Effects of including Sweet Bran or modified distillers grains in the diet of feedlot steers and sorting at terminal implant on growth performance, feeding behavior, and liver abscess occurrence.

The objectives were to assess the effects of dietary Sweet Bran (Cargill Corn Milling, Blair, NE) on performance and feeding behavior of feedlot steers and determine if terminal implant pen sorting affects performance, feeding behavior, and liver abscess (LA) rate. Two hundred sixteen Angus-cross steers (253 ± 18 kg) were stratified by body weight (BW) to 36 pens. From d 0 to 60, diets contained 40% Sweet Bran (SWBR) or 25% modified distiller's grains and 15% dry rolled corn (MOD; n = 18 pens/treatment). On d 60, steers began transition within treatments to finishing diets containing 25% Sweet Bran or 25% modified distiller's grains (MDGS). On d 111, half of the pens for each dietary treatment were re-stratified by BW to pens (SORT) while the other half were returned to original pens (NOSORT; n = 9 pens/treatment). Steer BW and pen dry matter intake (DMI) were recorded monthly. Rate of feed disappearance was determined on d 5/6, 53/54, 104/105, and 117/118. Pen was the experimental unit for all analyses. The model included the fixed effect of diet for all pre-sort analyses; post-sort analyses included the fixed effects of diet, sort, and the interaction and the random effects of pen and the interaction of diet and pen. On d 60, SWBR had greater BW than MOD (P = 0.05), and SWBR had a greater average daily gain (ADG) from d 0 to 60 (P = 0.05). Though there were no differences after d 28, SWBR had greater DMI d 0 to 28 (P = 0.05). From d 60 to 88, SWBR tended to have lesser ADG than MOD (P = 0.09). Post-sort (d 111 to 196), SWBR tended to have lesser ADG than MOD (P = 0.06), and SORT had a greater rate of feed disappearance than NOSORT (d 117/118; P = 0.01); there were no differences on other dates (Diet: P ≥ 0.38). For final BW, there was a tendency for MOD to be greater than SWBR, and SORT tended to be greater than NOSORT (Diet: P = 0.06; Sort: P = 0.10). Pre- and post-sort ruminal pH had no treatment by day differences (P ≥ 0.77). LA incidence averaged 25%, though rate was not affected by diet, sorting, or the interaction (P ≥ 0.16). Overall, there were no dietary differences in feed disappearance rates, though SORT steers had greater rate of feed disappearance than NOSORT steers on d 117/118. Nominal differences in feeding behavior were noted and including Sweet Bran in the diet was beneficial in the growing period as cattle adjusted to the feedlot.

Effects of increasing supplemental zinc in beef feedlot steers administered a steroidal implant and beta agonist.

Ninety-two Angus-crossbred steers (424 ±â€…28.3 kg initial body weight) were used in a 98-d study to assess the effects of increasing Zn supplementation on cattle performance, liver and plasma trace mineral concentrations, blood metabolites, and carcass characteristics. All steers were implanted with a Component TE-200 (200 mg trenbolone acetate + 20 mg estradiol; Elanco Animal Health, Greenfield, IN) on d 0 and fed 300 mg‧steer-1‧d-1 of ractopamine hydrochloride (Zoetis, Parsippany, NJ) from d 70 to 98. Cattle were fed via GrowSafe bunks (GrowSafe Systems Ltd., Airdrie, AB, Canada), and steer served as the experimental unit (n = 22 or 23 steers/treatment). Supplemental Zn was administered through the diet at 0, 100, 150, or 180 mg Zn/kg on a dry matter basis from ZnSO4 (Zn0, Zn100, Zn150, or Zn180, respectively). Cattle were weighed on d -1, 0, 9/10, 20, 41, 59, 69, 70, 78/79, 97, and 98. Blood was collected on d 0, 9/10, 69, 78/79, and 97, and liver biopsies on d 9/10 and 78/79 (n = 12 steers/treatment). Data were analyzed as a complete randomized design. Contrast statements were formed to test the linear, quadratic, and cubic effects of Zn supplementation and test Zn0 vs. Zn supplementation. Day 10 and 70 body weight (BW) and d 0 to 10 and 0 to 70 average daily gain were linearly increased with Zn supplementation (P ≤ 0.05), and greater for Zn supplemented steers (P ≤ 0.03). No effects of Zn supplementation were observed on final BW, dressing percentage, ribeye area, 12th rib fat, or marbling (P ≥ 0.11). Hot carcass weight tended to be 7 kg greater for Zn supplemented steers than Zn0 (P = 0.07), and yield grade linearly increased with increasing Zn supplementation (P = 0.02). Day 10 liver Mn concentrations tended to quadratically decrease (P = 0.08) with increasing Zn supplementation, though d 79 liver Mn concentrations and arginase activity were not influenced by Zn (P ≥ 0.28). Day 10 liver arginase activity tended to be (r = 0.27; P = 0.07) and d 10 serum urea nitrogen was correlated with d 10 liver Mn (r = 0.55; P < 0.0001). Zinc supplementation linearly increased d 10 liver Zn and d 10, 69, 79, and 97 plasma Zn concentrations (P ≤ 0.05). A cubic effect of Zn was observed on d 79 liver Zn (P = 0.01) with lesser liver Zn in Zn0 and Zn150 steers. These data suggest increasing dietary Zn improves growth directly following the administration of a steroidal implant and that steroidal implants and beta agonists differ in their effects on protein metabolism.

