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1.
J Laryngol Otol ; 135(10): 855-857, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34477050

RESUMO

OBJECTIVE: Recurrent acute otitis media is common in children. The preferred treatment measures for recurrent acute otitis media have a mixed evidence base. This study sought to assess baseline practice across ENT departments in England. METHODS: A national telephone survey of healthcare staff was conducted. Every ENT centre in England was contacted. A telephone script was used to ask about antibiotic and grommet use and duration in recurrent acute otitis media cases. RESULTS: Ninety-six centres (74 per cent) provided complete information. Recurrent acute otitis media treatment across England by ENT departments varied. The antibiotic first- and second-line prophylaxis offered varies, with trimethoprim used in 33 centres and 29 centres not offering any antibiotics. The timing or choice about when to use grommets also varies, but 87 centres (91 per cent) offer grommet surgery at one stage. CONCLUSION: The treatments received by children in England for recurrent acute otitis media vary by centre; collaborative research in this area is advised.


Assuntos
Ventilação da Orelha Média/estatística & dados numéricos , Otite Média/tratamento farmacológico , Otolaringologia/estatística & dados numéricos , Inquéritos e Questionários/normas , Doença Aguda , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Anti-Infecciosos Urinários/administração & dosagem , Anti-Infecciosos Urinários/uso terapêutico , Criança , Resistência Microbiana a Medicamentos , Inglaterra/epidemiologia , Humanos , Ventilação da Orelha Média/métodos , Otite Média/cirurgia , Otolaringologia/organização & administração , Assistência Individualizada de Saúde/estatística & dados numéricos , Recidiva , Medicina Estatal/organização & administração , Inquéritos e Questionários/estatística & dados numéricos , Trimetoprima/administração & dosagem , Trimetoprima/uso terapêutico
2.
J Chem Phys ; 155(4): 045101, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34340389

RESUMO

Understanding the permeation of biomolecules through cellular membranes is critical for many biotechnological applications, including targeted drug delivery, pathogen detection, and the development of new antibiotics. To this end, computer simulations are routinely used to probe the underlying mechanisms of membrane permeation. Despite great progress and continued development, permeation simulations of realistic systems (e.g., more complex drug molecules or biologics through heterogeneous membranes) remain extremely challenging if not intractable. In this work, we combine molecular dynamics simulations with transition-tempered metadynamics and techniques from the variational approach to conformational dynamics to study the permeation mechanism of a drug molecule, trimethoprim, through a multicomponent membrane. We show that collective variables (CVs) obtained from an unsupervised machine learning algorithm called time-structure based Independent Component Analysis (tICA) improve performance and substantially accelerate convergence of permeation potential of mean force (PMF) calculations. The addition of cholesterol to the lipid bilayer is shown to increase both the width and height of the free energy barrier due to a condensing effect (lower area per lipid) and increase bilayer thickness. Additionally, the tICA CVs reveal a subtle effect of cholesterol increasing the resistance to permeation in the lipid head group region, which is not observed when canonical CVs are used. We conclude that the use of tICA CVs can enable more efficient PMF calculations with additional insight into the permeation mechanism.


Assuntos
Farmacocinética , Aprendizado de Máquina não Supervisionado , Algoritmos , Colesterol/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Fosfatidilcolinas/química , Termodinâmica , Trimetoprima/química
3.
Methods Mol Biol ; 2312: 237-251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228294

RESUMO

Chemical control of protein localization is a powerful approach for manipulating mammalian cellular processes. Self-localizing ligand-induced protein translocation (SLIPT) is an emerging platform that enables control of protein localization in living mammalian cells using synthetic self-localizing ligands (SLs). We recently established a chemogenetic SLIPT system, in which any protein of interest fused to an engineered variant of Escherichia coli dihydrofolate reductase, DHFRiK6, can be rapidly and specifically translocated from the cytoplasm to the inner leaflet of the plasma membrane (PM) using a trimethoprim (TMP)-based PM-targeting SL, mDcTMP. The mDcTMP-mediated PM recruitment of DHFRiK6-fusion proteins can be efficiently returned to the cytoplasm by subsequent addition of free TMP, enabling temporal and reversible control over the protein localization. Here we describe the use of this mDcTMP/DHFRiK6-based SLIPT system for inducing (1) reversible protein translocation and (2) synthetic activation of the Raf/ERK pathway. This system provides a simple and versatile tool in mammalian synthetic biology for temporally manipulating various signaling molecules and pathways at the PM.


