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1.
Environ Sci Pollut Res Int ; 31(17): 26261-26281, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38499921

RESUMO

Nutrient imbalances may negatively affect the health status of forests exposed to multiple stress factors, including drought and bark beetle calamities. We studied the origin of base cations in runoff from a small Carpathian catchment underlain by base-poor flysch turbidites using magnesium (Mg), calcium (Ca) and strontium (Sr) isotope composition of 10 ecosystem compartments. Our objective was to constrain conclusions drawn from long-term hydrochemical monitoring of inputs and outputs. Annual export of Mg, Ca and Sr exceeds 5-to-15 times their atmospheric input. Mass budgets per se thus indicate sizeable net leaching of Mg, Ca and Sr from bedrock sandstones and claystones. Surprisingly, δ26Mg, δ44Ca and 87Sr/86Sr isotope ratios of runoff were practically identical to those of atmospheric deposition and soil water but significantly different from bedrock isotope ratios. We did not find any carbonates in the studied area as a hypothetical, easily dissolvable source of base cations whose isotope composition might corroborate the predominance of geogenic base cations in the runoff. Marine carbonates typically have lower δ26 Mg and 87Sr/86Sr ratios, and silicate sediments often have higher δ26Mg and 87Sr/86Sr ratios than runoff at the study site. Mixing of these two sources, if confirmed, could reconcile the flux and isotope data.


Assuntos
Cálcio , Magnésio , Cálcio/análise , Magnésio/análise , Ecossistema , Monitoramento Ambiental , Isótopos de Estrôncio/análise , Isótopos , Cátions , Carbonatos
2.
Vaccine ; 42(7): 1648-1655, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38342718

RESUMO

Vaccination against measles is one of the most effective public health interventions which has saved millions of lives and interrupted circulation of the natural virus in the population. However, it is widely accepted that the immunity after vaccination can wane, especially in those who have had no contact with the virus. This study aimed to classify the particular birth cohorts of adults with regard to their exposure to the wild measles virus in the population with a long history of mandatory vaccination. We introduced two methods. In the first, we estimated the probability of exposure to the wild virus through an analysis of antibody levels from the Immunologic Survey performed in the Slovak Republic in 2018, while the second was based on historical epidemiological data. Both methods resulted in similar estimations. Cohorts born in Slovakia before 1964 can be considered to be cohorts in which most people were exposed to the wild measles virus. Cohorts born after 1977 can be designated as cohorts that most likely did not come into the contact with the wild virus. Cohorts born between 1965 and 1976 are composed of a mixture, with a decreasing proportion of people exposed to the wild virus with increasing year of birth. The proposed methods can help identify potential immunity gaps in the adult population. They can be applied in other countries with high measles vaccination coverage to estimate the probability of exposure to the wild measles virus in particular birth cohorts.


Assuntos
Vírus do Sarampo , Sarampo , Adulto , Humanos , Estudos Soroepidemiológicos , Sarampo/epidemiologia , Sarampo/prevenção & controle , Vacinação , Probabilidade , Vacina contra Sarampo , Anticorpos Antivirais/análise
3.
Eur J Med Chem ; 266: 116130, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38218127

RESUMO

Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.


Assuntos
Doença de Alzheimer , Doença Hepática Induzida por Substâncias e Drogas , Fármacos Neuroprotetores , Piperidinas , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de N-Metil-D-Aspartato , Tacrina/química , Inibidores da Colinesterase/química , Sítios de Ligação , Colinesterases , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico
4.
Micromachines (Basel) ; 15(1)2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38258221

RESUMO

This paper presents the measurement and evaluation of the surfaces of molds produced using additive technologies. This is an emerging trend in mold production. The surfaces of such molds must be treated, usually using laser-based alternative machining methods. Regular evaluation is necessary because of the gradually deteriorating quality of the mold surface. However, owing to the difficulty in scanning the original surface of the injection mold, it is necessary to perform surface replication. Therefore, this study aims to describe the production of surface replicas for in-house developed polymer molds together with the determination of suitable descriptive parameters, the method of comparing variances, and the mean values for the surface evaluation. Overall, this study presents a new summary of the evaluation process of replicas of the surfaces of polymer molds. The nonlinear regression methodology provides the corresponding functional dependencies between the relevant parameters. The statistical significance of a neural network with two hidden layers based on the principle of Rosenblatt's perceptron has been proposed and verified. Additionally, machine learning was utilized to better compare the original surface and its replica.