Effect of zinc source and implant strategy on performance, carcass characteristics, and trace mineral concentrations in finishing feedlot steers.

Seventy-two Angus-crossbred steers (411 ± 16 kg) were assigned to a 2 × 3 factorial arrangement of treatments to examine the effects of blended Zn source supplementation on performance, carcass characteristics, and trace mineral parameters of steers administered no implant or a two-implant program. Factors included implant (IMP) strategies and Zn supplementation. During the 126-d study, steers were either not implanted (NoIMP) or implanted (IS/200; Elanco, Greenfield, IN) on days 0 (Component TE-IS; 80 mg trenbolone acetate + 16 mg estradiol) and 57 (Component TE-200; 200 mg trenbolone acetate + 20 mg estradiol). All steers were fed 70 mg Zn/kg on a dry matter (DM) basis from ZnSO4 + 30 mg Zn/kg DM from either basic ZnCl (Vistore Zn, Phibro Animal Health, Teaneck, NJ), Zn glycinate (Gemstone Zn, Phibro Animal Health), or ZnSO4 (ZnB, ZnG, or ZnS, respectively). Steers were blocked by weight into pens of 6 and fed a dry rolled corn-based diet via GrowSafe bunks (GrowSafe Systems Ltd.; Airdrie, AB, Canada). Data were analyzed using the Mixed Procedure of SAS, with fixed effects of Zn, IMP, and the interaction. Steer was the experimental unit (n = 12 steers/treatment). Liver and muscle collected on days -5, 14, 71, and 120 were analyzed for Zn concentration, and data were analyzed as repeated measures (repeated effect = Day). An IMP × Zn tendency (P = 0.07) was observed for day 126 body weight with no effects of Zn within NoIMP, whereas ZnS tended to be heavier than ZnB with ZnG intermediate within IS/200. Carcass-adjusted overall feed efficiency (G:F) was greatest for ZnS (Zn; P = 0.02). Implanted cattle had greater DM intake, G:F, and carcass-adjusted performance (P ≤ 0.01). Liver Zn concentrations were greater for IS/200 by day 120 (IMP × Day; P = 0.02). Within IS/200, ZnG tended to have greater muscle Zn than ZnS, whereas ZnB was intermediate (Zn × IMP; P = 0.09). No Zn or IMP × Zn (P ≥ 0.12) effects were observed for carcass data. However, IS/200 had greater hot carcass weight, dressing percentage, and ribeye area than NoIMP (P ≤ 0.001). These data suggest that implants improve growth and influence Zn metabolism. Future work should examine Zn sources and supplementation alongside implant strategies.

SB206, a Nitric Oxide-Releasing Topical Medication, Induces the Beginning of the End Sign and Molluscum Clearance.