Assuntos
Engenharia Celular , Proteínas de Escherichia coli/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas Genéticas , Biologia Sintética , Tetra-Hidrofolato Desidrogenase/genética , Trimetoprima/farmacologia , Técnicas de Cultura de Células , Membrana Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Microscopia de Fluorescência , Transporte Proteico , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Tetra-Hidrofolato Desidrogenase/metabolismo , Quinases raf/metabolismo
4.
J Antimicrob Chemother ; 76(12 Suppl 2): ii7-ii13, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312654

RESUMO

OBJECTIVES: Data on antibiotic consumption in the community were collected from 30 EU/EEA countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of the main antibiotic groups. METHODS: For the period 1997-2017, data on consumption of antibiotics, i.e. antibacterials for systemic use (ATC group J01), in the community, aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Antibiotic consumption was analysed based on ATC-3 groups, and presented as trends, seasonal variation, presence of change-points and compositional changes. RESULTS: In 2017, antibiotic consumption in the community expressed in DDD per 1000 inhabitants per day varied by a factor 3.6 between countries with the highest (Greece) and the lowest (the Netherlands) consumption. Antibiotic consumption in the EU/EEA did not change significantly over time. Antibiotic consumption showed a significant seasonal variation, which decreased over time. The number of DDD per package significantly increased over time. The proportional consumption of sulphonamides and trimethoprim (J01E) relative to other groups significantly decreased over time, while the proportional consumption of other antibacterials (J01X) relative to other groups significantly increased over time. CONCLUSIONS: Overall, antibiotic consumption in the community in the EU/EEA did not change during 1997-2017, while seasonal variation consistently decreased over time. The number of DDD per package increased during 1997-2017.


Assuntos
Antibacterianos , Infecções Bacterianas , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Uso de Medicamentos , União Europeia , Humanos , Trimetoprima
5.
J Antimicrob Chemother ; 76(12 Suppl 2): ii45-ii59, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312660

RESUMO

OBJECTIVES: Data on consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of tetracyclines, sulphonamides and trimethoprim and other antibacterials. METHODS: For the period 1997-2017, data on consumption of tetracyclines (ATC group J01A), sulphonamides and trimethoprim (ATC group J01E), and other antibacterials (ATC group J01X) in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials was analysed based on ATC-4 subgroups and presented as trends, seasonal variation, presence of change-points and compositional changes. RESULTS: In 2017, consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in the community expressed in DDD per 1000 inhabitants per day varied considerably between countries. Between 1997 and 2017, consumption of tetracyclines did not change significantly, while its seasonal variation significantly decreased over time. Consumption of sulphonamides and trimethoprim significantly decreased until 2006, and its seasonal variation significantly decreased over time. The consumption of other antibacterials showed no significant change over time or in seasonal variation. CONCLUSIONS: Consumption and composition of tetracyclines, sulphonamides and trimethoprim, and other antibacterials showed wide variations between EU/EEA countries and over time. This represents an opportunity to further reduce consumption of these groups in some countries and improve the quality of their prescription.


