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BACKGROUND: Patients with obstructive airway conditions, including chronic obstructive pulmonary disease (COPD), use nebulizers for drug delivery. Tidal breathing patterns employed by patients during nebulized drug delivery may vary. It is unclear whether different breathing patterns affect the emitted quantity of nebulized drug. This in vitro study evaluated whether different tidal breathing patterns that encompass a range that could be observed in COPD patients influence the emitted amount of nebulized arformoteroI. METHODS: Breath-simulation experiments used a Pari LC Plus nebulizer in combination with the Duraneb 3000 portable aerosol system. Four breathing patterns that could represent a range of tidal volumes and inspiratory and expiratory times observed in patients with COPD were studied. The amount of arformoterol on the inspiratory and expiratory filters, and the residual amount in the nebulizer bowl were determined via highpressure liquid chromatography. Results are expressed as a percent of the nominal dose (15 I-tg in 2 mL). RESULTS: The total amount of arformoterol on the inspiratory filter increased with a longer inspiratory phase of tidal breathing (ranging from 8.0% to 13.1%), while the expiratory filter dose remained similar (7.9% to 8.7%). The total emitted dose (expiratory and inspiratory amounts combined) for all patterns was 16.0% to 21.1% of the nominal dose. Retained arformoterol amount (not emitted) ranged from 55.9% to 62.3% of the nominal dose. CONCLUSIONS: These breath-simulation experiments suggest that only about 20% of the nominal 15-l-tg arformoterol dose was emitted from the nebulizer apparatus with each of the 4 tidal breathing patterns studied, and that a longer inspiratory phase was associated with greater inhaled dose. [ABSTRACT FROM AUTHOR]

BACKGROUND: Arformoterol, the (R,R) isomer of formoterol, is approved as an inhalation solution for the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Multiple nebulizer systems are commercially available. Different nebulizers can differ significantly in drug output, which may impact drug delivery and clinical efficacy. This study compared the aerosol properties of arformoterol delivered via 5 commonly used nebulizer systems for the home-care market. METHODS: The delivered dose of arformoterol inhalation solution (15 mug/2 mL) was collected in a glass Dreschel-type apparatus. The delivered amount in fine-droplet fraction was assessed with an Andersen cascade impactor, and droplet size (average median diameter and average percent < 5 mum) was evaluated via laser diffraction. Compressor flow rate measurements were taken after 1 min and 6 min by placing the flow meter in line with each system. RESULTS: The Pari LC Plus, Updraft II Opti-Neb, and NebuTech systems delivered similar amounts of the 15-mug nominal dose (from 23% to 25%). The Pari LC Star and Sidestream systems delivered slightly higher doses (31% and 35%, respectively). The nebulizer/compressor systems differed somewhat with respect to droplet size. The NebuTech delivered the lowest fine-droplet fraction (61%) via Andersen cascade impactor, and the smallest percent of droplets < 5 mum (40%) via laser diffraction. The Pari LC Star and Sidestream delivered the highest fine-droplet fraction (100% and 93%, respectively), and the greatest percent of droplets < 5 mum (84% and 88%). The fine-droplet fractions for the Updraft II Opti-Neb and Pari LC Plus were 93% and 89%, respectively, and the percent of droplets < 5 mum was about 67%. Compressor flow rates ranged from 3.2 L/min (Pari LC Plus) to 5.4 L/min (NebuTech). CONCLUSIONS: The results of this study demonstrate that the choice of nebulizer/compressor system can influence the aerosol properties of arformoterol inhalation solution and should be considered when prescribing nebulized medications. [ABSTRACT FROM AUTHOR]

Background: Most studies of the reproductive consequences of cigarette smoking base exposure on self-reported smoking habits. This study examines the relationship of birth outcomes to the timing and intensity of maternal active and passive smoking estimated both from self-reports and from cotinine concentration in maternal urine during early, middle, and late gestation.Method: This cohort study included 740 white and Hispanic women who obtained antenatal care at the East Boston Neighborhood Health Center between 1986 and 1992. At each antenatal visit, information on maternal active and passive smoking was obtained by a detailed questionnaire, and by measurement of urine cotinine concentrations. Infant birth outcomes were obtained from hospital records. Multiple linear regression was used to evaluate antenatal smoking variables on birth outcomes, with adjustment for maternal demographic characteristics, reproductive history, alcohol use, maternal weight and height, and infant gender.Results: The percentage of mothers who ever smoked cigarettes during pregnancy was 55.5% for white and 10.2% for Hispanic women. A significant inverse exposure-response relationship between cotinine concentration in maternal urine and infant size at birth was demonstrated. However, the relationship was less clear between maternal self-reported smoking status and these outcomes. For the entire gestation, a 1000 ng increase in mean urine cotinine concentration was associated with a 59 +/- 9 g reduction in birthweight, a 0.25 +/- 0.05 cm reduction in length, and a 0.12 +/- 0.03 cm reduction in head circumference, respectively. For maternal passive smoking, the much smaller magnitude of effect precludes firm conclusions.Conclusions: These data suggest that preventing and reducing active maternal smoking during pregnancy may have a beneficial impact on infant size at birth. [ABSTRACT FROM AUTHOR]

BACKGROUND: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB. OBJECTIVE: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age >35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram's staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7-10) and late (days 25-35) posttreatment visits. RESULTS: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, -8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, -3.7 to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, -6.6%; 95% CI, -25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram's staining. Both treatments were well tolerated. CONCLUSIONS: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics. [ABSTRACT FROM AUTHOR]

