Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Leading to Parasite Death

Leishmania infantum is a protozoan parasite that causes a vector borne infectious disease in humans known as visceral leishmaniasis (VL). This pathology, also caused by L. donovani, presently impacts the health of 500,000 people worldwide, and is treated with outdated anti-parasitic drugs that suffer from poor treatment regimens, severe side effects, high cost and/or emergence of resistant parasites. In previous works we have disclosed the anti-Leishmania activity of (-)-Epigallocatechin 3-O-gallate (EGCG), a flavonoid compound present in green tea leaves. To date, the mechanism of action of EGCG against Leishmania remains unknown. This work aims to shed new light into the leishmanicidal mode of action of EGCG. Towards this goal, we first confirmed that EGCG inhibits L. infantum promastigote proliferation in a concentration-dependent manner. Second, we established that the leishmanicidal effect of EGCG was associated with i) mitochondria depolarization and ii) decreased concentration of intracellular ATP, and iii) increased concentration of intracellular H2O2. Third, we found that the leishmanicidal effect and the elevated H2O2 levels induced by of EGCG can be abolished by PEG-catalase, strongly suggesting that this flavonoid kills L. infantum promastigotes by disturbing their intracellular redox balance. Finally, we gathered in silico and in vitro evidence that EGCG binds to trypanothione reductase (TR), a central enzyme of the redox homeostasis of Leishmania, acting as a competitive inhibitor of its trypanothione substrate.This work was supported by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Programa Estratégico de Apoio a Pesquisa em Saúde (PAPES/FIOCRUZ);, and Fundação Oswaldo Cruz (FIOCRUZ). EA-A is the ecipient of a research scholarship from Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq). JI was supported by a postdoctoral fellowship from Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq). JI is a recipient of a postdoctoral fellowship from Fundação Oswaldo Cruz (FIOCRUZ). HC is funded by Fundação para a Ciência e Tecnologia (FCT, Portugal) through the “Investigador FCT” contract IF/01244/2015

Vancouver simplified grading system with computed tomographic angiography for blunt aortic injury

ObjectiveDelineation of blunt aortic injury by computed tomographic angiography guides management of this potentially fatal injury. Two existing grading systems are problematic to apply and not linked to outcomes. A simplified computed tomographic angiography–based grading system, linked to clinical outcomes, was developed, and feasibility and reliability were evaluated.MethodsRetrospective review was performed of all blunt aortic injury cases presenting to a single provincial quaternary referral center designated for blunt aortic injury management between 2001 and 2009. Management, associated injuries, hospital survival, and cause of death were determined. Initial computed tomographic angiography was reviewed, and injuries were graded according to the new Vancouver simplified grading system by 2 study authors. Three additional trauma radiologists then graded the aortic injuries with the 2 existing systems and the simplified system. Interrater reliability was determined.ResultsForty-eight patients were identified. Two had minimal aortic injury (grade I), 7 had an intimal flap larger than 1 cm (grade II), 32 had traumatic pseudoaneurysm (grade III), 6 had active contrast extravasation (grade IV), and 1 could not be rated. Survivals were 100%, 90%, and 33% for grades I and II, III, and IV, respectively. Of grade III injuries, 14% were medically managed, 68% repaired endovascularly, and 18% repaired with open surgery. Interrater correlation was best with the simplified score, with only 0.5% of cases unable to be classified.ConclusionsThe Vancouver simplified blunt aortic injury grading system is easy to use and correlates with clinical outcomes. Prospective external validation is required

Does bariatric surgery prior to total hip or knee arthroplasty reduce post-operative complications and improve clinical outcomes for obese patients? Systematic review and meta-analysis.