The beginning of the end (BOTE) sign has been proposed to describe well-recognized clinical signs of inflammation (including erythema, induration, and scale) that predict imminent resolution of molluscum contagiosum (MC). This phenomenon has never been prospectively studied. An integrated analysis of two prospective, 12-week, randomized, double-blind clinical trials of topical nitric oxide-releasing SB206 gel evaluated an association between BOTE sign and MC lesion reduction. Of 707 randomized patients, ~80% exhibited BOTE signs regardless of treatment assignment. At week 12, MC lesion counts decreased from baseline by 50.7% for baseline BOTE+ versus 29.1% for BOTE- (P = 0.0015) vehicle-treated patients compared with a 63.3% decrease for baseline BOTE+ versus 51.7% for BOTE- (P = 0.0194) SB206-treated patients. Among vehicle-treated patients, 48 (22.3%) who were never BOTE+ had an 18.5% reduction from baseline in MC lesion counts versus a 34.0% reduction in 165 patients (76.7%) who experienced BOTE at any time, suggesting that the projected duration of lesion clearance for patients with 18-20 MC lesions is 15 months for BOTE- versus 6 months for BOTE+ patients. Patients who were both BOTE+ and treated with SB206 had the greatest reduction in MC lesion count. SB206 may trigger BOTE signs and shorten the duration of MC infection. The two studies whose data are analyzed in this study are registered at ClinicalTrials.gov with the identifiers NCT03927703 and NCT03927716.

Dietary zinc concentration and lipopolysaccharide injection affect circulating trace minerals, acute phase protein response, and behavior as evaluated by an ear-tag-based accelerometer in beef steers.

To assess plasma trace mineral (TM) concentrations, the acute phase protein response, and behavior in response to a lipopolysaccharide (LPS) challenge, 96 Angus cross steers (average initial body weight [BW]: 285 ± 14.4 kg) were sorted into two groups by BW (heavy and light; n = 48/group), fitted with an ear-tag-based accelerometer (CowManager SensOor; Agis, Harmelen, Netherlands), and stagger started 14 d apart. Consecutive day BW was recorded to start the 24-d trial (days -1 and 0). Dietary treatments began on day 0: common diet with either 30 (Zn30) or 100 (Zn100) mg supplemental Zn/kg DM (ZnSO4). On day 17, steers received one of the following injection treatments intravenously to complete the 2 × 3 factorial: 1) SALINE (~2-3 mL of physiological saline), 2) LOWLPS: 0.25 µg LPS/kg BW, or 3) HIGHLPS: 0.375 µg LPS/kg BW. Blood, rectal temperature (RT), and BW were recorded on day 16 (-24 h relative to injection), and BW was used to assign injection treatment. Approximately 6, 24 (day 18), and 48 (day 19) h after treatment, BW, RT, and blood were collected, and final BW recorded on day 24. Data were analyzed in Proc Mixed of SAS with fixed effects of diet, injection, diet × injection; for BW, RT, dry matter intake (DMI), plasma TM, and haptoglobin-repeated measures analysis were used to evaluate effects over time. Area under the curve analysis determined by GraphPad Prism was used for analysis of accelerometer data. Body weight was unaffected by diet or injection (P ≥ 0.16), but there was an injection × time effect for DMI and RT (P < 0.05), where DMI decreased in both LPS treatments on day 16, but recovered by day 17, and RT was increased in LPS treatments 6 h post-injection. Steers receiving LPS spent less time highly active and eating than SALINE (P < 0.01). Steers in HIGHLPS spent lesser time ruminating, followed by LOWLPS and then SALINE (P < 0.001). An injection × time effect (P < 0.001) for plasma Zn showed decreased concentrations within 6 h of injection and remained decreased through 24 h before recovering by 48 h. A tendency for a diet × time effect (P = 0.06) on plasma Zn suggests plasma Zn repletion occurred at a greater rate in Zn100 compared to Zn30. These results suggest that increased supplemental Zn may alter the rate of recovery of Zn status from an acute inflammatory event. Additionally, ear-tag-based accelerometers used in this study were effective at detecting sickness behavior in feedlot steers, and rumination may be more sensitive than other variables.

Initial Liver Copper Status in Finishing Beef Steers Fed Three Dietary Concentrations of Copper Affects Beta Agonist Performance, Carcass Characteristics, Lipolysis Response, and Muscle Inflammation Markers.