5.
J Med Entomol ; 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38085664

RESUMO

Proper fixing and long-term preservation of entomological evidence are essential in collections and research and crucial in applied fields such as forensic entomology. Incorrectly stored samples may lose important morphological features over time, rendering molecular analyses exceedingly difficult. The most effective method for preserving soft samples such as larvae is fluid preservation. It uses a combination of a wide range of fixatives and storage fluids. However, very little comparative work has been done to determine the effects of long-term storage on sample quality in terms of color, shape, and DNA stability. Moreover, the current golden standard in forensic entomology has been tailored for age estimation of larvae of Diptera, which differ from larvae of Coleoptera in morphology and subsequently in applied methods. We compared the effects of combinations of 6 commonly used fixatives and 6 commonly used storage fluids on midsized larvae of the forensically important beetle, Necrodes littoralis (Linnaeus, 1758), in terms of color, shape, and suitability for DNA analyses over a 2-yr period. We were looking for combinations that can preserve specimens in a satisfactory state, can be used on a regular basis, do not require advanced protection or skills of the personnel, and are not toxic or too harmful to the environment. We found not only several methods that scored significantly better in the tested parameters compared with the golden standard but also several common methods that should be avoided. The effects of agents on each tested category are discussed in detail.

6.
Chem Biol Interact ; 385: 110735, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37802409

RESUMO

We report a green chemistry approach for preparation of oxime-functionalized ILs as AChE reactivators: amide/ester linked IL, l-alanine, and l-phenylalanine derived salts bearing pyridinium aldoxime moiety. The reactivation capacities of the novel oximes were evaluated towards AChE inhibited by typical toxic organophosphates, sarin (GB), VX, and paraoxon (PON). The studied compounds are mostly non-toxic up to the highest concentrations screened (2 mM) towards Gram-negative and Gram-positive bacteria cell lines and both filamentous fungi and yeasts in the in vitro screening experiments as well as towards the eukaryotic cell (CHO-K1 cell line). Introduction of the oxime moiety in initially biodegradable structure decreases its ability to biodegradation. The compound 3d was shown to reveal remarkable activity against the AChE inhibited by VX, exceeding conventional reactivators 2-PAM and obidoxime. The regularities on antidotal activity, cell viability, plasma stability, biodegradability as well as molecular docking study of the newly synthesized oximes will be used for further improvement of their structures.


Assuntos
Reativadores da Colinesterase , Líquidos Iônicos , Acetilcolinesterase/metabolismo , Simulação de Acoplamento Molecular , Oximas/farmacologia , Oximas/química , Antídotos , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Compostos de Piridínio/farmacologia , Compostos de Piridínio/química
7.
ACS Chem Biol ; 18(9): 1993-2002, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37622522

RESUMO

Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Qmeth), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Qmeth formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Qmeth-cysteine and Qmeth-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Indolquinonas , Metanfetamina , Humanos , Animais , Camundongos , Ratos , Tacrina/toxicidade , Biotransformação
8.
Eur J Med Chem ; 258: 115617, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37423128

RESUMO

Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).


Assuntos
Ácido Aminossalicílico , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Isoniazida/farmacologia , Ácido Aminossalicílico/farmacologia , Antituberculosos/química , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Metionina , Testes de Sensibilidade Microbiana
9.
Eur J Med Chem ; 258: 115611, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37421887

RESUMO

Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 µM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 µM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 µL/min/mg), sufficient aqueous solubility (>90 µM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-ß-d-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Animais , Antituberculosos/química , Oxirredutases do Álcool/química , Purinas/farmacologia , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Proteínas de Bactérias/metabolismo , Mamíferos/metabolismo
11.
Anal Bioanal Chem ; 415(16): 3137-3154, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37225900