Assuntos
Tetraciclinas , Trimetoprima , Antibacterianos/uso terapêutico , Uso de Medicamentos , União Europeia , Humanos , Sulfonamidas/uso terapêutico , Tetraciclinas/uso terapêutico , Trimetoprima/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-34097576

RESUMO

Sulphonamides (SAs) are widely used in animal husbandry. In our work, based on multi-walled carbon nanotubes, a novel residue method was developed for highly sensitive and determination trace levels of sulfamethoxazole, acetyl sulfamethoxazole and aditoprim in edible swine tissues by LC-MS/MS with magnetic solid-phase extraction. The samples were extracted using 2% ammoniated acetonitrile and purified by magnetic solid phase extraction (MSPE). Under the optimal conditions, good linearity was obtained ranging from 5 to 160 µg kg-1. The limits of detection (LOD) and quantification (LOQ) were 2 µg kg-1 and 5 µg kg-1 respectively. The average recoveries were 73.9-94.8% at different spiking levels. The inter-day RSDs were 6.2-10.7% and the intra-day RSDs were 2.4-5.4%. MSPE based on multi-walled carbon nanotubes was a simple and efficient method to enrich and separate the analyses and could be successfully applied for extraction of sulfamethoxazole, acetyl sulfamethoxazole and aditoprim residues in swine tissues.


Assuntos
Nanotubos de Carbono/química , Extração em Fase Sólida/métodos , Sulfametoxazol/análise , Extratos de Tecidos/análise , Trimetoprima/análogos & derivados , Animais , Cromatografia Líquida de Alta Pressão , Resíduos de Drogas/análise , Contaminação de Alimentos/análise , Humanos , Limite de Detecção , Fenômenos Magnéticos , Suínos , Espectrometria de Massas em Tandem , Trimetoprima/análise , Drogas Veterinárias/análise
7.
ACS Appl Mater Interfaces ; 13(26): 31066-31076, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34137247

RESUMO

The serious problem of pharmaceutical and personal care product pollution places great pressure on aquatic environments and human health. Herein, a novel coating photocatalyst was synthesized by adhering Ag-AgCl/WO3/g-C3N4 (AWC) nanoparticles on a polydopamine (PDA)-modified melamine sponge (MS) through a facile layer-by-layer assembly method to degrade trimethoprim (TMP). The formed PDA coating was used for the anchoring of nanoparticles, photothermal conversion, and hydrophilic modification. TMP (99.9%; 4 mg/L) was removed in 90 min by the photocatalyst coating (AWC/PDA/MS) under visible light via a synergistic photocatalytic-photothermal performance route. The stability and reusability of the AWC/PDA/MS have been proved by cyclic experiments, in which the removal efficiency of TMP was still more than 90% after five consecutive cycles with a very little mass loss. Quantitative structure-activity relationship analysis revealed that the ecotoxicities of the generated intermediates were lower than those of TMP. Furthermore, the solution matrix effects on the photocatalytic removal efficiency were investigated, and the results revealed that the AWC/PDA/MS still maintained excellent photocatalytic degradation efficiency in several actual water and simulated water matrices. This work develops recyclable photocatalysts for the potential application in the field of water remediation.


Assuntos
Nanopartículas/química , Trimetoprima/química , Catálise/efeitos dos fármacos , Grafite/química , Grafite/efeitos da radiação , Indóis/química , Indóis/efeitos da radiação , Luz , Nanopartículas/efeitos da radiação , Compostos de Nitrogênio/química , Compostos de Nitrogênio/efeitos da radiação , Óxidos/química , Óxidos/efeitos da radiação , Polímeros/química , Polímeros/efeitos da radiação , Prata/química , Prata/efeitos da radiação , Compostos de Prata/química , Compostos de Prata/efeitos da radiação , Temperatura , Triazinas/química , Triazinas/efeitos da radiação , Tungstênio/química , Tungstênio/efeitos da radiação , Purificação da Água/métodos
8.
Molecules ; 26(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070523