Ninety-three Angus-crossbred steers (470 ± 35 kg) were assigned to a 3 × 2 factorial to determine the effects of Cu status and beta agonist (BA) on performance, carcass characteristics, lipolytic rate, and muscle inflammation. Factors included Cu supplementation (mg Cu/kg dry matter (DM)) at: 0 (LO), 10 (MED), or 20 (HI) from Cu amino acid complex (Availa Cu; Zinpro) with no BA (NoRAC) or 300 mg·steer-1·day-1 of ractopamine hydrochloride (RAC; Optaflexx; Elanco) for final 28 days of 88-day trial. Linear and quadratic effects of Cu status within BA treatment were tested. Pre-BA gain was not affected by Cu supplementation (p ≥ 0.57), although day 53 liver Cu quadratically increased (p = 0.01). Average daily gain and muscle IL-8 gene expression quadratically increased (p ≤ 0.01), with MED having greatest gain and gene expression. Ribeye area tended to quadratically increase with Cu supplementation within RAC (p = 0.08). In vitro basal lipolytic rate tended to quadratically increase with Cu supplementation within RAC (p = 0.11), while stimulated lipolytic rate tended to linearly increase within NoRAC (p = 0.10). These data suggest lipolysis and the BA response of steers are influenced by dietary and liver Cu concentrations.

Effect of bis-glycinate bound zinc or zinc sulfate on zinc metabolism in growing lambs.

To assess the efficacy of bis-glycinate bound Zn, 36 crossbred wethers (34 ± 2 kg) were sorted by body weight into three groups and stagger started on a Zn-deficient diet (18 mg Zn/kg dry matter [DM]; 22.5% neutral detergent fiber [NDF]) for 45 d prior to a 15-d metabolism period (10 d adaptation and 5 d collection). On day 46, lambs were randomly assigned to dietary treatments (four lambs treatment-1group-1): no supplemental Zn (CON) or 15 mg supplemental Zn/kg DM (ZINC) as Zn sulfate (ZS) or bis-glycinate (GLY; Plexomin Zn, Phytobiotics). Blood was collected from all lambs on days 1, 44, 56, and 61. Liver, jejunum, and longissimus dorsi samples were collected after euthanasia on day 61. Gene expression was determined via quantitative real-time polymerase chain reaction. Data were analyzed using ProcMixed of SAS (experimental unit = lamb; fixed effects = treatment, group, and breed) and contrast statements assessed the effects of supplemental Zn concentration (ZINC vs. CON) and source (GLY vs. ZS). After 15 d of Zn supplementation, plasma Zn concentrations were greater for ZINC vs. CON and GLY vs. ZS (P ≤ 0.01); tissue Zn concentrations were unaffected (P ≥ 0.27). Liver Cu concentrations were lesser for ZINC vs. CON (P = 0.03). Longissimus dorsi Mn concentrations were greater for ZINC vs. CON (P = 0.05) and tended to be lesser for GLY vs. ZS (P = 0.09). Digestibility of DM, organic matter (OM), and NDF was lesser for ZINC vs. CON (P ≤ 0.05); acid detergent fiber digestibility tended to be greater for GLY vs. ZS (P = 0.06). Nitrogen retention (g/d) tended to be greater for GLY vs. ZS (P = 0.10), and N apparent absorption was lesser for ZINC vs. CON (P = 0.02). Zinc intake, fecal output, retention, and apparent absorption were greater for ZINC vs. CON (P ≤ 0.01). Apparent absorption of Zn was -5.1%, 12.8%, and 15.0% for CON, ZS, and GLY, respectively. Nitrogen and Zn retention and apparent absorption were not correlated for CON (P ≥ 0.14) but were positively correlated for ZINC (retention: P = 0.02, r = 0.52; apparent absorption: P < 0.01, r = 0.73). Intestinal expression of Zn transporter ZIP4 was lesser for ZINC vs. CON (P = 0.02). Liver expression of metallothionein-1 (MT1) tended to be greater for GLY vs. ZS (P = 0.07). Although Zn apparent absorption did not differ between sources (P = 0.71), differences in post-absorptive metabolism may be responsible for greater plasma Zn concentrations and liver MT1 expression for GLY-supplemented lambs, suggesting improved bioavailability of GLY relative to ZS.

The Crossroads between Zinc and Steroidal Implant-Induced Growth of Beef Cattle.

Growth-promoting technologies such as steroidal implants have been utilized in the beef industry for over 60 years and remain an indispensable tool for improving economic returns through consistently improved average daily gain via increased skeletal muscle hypertrophy. Zinc has been implicated in skeletal muscle growth through protein synthesis, satellite cell function, and many other growth processes. Therefore, the objective of this review was to present the available literature linking Zn to steroidal implant-induced protein synthesis and other metabolic processes. Herein, steroidal implants and their mode of action, the biological importance of Zn, and several connections between steroidal implants and Zn related to growth processes are discussed. These include the influence of Zn on hormone receptor signaling, circulating insulin-like growth factor-1 concentrations, glucose metabolism, protein synthesis via mTOR, and satellite cell proliferation and differentiation. Supplemental Zn has also been implicated in improved growth rates of cattle utilizing growth-promoting technologies, and steroidal implants appear to alter liver and circulating Zn concentrations. Therefore, this review provides evidence of the role of Zn in steroidal implant-induced growth yet reveals gaps in the current knowledge base related to optimizing Zn supplementation strategies to best capture growth performance improvements offered through steroidal implants.