Many producers reseed old pasture (OP) with the objective of improving lamb performance. Old pasture was reseeded with perennial ryegrass plus white clover (RGC), RGC plus chicory (CG), RGC plus tyfon (TG), chicory (C), or tyfon (T) to generate five treatments. In addition, a contiguous block of OP was included in the study for comparative purposes. Lambs (n = 286) were assigned to one of the five treatments plus the section of OP from just after weaning until slaughter. Grazing commenced 45 days after the desiccation of OP for reseeding. All lambs were managed by rotational grazing and drafted for slaughter at a specified target BW. No concentrate supplement was offered during the study. For the RGC, CG, TG, C and T treatments and the OP section, the average herbage NDF concentrations were 524, 473, 402, 352, 256 and 565 (SE 15.4) g/kg DM; total grazing days were 5 213, 4 005, 4 466, 2 262, 3 496 and 3 677 (SE 629.3); BW gain to slaughter was 211, 175, 205, 211, 199 and 203 (SE 9.5) g/day; days to slaughter were 91, 100, 84, 86, 78 and 88 (SE 4.8). Compared to RGC, the C, T, CG and TG treatments had lower herbage NDF concentrations (P < 0.05), and there was no difference (P > 0.05) for BW gain or days to slaughter. Chicory yielded significantly fewer (P < 0.05) grazing days, but tended to give a higher (P < 0.06) carcass weight than RGC. It is concluded that neither reseeding OP with RGC, including either C or T with RGC as a multispecies sward, nor growing pure stands of C or T increased (P < 0.05) lamb BW gain from weaning to slaughter or reduced days to slaughter., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Intestinal atresia is an under-diagnosed congenital defect in cattle. It results in complete occlusion of the intestinal lumen and, unless surgically corrected, results in death or euthanasia of the affected calf. There is limited information on the incidence of this condition or on risk factors, including predisposing alleles, associated with the defect. In this study, active surveillance of 39 dairy farms over 8 years identified 197 cases of intestinal atresia among 56 454 calves born, an incidence of 0.35%. The majority of cases (83%) had occlusion of the jejunum, although cases with blockage of the colon (14%) or anus (4%) were also identified. The defect was twice as common in male as in female calves (p < 0.0001), and was more common in progeny of older cows than in progeny of first or second lactation cows (p < 0.001). Year and farm of birth were also significantly associated with incidence (p < 0.05). The incidence of intestinal atresia was highest among the progeny of three related Jersey sires, suggesting that a gene for intestinal atresia was segregating within this family. Linkage analysis utilising 28 affected progeny of two half-sib putative carrier sires identified two putative quantitative trait loci associated with the defect, on chromosomes 14 and 26, although no clear candidate genes were identified. There was no evidence of a sire-effect among the progeny of Holstein-Friesian sires. However, a case-control genome-wide association study involving 91 cases and 375 healthy controls, identified 31 SNP in 18 loci as associated with the defect in this breed. These data suggest that intestinal atresia in dairy calves is not a simple Mendelian trait as previously reported but a complex multigenic disorder., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Sepsis is the body's response to an infection. Existing diagnostic testing equipment is not available in primary care settings and requires long waiting times. Lateral flow devices (LFDs) could be employed in point-of-care (POC) settings for sepsis detection; however, they currently lack the required sensitivity. Herein, LFDs are constructed using 150-310 nm sized selenium nanoparticles (SeNPs) and are compared to commercial 40 nm gold nanoparticles (AuNPs) for the detection of the sepsis biomarker interleukin-6 (IL-6). Both 310 and 150 nm SeNPs reported a lower limit of detection (LOD) than 40 nm AuNPs (0.1 ng/mL compared to 1 ng/mL), although at the cost of test line visual intensity. This is to our knowledge the first use of larger SeNPs (>100 nm) in LFDs and the first comparison of the effect of the size of SeNPs on assay sensitivity in this context. The results herein demonstrate that large SeNPs are viable alternatives to existing commercial labels, with the potential for higher sensitivity than standard 40 nm AuNPs., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The potential for porous silica to serve as an effective anti-obesity agent has received growing attention in recent years. However, neither the exact pharmacological mechanism nor the fundamental physicochemical properties of porous silica that drive its weight-lowering effect are well understood. Subsequently, in this study, an advanced in vitro digestion model capable of monitoring lipid and carbohydrate digestion was employed to elucidate the effect of porous silica supplementation on digestive enzyme activities. A suite of porous silica samples with contrasting physicochemical properties was investigated, where it was established that the inhibitory action of porous silica on digestive enzyme functionality was strongly dependent on porous nanostructure, particle size and morphology, and surface chemistry. Insights derived from this study validate the capacity of porous silica to impede the digestive processes mediated by pancreatic lipase and α-amylase within the gastrointestinal tract, while the subtle interplay between porous nanostructure and enzyme inhibition indicates that the anti-obesity effect can be optimized through strategic particle design.

A simple quantitative reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for assay determination of cannabidiol and tetrahydrocannabinol in hemp oil infused products. The RP-HPLC method was developed and optimized for the mobile phase composition, flow rate, column selection and detector wavelength. An isocratic elution of samples were performed on SOLAS 100 Å C18 150 mm × 4.6 mm, 5 μm column with a mobile phase containing 75/25 acetonitrile/water v/v, with a flow rate of 1.5 mL/min by using an ultraviolet-visible (UV/Vis) detector operating at 214 nm. The RP-HPLC method was validated to meet regulatory requirements which covers specificity, accuracy, range, linearity, precision, system suitability and robustness. The validated assay test method was applied successfully to quantify cannabidiol and tetrahydrocannabinol in commercial hemp oil infused products such as tablets, soft gel capsules, plant extract oils, oral drops, tincture, and beverage enhancers. All the test results were found acceptable as per ICH guidelines, and this confirmed the feasibility of this method for its intended use in regular quality control and assay of cannabidiol and tetrahydrocannabinol in hemp oil infused products., (© 2022. The Author(s).)

The effects of first-joining age (7 or 19 months) and genotype on ewe performance when joined to lamb at 2 years, and the performance of their progeny, were evaluated using 424 ewes, representing 3 genotypes: Belclare (Bel), Suffolk × Belclare (Suf × Bel) and Suffolk-type (≥75% Suffolk ancestry (Suf75)). Ewes were managed in a grass-based system. Ewes first joined at 7 months were lighter (p < 0.01) at 19 months and immediately post lambing; otherwise, age at first joining had no effects (p > 0.05) on ewes or their progeny and there were no important interactions with genotype. Bel and Suf × Bel had larger litters (p < 0.001) and reared more lambs per ewe joined (p < 0.01) than Suf75. Ewe genotype had no effect (p > 0.05) on proportion failing to lamb, incidence of lambing assistance, lamb mortality, ewe survival to 31 months, or progeny performance. Increasing the body weight of ewes at 7 months of age increased the probability (p < 0.02) of rearing 1 or more lambs at 2 years and there was no interaction with genotype. It is concluded that age at first joining had no negative impact on the performance of ewes or their progeny.

