Impact of maternal live yeast supplementation to sows on intestinal inflammatory cytokine expression and tight junction proteins in suckling and weanling piglets.

Recent studies have highlighted the importance of maternal nutrition during gestation and lactation in modulating the gastrointestinal development and health of offspring. Therefore, the objective of this study was to determine the effects of live yeast (LY) supplementation to sows during late gestation and throughout lactation on markers of gut health of piglets prior to weaning and immediately postweaning. On day 77 of gestation, forty sows were allotted based on parity and expected farrowing dates to two dietary treatments: without (CON) or with (LY) supplementation at 0.05% and 0.1% of diet during gestation and lactation, respectively. On postnatal days (PND) 0, 10, 18, and postweaning days (PWD) 7 and 14, one piglet from each of 10 sows per treatment were selected for intestinal tissue collection (n = 10). Real-time PCR and western blotting analyses were used to determine the mucosal expression of immune and antioxidant-regulatory genes and tight junction markers of gut health in the duodenum, jejunum, and ileum. Inflammatory and tight junction markers on PND 0 were not affected by maternal dietary treatment. On PND 18, maternal LY supplementation increased (P < 0.05) mRNA expression of interleukin (IL)-6 and tended (P = 0.08) to increase expression of IL-10 in the ileal muocsa. Maternal LY supplementation also increased (P < 0.05) expression of IL-1ß in the ileal mucosa on PWD 14. Likewise, expression of superoxide dismutase (SOD) 1 was increased (P < 0.05) by LY on PND 10, 18, and PWD 14, with a tendency (P = 0.09) for a greater mRNA abundance of catalase on PND 14 in the ileal mucosa. Compared to CON piglets, LY piglets had a higher (P < 0.05) protein abundance of E-cadherin in the jejunal mucosa on PND 0, PWD 7, and PWD 14. Levels of occludin and claudin-4 were also higher (P < 0.05) in the jejunum of LY piglets on PWD 14. No differences were found in jejunal histomorphological measurements between treatments. In conclusion, this study shows that maternal LY supplementation affects key markers of gut health and development in the offspring that may impact the future growth potential and health of newborn piglets.

Increasing evidence supports the benefits of improving sow nutrition during gestation and lactation to promote gastrointestinal development and overall health of piglets. The objective of this research was to investigate the effects of maternal live yeast (LY) supplementation to sows during late gestation and lactation periods on the intestinal health of suckling and weaned piglets. Sows were fed LY during gestation and lactation and piglets were killed for sampling at different time points to track the temporal effect of maternal LY supplementation on changes in markers of intestinal health and development on postnatal days 0, 10, and 18, and postweaning days 7 and 14. Results showed that maternal LY supplementation affected several markers of health and development in the offspring, especially the expression of tight junction proteins, inflammatory cytokines, and antioxidant enzymes. These results indicate that nutritional intervention during gestation and lactation could serve as an effective strategy for raising piglets with better health and growth performance.

Effects of early-life cecal microbiota transplantation from divergently selected inbred chicken lines on growth, gut serotonin, and immune parameters in recipient chickens.

Recent studies have revealed that fecal microbiota transplantation exerts beneficial effects on modulating stress-related inflammation and gastrointestinal health of the host. The aim of this study was to examine if cecal microbiota transplantation (CMT) presents similar efficiency in improving the health status of egg-laying strain chickens. Chicken lines 63 and 72 divergently selected for resistance or susceptibility to Marek's disease were used as CMT donors. Eighty-four d-old male recipient chicks (a commercial DeKalb XL layer strain) were randomly assigned into 3 treatments with 7 replicates per treatment and 4 birds per replicate (n = 7): saline (control, CTRL), cecal solution of line 63 (63-CMT), and cecal solution of line 72 (72-CMT) for a 16-wk trial. Cecal transplant gavage was conducted once daily from d 1 to d 10, then boosted once weekly from wk 3 to wk 5. The results indicated that 72-CMT birds had the highest body weight and ileal villus/crypt ratio among the treatments at wk 5 (P ≤ 0.05); and higher heterophil/lymphocyte ratios than that of 63-CMT birds at wk 16 (P < 0.05). 72-CMT birds also had higher levels of plasma natural IgG and Interleukin (IL)-6 at wk 16, while 63-CMT birds had higher concentrations of ileal mucosal secretory IgA at wk 5 and plasma IL-10 at wk 16 (P < 0.05), with a tendency for lower mRNA abundance of splenic IL-6 and tumor necrosis factor (TNF)-α at wk 16 (P = 0.08 and 0.07, respectively). In addition, 72-CMT birds tended to have the lowest serotonin concentrations (P = 0.07) with the highest serotonin turnover in the ileum at wk 5 (P < 0.05). There were no treatment effects on the levels of plasma corticosterone and testosterone at wk 16 (P > 0.05). In conclusion, early postnatal CMT from different donors led to different patterns of growth and health status through the regulation of ileal morphological structures, gut-derived serotonergic activities, peripheral cytokines, and antibody production in recipient chickens.