Zinc supplementation strategies in feedlot heifers receiving an extended-release implant or an aggressive re-implant program.

Two hundred eight Angus-crossbred heifers (291 ± 23 kg) from four sources were used in a randomized complete block design. The objective of the study was to determine the effects of implant strategy and Zn supplementation on performance, carcass characteristics, muscle fiber diameter, and mineral status of heifers. Heifers were assigned to a 2 × 2 factorial study for 168 d, and factors included Zn and implant (IMP). Heifers were supplemented Zn (mg/kg dry matter [DM]; ZnSO4) at national (30; NRC) or industry (100; IND) recommendations. Implant strategies (Merck Animal Health, Madison, NJ) included extended-release Revalor-XH on day 0 (REV-XH; 20 mg estradiol + 200 mg trenbolone acetate) containing four uncoated pellets and six coated pellets or the uncoated implant Revalor-200 on day 0 and again on day 91 (REV-200; 20 mg estradiol + 200 mg trenbolone acetate). Heifers were blocked by weight within source to pens of five or six heifers per pen (nine pens per treatment). A corn silage-based diet was fed during the growing period (days 0-55) followed by transition to a corn-based finishing diet. Weights were taken consecutively on days -1/0, 55/56, and 167/168. Liver and muscle from the longissimus thoracis were collected from one heifer per pen on days -5, 14, 105, and 164. Data were analyzed via Mixed Procedure of SAS. Average daily gain (ADG) and liver mineral used Period as the repeated effect. Corresponding to periods of high hormone payout from each implant, days 0-28 and 91-120 ADG were greatest for REV-200, whereas REV-XH numerically peaked during days 56-91 (IMP × Period; P = 0.02). Day 91 IND body weight tended to be heavier (P = 0.06) and day 120 body weight was heavier (P = 0.05) than NRC heifers. No effect of Zn or IMP on final body weight was observed (P ≥ 0.21). Muscle fiber cross-sectional diameter on day 164 was greater (P = 0.05) in IND than NRC. Liver Mn concentrations decreased by day 14 regardless of implant, though days 105 and 164 concentrations were lesser for REV-200 than REV-XH (IMP × Period; P = 0.02). No effects of Zn, IMP, or the interaction were observed for carcass-adjusted gain to feed, days 0-168 DM intake, hot carcass weight, or ribeye area (P ≥ 0.11). The nominal differences in performance between implant strategies suggest that extended-release implants may be an effective implant strategy to replace re-implant programs in heifers, whereas the improved performance of heifers fed IND vs. NRC during times of peak hormone payout suggests a role for Zn in periods of rapid growth.

Anabolic Implants Varying in Hormone Type and Concentration Influence Performance, Feeding Behavior, Carcass Characteristics, Plasma Trace Mineral Concentrations, and Liver Trace Mineral Concentrations of Angus Sired Steers.

Fifty Angus-sired steers were utilized to evaluate the effects of anabolic implants varying in hormone type and concentration on performance, carcass traits, and plasma and liver trace mineral concentrations over 129 d. Steers were stratified by weight into one of four (n = 12 or 13/treatment) implant treatments: (1) estradiol (E2; 25.7 mg E2; Compudose, Elanco Animal Health, Greenfield, IN, USA), (2) trenbolone acetate (TBA; 200 mg TBA; Finaplix-H, Merck Animal Health, Madison, NJ, USA), (3) combination implant (ETBA; 120 mg TBA + 24 mg E2; Revalor-S, Merck Animal Health), or (4) no implant (CON). Steers were randomly assigned to pens equipped with GrowSafe bunks and fed a corn and barley-based finishing ration. Overall average daily gain and body weight were greater for ETBA and TBA than CON (p ≤ 0.04), but not E2 (p ≥ 0.12). Feed efficiency and hot carcass weight were only greater than CON for ETBA (p ≤ 0.03). Plasma and d 2 liver Zn concentrations were lesser for ETBA than CON (p ≤ 0.01) and d 10 liver Mn was lesser (p = 0.0003) for TBA than CON. These data indicate that implants containing TBA influence growth and trace mineral parameters, though more work investigating this relationship is necessary.