For the first time, a simple and robust HPLC method has been developed for dissolution studies for cannabidiol (CBD) in hemp oil products. An isocratic elution of samples performed on SOLAS™ C18 150 mm x 4.6 mm, 5 μm column with a mobile phase consisting of 75:25 acetonitrile-water v/v, delivered at a flow rate 1.5 mL/minutes to variable wavelength detector using 214 nm. An in-house validated assay test was executed for calculating the purity of hemp oil products and also for considering the dissolution medium to be used. For dissolution studies, equivalent of 5 mg and/or 10 mg of the active was introduced into 500 mL of simulated gastric and intestinal fluids separately, and dissolution was performed at 50 rpm using paddles for 180 min. Dissolution profiles for hemp oil products purchased from the United States and Europe were compared. Additionally, dissolution testing was conducted to study the effect of percentage CBD release on increased agitation speed of 75 and 100 rpm and also, on extended dissolution runtime of 240 min., (Copyright © 2021. Published by Elsevier Inc.)

Two ways of reducing the cost of replacements are increasing litter size and number of litters produced; thus, the total weight of lamb carcass output per ewe lifetime. The effects of ewe genotype on the performance of ewes lambing at 1 year and of their progeny to slaughter, and the effect of age at first joining (7 or 19 months) on BW at ~19 months and survival to joining at 19 months were evaluated over two consecutive years, using 460 ewe lambs from three genotypes: Belclare (Bel), Suffolk × Belclare (Suf × Bel) and ≥ 75% Suffolk ancestry (Suf75). Lambs from the three genotypes were at a similar proportion of mature BW and half of the lambs, within genotype, were allocated to be joined for the first time at 7 or 19 months. The ewe lambs were managed in a grass-based rotational-grazing system, except when housed from December to March on a grass silage-based diet. Belclare ewes had larger litters (P < 0.001), reared more lambs per ewe joined (P < 0.01), were lighter at lambing and at 19 months (P < 0.01), were of smaller body size at 19 months (P < 0.001) and their progeny were lighter at weaning (P < 0.05) relative to Suf75 genotype; the Suf × Bel ewes were intermediate for most traits but had a significantly lower litter size (P < 0.05) than Bel ewes. Progeny from Suf × Bel ewes were 17 days younger at slaughter (P < 0.01) relative to those from Bel ewes. Ewe genotype had no effect (P > 0.05) on lamb mortality (born dead, total mortality to weaning), lambing assistance, number of ewes that failed to lamb, or on ewe survival to 19 months of age. Increasing ewe BW at joining increased the probability (P < 0.001) of rearing at least one lamb and this effect was consistent across genotypes. There were significant relationships (P < 0.001) between ewe BW at lambing and lamb BW at birth and at weaning of 0.053 (SE 0.0089) kg and 0.29 (SE 0.049) kg, respectively. Ewes that lambed at 1 year were 2 kg lighter (P < 0.001) at 19 months of age and had a smaller body size (P < 0.01) relative to those not joined. It is concluded that ewe genotype had a significant effect on number of lambs reared, and thus lamb carcass output. Whilst lambing at 1 year reduced BW by 2 kg when joined at 19 months, it did not affect ewe survival to that stage., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

In many countries, daily herbage accumulation on pasture declines towards zero during the winter period; thus, many pregnant ewes are housed and offered conserved forages supplemented with concentrate prior to parturition. The effects of forage type and feed value (FV), offering soybean meal with maize silage during mid and late pregnancy, and concentrate feed level in late pregnancy on the performance of ewes and their progeny (to slaughter) were evaluated. Ewes (n = 151) were assigned to one of nine treatments from mid-pregnancy until lambing. Medium FV and high FV grass silages (metabolisable energy concentrations of 10.7 and 12.0 MJ/kg DM) were offered ad libitum supplemented with either 15 or 25 kg concentrate/ewe during late pregnancy. Low and high DM maize silages (starch concentrations of 80 and 315 g/kg DM) were offered ad libitum either alone or with soybean meal (200 g/d) and supplemented with 15 kg concentrate during late pregnancy. A final treatment consisted of high FV grass silage supplemented with 5 kg soybean/ewe over the final 4 weeks of pregnancy. Ewes and lambs were put to pasture in a rotational-grazing system within 3 days of lambing. There were no interactions (P > 0.05) between grass silage FV and concentrate feed level for ewe or lamb traits. Increasing grass silage FV increased food intake (P < 0.001) during late pregnancy, ewe BW and body condition score (BCS) at lambing (P < 0.001), lamb BW at birth (P < 0.001) and weaning (P < 0.05), and reduced age at slaughter (P = 0.06). Increasing concentrate feed level increased metabolisable energy (P < 0.05) intake during late pregnancy but had no effect (P > 0.05) on ewe or lamb performance. Increasing maize DM at harvest and offering soybean meal with maize silage increased food intake (P < 0.001) and ewe BW and BCS at lambing (P < 0.05 or P < 0.01). Offering soybean meal with maize silage increased lamb BW at birth (P < 0.01) and reduced age at slaughter (P < 0.05). Reducing supplementation of high FV grass silage to 5 kg of soybean meal had no effect (P > 0.05) on animal performance. Replacing grass silage with maize silage did not affect (P > 0.05) BW gain of lambs. It is concluded that increasing the FV of the grass silage offered during pregnancy had the greatest positive impact on ewe and lamb performance., (Copyright © 2020. Published by Elsevier B.V.)

Background and Objectives: Impaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models., Design, Setting, Participants, & Measurements: In a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.73 m 2 , and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters., Results: Of 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group (difference -15%; -31 to 4; P =0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups., Conclusions: Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease., Clinical Trial Registry Name and Registration Number: A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591., (Copyright © 2021 by the American Society of Nephrology.)

Aims/hypothesis: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension., Methods: This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment., Results: Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of -0.7 (-1.8, 0.4) mmol/l for fasting plasma glucose, -0.7 (-1.1, -0.2) mmol/l for total cholesterol, -0.5 (-1.0, -0.1) mmol/l for LDL-cholesterol, -23 (-56, 9) for HOMA-IR in those not being treated with insulin, and -5 (-10, 1) mmHg and 3 (-1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients., Conclusions/interpretation: In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat., Trial Registration: ClinicalTrials.gov NCT03091920., Funding: This trial was funded by Cyclerion Therapeutics.

