Gastrointestinal disease is the most common cause of mortality in dairy calves. Septicemia is an important sequela of diarrhea, and the possibility of bacteremia is the primary justification for empirical antimicrobial therapy. Prior reports estimate that approximately onethird of diarrheic calves are bacteremic; however, those estimates may not be representative of routine cases in heifer calves on commercial dairy operations early in the course of disease. We hypothesized that the prevalence of bacteremia in calves with diarrhea and systemic signs of illness is less than prior estimates (~31%), and that clinical signs or hematological values would be associated with the presence or absence of bacteremia. Female calves less than 21 d of age with and without diarrhea were enrolled from 2 commercial dairy farms over a 10-wk period. Diarrheic calves were enrolled if they were newly diagnosed, had loose to watery stool, had either dehydration (assessed by skin tent and eye position) or depression (assessed by suckle reflex and standing ability), and had no prior antimicrobial treatments. Complete health assessments were conducted at 0, 7, and 14 d following enrollment. An aseptic jugular venous sample was collected and cultured using aerobic and anaerobic methods, and bacterial species were identified using mass spectrometry. Poisson regression models were used to identify associations with bacteremia and compute adjusted prevalence ratios. The prevalence of bacteremia in diarrheic and healthy calves was 9.26% (10/108, 95% confidence interval: 4.5-16%) and 14.8% (4/27, 95% confidence interval: 1.4-28.2%), respectively. Among calves with diarrhea, those with a fever (>39.7°C) or depression were 4.8 and 6.5 times more likely, respectively, to have bacteremia. Only 1 of 47 calves (2%) without signs of depression was bacteremic. The prevalence of bacteremia in diar-rheic calves with signs of systemic illness (depression or dehydration) was significantly lower than previous estimates, and bacteremia was rare among calves without observed depression. Antimicrobial therapy targeting bacteremia is not currently justified in routine cases of diarrhea in preweaning calves without signs of depression. These results suggest a substantial opportunity for more targeted antimicrobial therapy to improve antimicrobial stewardship.
Context Antimicrobial resistant bacteria (AMRB) are transmitted from animals to humans and vice versa through many pathways, and AMRB has been an issue on farms and in food production systems. Aims The aim of this exploratory study was to understand what preventative measures farmers may or may not be using to decrease human and animal exposure to AMRB in Central Michigan, and develop a set of measures for biosecurity behaviours. Methods Participants selected for the study were involved in commercial animal husbandry in central Michigan. Data from farmers were collected via a mixed methods approach. Semistructured interviews and a structured questionnaire were administered, based on the theory of planned behaviour. Data were analysed using Spearman’s rank correlation and thematic analyses. Key results There were no associations between sex, level of education or personal income with biosecurity beliefs or behaviours. There was a positive correlation between farm revenue and the presence of pests in animal holding areas, and how often farmers quarantine new animals before adding them to their herd or flock. The farmers interviewed had increased perceived control over implementing biosecurity measures that are perceived as simple and fast to implement. Conclusions Generally, the farmers believed they could affect AMRB on their farms, but were not always engaging in biosecurity behaviours. Implications Understanding farmers’ perceptions and beliefs of biosecurity practices may help develop efficient and effective outreach, education and extension services.
The bromodomain and extra-terminal (BET) domain family of proteins, which include its prototypical member Brd4, is implicated in a variety of cancers and viral infections due to their interaction with cellular and viral proteins. BET proteins contain two bromodomains, a common protein motif that selectively binds acetylated lysine on histones. However, they are structurally distinct from other bromodomain-containing proteins because they encode a unique C-terminal extra-terminal (ET) domain that is important for the protein–protein interactions including jumonji C-domain-containing protein 6 (JMJD6) and histone–lysine N-methyltransferase NSD3 (NSD3). Brd4 functions primarily during transcription as a passive scaffold linking cellular and viral proteins to chromatin. The rapid development of clinical inhibitors targeting Brd4 highlights the importance of this protein as an anticancer target. Current therapeutic approaches focus on the development of small molecule acetylated lysine mimics of histone marks that block the ability of the bromodomains to bind their chromatin marks. Thus far, bromodomain-targeted agents have shown dose-limiting toxicities due to off-target effects on other bromodomain-containing proteins. Here, we exploited a viral–host protein interaction interface to design peptides for the disruption of BET protein function. A murine leukemia virus (MLV) integrase-derived peptide (ET binding motif, EBM) and its shorter minimal binding motif (pentapeptide LKIRL) were sufficient to directly bind the Brd4 ET domain and reduce cellular proliferation of an acute myeloid leukemia cell line. Using computational and biochemical approaches, we identified the minimal essential contacts between EBM and LKIRL peptides and the Brd4 ET domain. Our findings provide a structural foundation for inhibiting BET/Brd4-mediated cancers by targeting the ET domain with small peptide-based inhibitors.
BackgroundStressed and hospitalized goats are at risk of developing abomasal (gastric) ulceration, but there is a paucity of pharmacokinetic studies for proton pump inhibiting drugs, such as, esomeprazole in goats.ObjectivesThe objectives for this study were to estimate plasma pharmacokinetic parameters for esomeprazole in adult goats after intravenous (IV) and subcutaneous (SQ) administration. A secondary objective was to describe the plasma kinetics of the metabolite esomeprazole sulfone after IV and SC administration in goats.Materials and methodsEsomeprazole was administered to 5 adult goats in a crossover study at doses of 1 mg/kg IV or 2 mg/kg SC. Plasma samples were collected over 36 h and analyzed via reverse phase HPLC to determine concentrations of esomeprazole and esomeprazole sulfone. Pharmacokinetic parameters were derived via non-compartmental analysis.ResultsFollowing IV administration, mean values for plasma clearance (Cl), elimination half-life [T1/2 (λz)], C0, and volume of distribution (Vz) of esomeprazole were estimated at 24.9 mL/min/kg, 6 min, 2.324 μg/mL, and 0.23 L/kg, respectively. After SC administration elimination half-life, maximum concentration (Cmax) and time to maximum concentration (Tmax) of esomeprazole were estimated at 29 min, 1.038 μg/mL, and 22 minutes respectively. Maximum concentrations of the sulfone metabolite were 32 and 18 ng/mL after IV and SC administration.ConclusionEsomeprazole was rapidly eliminated from plasma after both IV and SC injection in goats. The elimination half-life in goats appears to be shorter than reported in dogs, as well as less than that reported for pantoprazole in goats. The sulfone metabolite was detected and also rapidly eliminated from the plasma after both IV and SC administration. Additional pharmacodynamic investigations are needed to determine the efficacy of esomeprazole on abomasal (gastric) acid suppression in goats and could include larger doses or additional routes of administration.
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