RESUMO

In mass spectrometry (MS)-based metabolomics, there is a great need to combine different analytical separation techniques to cover metabolites of different polarities and apply appropriate multi-platform data processing. Here, we introduce AriumMS (augmented region of interest for untargeted metabolomics mass spectrometry) as a reliable toolbox for multi-platform metabolomics. AriumMS offers augmented data analysis of several separation techniques utilizing a region-of-interest algorithm. To demonstrate the capabilities of AriumMS, five datasets were combined. This includes three newly developed capillary electrophoresis (CE)-Orbitrap MS methods using the recently introduced nanoCEasy CE-MS interface and two hydrophilic interaction liquid chromatography (HILIC)-Orbitrap MS methods. AriumMS provides a novel mid-level data fusion approach for multi-platform data analysis to simplify and speed up multi-platform data processing and evaluation. The key feature of AriumMS lies in the optimized data processing strategy, including parallel processing of datasets and flexible parameterization for processing of individual separation methods with different peak characteristics. As a case study, Saccharomyces cerevisiae (yeast) was treated with a growth inhibitor, and AriumMS successfully differentiated the metabolome based on the augmented multi-platform CE-MS and HILIC-MS investigation. As a result, AriumMS is proposed as a powerful tool to improve the accuracy and selectivity of metabolome analysis through the integration of several HILIC-MS/CE-MS techniques.


Assuntos
Metabolômica , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Metabolômica/métodos , Metaboloma , Eletroforese Capilar/métodos
12.
3D Print Addit Manuf ; 10(2): 236-244, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37095867

RESUMO

A necessity to distinguish between the influence of powder shape and size (particle size distribution) is especially demanding for highly filled metal powder feedstocks employed in additive manufacturing and powder injection molding. As their processability is evaluated through rheological behavior, the study focuses on the effect of powder size/shape on a wall slip, which is a typical phenomenon determining flow performance of these materials. Water and gas atomized 17-4PH stainless steel powders with D 50 of about 3 and 20 µm are admixed into a binder containing low-density polyethylene, ethylene vinyl acetate, and paraffin wax. Mooney analysis to intercept the slip velocity of 55 vol. % filled compounds reveals that wall slip effect appears to vary significantly with size and shape of metal powders-round shaped and large particles are the most prone to the wall slip. However, the evaluation is affected by the type of the flow streams resulting from the geometry of the dies-conical dies reduce the slip up to 60% in case of fine and round particles.

13.
Environ Pollut ; 328: 121609, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37044255

RESUMO

Transect sampling is an under-exploited tool in isotope studies of atmospheric pollution. Few studies have combined Zn and Pb isotope ratios to investigate whether atmospheric pollution at a receptor site is dominated by a different anthropogenic source of each of these toxic elements. It has been also unclear whether pollution abatement strategies in Central Europe have already resulted in regionally well-mixed background isotope signature of atmospheric Zn and Pb. Zinc and lead isotope ratios were determined in snow collected along a rural transect downwind from the Upper Silesian industrial area (southern Poland). Spatial and temporal gradients in δ66Zn and 206Pb/207Pb ratios at four sites were compared with those of ore and coal collected in eight Czech and Polish mining districts situated at distances of up to 500 km. Snow pollution was extremely high 8 km from Olkusz in 2011 (1670 µg Zn L-1; 240 µg Pb L-1), sharply decreased between 2011 and 2018, and remained low in 2019-2021. Snow pollution was lower at sites situated 28-68 km from Olkusz. Across study sites, mean δ66Zn and 206Pb/207Pb ratios of snow were -0.13‰ and 1.155, respectively. With an increasing distance from Olkusz, the δ66Zn values first increased and then decreased, while the 206Pb/207Pb ratios first decreased and then increased. The δ66Zn values in snow plotted closer to those of Upper Silesian ores (-0.20‰) than to the δ66Zn values of Upper Silesian stone coal (0.52‰), showing predominance of smelter-derived over power-plant derived Zn pollution. The 206Pb/207Pb ratios of Upper Silesian coal (1.171) and Upper Silesian ores (1.180) were higher compared to those of snow. A206Pb/207Pb vs.208Pb/207Pb plot identified legacy pollution from leaded gasoline as the low-radiogenic mixing end-member. Across the transect sites, only the last sampling campaign exhibited a high degree of isotope homogenization for both Zn and Pb.


Assuntos
Poluição Ambiental , Chumbo , Zinco/análise , Isótopos/análise , Carvão Mineral , Monitoramento Ambiental/métodos
14.
Am J Epidemiol ; 192(8): 1379-1385, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-36935110

RESUMO

We aimed to quantify rates of waning immunity after measles vaccination from seroprevalence data collected in a study of a population with high vaccination coverage and a fixed vaccination schedule. Data were collected during a national survey (the Immunological Survey) carried out in the Slovak Republic in 2018. The average rate of waning immunity against measles after the first dose of measles, mumps, and rubella (MMR) vaccine (ages 1.5-10 years) was 9.7% per year from the geometric mean titer value of 2,634 mUI/mL. The average waning rate after the second dose of MMR vaccine (ages 10-33 years) was significantly lower: 4.8% per year from the lower geometric mean titer of 1,331 mUI/mL. This decline in antibody levels suggests that vaccine-induced protection may be compromised and results in an increase in the proportion of seronegative/borderline individuals. These outcomes may provide a valuable source for critical assessment of direct and indirect effects of MMR vaccination.


