Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Strategic supplementation of growing cattle on tropical pastures improves nutrient use and animal performance, with fewer days required on the finishing phase

Context: Cattle grazing tropical forages usually perform below genetic potential due to limited nutrient intake. Aims: Four experiments were conducted to evaluate supplementation strategies on performance and metabolism of cattle grazing intensively managed marandu palisade grass (Urochloa brizantha). Methods: Experiment 1 evaluated the average daily gain (ADG) of 72 young bulls (222 ± 25 kg bodyweight, BW) grazing palisade grass and supplemented (22% crude protein, CP) at 0.0%, 0.3%, 0.6% and 0.9% BW, and their ADG during the feedlot finishing phase. Experiment 2 evaluated the ADG of 80 bulls (240 ± 18 kg BW) grazing palisade grass and supplemented with energy (11.3% CP) or three protein sources (≈20.5% CP) at 0.6% BW. Experiment 3 investigated intake, rumen parameters and digestibility of nutrients in fistulated steers (410 ± 8.6 kg BW) fed an energy supplement, that is, ground corn, at 0.0%, 0.3%, 0.6% and 0.9% BW, with a parallel in vitro study of fermentation kinetics (Experiment 4). Key results: Increased levels of supplementation resulted in linear increases (P 0.05) in ADG, SR and BW gain per area among supplemental sources of protein or the energy supplement. Increasing energy levels caused a linear decrease (P 0.05) fibre degradability. Corn supplementation also caused a linear decrease (P < 0.05) in acetate: propionate ratio, in ruminal ammonia-N and in N excretion, and a linear increase (P < 0.05) in rumen propionate concentration, in microbial synthesis and in N retention. The supplementation increased BW at the start of the feedlot phase, resulting in similar hot carcass weights with fewer days on feed and no effects on meat quality. Conclusions: Overall, despite the source utilised, supplementation increased ADG, SR and BW gain per area, with fewer days being required on the finishing period. Implications: Having adequate supplementation strategies in place will help producers increase the efficiency of their systems

Immunoglobulin G profile in hyperacute rejection after multivisceral xenotransplantation

Galvao FHF, Soler W, Pompeu E, Waisberg DR, Mello ES, Costa ACL, Teodoro W, Velosa AP, Capelozzi VL, Antonangelo L, Catanozi S, Martins A, Malbouisson LMS, Cruz RJ, Figueira ER, Filho JAR, Chaib E, D'Albuquerque LAC. Immunoglobulin G profile in hyperacute rejection after multivisceral xenotransplantation. Xenotransplantation 2012; 19: 298304. (c) 2012 John Wiley & Sons A/S. Abstract: Introduction: Xenotransplantation is a potential solution for the high mortality of patients on the waiting list for multivisceral transplantation; nevertheless, hyperacute rejection (HAR) hampers this practice and motivates innovative research. In this report, we describe a model of multivisceral xenotransplantation in which we observed immunoglobulin G (IgG) involvement in HAR. Methods: We recovered en bloc multivisceral grafts (distal esophagus, stomach, small intestine, colon, liver, pancreas, and kidneys) from rabbits (n = 20) and implanted them in the swine (n = 15) or rabbits (n = 5, control). Three hours after graft reperfusion, we collected samples from all graft organs for histological study and to assess IgG fixation by immunofluorescence. Histopathologic findings were graded according to previously described methods. Results: No histopathological features of rejection were seen in the rabbit allografts. In the swine-to-rabbit grafts, features of HAR were moderate in the liver and severe in esophagus, stomach, intestines, spleen, pancreas, and kidney. Xenograft vessels were the central target of HAR. The main lesions included edema, hemorrhage, thrombosis, myosites, fibrinoid degeneration, and necrosis. IgG deposition was intense on cell membranes, mainly in the vascular endothelium. Conclusions: Rabbit-to-swine multivisceral xenotransplants undergo moderate HAR in the liver and severe HAR in the other organs. Moderate HAR in the liver suggests a degree of resistance to the humoral immune response in this organ. Strong IgG fixation in cell membranes, including vascular endothelium, confirms HAR characterized by a primary humoral immune response. This model allows appraisal of HAR in multiple organs and investigation of the livers relative resistance to this immune response

On the search for potential anti-Trypanosoma cruzi drugs: Synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-beta-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC50/24 h values in the range of 10.9-101.5 mu M. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies. (C) 2012 Elsevier Masson SAS. All rights reserved.CNPqCNPqFAPEMIGFAPEMIG [APQ-04166-10]FAPESPFAPESP [2009/14184-0, 2009/51812-0]PRONEMFACEPEPRONEM-FACEPE [APQ-232106/10]PRONEX-FAPERJ [E-26/110.574/2010]PRONEX, FAPERJCNE-FAPERJ [Proc. 101.579/2010]CNEFAPERJINCT_ifINCT_ifCAPESCAPE