The Galway sheep population is the only native Irish sheep breed and this livestock genetic resource is currently categorised as 'at-risk'. In the present study, comparative population genomics analyses of Galway sheep and other sheep populations of European origin were used to investigate the microevolution and recent genetic history of the breed. These analyses support the hypothesis that British Leicester sheep were used in the formation of the Galway. When compared to conventional and endangered breeds, the Galway breed was intermediate in effective population size, genomic inbreeding and runs of homozygosity. This indicates that, although the Galway breed is declining, it is still relatively genetically diverse and that conservation and management plans informed by genomic information may aid its recovery. The Galway breed also exhibited distinct genomic signatures of artificial or natural selection when compared to other breeds, which highlighted candidate genes that may be involved in production and health traits., (Copyright © 2019 McHugo, Browett, Randhawa, Howard, Mullen, Richardson, Park, Magee, Scraggs, Dover, Correia, Hanrahan and MacHugh.)

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) received once-daily praliciguat for 14 days before up-titrating for 7 days (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight-based). All doses were tolerated. No serious or severe adverse events (AEs) were reported. The most common AEs in praliciguat recipients were headache and symptoms consistent with blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, electrocardiographic, or platelet function findings indicative of a safety concern. Pharmacokinetics were dose proportional, with an effective half-life of 24-37 hours, supporting once-daily dosing. Praliciguat produced dose-related increases in plasma cGMP consistent with stimulation of sGC. Repeated once-daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

The aim of this study was to investigate the properties and to functionally characterize the cervical mucus that modulates sperm transport through the cervix by using ewe breeds with a divergent pregnancy rate (Belclare and Suffolk; high and low, respectively) following cervical insemination using frozen-thawed semen. Sperm number, as well as sialic acid and fucose content in both the channels and in the lumen of different regions of the cervix were quantified in inseminated Belclare and Suffolk ewes. Expression of glycosyltransferase and MUC genes, glycosidase activity and sialic acid speciation in follicular phase cervical tissue and mucus were assessed. More spermatozoa were found in the cervical channels in the region closest to the cervical os in Belclare than Suffolk ewes (P < 0.05) and Suffolk ewes had a higher sialic acid content in the cervical channels than Belclare ewes (P < 0.05) in all regions of cervix. Suffolk ewes had significantly higher expression of FUT1, ST6GAL1 and MUC5AC than Belclare ewes. There was no difference between the breeds in glycosidase activity (P > 0.05). Levels of Neu5Ac were higher in Belclare than Suffolk ewes (P < 0.05) and levels of Neu5Gc was higher in Suffolk than Belclare ewes (P < 0.05). Competitive sperm penetration assays demonstrated that frozen-thawed sperm progression increased when cervical mucus was incubated with sialyllactose prior to a sperm penetration test (P < 0.05). These results suggest that the difference between Belclare and Suffolk ewes in sperm transport with frozen-thawed semen is due to the higher concentration of sialic acid within channels, which binds to spermatozoa and reduces their ability to traverse the cervix.

Targeted selective treatment (TST) has been proposed as a sustainable method of gastrointestinal nematode control that reduces the number of anthelmintic treatments administered, thereby preserving a susceptible nematode population in refugia. In order to minimise the impact of withholding treatment on animal performance, animals that would benefit most should be selected for treatment. However, the most suitable criteria for selecting which animals to treat remain a subject of research. The impact of implementing a TST strategy based on lamb live weight was investigated, and whether heavy lambs were more resilient than light lambs if left untreated. The study was conducted using weaned lambs on 3 sheep farms, and over 2 years. On each farm lambs were weighed and divided into heavy, medium and light weight classes. Within the heavy (n = 225) and light (n = 218) weight classes lambs were randomly allocated to two treatments; anthelmintic treatment or no anthelmintic treatment. All lambs in the medium weight class were treated. Animal performance and parasitological parameters were assessed over a 28-day period. Anthelmintic treatment had a significant effect (P < 0.01) on faecal egg count, average daily weight gain, body condition score and dag score; there was no treatment by weight class interaction. Anthelmintic treatment had no effect on plasma pepsinogen concentration or on blood leukocyte numbers. Withholding anthelmintic treatment from lambs therefore had a negative effect on worm egg count and animal performance with no evidence that heavy lambs were more resilient than light lambs when left untreated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Three mesoporous silica excipients (Syloid® silicas AL-1 FP, XDP 3050 and XDP 3150) were formulated with a model drug known for its poor aqueous solubility, namely phenylbutazone, in an attempt to enhance the extent and rate of drug dissolution. Although other forms of mesoporous silica have been investigated in previous studies, the effect of inclusion with these specific Syloid® silica based excipients and more interestingly, with phenylbutazone, is unknown. This work reports a significant enhancement for both the extent and rate of drug release for all three forms of Syloid® silica at a 1:1 drug:silica ratio over a period of 30 min. An explanation for this increase was determined to be conversion to the amorphous form and an enhanced drug loading ability within the pores. Differences between the release profiles of the three silicas were concluded to be a consequence of the physicochemical differences between the three forms. Overall, this study confirms that Syloid® silica based excipients can be used to enhance dissolution, and potentially therefore bioavailability, for compounds with poor aqueous solubility such as phenylbutazone. In addition, it has been confirmed that drug release can be carefully tailored based on the choice of Syloid® silica and desired release profile.

Gastrointestinal nematode infection is a constraint on sheep production worldwide. Selective breeding programmes to enhance resistance to nematode infection are currently being implemented in a number of countries. Identification of loci associated with resistance to infection or causative mutations for resistance would enable more effective selection. Loci associated with indicator traits for nematode resistance has been identified in previous studies. In this study, Scottish Blackface, Texel and Suffolk lambs were used to validate the effects at eight genomic regions previously associated with nematode resistance (OAR3, 4, 5, 7, 12, 13, 14, 21). No SNP was significantly associated with nematode resistance at the region-wide level but seven SNPs in three of the regions (OAR4, 12, 14) were nominally associated with trichostrongyle egg count in this study and six of these were also significant when fitted as single SNP effects. Nematodirus egg count was nominally associated with SNPs on OAR3, 4, 7 and 12., (© 2018 Stichting International Foundation for Animal Genetics.)