RESUMO

The pace of industrialization and rapid population growth in countries such as India entail an increased input of industrial and sanitary organic micropollutants, the so-called emerging contaminants (EC), into the environment. The emission of EC, such as pharmaceuticals, reaching Indian water bodies causes a detrimental effect on aquatic life and ultimately on human health. However, the financial burden of expanding sophisticated water treatment capacities renders complementary, cost-efficient alternatives, such as adsorption, attractive. Here we show the merits of washed and milled pigeon pea husk (PPH) as low-cost adsorbent for the removal of the EC trimethoprim (TMP) and atenolol (ATN) that are among the most detected pharmaceuticals in Indian waters. We found a linear increase in adsorption capacity of PPH for TMP and ATN at concentrations ranging from 10 to 200 µg/L and from 50 to 400 µg/L, respectively, reflecting the concentrations occurring in Indian water bodies. Investigation of adsorption kinetics using the external mass transfer model (EMTM) revealed that film diffusion resistance governed the adsorption process of TMP or ATN onto PPH. Moreover, analysis of the adsorption performance of PPH across an extensive range of pH and temperature illustrated that the highest adsorption loadings achieved concurred with actual conditions of Indian waters. We anticipate our work as starting point towards the development of a feasible adsorbent system aiming at low-cost water treatment.


Assuntos
Anti-Infecciosos Urinários/isolamento & purificação , Atenolol/isolamento & purificação , Biodegradação Ambiental , Cajanus/química , Trimetoprima/isolamento & purificação , Poluentes Químicos da Água/isolamento & purificação , Antagonistas de Receptores Adrenérgicos beta 1/isolamento & purificação , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Termodinâmica
9.
Molecules ; 26(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064068

RESUMO

In view of the rising relevance of emerging pollutants in the environment, this work studies the photodegradation of three antibiotics, evaluating the effects of the pH of the medium and the concentration of dissolved organic matter. Simulated light (with a spectrum similar to that of natural sunlight) was applied to the antibiotics Ciprofloxacin (Cip), Clarithromycin (Cla) and Trimethoprim (Tri), at three different pH, and in the presence of different concentrations of humic acids. The sensitivity to light followed the sequence: Cip > Cla > Tri, which was inverse for the half-life (Tri > Cla > Cip). As the pH increased, the half-life generally decreased, except for Cla. Regarding the kinetic constant k, in the case of Cip and Tri it increased with the rise of pH, while decreased for Cla. The results corresponding to total organic carbon (TOC) indicate that the complete mineralization of the antibiotics was not achieved. The effect of humic acids was not marked, slightly increasing the degradation of Cip, and slightly decreasing it for Tri, while no effect was detected for Cla. These results may be relevant in terms of understanding the evolution of these antibiotics, especially when they reach different environmental compartments and receive sunlight radiation.


Assuntos
Antibacterianos/efeitos da radiação , Ciprofloxacina/efeitos da radiação , Claritromicina/efeitos da radiação , Substâncias Húmicas , Concentração de Íons de Hidrogênio , Luz , Trimetoprima/efeitos da radiação , Antibacterianos/química , Ciprofloxacina/química , Claritromicina/química , Escuridão , Meia-Vida , Cinética , Trimetoprima/química
10.
Artigo em Inglês | MEDLINE | ID: mdl-33979269

RESUMO

Antimicrobial resistance is a major concern for human and animal health, projected to deteriorate with time and given current trends of antimicrobial usage. Antimicrobial use, particularly in healthcare and agriculture, can result in the release of antimicrobials into surface waters, promoting the development of antibiotic resistance in the environment, and potentially leading to human health risks. This study reviews relevant literature, and investigates current European and Irish antimicrobial usage trends in humans and animals, as well as potential pathways that antibiotics can take into surface waters following use. Reported levels in the aquatic environment are summarized, with particular focus on Ireland. There are relatively few studies examining Irish water bodies or sewage effluent for antibiotic residues, however, five antibiotics, namely azithromycin, ciprofloxacin, clarithromycin, metronidazole, and trimethoprim, have been measured in Irish waters, in concentrations predicted to select for resistance. Numerous isolates of multi-drug resistant bacteria have also been found in water bodies throughout Ireland and Europe. The value of risk assessment methodologies in understanding risks posed by antibiotic residues is reviewed including the advantages and disadvantages of specific approaches. Hazard quotient and bespoke Monte Carlo approaches are predominant risk assessment tools used to examine antimicrobial release and their complex pathways. This study highlights the need for monitoring of antimicrobial releases and the potential for resistance development, persistence and transmission while highlighting the role of risk assessment methodologies in assessing potential human and environmental health impacts.


