A spectral voltammetric and chromatographic investigation of the complexation of oxytetracycline hydrochloride to metals of varying valency

The research work presented here is concerned with how a systematic study of the acid - base equilibria, polarographic and chromatographic behaviour of an antibiotic and its corresponding metal complexes can aid in the development of a sensitive analytical method to speciate these compounds. The antibiotic studied here was one of the most used of all broad spectrum antibiotics namely oxytetracyclme hydrochloride. A systematic study of the acid - base equilibria yielded four pK^ values pK^ = 3 3, pK^ = 7.5, pK^ = 9.7 and pK^ = 10.4. A systematic study in different buffers also using ultraviolet spectroscopy yielded information which was important in determining at which sites the metals studied were binding to the antibiotic. The Cu(II), Ni(II), Co(II) and Mg(II) ions binding in a similar fashion to the BCD chromophore of the antibiotic and the Fe(II) and Fe(III) ions binding in a different manner to the A chromophore of the antibiotic. The polarographic study yielded information which was important in the identification of the process of reduction of oxytetracyclme hydrochloride. The first peak of reduction being due to the carbonyl group and its conjugated double bond in the A chromophore. The remaining reduction peaks being due to the carbonyl groups and their conjugated double bonds in the BCD chromophore. The polarographic information was also important in determining at which sites the metals studied were binding to the antibiotic , the results obtained for this were in good agreement with the spectroscopic study. A systematic study of the chromatographic behaviour of oxytetracycline hydrochloride and its corresponding metal complexes yielded information which was important in the development of an analytical method for the speciation of these antibiotic-metal complexes. The retention times obtained also reflected different binding sites in the case of the Fe(II) ion. The lability of these complexes is also discussed

Impaired myocardial relaxation with exercise determines peak aerobic exercise capacity in heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by impaired exercise capacity due to shortness of breath and/or fatigue. Assessment of diastolic dysfunction at rest and with exercise may provide insight into the pathophysiology of exercise intolerance in HFpEF. Aims To measure echocardio-Doppler-derived parameters of diastolic function as they relate to various indices of aerobic exercise capacity in HFpEF. Methods We selected 16 subjects with clinically stable HFpEF, no evidence of volume overload, but impaired functional capacity by cardiopulmonary exercise testing [peak oxygen consumption (VO2)]. We measured the transmitral E and A flow velocities, E/A ratio, and E deceleration time (DT) and tissue Doppler E′ velocity. We also indexed the E′ to the DT, as additional measure of impaired relaxation (E′DT), and calculated the diastolic functional reserve index (DFRI), as the product of E′ at rest and change in E′ with exercise. Results E′ velocity, at rest and peak exercise, as well as the DFRI positively correlated with peak VO2, whereas DT, E′DT, and E/E′ with exercise inversely correlated with peak VO2. Of note, the E′DT at rest also significantly predicted E′ velocity at peak exercise (R = +0.81, P \u3c 0.001). Exercise E′ was the only independent predictor of peak VO2 at multivariable analysis (R = +0.67, P = 0.005). Conclusions The E′ velocity at peak exercise is a strong and independent predictor of aerobic exercise capacity as measured by peak VO2 in patients with HFpEF, providing the link between abnormal myocardial relaxation with exercise and impaired aerobic exercise capacity in HFpEF

Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) level above and below the proposed cut-off. Methods Stable patients (n = 30) with left ventricular (LV) ejection fraction ≥ 50% were eligible if they had a diagnosis of HF according to the European Society of Cardiology diagnostic criteria. Characteristics of patients with NT-proBNP below (≤125 pg/mL) and above (\u3e125 pg/mL) the diagnostic criterion were compared. Results There were 19 (66%) women with median age 54 years. Half were African American (16, 53%), and most were obese. There were no significant differences in clinical characteristics or medication use between groups. LV end-diastolic volume index was greater in high NT-proBNP patients (P = 0.03). Left atrial volume index, E/e\u27 ratio, and E/e\u27 ratio at peak exercise were not significantly different between NT-proBNP groups. Peak oxygen consumption (VO2), VO2 at ventilatory threshold, and ventilatory efficiency measures were impaired in all patients and were not significantly different between high and low NT-proBNP patients. Conclusions NT-proBNP was below the proposed diagnostic cut-off point of 125 pg/mL in half of this obese study cohort. Cardiac diastolic dysfunction and cardiorespiratory fitness were not significantly different between high and low NT-proBNP patients. These data indicate that excluding the diagnosis of HFpEF based solely on NT-proBNP levels should be discouraged

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of con-firmed HF cases in the United States. However, there are no highly effective evidence-basedtreatments currently available for these patients. Inflammation correlates positively withadverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, hasbeen implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clini-cal trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 ran-domized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespi-ratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation inpatients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpointswill be placebo-corrected interval changes in peak oxygen consumption and ventilatory effi-ciency at week 12. In addition, secondary and exploratory analyses will investigate the effectsof IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function,quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinicaltrial will add to the growing body of evidence on the role of inflammation in cardiovascular dis-ease, specifically focusing on patients with HFpEF