Plane of nutrition (PN) offered to ewe replacements during the rearing phase (8 to 17 months) affects BW at joining and may affect reproductive performance when joined at ~19 months. The effects of PN offered to ewe replacements during their first winter (winter&#95;1) and second summer (summer&#95;2) were evaluated over 3 consecutive years, using 287 spring-born ewe lambs, representing four genotypes (Belclare (Bel), Charmoise×Scottish Blackface (C×SBF), Bel×SBF (Bel×SBF), Bel×SBF that were heterozygous either FecGH or FecXG mutations that increase ovulation rate (OR) (BelMG×SBF)). During extended (deferred) grazing in winter&#95;1 (November to March) the lambs were offered herbage DM allowances (HA) of 0.75 (L) or 1.75 (H) kg/day. During summer&#95;2 (March to August) the replacements were set stocked to maintain sward heights of 4 (L) or 6 (H) cm, thus yielding a 2×2 factorial design for the nutrition treatments (71 to 73 animals/treatment). Increasing HA during winter&#95;1, and residual sward height during summer&#95;2, increased (P0.05) on OR. Mean BW at joining was 53.3, 56.8, 56.6 and 61.7 (SEM 0.74) kg for ewes offered the LL, LH, HL and HH treatments, respectively. Mean OR of C×SBF and BelMG×SBF differed (P<0.001) from that of Bel×SBF by -0.58 and +0.47, respectively. Correlations between linear measurements (LMs) of body size and BW at 7, 12 and 17 months were all positive and significant (P<0.001). The precision of the set of LMs as a predictor of BW at joining improved with age (R 2 0.46, 0.54 and 0.74 at 7, 12 and 17 months) but BW at a given age was a better predictor at all age time points. Chest girth was the best predictor, among the LMs, of BW at joining and its explanatory power increased with age. Equations developed using LMs at 7, 12 or 17 months, to predict BW at joining exhibited biases of -2.1, -1.5 and +0.9 kg, respectively. It is concluded that whilst altering PN during the rearing phase changed BW by 16% it had no effect on OR. There was no interaction (P>0.05) between the PN offered during winter&#95;1 and summer&#95;2, or PN and ewe genotype for BW at joining or OR. LMs, either at 7, 12 or 17 months of age, are useful predictors of BW at joining.

Plane of nutrition (PN) offered to ewe replacements during the rearing phase (8 to 17 months) and first pregnancy may affect reproductive and progeny performance when replacements are joined at ~19 months. The effects of PN offered to spring-born ewe replacements during their first winter (winter&#95;1), second summer (summer&#95;2) and subsequent winter (mid and late pregnancy; winter&#95;2) were evaluated, over 3 consecutive years, using 287 ewe lambs of four genotypes: Charmoise×Scottish Blackface (C×SBF), Belclare×SBF (Bel×SBF), Belclare (Bel) and Belclare×SBF (heterozygous for a gene, either FecGH or FecXG mutations, that increases ovulation rate: BelMG×SBF). Ewe lambs were offered, daily, a deferred-grazed herbage allowance (HA) of either 0.75 or 1.75 kg dry matter during winter&#95;1. During summer&#95;2 the replacements were set-stocked to maintain sward heights of 4 or 6 cm. Ewes were housed during mid and late pregnancy (winter&#95;2) and offered either medium or high-feed-value grass silage, thus yielding a 2×2×2 factorial design. Increasing HA during winter&#95;1 and residual sward height during summer&#95;2 increased ewe BW post joining (P0.05) on number of lambs reared. Increasing HA during winter&#95;1 increased lamb BW at birth (P<0.05) and reduced carcass fat score (P<0.05). There was a significant interaction between PN offered during winter&#95;1 and summer&#95;2 for average daily gain (ADG) from birth to 5 weeks (P<0.01) and from 5 to 10 weeks (P<0.05): progeny of replacements that experienced either a high or low PN throughout the rearing phase had lower ADG than lambs born to the replacements that experienced a low PN only during winter&#95;1 or summer&#95;2. Increasing PN during winter&#95;2 increased ewe BW (P<0.001), lamb BW at birth (P<0.001) and weaning (P<0.05) and reduced the proportion of ewes that failed to lamb (P<0.01). Ewe genotype had a significant (P<0.001) effect on litter size (1.48 to 2.45), number of lambs reared, lamb BW at birth and weaning, lamb ADG and age at slaughter. It is concluded that, among the nutrition treatments examined, increasing PN during mid and late pregnancy had the greatest effect on ewe and progeny performance. Although increasing PN offered during winter&#95;1 increased lamb birth BW, PN offered during summer&#95;2 had no effect on lamb performance. There were no significant interactions between PN and ewe genotype.