Reduction in Schedule II opioid prescribing by primary care -providers, orthopedic and general surgeons, and pain -management specialists following the implementation of a State House Bill and an Institutional Controlled Substance Task Force.

OBJECTIVE: Prescription opioid misuse represents a social and economic challenge in the United States. We evaluated Schedule II opioid prescribing practices by primary care providers (PCPs), orthopedic and general surgeons, and pain management specialists. DESIGN: Prospective evaluation of prescribing practices of PCPs, orthopedic and general surgeons, and pain management specialists over 5 years (October 1, 2014-September 30, 2019) in an outpatient setting. METHODS: An analysis of Schedule II opioid prescribing following the implementation of federal and state guidelines and evidence-based standards at our institution. RESULTS: There were significantly more PCPs, orthopedic and general surgeons, and pain management specialists with a significantly increased number who prescribed Schedule II opioids, whereas there was a simultaneous significant decline in the average number of Schedule II opioid prescriptions per provider, Schedule II opioid pills prescribed per provider, and Schedule II opioid pills prescribed per patient by providers. The average number of Schedule II opioid prescriptions with a quantity >90 and Opana/Oxycontin prescriptions per PCP, orthopedic surgeon, and pain management specialist significantly decreased. The total morphine milligram equivalent (MME)/day of Schedule II opioids ordered by PCPs, orthopedic and general surgeons, and pain management specialists significantly declined. The ages of the providers remained consistent throughout the study. CONCLUSIONS: This study reports the implementation of federal and state regulations and institutional evidence-based guidelines into primary care and medical specialty practices to reduce the number of Schedule II opioids prescribed. Further research is warranted to determine alternative therapies to Schedule II opioids that may alleviate a patient's pain without initiating or exacerbating a potentially lethal opioid addiction.

Replacing dietary antibiotics with 0.20% l-glutamine in swine nursery diets: impact on intestinal physiology and the microbiome following weaning and transport.

Previous research demonstrates that supplementing 0.20% l-glutamine (GLN) in the diets of newly weaned and transported pigs improves growth rate to a similar extent as providing dietary antibiotics (AB). However, research comparing the effects of GLN vs. AB on intestinal physiology and the microbiome is limited. Therefore, the study objective was to compare the effects of supplementing nursery diets with GLN, AB, or no dietary antibiotics (NA) on intestinal physiology and the microbiome of pigs in a production environment following weaning and transport. Mixed-sex piglets (N = 480; 5.62 ± 0.06 kg body weight [BW]) were weaned (18.4 ± 0.2 d of age) and transported for 12 h in central Indiana, for two replicates, during the summer of 2016 and the spring of 2017. Pens were blocked by BW and allotted to one of the three dietary treatments (n = 10 pens/dietary treatment/replicate [8 pigs/pen]): AB (chlortetracycline [441 ppm] + tiamulin [38.6 ppm]), GLN (0.20% as-fed), or NA fed for 14 d. From day 14 to 34, pigs were fed common AB-free diets in two phases. On day 33, villus height:crypt depth tended to be increased (P = 0.07; 7.0%) in GLN and AB pigs vs. NA pigs. On day 33, glucagon-like peptide 2 (GLP-2) mRNA abundance was decreased (P = 0.01; 50.3%) in GLN and NA pigs vs. AB pigs. Crypt depth was increased overall on day 33 (P = 0.01; 16.2%) during the spring replicate compared with the summer replicate. Villus height:crypt depth was reduced (P = 0.01; 9.6%) during the spring replicate compared with the summer replicate on day 33. On day 13, tumor necrosis factor-alpha and occludin mRNA abundance was increased (P ≤ 0.04; 45.9% and 106.5%, respectively) and zonula occludens-1 mRNA abundance tended to be greater (P = 0.10; 19.2%) in the spring replicate compared with the summer replicate. In addition, AB pigs had increased (P = 0.01; 101.3%) GLP-2 mRNA abundance compared with GLN and NA pigs. Microbiome analysis indicated that on day 13, dietary treatment altered the microbiota community structure (P = 0.03). Specifically, the AB pigs tended to be distinct from both the NA and GLN pigs (P = 0.08), and Lactobacillus was increased nearly 2-fold in AB compared with NA pigs (q = 0.04) and GLN pigs (q = 0.22). In conclusion, GLN supplementation tended to improve some morphological markers of intestinal health similarly to AB pigs, while the microbiome composition in GLN pigs was more similar to NA pigs than AB pigs.

Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.