Assessment of left and right ventricular systolic function in dogs with multicentric lymphoma.

OBJECTIVE: Myocardial dysfunction in cardio-oncology is generally thought to be related to the cardiotoxicity of chemotherapy treatment. However, it is known that some tumors have direct effects on myocardial function. These effects have already been studied in man, but there are no publications of these of the effects in dogs. Novel advanced echocardiographic techniques may allow early detection of myocardial dysfunction when compared to conventional echocardiographic techniques. This study aims to assess myocardial systolic function in dogs with multicentric lymphoma prior to initiation of chemotherapy. ANIMALS: Fifteen dogs with multicentric lymphoma and nineteen healthy dogs. METHODS: Case-control study. Dogs with multicentric lymphoma and healthy control dogs underwent physical examination, electrocardiography, systolic blood pressure measurement, standard and speckle tracking echocardiography to assess biventricular systolic function. RESULTS: There were no differences between groups in terms of ejection fraction, fractional shortening, left ventricular systolic and diastolic diameter, tricuspid annular plane systolic excursion, mitral annular plane systolic excursion and fractional area change of the right ventricle (RV). However, there was a reduction in the values of global circumferential strain (p = 0.0003), RV strain (p = 0.01) and RV tissue motion annular displacement (p < 0.05) in the dogs with lymphoma when compared to the control group. CONCLUSIONS: Speckle tracking techniques appear to demonstrate early systolic dysfunction, primarily affecting the RV, in dogs with lymphoma prior to chemotherapy treatment.

P-Wave Terminal Force in Dogs With Myxomatous Mitral Valve Disease.

P-wave terminal force (PTF) is accepted as an electrocardiographic criteria to assess left atrial abnormalities in humans. In this study, the applicability of PTF in dogs with myxomatous mitral valve disease (MMVD) was evaluated, and compared its ability to identify left atrial dilatation with 4 other P-wave derived parameters. Seventy-four dogs with echocardiographically diagnosed MMVD were recruited for this prospective cross-sectional study. Also, 47 healthy dogs were included to serve as controls. All dogs underwent physical, electrocardiographic and standard echocardiographic examinations prior to enrollment. Electrocardiographic measurements were obtained from simultaneous recordings at three different locations for precordial lead V1. PTF was defined as the deflection following the second half of the P-wave, and was best documented at the first and third right intercostal spaces. In those locations, the P-wave was negative and P-wave terminal force was recognized as a positive undulation in baseline following P-wave. P-wave terminal force and P-wave duration measured from recordings obtained at either the first or third right intercostal spaces had poor to weak correlations (P < .05) with echocardiographic surrogates of cardiac remodeling and congestion. In dogs with MMVD, only P-wave duration and P-wave area distinguished normal and dilated left atria (P < .05). In conclusion, PTF had positive polarity and was best recorded when precordial lead V1 electrode was placed at the most cranial right intercostal locations. PTF failed to reliably identify left atrial enlargement in dogs with MMVD.

Congenital Heart Disease in Dogs: A Retrospective Study of 95 Cases.

The aim of the study was to estimate the prevalence of congenital heart diseases in dogs attending 2 veterinary hospitals in Brazil and to identify possible associations between these conditions and epidemiological characteristics. A retrospective study was carried out in the cardiology sections of 2 veterinary hospitals during a period of 70 months from January 2012 and October 2017. Of a total of 6710 dogs that attended the cardiology sections of the hospitals, 109 congenital heart diseases were identified in 95 patients, representing a prevalence of 1.6%. Findings consistent with previous literature included subaortic stenosis and pulmonic stenosis as the most commonly diagnosed conditions, in addition to a higher predisposition of females to patent ductus arteriosus (PDA). In contrast, the novel findings included a higher prevalence of atrial septal defect and a lower prevalence of patent ductus arteriosus. The majority of the animals included were over 1 year of age at the time of diagnosis (67%) especially in the subaortic stenosis group. Also, a predisposition of the Maltese to ventricular septal defect was observed. The information obtained in the present study contributes to research that describes epidemiological characteristics of dogs with congenital heart disease in a previously unreported location.