Maternal nutrition during pregnancy is a major environmental influence on foetal development with consequent effects on postnatal performance. We hypothesised that the level of intake of digestible undegraded protein (DUP) by the dam in late pregnancy would impact on the effectiveness of the immune response by offspring to gastrointestinal nematode infection. Eighty-five twin/triplet-bearing ewes, which were indoors from mid-pregnancy, were randomly assigned to 4 treatment groups for the final 6 weeks of pregnancy. Treatments were silage plus one of two iso-energetic and iso-nitrogenous concentrates (differing in DUP concentration; 29 and 94g/kg DM) offered at one of two feed levels (18/30 and 24/35kg in total for twin/triplet-bearing ewes, respectively). Ewes with triplets had one lamb removed at birth so that all ewes nursed 2 lambs when put to pasture as one flock in a 5-paddock rotational grazing system; all lambs were slaughtered after 29 weeks. Faecal egg count (FEC) and levels of serum IgA and IgE specific for Teladorsagia circumcincta were assessed for all lambs at various time points between 10 weeks of age and slaughter. Animal performance (live weight, live-weight gain, carcass weight) was recorded for all lambs. Worm burden at slaughter was determined for a sample of 12 lambs from each treatment. Nematodirus spp. FEC, 'other strongyles' FEC, and serum IgA and IgE specific for T. circumcincta were unaffected either by the concentration of DUP in the concentrate or by the level of concentrate offered to ewes in late pregnancy (P>0.1). Likewise, the dietary regime of the dams had no effect on lamb performance (P>0.1). It is concluded that increasing the DUP intake of ewes in late pregnancy had no effect on the immune response of their offspring to gastrointestinal nematode infection acquired through grazing naturally infected pasture., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ewes experience a temporary decline in resistance to gastrointestinal nematodes (GIN) during the periparturient period, characterised by a rise in faecal egg count (FEC) that represents a major source of pasture contamination for naïve progeny. The aim of this study was to assess the effect of level of supplementation with digestible undegraded protein (DUP) during the last 6 weeks of pregnancy on periparturient FEC and the performance of ewes with a naturally acquired parasite infection. Eighty-five Belclare and Belclare x Scottish Blackface twin/triplet-bearing ewes were allocated to 1 of 4 dietary groups representing the combination of 2 concentrates (DUP concentration 29 and 94g/kg dry matter) with 2 levels of concentrate during the final 6 weeks of gestation (18 and 30kg in total for ewes with twins; 24 and 35kg for ewes with triplets). All ewes were housed during the pre-partum feeding period and offered grass silage ad libitum; food intake was recorded daily. The intake of DUP varied from 26 to 72g/d among treatments and was reflected in variation of 0.76 to 1.20 in metabolizable protein supply as a proportion of requirements. After lambing, ewes and lambs grazed on permanent sheep pasture, without concentrate supplementation, until weaning (14 weeks post lambing). The variables studied, from week 6 pre-lambing up to week 10 post-lambing, included: FEC, serum pepsinogen concentration, body weight (BW) and body condition score (BCS). The effect of week (relative to lambing date) on FEC was highly significant (P<0.001). However, diet did not influence FEC (P>0.05) at any stage either pre- or post-partum. Pepsinogen concentration also varied with time but was not influenced by dietary treatment (P>0.05). The changes in BW and BCS from 6 weeks before lambing to weaning were not affected by the concentration of DUP in the supplement but ewes on treatments involving the higher level of supplementation lost less BW and BCS (P<0.001). The results of this study indicate that the level of DUP supplementation during the last 6 weeks of pregnancy does not affect FEC, BW or BCS of housed ewes with a naturally acquired GIN infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Between 2013 and 2015 the Department of Agriculture, Food and the Marine (DAFM) administered a sheep technology adoption programme (STAP), with the aim of increasing profitability on Irish sheep farms by encouraging the adoption of best management practices. One of the options available to STAP participants was to test the efficacy of the anthelmintic treatment (benzimadazole, levamisole or macrocyclic lactone) used in their flocks by means of a drench test, which is a modification of the faecal egg count reduction test; individual faecal samples were collected from the same group of lambs before and after anthelmintic treatment, the number of eggs present pre and post treatment was subsequently determined from a pooled sample., Results: In total, 4211 drench tests were undertaken by farmers during the 3 years of the programme. Information on the anthelmintic product used was available for 3771 of these tests; anthelmintics from the classes benzimidazole (BZ), levamisole (LV) and macrocyclic lactone (ML) (avermectins (AVM) plus moxidectin (MOX)) were used in 42.0%, 23.4% and 32.5% of tests, respectively. The remaining 2.1% of tests involved an inappropriate product. The efficacy of treatment against 'other trichostrongyles' (excluding Nematodirus spp and Strongyloides papillosus .) could be established for 1446 tests, and 51% of these tests were considered effective (i.e. a reduction of faecal egg count (FEC) ≥ 95%). There was a significant difference among the drug groups in efficacy; 31.5%, 51.9%, 62.5% and 84% of treatments were considered effective for BZ, LV, AVM, MOX, respectively. The efficacy of treatment against Nematodirus spp. could be established for 338 tests and the overall efficacy was 96%., Conclusions: Due to the significant difference among the anthelmintic classes for efficacy against 'other trichostrongyles' along with the high level of efficacy against Nematodirus spp., a genus for which anthelmintic resistance is rarely reported, it is concluded that anthelmintic resistance was responsible for the majority of the anthelmintic treatment failures observed.

The effects of supplementing lambs with Co, either alone or in combination with vitamin B and Se, were evaluated over the period from weaning to selection for slaughter. Two hundred and five recently weaned (at 14 wk [SD 0.44] of age), spring-born lambs of various crossbred genotypes were stratified, within genotype, by BW and gender and allocated to 3 groups, which were then allocated at random to one of the following treatments: no supplement (Control), a supplement containing Co only (Co-only), or a supplement containing Co, vitamin B, and Se (VitMin). The concentration of Co in the Co-only supplement was 2.1 mg/mL (as cobalt sulfate); the VitMin supplement contained Co (10 mg/mL, as cobalt acetate), vitamin B (200 μg/mL), and Se (0.25 mg/mL, as sodium selenite). Lambs on the Co-only and VitMin treatments received, every 14 d, 10 and 2.1 mL, respectively, of oral drench. Lambs were managed in a rotational-grazing system from 12 July (swards predominantly ) and selected for slaughter, on the basis of BW, after 45, 73, or 115 d; all remaining lambs were slaughtered on d 157. Supplementation, with Co-only or VitMin, increased BW at slaughter ( < 0.01), ADG ( < 0.001), carcass weight ( < 0.001), dressing percentage ( < 0.001), carcass fat score ( < 0.05), and the proportion selected for slaughter by d 73 ( < 0.05) and 115 ( < 0.01). Relative to the Control, the benefit to ADG from supplementation increased as the season advanced. Therefore, supplementation did not alter ( = 0.82) ADG between d 1 and 45 but increased ADG over the intervals d 45 to 73 ( < 0.01), d 73 to 115 ( < 0.001), and d 115 to 157 ( < 0.001). There was no difference ( > 0.05) between the Co-only and the VitMin treatments for ADG, carcass weight, fat score, or dressing percentage. Supplementation with Co increased liver Co concentration ( < 0.001), and lambs supplemented with VitMin had greater liver Co concentration than lambs supplemented with Co-only ( < 0.05); the concentrations were 0.18, 0.85, and 1.18 μmol/L for the Control, Co-only, and VitMin treatments, respectively. Treatment had no effect ( = 0.65) on the concentration of Se in kidney tissue. It is concluded that supplementation with Co increased lamb performance after weaning, that response to supplementation increased as the grazing season progressed, and that no extra benefit in performance resulted from augmenting supplementary Co with B and Se.