Assuntos
Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Humanos , Vacina contra Sarampo-Caxumba-Rubéola , Rubéola (Sarampo Alemão)/epidemiologia , Rubéola (Sarampo Alemão)/prevenção & controle , Estudos Soroepidemiológicos , Anticorpos Antivirais , Sarampo/epidemiologia , Sarampo/prevenção & controle , Caxumba/epidemiologia , Caxumba/prevenção & controle , Vacinação
15.
Environ Sci Pollut Res Int ; 30(16): 48232-48247, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36752921

RESUMO

Soil solution chemistry depends largely on mineralogy and organic matter properties of soil horizons with which they interact. Differing lithologies within a given catchment area can influence variability in soil cation exchange capacities and affect solute transport. Zero-tension and tension lysimeters were used to evaluate the fast transport of solutes in the topsoil vs. slow diffusional matrix flow at the subsoil of three contrasting lithology catchments in a mid-elevation mountain forest. Our aim was to test the feasibility of lysimeters' hydrochemical data as a gauge for legacy subsoil pollution. Due to contrasting lithologies, atmospheric legacy pollution prevailing at the soil-regolith interface is differently yet consistently reflected by beryllium, lead, and chromium soil solution concentrations of the three catchments. Geochemical (dis)equilibrium between the soil and soil matrix water governed the hydrochemistry of the soil solutions at the time of collection, potentially contributing to decreased dissolved concentrations with increased depths at sites with higher soil pH. A complementary isotopic δ18O runoff generation model constrained potential seasonal responses and pointed to sufficiently long water-regolith interactions as to permit important seasonal contributions of groundwater enriched in chemical species to the topsoil levels. Our study also reflects subsoil equilibration with atmospheric solutes deposited at the topsoil and thus provides guidance for evaluating legacy pollution in soil profiles derived from contrasting lithology.


Assuntos
Monitoramento Ambiental , Água Subterrânea , Metais , Solo , Metais/análise , Solo/química , Água , Poluentes da Água/análise
16.
Sci Total Environ ; 869: 161697, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36690116

RESUMO

Nitrogen (N) deposition, a key process of atmospheric self-cleaning, represents an important pathway for nutrients and pollutants to ecosystems. Enhanced N deposition flux contributes to acidification, eutrophication and loss of biodiversity. N-NO3- concentrations in rime and snow were measured at 10 Czech plots situated in borderline mountains in 2009-2011 winters. The results were put in context with data-driven geostatistical modelling results of annual wet vertical and horizontal deposition. Our hypotheses were that: (i) rime and snow would be more polluted in the highly industrialized north than in the south, (ii) the N-NO3- concentrations would differ in the three winters studied, and (iii), that N-NO3- rime deposition is not negligible in Central European mountain ranges. Our results indicated that winter N-NO3- concentrations were significantly higher in rime than in snow and that there were much larger between-site differences in N-NO3- concentrations for rime than for snow. Relatively large differences were found between individual years. Atmospheric input of N-NO3- in winter was dominated by vertical deposition, i.e., snow. Modelled results showed that mean winter rime deposition corresponded to about 6-25 %, and mean winter snow deposition made up 25-72.5 % of mean annual N-NO3- wet-only deposition. Model N-NO3-occult deposition estimated from throughfall and total (wet and dry) deposition is highly uncertain, however: N throughfall is not a relevant proxy for estimation of realistic total N deposition due to N exchange between the tree canopy and atmosphere.

17.
ACS Infect Dis ; 9(1): 79-96, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36577009

RESUMO

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).