Hancornia speciosa serum fraction latex stimulates the angiogenesis and extracellular matrix remodeling processes.

The Hancornia speciosa latex reveals angiogenic, osteogenic, and anti-inflammatory properties, which present its potential for developing of wound healing drugs; however, the latex compounds responsible for angiogenesis remain unknown. One strategy to screen these active compounds is evaluation of latex fractions. This study aimed to obtain different fractions of latex and evaluate its angiogenic activity separately using the chick chorioallantoic membrane (CAM) assay. The serum (SE) fraction was responsible for angiogenesis, which was subject to biochemical characterization and computational simulations in order to understand the contribution of H. speciosa latex in wound healing process. Our results revealed weak antioxidant potential and absence of antimicrobial activity in the SE fraction. Phytochemical analysis identified chlorogenic acids (CGA) as the main compound of SE fraction. CGA bioactivity predictions identify different molecules associated with extracellular matrix (ECM) remodeling, such as metalloproteinases, which also are overexpressed in our CAM assay experiment. Docking simulations revealed the interactions between CGA and matrix metalloproteinase 2. In conclusion, SE latex fraction stimulates angiogenesis and may influence ECM remodeling. These properties may contribute to the wound healing process, and also confirm the widespread use of this plant.

HPLC-PDA method validated for the determination of hibalactone in Hydrocotyle umbellata subterraneous parts and its ultrasound-assisted extraction optimization

ABSTRACT In this work, we developed and validated a HPLC-PDA method for the quantification of hibalactone in Hydrocotyle umbellata L., Araliaceae, subterraneous parts extracts and optimized its ultrasound-assisted extraction. Chromatographic separations were carried out with an isocratic mobile phase of acetonitrile/methanol/water (10:65:25), a flow of 0.8 ml min−1, detection at 290 nm and C18 column (250 × 4.6 mm, 5 µm). The method validation parameters were determined according to Brazilian legislation. The optimization of the hibalactone ultrasound-assisted extraction was performed using Box-Behnken design and response surface methodology. The HPLC method for hibalactone quantification proved to be selective, linear, precise, accurate and robust, being useful for the analysis of hibalactone in H. umbellata subterraneous parts extracts. The optimal ultrasound-assisted extraction conditions were obtained with solid-to-liquid ratio of 1:5 g ml−1, ethanolic strength of 70% (v/v) and temperature of 65 °C. The results can provide support of the quality control and standardization of raw materials from H. umbellata.

Assessment of longitudinal systolic function using tissue motion annular displacement in healthy dogs.

INTRODUCTION: Left ventricular systolic function is one of the main parameters studied in echocardiography. Longitudinal systolic function, however, is less commonly evaluated in routine examinations but may provide early information on systolic dysfunction. The movement of the mitral annulus toward the apex has already been determined as a method for evaluation of longitudinal systolic function in dogs, but the study of this movement by speckle tracking with the tissue motion annular displacement (TMAD) technique has not yet been evaluated. ANIMALS: One hundred fifty-three client-owned healthy dogs. METHODS: Cross-sectional study. One hundred fifty-three client-owned healthy dogs underwent physical examination, electrocardiography, blood pressure measurement, and a standard and speckle tracking echocardiography. Systolic function was evaluated by global longitudinal strain (GLS) and TMAD. These parameters were compared with the standard echocardiographic data. RESULTS: A correlation was found between GLS, TMAD, and body weight. Tissue motion annular displacement and GLS were significantly correlated (p < 0.001) with other surrogates of systolic function, including ejection fraction and fractional shortening. There were no differences in TMAD between sexes. The coefficient of variation (CV) of the intraobserver evaluation in the global TMAD (CV 4.44) was slightly higher than that in the GLS (CV 3.74). Also, TMAD was not influenced by heart rhythm and could be acquired more rapidly than GLS. CONCLUSIONS: Tissue motion annular displacement is a rapid and reproducible method for the assessment of left ventricle longitudinal function in healthy dogs. However, more studies are needed to validate the real clinical applicability of TMAD in animals with heart diseases.

In Silico Design of New Inhibitors of Guanine Phosphoribosyltransferase (GPRT) from Giardia lamblia as Antiparasitic Drug Candidates.