Assuntos
Antibacterianos , Poluentes Químicos da Água , Animais , Antibacterianos/farmacologia , Ciprofloxacina/análise , Resistência Microbiana a Medicamentos , Monitoramento Ambiental , Humanos , Trimetoprima , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
11.
Chemosphere ; 274: 129900, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33979944

RESUMO

The burden of the human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) infection has transformed the African continent into a major consumer of antiretrovirals (ARVs) drugs. In addition to HIV burden, the African continent has also a high incidence of tuberculosis (TB) and has been experiencing recurring outbreaks of several other viral, bacterial, and parasitic epidemic diseases. The novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2 or Covid-19) pandemic outbreak is adding to the continent's infectious diseases burden as experts are predicting that it will be here for a long time. One of the consequences of these infectious diseases is that antiviral and antibiotic compounds have become some of the most consumed pharmaceuticals on the continent. Many of these drugs have been frequently detected in surface waters across Africa. There is limited information available on the adverse effects of the mixtures of different types of pharmaceuticals in African aquatic environments on fish reproduction. The present study investigated the effects of the ARV drug nevirapine (NVP - 1.48 and 3.74 µg/L) and its mixture with the antibiotic sulfamethoxazole (3.68 µg/L) and trimethoprim (0.87 µg/L) on O. mossambicus gonads using histopathological endpoints as biomarkers. The fish (n = 52) were exposed for 30 days in a static renewal system. Female O. mossambicus exposed to nevirapine (3.74 µg/L) and to NVP - antibiotic mixture recorded higher ovary indices. Statistically significant differences were found in female ovary indices between the fish exposed to NVP (3.74 µg/L) and the control fish (p = 0.002) as well as between the fish exposed to the NVP - antibiotic mixture and the control fish (p = 0.009). The main observed histopathological changes in the ovaries were increased vitellogenic oocyte atresia and vacuolation of the interstitial tissue in the fish exposed to NVP - antibiotic mixture. It is evident that the presence of NVP - antibiotics mixture in water triggered the observed histopathology in female fish ovaries. The detected abnormal high rate of atretic oocytes could result in impaired fish reproduction.


Assuntos
COVID-19 , Infecções por HIV , Preparações Farmacêuticas , Tilápia , África , Animais , Antibacterianos/toxicidade , Feminino , Humanos , Nevirapina/toxicidade , Ovário , SARS-CoV-2 , Sulfametoxazol , Trimetoprima/toxicidade
12.
Nat Commun ; 12(1): 2949, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011959

RESUMO

The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4'-desmethyltrimethoprim (4'-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4'-DTMP than in the presence of TMP. We find that 4'-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.


Assuntos
Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Resistência a Trimetoprima/genética , Trimetoprima/análogos & derivados , Substituição de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Cristalografia por Raios X , Evolução Molecular Direcionada , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/genética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Genes Bacterianos , Genótipo , Humanos , Modelos Moleculares , Mutação , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/genética , Trimetoprima/química , Trimetoprima/farmacologia
13.
J Vis Exp ; (170)2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33900288

RESUMO

Chromatin-associated condensates are implicated in many nuclear processes, but the underlying mechanisms remain elusive. This protocol describes a chemically-induced protein dimerization system to create condensates on telomeres. The chemical dimerizer consists of two linked ligands that can each bind to a protein: Halo ligand to Halo-enzyme and trimethoprim (TMP) to E. coli dihydrofolate reductase (eDHFR), respectively. Fusion of Halo enzyme to a telomere protein anchors dimerizers to telomeres through covalent Halo ligand-enzyme binding. Binding of TMP to eDHFR recruits eDHFR-fused phase separating proteins to telomeres and induces condensate formation. Because TMP-eDHFR interaction is non-covalent, condensation can be reversed by using excess free TMP to compete with the dimerizer for eDHFR binding. An example of inducing promyelocytic leukemia (PML) nuclear body formation on telomeres and determining condensate growth, dissolution, localization and composition is shown. This method can be easily adapted to induce condensates at other genomic locations by fusing Halo to a protein that directly binds to the local chromatin or to dCas9 that is targeted to the genomic locus with a guide RNA. By offering the temporal resolution required for single cell live imaging while maintaining phase separation in a population of cells for biochemical assays, this method is suitable for probing both the formation and function of chromatin-associated condensates.


Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimologia , Multimerização Proteica , Telômero/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Trimetoprima/metabolismo , Proteínas de Escherichia coli/química , Humanos , Ligantes , Ligação Proteica , Tetra-Hidrofolato Desidrogenase/química , Trimetoprima/química
14.
Aust Vet J ; 99(8): 351-355, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33904161

RESUMO

CASE REPORT: A 1-year-old, neutered male German Shepherd was presented with a 5-month history of episodic lethargy, intermittent fever, weight loss and a hunched posture. The dog was diagnosed with presumptive microsporidian meningoencephalitis based on cytological findings on cerebrospinal fluid analysis and a positive PCR test. The dog initially responded favourably to a 4-week course of trimethoprim-sulfadiazine, pyrimethamine and fenbendazole, and remained well for 12 weeks following cessation of treatment. Disease then recurred, and despite an initial positive response to treatment, he deteriorated and was euthanased 11 weeks later, 7.5 months after definitive diagnosis and 13 months after clinical signs were first reported. CONCLUSION: To the authors knowledge, this is the first case of canine microsporidiosis in Australia.


Assuntos
Doenças do Cão , Microsporidiose , Animais , Austrália , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Cães , Masculino , Microsporidiose/veterinária , Trimetoprima
15.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916202

RESUMO

Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds (1-18) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (hDHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds 13-14 (49.89% and 43.85%) and 17-18 (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2, and poly (dG-dC)2. With the exception of compounds 9 (IC50 = 56.05 µM) and 11 (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against hDHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards hDHFR. Derivatives 2, 6, 13, 14, and 16 were found to be the most potent hDHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30.


Assuntos
Antagonistas do Ácido Fólico/síntese química , Trimetoprima/análogos & derivados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
18.
Oper Neurosurg (Hagerstown) ; 20(4): 323, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33718955
19.
Rev. iberoam. micol ; 38(1): 5-8, ene.-mar. 2021. ilus
Artigo em Inglês | IBECS | ID: ibc-202387

RESUMO

BACKGROUND: Paracoccidioidomycosis (PCM) is an endemic disease in Latin America. In immunocompetent hosts, PCM occurs in two main clinical forms: acute and chronic. However, in HIV-infected patients PCM may show up simultaneous manifestations of acute and chronic forms. CASE REPORT: We present the case of a patient diagnosed with HIV who had disseminated skin lesions and generalized lymphadenopathy, as well as respiratory and central nervous system involvement. The PCM diagnosis was confirmed by direct KOH examination, double immunodiffusion and the isolation of the fungus in samples of an abscess in the subcostal region. The isolate was identified as Paracoccidioides brasiliensis S1 by species-specific PCR using primers for protein-coding gene GP43 (exon 2) followed by PCR-RFLP of the alpha-tubulin gene. CONCLUSIONS: There are few data in literature reporting species-specific molecular identification of Paracoccidioides in HIV/PCM patients. Therefore, this case report may contribute to improve the knowledge about this severe disease, its causative cryptic species, and its consequences to patients