Impact of different dosing regimens of clopidogrel on systemic oxidative stress in patients undergoing elective percutaneous coronary intervention.

n/

Grassland plant and invertebrate species richness increases from mowing are mediated by impacts on soil chemistry

Pasture and improved grasslands are commonly managed by a combination of artificial fertilisation and biomass removal, but a deeper understanding of how management options interact over the long-term are required to improve sustainability. Studies of multi-trophic responses to these options can provide important insights for biodiversity and soil management, particularly when they cover long time periods. In this study, we provide a novel perspective on long-term experimental field studies of grassland management by examining the direct and indirect effects of N fertilisation and mowing (with biomass retention and removal) on above-ground biodiversity, below-ground soil chemistry and their interactions. Our experimental treatments were applied annually from 1994 in medium to high soil fertility conditions on a non-native pastoral farm in New Zealand, and analysis of data to 2013 show that in general, plants and soil properties did not respond to N fertiliser treatments. In response to mowing regimes, soil properties exhibited subtle, but annually varying changes mostly related to biomass retention or removal, and plant richness was consistently higher under all mowing treatments. The management regime with the greatest gains in diversity also depended on year of study. We further analysed the indirect effects of mowing treatments on plant and arthropod richness via soil properties using structural equation modelling, and found that the impact of mowing is likely to be mediated by soil chemistry changes. In particular, the direct positive impact of mowing on plant richness may be offset by changes to soil properties, depending on whether biomass is retained or removed. We suggest that management regime effects on soil chemistry may limit plant composition changes to those species able to take advantage of altered conditions. These findings suggest that management to improve grassland diversity and soil conditions should consider the abiotic history and conditions of the site

Metabolic Modulation Predicts Heart Failure Tests Performance

The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO2), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO2 slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with a left ventricular ejection fraction \u3c 50%, predominantly males African American, presenting a high frequency of diabetes, hyperlipidemia, and hypertension were used in the study. MRA revealed that metabolic models for VE/VCO2 and Peak VO2 were the most fitted models, and the highest predictors’ coefficients were from Acylcarnitine C18:2, palmitic acid, citric acid, asparagine, and 3-hydroxybutiric acid. Metabolic Pathway Analysis (MetPA) used predictors to identify the most relevant metabolic pathways associated to the study, aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP). Metabolite Set Enrichment Analysis (MSEA) found associations of our findings with pre-existing biological knowledge from studies of human plasma metabolism as brain dysfunction and enzyme deficiencies associated with lactic acidosis. Our results indicate a profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction in patients with HF tests poor performance. The insights resulting from this study coincides with what has previously been discussed in existing literature thereby supporting the validity of our findings while at the same time characterizing the metabolic underpinning of CPET and HFBio

Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague-Dawley rats

The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague-Dawley (SD) rats.We determined the effect of AgNPs generated from a spark generator (mass concentration: 600-800 μg/mm(3); mean diameter: 13-16 nm; total lung doses: 8 [Low] and 26-28 [High] μg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function.In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains.Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs

Molecular Predictors of Anakinra Treatment Success in Heart Failure Patients with Reduced Ejection Fraction

Background. Kineret (Anakinra) is an interleukin-1 antagonist that is under investigation for its novel clinical application treating patients that have heart failure with reduced (\u3c50%) ejection fraction (HFrEF). A prior study from our group indicated that Anakinra may restore heart function by addressing dysregulations in HFrEF metabolic pathways. Herein, we attempt to elicit Anakinra’s effects on both metabolome and lipidome. Methods. Lipids and metabolites that had previously been quantified by mass spectrometry (MS) from patients (n=49) who had ≥2 mg/L of high-sensitivity C-reactive protein (hs-CRP) were mTIC normalized and transformed. We conducted a stepwise Linear Discriminant Analysis (r- LDA) to test Anakinra (2 and 12 weeks) vs placebo for separation from combined baseline. Metabolic pathway analysis was performed with Fisher’s exact test algorithm for detection of over-represented and enriched analytes. Univariate analysis (one tailed t-test p\u3c0.05) compared placebo and Anakinra after 12-weeks for effect(s). Metaboanalyst 4.0, JMP Pro 14.0, and a proprietary package in R (version 3.4.4) were the software for all analyses and data wrangling. Results. Analytes such as acylcarnitines C10:0 and C16:0 and hsCRP showed significant improvements after 12 weeks of Anakinra, leading to improved mitochondrial function, reduced inflammation, and overall better health outcomes. Statistically significant (p\u3c0.05) pathways including the citrate cycle, cysteine and methionine metabolism, galactose metabolism among others were associated with treatment. Conclusions. We were able to determine significant alterations to metabolomic and lipidomic concentrations after 12 weeks of Anakinra therapy. Our biochemical analyses verifies that Anakinra did improve heart function within our HFrEF pilot cohort.https://scholarscompass.vcu.edu/gradposters/1081/thumbnail.jp