BACKGROUND: Guanine phosphoribosyltransferase (GPRT) is a very attractive target for the development of new drugs against G. lamblia because of its critical role in the synthesis of DNA and RNA. Herein we report the use of in silico approaches to identify potential G. lamblia GPRT inhibitors. METHODS: Analyses of the binding site of the enzyme accomplished through the use of several methods allowed the construction of a pharmacophore model, which was screened against a database of commercial substances. The resulting retrieved compounds were then screened against GPRT by consensus docking with two different methods, and the top 10% scored compounds had their poses visually inspected. Root Mean Square Deviation (RMSD) values ≤ 2.0 Å were used to define a consensual pose while RMSD values between 2 and 3 Å defined a partial consensus. Main toxicity endpoints were predicted through substructural analyses. RESULTS: From the 1,230 compounds retrieved in the pharmacophore-based screening, eleven had their binding modes consensually ascribed by the docking methods, suggesting a better selectivity for the parasite enzyme in comparison to the human counterpart by avoiding steric bumps with a flexible loop in the human enzyme binding site. One compound, ZINC38139588, was predicted to be totally devoid of toxicity, being perhaps the most promising of this series. CONCLUSION: Through rigorously validated docking protocols, we predicted the binding mode of these compounds in the GPRT binding site. The use of a consensus docking strategy yielded more reliable predictions of the binding modes to guide the future biological assays.

Blood pressure and renal injury in dogs with visceral leishmaniasis / Pressão sanguínea e lesão renal em cães com leishmaniose visceral

Systemic hypertension is known to be a common consequence of chronic renal disease, which is frequently diagnosed in dogs with visceral leishmaniasis. Although many veterinary investigations have looked at the renal injury caused by Leishmania spp., the role played by this complication in the development of arterial hypertension documented in some animals with visceral leishmaniasis is not completely understood. In this study, 18 adult dogs with naturally-occurring visceral leishmaniasis and varying clinical signs underwent an indirect blood pressure measurement. Also, sera and spot urine were used for laboratory tests. The median systolic blood pressure was 135.2mmHg (95% confidence interval: 128.5-147.7), median mean arterial pressure was 105.8mmHg (98.3-110.4), and median diastolic arterial pressure was 88.5mmHg (77.8-92.5). No differences existed between asymptomatic and symptomatic animals regarding arterial pressure, and no correlations were documented between blood pressure and serum creatinine, blood urea, urine protein-to-creatinine ratio, urine specific gravity, and the fractional excretion of sodium and potassium. Although an association between hypertension and the identification of inflammation on histopathology could not be demonstrated in hypertensive animals, the assessment of kidney samples from 12 dogs indicated mild inflammation with a lymphoplasmacytic infiltrate (6/12), moderate inflammation with multifocal lymphoplasmacytic and histiocytic infiltrates (3/12), and multifocal degeneration and protein casts (2/12). Anti-Leishmania spp. immunohistochemistry assays stained the renal epithelium in 2/12 of the animals. Even though mild systemic hypertension was documented in a small subset of animals, no relationship between the severity of clinical signs and hypertension could be anticipated.(AU)

A hipertensão sistêmica é reconhecida como uma consequência comum da doença renal crônica, cujo diagnóstico é frequente em cães com leishmaniose visceral. Embora muitas pesquisas veterinárias tenham investigado a lesão renal causada pela Leishmania spp., o papel dessa complicação no desenvolvimento da hipertensão arterial documentada em alguns animais com leishmaniose visceral ainda não é completamente compreendido. Neste estudo, 18 cães adultos com diagnóstico de leishmaniose visceral e sinais clínicos variáveis foram submetidos à avaliação indireta da pressão arterial. Além disso, foram coletados soro e urina para análises laboratoriais. As medianas das pressões arteriais sistólica, média e diastólica foram 135,2mmHg (intervalo de confiança de 95%: 128,5-147,7), 105,8mmHg (98,3-110,4) e 88,5mmHg (77,8-92,5), respectivamente. Não foram constatadas diferenças entre os cães assintomáticos e sintomáticos em relação à pressão arterial, assim como não houve correlação entre a pressão arterial e a creatinina e uréia séricas, relação proteína-creatinina urinária, densidade urinária e excreção fracionada de sódio e potássio. Embora não tenha sido evidenciada associação entre hipertensão arterial e inflamação do tecido renal à histopatologia, a avaliação das amostras oriundas de 12 cães indicou inflamação leve, com infiltrado linfoplasmocitário (6/12), inflamação moderada com infiltrados linfoplasmocitário e histiocítico multifocais (3/12), além de degeneração multifocal e cilindros protéicos (2/12). Ensaios imunoistoquímicos anti-Leishmania spp. marcaram o epitélio renal em 2/12 animais. Apesar de hipertensão leve ter sido documentada em uma pequena parcela dos cães estudados, não se evidenciou relação entre a severidade dos sinais clínicos e o desenvolvimento de hipertensão arterial.(AU)