ANTECEDENTES: La paracoccidioidomicosis (PCM) es una enfermedad endémica en Latinoamérica. En los pacientes inmunocompetentes, la PCM cursa con dos principales formas: aguda y crónica. Sin embargo, los pacientes infectados por el VIH pueden presentar manifestaciones simultáneas de las dos formas clínicas. CASO CLÍNICO: Se presenta el caso de un paciente VIH-positivo, con lesiones cutáneas diseminadas, linfadenopatía generalizada y afectación del sistema nervioso central y respiratorio. El diagnóstico de PCM se confirmó mediante un examen directo con KOH, doble inmunodifusión y el aislamiento del hongo en cultivo, a partir de muestras de un absceso en la región subcostal. La cepa aislada se identificó como Paracoccidioides brasiliensis S1 mediante PCR especie-específica del gen codificador de la proteína GP43 (exón 2), seguida de PCR-RFLP del gen de la alfa-tubulina. CONCLUSIONES: Existen pocos datos en la literatura que describan la identificación molecular especie-específica de Paracoccidioides en pacientes con VIH/PCM. Por lo tanto, la presentación de este caso clínico puede contribuir a mejorar el conocimiento sobre esta enfermedad grave, la especie críptica implicada y sus consecuencias para los pacientes


Assuntos
Humanos , Masculino , Adulto , Paracoccidioidomicose/diagnóstico por imagem , Paracoccidioidomicose/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/complicações , Paracoccidioidomicose/complicações , Paracoccidioides , Paracoccidioidomicose/etiologia , Reação em Cadeia da Polimerase/métodos , Anfotericina B/administração & dosagem , Sulfametoxazol/administração & dosagem , Trimetoprima/administração & dosagem , Dermatopatias/complicações , Dermatopatias/tratamento farmacológico
20.
Rev. iberoam. micol ; 38(1): 19-22, ene.-mar. 2021. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-202394

RESUMO

BACKGROUND: Cryptococcosis is a severe universally distributed mycosis which mainly affects immunocompromised hosts. This mycosis is caused by yeasts of two species complex of the genus Cryptococcus: Cryptococcus neoformans and Cryptococcus gattii. Meningeal cryptococcosis is the most frequent clinical presentation of this disseminated mycosis. The oral mucosa involvement is extremely unusual. CASE REPORT: We present a case of cryptococcosis with an unusual clinical form. The patient was assisted because she had an ulcerated lesion on the lingual mucosa. Encapsulated yeasts compatible with Cryptococcus were found in microscopic exams of wet preparations from lingual ulcer clinical samples obtained for cytodiagnosis and mycological studies. Cryptococcus neoformans (C. neoformans var. grubii VNI) was isolated in culture. This patient did not know her condition of HIV seropositive before the appearance of the tongue lesion. CONCLUSIONS: The involvement of the oral mucosa is uncommon in this fungal infection, but is important to include it in the differential diagnosis in HIV positive patients


ANTECEDENTES: La criptococosis es una micosis grave de distribución universal que afecta principalmente a los huéspedes inmunodeficientes. Se han definido dos complejos de especies patógenas: Cryptococcus neoformans y Cryptococcus gattii. La meningoencefalitis es la presentación clínica más frecuente de esta micosis sistémica. La afectación de la mucosa oral es extremadamente rara. CASO CLÍNICO: Presentamos el caso de una paciente VIH positiva con una forma clínica inusual de criptococosis. La enferma presentaba una lesión ulcerada en la punta de la lengua. El examen microscópico en fresco de la escarificación y de la biopsia de esta lesión mostraron levaduras capsuladas compatibles con Cryptococcus. Se obtuvo Cryptococcus neoformans (C. neoformans var. grubii VNI) en los cultivos. La paciente conoció su estado inmunológico (infección por VIH) en el contexto de esta enfermedad oportunista. CONCLUSIONES: La afectación de la mucosa oral es poco común en esta infección fúngica, pero es importante incluirla en el diagnóstico diferencial en pacientes VIH positivos


Assuntos
Humanos , Feminino , Adulto , Criptococose/diagnóstico , Infecções por HIV/complicações , Língua/patologia , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus neoformans/isolamento & purificação , Cryptococcus neoformans/virologia , Língua/microbiologia , Mucosa Bucal/microbiologia , Diagnóstico Diferencial , Microscopia/métodos , Trimetoprima/administração & dosagem , Sulfametoxazol/administração & dosagem , Antirretrovirais/administração & dosagem
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