Gastrointestinal nematode (GIN) infection of ruminants represents a major health and welfare challenge for livestock producers worldwide. The emergence of anthelmintic resistance in important GIN species and the associated animal welfare concerns have stimulated interest in the development of alternative and more sustainable strategies aimed at the effective management of the impact of GINs. These integrative strategies include selective breeding using genetic/genomic tools, grazing management, biological control, nutritional supplementation, vaccination and targeted selective treatment. In this review, the logic of selecting for "resistance" to GIN infection as opposed to "resilience" or "tolerance" is discussed. This is followed by a review of the potential application of immunogenomics to genetic selection for animals that have the capacity to withstand the impact of GIN infection. Advances in relevant genomic technologies are highlighted together with how these tools can be advanced to support the integration of immunogenomic information into ruminant breeding programmes., (© 2016 John Wiley & Sons Ltd.)

Gastrointestinal nematodes are a serious cause of morbidity and mortality in grazing ruminants. The major ovine defence mechanism is acquired immunity, with protective immunity developing over time in response to infection. Nematode resistance varies both within and between breeds and is moderately heritable. A detailed understanding of the genes and mechanisms involved in protective immunity, and the factors that regulate this response, is required to aid both future breeding strategies and the development of effective and sustainable nematode control methods. The aim of this study was to compare the abomasal lymph node transcriptome of resistant and susceptible lambs in order to determine biological processes differentially expressed between resistant and susceptible individuals. Scottish Blackface lambs, with divergent phenotypes for resistance, were challenged with 30,000 Teladorsagia circumcincta larvae (L3), and abomasal lymph nodes recovered at 7 and 14days post-infection (dpi). High-throughput sequencing of cDNA from the abomasal lymph node was used to quantitatively sample the transcriptome with an average of 32 million reads per sample. A total of 194 and 144 genes were differentially expressed between resistant and susceptible lambs at 7 and 14 dpi respectively. Differentially expressed networks and biological processes were identified using Ingenuity Pathway Analysis. Genes involved in the inflammatory response, attraction of T lymphocytes and binding of leukocytes were more highly expressed in resistant animals at 7 dpi and in susceptible animals at 14 dpi indicating that resistant animals respond to infection earlier than susceptible animals. Twenty-four Single Nucleotide Polymorphisms (SNP) within 11 differentially expressed genes, were tested for association with gastrointestinal nematode resistance in the Scottish Blackface lambs. Four SNP, in 2 genes (SLC30A2 and ALB), were suggestively associated with faecal egg count. In conclusion, a large number of genes were differentially expressed in the abomasal lymph node of resistant and susceptible lambs responding to gastrointestinal nematode challenge. Resistant Scottish Blackface lambs appear to generate an earlier immune response to T. circumcincta. In susceptible lambs this response appears to be delayed. SNP in 2 differentially expressed genes were suggestively associated with faecal egg count indicating that differentially expressed genes may be considered candidate loci for mediating nematode resistance., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Texel lambs are known to be more resistant to gastrointestinal nematode (GIN) infection than Suffolk lambs, with a greater ability to limit infection. The objectives of this study were to: 1) profile the whole transcriptome of abomasal lymph node tissue of GIN-free Texel and Suffolk lambs; 2) identify differentially expressed genes and characterize the immune-related biological pathways and networks associated with these genes. Abomasal lymph nodes were collected from Texel (n = 6) and Suffolk (n = 4) lambs aged 19 weeks that had been GIN-free since 6 weeks of age. Whole transcriptome profiling was performed using RNA-seq on the Illumina platform. At the time of conducting this study, a well annotated Ovine genome was not available and hence the sequence reads were aligned with the Bovine (UMD3.1) genome. Identification of differentially expressed genes was followed by pathway and network analysis. The Suffolk breed accounted for significantly more of the differentially expressed genes, (276 more highly expressed in Suffolk v 162 in Texel; P < 0.001). The four most significant differentially expressed pathways were all related to immunity and were classified as: Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Activation of IRF by Cytosolic Pattern Recognition Receptors, Role of RIG-I-like Receptors in Antiviral Innate Immunity, and Interferon Signaling. Of significance is the fact that all of these four pathways were more highly expressed in the Suffolk. These data suggest that in a GIN-free environment, Suffolk lambs have a more active immune profile relative to the Texel: this immune profile may contribute to the poorer efficiency of response to a GIN challenge in the Suffolk breed compared to the Texel breed.

While Texel lambs have increased resistance to infection with the gastrointestinal nematode Teladorsagia circumcincta compared to Suffolk lambs, the underlying resistance mechanisms are still unknown. The aim of this study was to compare parasitological, humoral and cellular responses of Texel and Suffolk lambs over time following a single experimental infection with T. circumcincta. Gastrointestinal nematode free (but not naïve) lambs received a single oral dose of 3 × 104 infective T. circumcincta larvae. The variables examined included worm burden, mucosal and serum IgA, abomasal mast cells and eosinophils, haematological parameters and plasma pepsinogen. Texel lambs had significantly lower worm burden on day 14 and lower plasma pepsinogen concentration from day 14 onwards than Suffolks and their response in mucosal IgA to infection occurred earlier. The results from the study suggest that an earlier local IgA response in the Texel contributes to the resistant characteristics of the breed, while the increased level of plasma pepsinogen in the Suffolk lambs implies greater abomasal tissue damage arising from the nematode infection.