Brain mechanisms that underlie the effects of motivational audiovisual stimuli on psychophysiological responses during exercise.

Motivational audiovisual stimuli such as music and video have been widely used in the realm of exercise and sport as a means by which to increase situational motivation and enhance performance. The present study addressed the mechanisms that underlie the effects of motivational stimuli on psychophysiological responses and exercise performance. Twenty-two participants completed fatiguing isometric handgrip-squeezing tasks under two experimental conditions (motivational audiovisual condition and neutral audiovisual condition) and a control condition. Electrical activity in the brain and working muscles was analyzed by use of electroencephalography and electromyography, respectively. Participants were asked to squeeze the dynamometer maximally for 30s. A single-item motivation scale was administered after each squeeze. Results indicated that task performance and situational motivational were superior under the influence of motivational stimuli when compared to the other two conditions (~20% and ~25%, respectively). The motivational stimulus downregulated the predominance of low-frequency waves (theta) in the right frontal regions of the cortex (F8), and upregulated high-frequency waves (beta) in the central areas (C3 and C4). It is suggested that motivational sensory cues serve to readjust electrical activity in the brain; a mechanism by which the detrimental effects of fatigue on the efferent control of working muscles is ameliorated.

Endo-xylanase GH11 activation by the fungal metabolite eugenitin.

Eugenitin, a chromone derivative and a metabolite of the endophyte Mycoleptodiscus indicus, at 5 mM activated a recombinant GH11 endo-xylanase by 40 %. The in silico prediction of ligand-binding sites on the three-dimensional structure of the endo-xylanase revealed that eugenitin interacts mainly by a hydrogen bond with a serine residue and a stacking interaction of the heterocyclic aromatic ring system with a tryptophan residue. Eugenitin improved the GH11 endo-xylanase activity on different substrates, modified the optimal pH and temperature activities and slightly affected the kinetic parameters of the enzyme.

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors.

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson's disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Dehydromonocrotaline inhibits mitochondrial complex I. A potential mechanism accounting for hepatotoxicity of monocrotaline.

Monocrotaline is a pyrrolizidine alkaloid present in plants of the Crotalaria species, which causes cytotoxicity and genotoxicity, including hepatotoxicity in animals and humans. It is metabolized by cytochrome P-450 in the liver to the alkylating agent dehydromonocrotaline. We evaluated the effects of monocrotaline and its metabolite on respiration, membrane potential and ATP levels in isolated rat liver mitochondria, and on respiratory chain complex I NADH oxidase activity in submitochondrial particles. Dehydromonocrotaline, but not the parent compound, showed a concentration-dependent inhibition of glutamate/malate-supported state 3 respiration (respiratory chain complex I), but did not affect succinate-supported respiration (complex II). Only dehydromonocrotaline dissipated mitochondrial membrane potential, depleted ATP, and inhibited complex I NADH oxidase activity (IC50=62.06 microM) through a non-competitive type of inhibition (K(I)=8.1 microM). Therefore, dehydromonocrotaline is an inhibitor of the activity of respiratory chain complex I NADH oxidase, an action potentially accounting for the well-documented monocrotaline's hepatotoxicity to animals and humans. The mechanism probably involves change of the complex I conformation resulting from modification of cysteine thiol groups by the metabolite.