Investigating the effects of a novel rumen-protected folic acid supplement on feedlot performance and carcass characteristics of beef steers.

Angus-crossbred steers (n = 180; 292 ± 18 kg) from a single ranch were used to investigate the effects of a novel rumen-protected folic acid (RPFA) supplement on feedlot performance and carcass characteristics. On d 0, steers were blocked by body weight to pens (5 steers/pen), and pens within a block were randomly assigned to dietary treatments (n = 6 pens/treatment): target intake of 0 (CON), 30 (RPFA-30), 60 (RPFA-60), 90 (RPFA-90), 120 (RPFA-120), or 150 (RPFA-150) mg RPFA·steer-1·d-1. Steers were weighed before feeding on d -1, 0, 55, 56, 86, 87, 181, and 182. Pen average daily gain (ADG), dry matter intake (DMI), and gain:feed (G:F) were calculated for growing (d 0 to 56), dietary transition (d 56 to 87), finishing (d 87 to 182), and overall (d 0 to 182). Liver and blood samples were collected from two steers/pen before trial initiation and at the end of growing and finishing. Steers were slaughtered on d 183, and carcass data were collected after a 48-h chill. Data were analyzed as a randomized complete block design using ProcMixed of SAS 9.4 (fixed effects of treatment and block; experimental unit of pen). Liver abscess scores were analyzed using the Genmod Procedure of SAS 9.4. Contrast statements assessed the polynomial effects of RPFA. Supplemental RPFA linearly increased plasma folate at the end of growing and finishing (P < 0.01), and linearly decreased plasma glucose at the end of growing (P = 0.01). There was a cubic effect of RPFA on liver folate at the end of growing (P = 0.01), driven by lesser concentrations for RPFA-30, RPFA-60, and RPFA-150. Growing period ADG and G:F were greatest for CON and RPFA-120 (cubic P ≤ 0.03). Transition period DMI was linearly increased due to RPFA (P = 0.05). There was a tendency for a cubic effect of RPFA on the percentage of livers with no abscesses (P = 0.06), driven by a greater percentage of non-abscessed livers in RPFA-30 and RPFA-60. Despite supplementing 1 mg Co/kg DM, and regardless of treatment, plasma vitamin B12 concentrations were low (<200 pg/mL), which may have influenced the response to RPFA as vitamin B12 is essential for recycling of folate.

Efficacy and tolerability of an investigational nitric oxide-releasing topical gel in patients with molluscum contagiosum: A randomized clinical trial.

BACKGROUND: Although a variety of ablative, topical, and systemic therapies are used for molluscum contagiosum (MC), none has been well studied or approved by the US Food and Drug Administration. OBJECTIVES: To compare the efficacy and tolerability of topical SB206 (berdazimer sodium gel coadministered with hydrogel) with vehicle. METHODS: A 12-week, phase 2, multicenter, randomized, double-blind, vehicle-controlled clinical trial of topical SB206. RESULTS: A total of 256 patients (mean age, approximately 7 years) participated. Of patients who completed 12 weeks of treatment (n = 217), all MC lesions cleared in 20.0% of patients who received vehicle compared with 13.2%, 41.0%, and 35.1% of patients treated with twice daily SB206 4%, 8%, and 12%, respectively, and 41.9% of patients treated with once daily SB206 12%. Application-site erythema occurred in 10.6% of patients treated with SB206. Application-site reactions were the most common adverse events leading to treatment discontinuation, affecting 2 patients (approximately 4%) in each of the SB206 4%, 8%, and 12% twice daily groups and 0 patients in the vehicle or SB206 12% once daily groups. LIMITATIONS: A larger study is needed to confirm the efficacy of SB206 12% once daily and provide additional safety assessments. CONCLUSION: Of the doses studied, SB206 12% applied once daily provided the best balance between MC lesion clearance and tolerability for evaluation in a larger study.

The influence of supplemental zinc and dietary fiber concentration on mineral retention of beef steers.

