were produced. Our study suggests that the electrical remodelling is a key factor to generate anatomical re-entries around the pulmonary veins.
Friedreich's ataxia (FRDA) is the most common form of autosomal recessive ataxia caused by a deficit in the mitochondrial protein frataxin. Although demyelination is a common symptom in FRDA ...patients, no multicellular model has yet been developed to study the involvement of glial cells in FRDA. Using the recently established RNAi lines for targeted suppression of frataxin in Drosophila, we were able to study the effects of general versus glial-specific frataxin downregulation. In particular, we wanted to study the interplay between lowered frataxin content, lipid accumulation and peroxidation and the consequences of these effects on the sensitivity to oxidative stress and fly fitness. Interestingly, ubiquitous frataxin reduction leads to an increase in fatty acids catalyzing an enhancement of lipid peroxidation levels, elevating the intracellular toxic potential. Specific loss of frataxin in glial cells triggers a similar phenotype which can be visualized by accumulating lipid droplets in glial cells. This phenotype is associated with a reduced lifespan, an increased sensitivity to oxidative insult, neurodegenerative effects and a serious impairment of locomotor activity. These symptoms fit very well with our observation of an increase in intracellular toxicity by lipid peroxides. Interestingly, co-expression of a Drosophila apolipoprotein D ortholog (glial lazarillo) has a strong protective effect in our frataxin models, mainly by controlling the level of lipid peroxidation. Our results clearly support a strong involvement of glial cells and lipid peroxidation in the generation of FRDA-like symptoms.
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