AIMS: Our aim was to determine whether, based on the current literature, bariatric surgery prior to total hip (THA) or total knee arthroplasty (TKA) reduces the complication rates and improves the outcome following arthroplasty in obese patients. METHODS: A systematic literature search was undertaken of published and unpublished databases on the 5 November 2015. All papers reporting studies comparing obese patients who had undergone bariatric surgery prior to arthroplasty, or not, were included. Each study was assessed using the Downs and Black appraisal tool. A meta-analysis of risk ratios (RR) and 95% confidence intervals (CI) was performed to determine the incidence of complications including wound infection, deep vein thrombosis (DVT), pulmonary embolism (PE), revision surgery and mortality. RESULTS: From 156 potential studies, five were considered to be eligible for inclusion in the study. A total of 23 348 patients (657 who had undergone bariatric surgery, 22 691 who had not) were analysed. The evidence-base was moderate in quality. There was no statistically significant difference in outcomes such as superficial wound infection (relative risk (RR) 1.88; 95% confidence interval (CI) 0.95 to 0.37), deep wound infection (RR 1.04; 95% CI 0.65 to 1.66), DVT (RR 0.57; 95% CI 0.13 to 2.44), PE (RR 0.51; 95% CI 0.03 to 8.26), revision surgery (RR 1.24; 95% CI 0.75 to 2.05) or mortality (RR 1.25; 95% CI 0.16 to 9.89) between the two groups. CONCLUSION: For most peri-operative outcomes, bariatric surgery prior to THA or TKA does not significantly reduce the complication rates or improve the clinical outcome. This study questions the previous belief that bariatric surgery prior to arthroplasty may improve the clinical outcomes for patients who are obese or morbidly obese. This finding is based on moderate quality evidence. Cite this article: Bone Joint J 2016;98-B:1160-6

Enhancement of Muscle Shortening Torque Preloaded with Muscle Lengthening is Joint-Specific

Our cross-sectional study aimed to investigate joint specificity of concentric muscle torque enhancement after a maximum eccentric contraction for the knee versus ankle joints across two different movement velocities (120°/s and 180°/s). After a familiarization session, 22 healthy young adults randomly performed concentric (CONC) and maximum eccentric preloaded concentric (EccCONC) muscle strength tests of the knee extensors and ankle plantar flexors of the non-dominant leg on an isokinetic strength testing device. We calculated the ratio between EccCONC and CONC (EccCONC/CONC) for all the conditions as the marker of concentric muscle torque enhancement. Separate two-way (joints x velocity) within repeated measures ANOVAs were used to determine joint-specific torque differences at 120°/s and 180°/s. CONC and EccCONC were greater for the knee extensors versus ankle plantar flexors at 120°/s and 180°/s (32.86%–102%; p \u3c 0.001 for both); however, EccCONC/CONC was greater for the ankle plantar flexors than knee extensors at 120°/s (52.4%; p \u3c 0.001) and 180°/s (41.9%; p \u3c 0.001). There was a trend of greater EccCONC/CONC for the knee extensors at 180°/s than 120°/s (6.6%; p = 0.07). Our results show that greater concentric muscle torque enhancement after a maximal eccentric contraction occurs for the ankle plantar flexors versus knee extensors. Whether the joint-specificity of concentric muscle torque enhancement after a maximal eccentric contraction differentially affects sports performance is unknown. Our data provide a reference framework to investigate joint-specific concentric muscle torque enhancement for general and clinical athletic populations. © 2023, Termedia Publishing House Ltd.. All rights reserved

Genomic diversity of EPEC associated with clinical presentations of differing severity

Enteropathogenic Escherichia coli (EPEC) are diarrhoeagenic E. coli, and are a significant cause of gastrointestinal illness among young children in developing countries. Typical EPEC are identified by the presence of the bundle-forming pilus encoded by a virulence plasmid, which has been linked to an increased severity of illness, while atypical EPEC lack this feature. Comparative genomics of 70 total EPEC from lethal (LI), non-lethal symptomatic (NSI) or asymptomatic (AI) cases of diarrhoeal illness in children enrolled in the Global Enteric Multicenter Study was used to investigate the genomic differences in EPEC isolates obtained from individuals with various clinical outcomes. A comparison of the genomes of isolates from different clinical outcomes identified genes that were significantly more prevalent in EPEC isolates of symptomatic and lethal outcomes than in EPEC isolates of asymptomatic outcomes. These EPEC isolates exhibited previously unappreciated phylogenomic diversity and combinations of virulence factors. These comparative results highlight the diversity of the pathogen, as well as the complexity of the EPEC virulence factor repertoire

Using salt counterions to modify β2-agonist behaviour in vivo

This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. © 2016 American Chemical Society.There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol’s behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug’s physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.Peer reviewe

Pré-tratamento de águas residuárias da suinocultura para aumentar a disponibilidade de fósforo e magnésio.

Este trabalho avaliou a influência da adição de ácido sulfúrico para o ajuste de pH e sua relação com a concentração de fósforo total (Ptotal), magnésio (Mg), Cálcio (Ca), amônia (NH3) e carbono orgânico total (COT) contido na água residuária proveniente da suinocultura