Assuntos
Ácido Aminossalicílico , COVID-19 , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Pirazinamida/farmacologia , Ácido Aminossalicílico/farmacologia , Peixe-Zebra , SARS-CoV-2 , Antituberculosos/química , Tuberculose/tratamento farmacológico , Lactonas
18.
Environ Pollut ; 316(Pt 1): 120518, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341823

RESUMO

Antimony (Sb) concentrations were measured in wet atmospheric deposition at 10 high-elevation sites in the Czech Republic (Central Europe) during three winter seasons (2009-2011). Soluble and insoluble Sb forms were quantified in snow (vertical deposition) and rime (horizontal deposition) on mountain summits located equidistantly near the Czech borders with Austria, Germany and Poland. The highest Sb concentrations were found in the soluble form in rime (0.47 µg L-1), while the lowest Sb concentrations were those in the insoluble form in snow (0.017 µg L-1). The estimated average Sb deposition rate in Central Europe amounted to 1.3. 10-4 g m-2 yr-1. Most Sb was deposited in the soluble form in snow (7.9. 10-5 g m-2 yr-1), followed by the soluble form in rime (3.5. 10-5 g m-2 yr-1). The corresponding insoluble fraction contained less Sb, namely 1.2. 10-5 g m-2 yr-1 in snow and 2.3. 10-6 g m-2 yr-1 in rime. The average Sb deposition in Central Europe, measured at an altitude of 1000 m a.s.l., was by six orders of magnitude higher compared to Sb deposition in the Arctic (7. 10-10 g m-2 yr-1), and by four orders of magnitude lower compared to Sb deposition in a Sb-Hg mining district in China (7 g m-2 yr-1). Using the HYSPLIT model, backward trajectories of air masses indicated that the Sb sources were predominantly situated in Upper and Lower Silesia.


Assuntos
Poluentes Atmosféricos , Antimônio , Antimônio/análise , Monitoramento Ambiental , Neve , Europa (Continente) , Mineração , Poluentes Atmosféricos/análise
19.
Vaccines (Basel) ; 10(11)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36366366

RESUMO

The aim of this study was to evaluate the differences in attitudes towards vaccination against COVID-19 among secondary school teachers and outpatient physicians. A cross-sectional study was realised using anonymous questionnaires. The EPI Info 7 program and R software, version 4.0.2 were used for statistical analysis. The questionnaire was completed by 868 respondents (teaching staff N = 451; outpatient physician N = 417). The number of employees vaccinated against COVID-19 was 742 (85.5%). The number of those vaccinated against COVID-19 and influenza (last season) was 192 (21.9%). The statistically significant predictors were the level of fear of COVID-19 (OR 1.40; 95% CI 1.29-1.52), profession-outpatient physicians (OR 2.56; 95% CI 1.55-4.23), history of COVID-19 (OR 0.34; 95% CI 0.22-0.54), gender (OR 0.55; 95% CI 0.33-0.89) and influenza vaccination at any time in the past (OR 3.52; 95% CI 1.10-11.31). The strongest motivation for vaccination against COVID-19 among physicians was the prevention of the spread of COVID-19 during the performance of their profession (N = 336; 87%); among teachers, it was the protection of family members (N = 258; 73%). The most common reason for vaccine hesitancy was concern about vaccine safety (N = 80; 63.5%).

20.
Artigo em Inglês | MEDLINE | ID: mdl-36231966

RESUMO

The aim of this study was to assess prevalence and associated risk factors of burnout syndrome among healthcare workers (HCWs), especially among nurses during the pandemic of COVID-19. The sample of the cross-sectional study consists of 201 employees of University Hospital. The Maslach Burnout Inventory-Human Services Survey for Medical Personnel (MBI-HSS MP) was used. An anonymous questionnaire was administered between 15 January and 1 February 2022. The majority of HCWs were female (79.4%). Overall, 69.2% displayed high levels of emotional exhaustion (EE), 35.3% high levels of depersonalization (DP), and 35.5% low levels of personal accomplishment (PA). Burnout was frequent among staff working in COVID units (EE 76.1%; DP 47.8%; and PA 46.7%). Burnout in EE and DP (70.7% and 36.6%, respectively) significantly prevailed in nurses working in COVID-19 units compared to non-frontline nurses (59.6 and 21.1%, respectively). Prevalence of burnout in PA was significantly higher in nurses working in non-COVID-19 units (47.4% vs. 29.3%). It is crucial to pay attention to the high prevalence of burnout syndrome in HCWs, especially in nurses, and not only in the frontline.


Assuntos
Esgotamento Profissional , COVID-19 , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/psicologia , COVID-19/epidemiologia , Estudos Transversais , Feminino , Hospitais Universitários , Humanos , Masculino , Prevalência , Inquéritos e Questionários
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