The objective was to determine if zinc (Zn) retention improved with supplemental Zn above recommended concentrations with increasing dietary fiber concentration. Angus steers (n = 32; 309 ± 4.2 kg body weight [BW]) with GeneMax gain scores of 3, 4, or 5 were utilized in a 2 × 2 factorial arrangement (8 steers per treatment). Steers were stagger started (four blocks of eight steers) and stratified by BW within growing diets to one of two Zn strategies (ZNTRT), no supplemental Zn (analyzed 36 mg Zn/kg dry matter [DM]; CON) or supranutritional Zn (CON + 60 mg Zn/kg DM as ZnSO4 + 60 mg Zn/kg DM as Zn-amino acid complex; SUPZN). Dietary fiber strategies (FIBER) were formulated to target two fiber supplementation rates representing high fiber (HF; ~35% neutral detergent fiber [NDF]) or low fiber (LF; ~25% NDF). Within block, steers received HF for 60 d; then pens were randomly assigned to LF or HF for finishing. Steers fed LF were transitioned for 15 d; on day 75, steers were moved to metabolism crates and adapted for 10 d, followed by 5 d of total fecal and urine collection. Retention of Zn, Mn, Fe, Cu, and N were calculated. The model for analysis of metabolism data included the fixed effects of ZNTRT, FIBER, block, and the interaction of ZNTRT × FIBER, with the three-way interaction of ZNTRT × FIBER × block as random. Steer was the experimental unit (n = 8 per treatment combination). Zinc did not affect initial 60-d performance (P ≥ 0.62). DM and organic matter digestibility were lesser (P = 0.02) and N digestibility tended to be lesser (P = 0.07) in CON vs. SUPZN. Intake and digestibility of NDF and acid detergent fiber were greater (P ≤ 0.01) in HF vs. LF. Digestibility and retention of N as a percentage of intake were greater (P ≤ 0.04) whereas N retention as grams per day tended to be greater in HF vs. LF (P = 0.06). Apparent absorption of Zn tended to be greater (P = 0.06) in CON vs. SUPZN. A ZNTRT × FIBER effect was identified for Zn retention (milligrams per day; P = 0.01) where within SUPZN Zn retention was greater in HF vs. LF (P < 0.01). Apparent absorption and retention of Zn were greater (% of intake; P ≤ 0.02) in HF vs. LF. Apparent absorption of Cu, Fe, and Mn was unaffected by ZNTRT or FIBER (P ≥ 0.24). Increasing dietary Zn increased Zn retained regardless of changes in coefficient of absorption. In addition, dietary fiber content may impact trace mineral and N metabolism by steers, potentially due to increased release of these nutrients from feed as fiber digestibility increases. It appears dietary Zn concentrations and diet composition influence trace mineral absorption in beef steers.

Orally available and efficacious α4ß1/α4ß7 integrin inhibitors.

A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.

PEG conjugates of potent α4 integrin inhibitors, maintaining sustained levels and bioactivity in vivo, following subcutaneous administration.

Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.

Arylsulfonamide pyrimidines as VLA-4 antagonists.

A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.

Effects of an alpha-4 integrin inhibitor on restenosis in a new porcine model combining endothelial denudation and stent placement.

Restenosis remains the main complication of balloon angioplasty and/or stent implantation. Preclinical testing of new pharmacologic agents preventing restenosis largely rely on porcine models, where restenosis is assessed after endothelial abrasion of the arterial wall or stent implantation. We combined endothelial cell denudation and implantation of stents to develop a new clinically relevant porcine model of restenosis, and used this model to determine the effects of an α4 integrin inhibitor, ELN 457946, on restenosis. Balloon-angioplasty endothelial cell denudation and subsequent implantation of bare metal stents in the left anterior descending coronary, iliac, and left common carotid arteries was performed in domestic pigs, treated with vehicle or ELN 457946, once weekly via subcutaneous injections, for four weeks. After 1 month, histopathology and morphometric analyses of the arteries showed complete healing and robust, consistent restenotic response in stented arteries. Treatment with ELN 457946 resulted in a reduction in the neointimal response, with decreases in area percent stenosis between 12% in coronary arteries and 30% in peripheral vessels. This is the first description of a successful pig model combining endothelial cell denudation and bare metal stent implantation. This new double injury model may prove particularly useful to assess pharmacological effects of drug candidates on restenosis, in coronary and/or peripheral arteries. Furthermore, the ELN 457946 α4 integrin inhibitor, administered subcutaneously, reduced inflammation and restenosis in stented coronary and peripheral arteries in pigs, therefore representing a promising systemic therapeutic approach in reducing restenosis in patients undergoing angioplasty and/or stent implantation.