Comparison of the Intestinal Pharmacokinetics of Two Different Florfenicol Dosing Regimens and Its Impact on the Prevalence and Phenotypic Resistance of E. coli and Enterococcus over Time.

In order to mitigate the food animal sector's role in the growing threat of antimicrobial resistance (AMR), the World Health Organization (WHO) suggests the use of lower tier antimicrobials, such as florfenicol. Florfenicol has two dosing schemes used to treat primarily bovine respiratory disease. In this study, the objective was to characterize the plasma and gastrointestinal pharmacokinetics of each dosing regimen and assess the effect of these dosing regimens on the prevalence of resistant indicator bacteria over time. Twelve steers underwent abdominal surgery to facilitate the placement of ultrafiltration probes within the lumen of the ileum and colon, as well as placement of an interstitial probe. Following surgery, cattle were dosed with either 20 mg/kg IM every 48 h of florfenicol given twice (n = 6) or a single, subcutaneous dose (40 mg/kg, n = 6). Plasma, interstitial fluid, gastrointestinal ultrafiltrate, and feces were collected. Pharmacokinetic analysis demonstrated high penetration of florfenicol within the gastrointestinal tract for both the high and low dose group (300%, 97%, respectively). There was no significant difference noted between dosing groups in proportion or persistence of phenotypically resistant bacterial isolates; however, the percent of resistant isolates was high throughout the study period. The recommendation for the use of a lower tier antimicrobial, such as florfenicol, may allow for the persistence of co-resistance for antibiotics of high regulatory concern.

Surgical ligation of patent ductus arteriosus in a dorper sheep.

OBJECTIVE: To report the diagnosis and treatment of a companion dorper wether with patent ductus arteriosus (PDA). STUDY DESIGN: Case report. ANIMAL: An 8-month-old dorper wether presented to its primary care veterinarian for a persistent cough and was referred for suspected heart failure on the basis of physical examination and thoracic radiography. A PDA was diagnosed on echocardiography. METHODS: The sheep underwent cardiac catheterization and angiogram to measure pulmonary arterial and right ventricular (RV) pressures, identify the morphology of the PDA, and determine whether an intravascular occlusion of the PDA was feasible. Pulmonary artery pressure was 84/53 mm Hg (mean = 66), and RV pressures were 79/5 mm Hg (mean = 45); these were consistent with pulmonary hypertension. The size and shape of the PDA precluded vascular occlusion. Instead, the PDA was ligate through a left fourth intercostal approach. RESULTS: The sheep improved clinically after surgery. The PDA seemed closed on echocardiogram 3 days after surgery. Measurement of postoperative fractional shortening was consistent with decreased left ventricular systolic function that had resolved according to follow-up echocardiography. CONCLUSION: We report the first known diagnostic evaluation and successful treatment of naturally occurring PDA in a companion sheep. CLINICAL SIGNIFICANCE: For economically valuable small ruminants, radiographs, echocardiography and cardiac catheterization can be used to diagnose and plan surgical treatment of PDAs, with a potential for a good long-term outcome.

Androgen receptor and histone lysine demethylases in ovine placenta.

Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR). Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs) to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE) in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.