The effects of high and medium feed value grass silage or maize silage (MS), each offered with a range of concentrate feed levels, and ad libitum concentrate on the performance of finishing lambs, which were either shorn or unshorn, were evaluated. Three silages were used: 1 medium feed value (MFV) and 1 high feed value (HFV) grass silage (DM digestibility [DMD] of 71.3% and 74.5%, respectively) and 1 MS (DM and starch concentrations of 30.9% and 35.3% DM, respectively). The 3 silages were offered ad libitum with daily allowances of 0.4, 0.8, or 1.2 kg concentrate per lamb. Two additional treatments were: 1) MS supplemented with 0.4 kg of a low CP (LP) concentrate and 2) concentrate offered ad libitum with 0.5 kg/d of HFV grass silage. These 11 dietary treatments were offered to 264 crossbred Suffolk lambs (initial BW = 39.0 kg), half of which were unshorn and half of which were shorn, for a 54-d finishing period, resulting in 22 treatments. Shearing increased forage DMI (P < 0.001) but did not alter (P > 0.05) carcass weight, carcass gain, or ADG, and there was no interaction with dietary treatment. Reducing CP concentration of the concentrate offered with MS did not alter (P > 0.05) feed intake or lamb performance. Increasing concentrate feed level increased feed DMI and lamb performance (P < 0.001). The linear response in ADG to increased concentrate supplementation was greater (P = 0.012) for MFV than HFV grass silage, and a corresponding difference in carcass gain approached significance (P = 0.075). The linear response was greater for grass silage than for MS for ADG (P < 0.01) and carcass gain (P = 0.019). The response in lamb performance from increased concentrate supplementation was linear for HFV grass silage and MS but quadratic (P < 0.05) for the MFV grass silage, reflecting the large response for this silage when concentrate supplement was increased from 0.4 to 0.8 kg. Relative to the MFV grass silage supplemented with 0.8 kg concentrate, the potential concentrate-sparing effects of the HFV grass silage and MS were 0.16 and 0.32 kg concentrate per lamb daily, respectively. It is concluded that shearing lambs that are housed during finishing reduces the efficiency of the conversion of ME to carcass gain. Maize silage can replace HFV grass silage in the diet of finishing lambs. The total dietary protein concentration for finishing lambs can be reduced to 9% DM without adversely affecting carcass gain.

The objective of this study was to identify Scottish Blackface lambs that were at the extremes of the spectrum of resistance to gastrointestinal nematodes and characterise their response to an experimental nematode challenge. Lambs (n = 90) were monitored for faecal egg count (FEC) (2 samples from each of 2 independent natural infections). The most resistant (n = 10) and susceptible (n = 10) individuals were selected and challenged with 30,000 Teladorsagia circumcincta larvae (L3) at 9 months of age. Response to infection was monitored by measuring FEC, plasma pepsinogen, serum antibodies against nematode larval antigens and haematology profile, until necropsy at 71 days post infection. Worm burden, worm fecundity and the level of anti-nematode antibodies in abomasal mucosa were determined at necropsy. FEC was consistently higher in susceptible animals (P < 0.05), validating the selection method. Worm fecundity was significantly reduced in resistant animals (P = 0.03). There was also a significant correlation (r = 0.88; P < 0.001) between the number of adult worms and FEC at slaughter. There was no effect of phenotype (resistance/susceptibility) on plasma pepsinogen or on haematology profile. Phenotype had a significant effect on the level of anti-nematode IgA antibodies in serum (P < 0.01), reflecting a higher peak in resistant animals at day 7 post infection. It is concluded that significant variation in the response to gastrointestinal nematode challenge exists within the Scottish Blackface population with resistant animals displaying significantly lower FEC, lower worm fecundity and higher concentration of anti-nematode IgA antibodies in serum., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The Finnish Landrace (Finnsheep) is a well known high-prolificacy sheep breed and has been used in many countries as a source of genetic material to increase fecundity of local breeds. Analyses to date have indicated that mutations with a large effect on ovulation rate are not responsible for the exceptional prolificacy of Finnsheep. The objectives of this study were to ascertain if: 1) any of 12 known mutations with large effects on ovulation rate in sheep, or 2) any other DNA sequence variants within the candidate genes GDF9 and BMP15 are implicated in the high prolificacy of the Finnish Landrace breed; using material from lines developed by divergent selection on ovulation rate. Genotyping results showed that none of 12 known mutations (FecBB, FecXB, FecXG, FecXGR, FecXH, FecXI, FecXL, FecXO, FecXR, FecGE, FecGH, or FecGT) were present in a sample of 108 Finnsheep and, thus, do not contribute to the exceptional prolificacy of the breed. However, DNA sequence analysis of GDF9 identified a previously known mutation, V371M, whose frequency differed significantly (P<0.001) between High and Low ovulation rate lines. While analysis of ovulation rate data for Finnsheep failed to establish a significant association between this trait and V371M, analysis of data on Belclare sheep revealed a significant association between V371M and ovulation rate (P<0.01). Ewes that were heterozygous for V371M exhibited increased ovulation rate (+0.17, s.e. 0.080; P<0.05) compared to wild type and the effect was non-additive (ovulation rate of heterozygotes was significantly lower (P<0.01) than the mean of the homozygotes). This finding brings to 13 the number of mutations that have large effects on ovulation rate in sheep and to 5, including FecBB, FecGE, FecXO and FecXGR, the number of mutations within the TGFβ superfamily with a positive effect on prolificacy in the homozygous state.

Loading a poorly water-soluble drug onto a high surface area carrier such as mesoporous silica (SBA-15) can increase the drug's dissolution rate and oral bioavailability. The loading method can influence subsequent drug properties including solid state structure and release rate. The objective of this research was to compare several loading processes in terms of drug distribution throughout the mesoporous silica matrix, drug solid state form and drug release properties. A model poorly water-soluble drug fenofibrate was loaded onto SBA-15 using; (i) physical mixing, (ii) melt, (iii) solvent impregnation, (iv) liquid CO₂ and (v) supercritical CO₂ methods. Physical mixing resulted in heterogeneous drug-loading, with no evidence of drug in the mesopores and the retention of the drug in its crystalline state. The other loading processes yielded more homogeneous drug-loading; the drug was deposited into the mesopores of the SBA-15 and was non-crystalline. All the processing methods resulted in enhanced drug release compared to the unprocessed drug with the impregnation, liquid and SC-CO₂ producing the greatest increase at t=30 min., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The effects of (i) medium and high feed value (MFV and HFV) maize silages and (ii) MFV and HFV grass silages, each in combination with a range of concentrate feed levels, on the performance of finishing lambs were evaluated using 280 Suffolk-X lambs (initial live weight 36.1 kg). The MFV and HFV maize silages represented crops with dry matter (DM) concentrations of 185 and 250 g/kg, respectively, at harvest, and had starch and metabolisable energy (ME) concentrations of 33 and 277 g/kg DM and 9.6 and 11.0 MJ/kg, respectively. HFV and MFV grass silages had DM and ME concentrations of 216 and 294 g/kg and 11.0 and 11.5 MJ/kg DM, respectively. A total of 13 treatments were involved. The four silages were offered ad libitum with daily concentrate supplements of 0.2, 0.5 or 0.8 kg per lamb. A final treatment consisted of concentrate offered ad libitum with 0.5 kg of the HFV grass silage daily. Increasing the feed value of grass silage increased (P < 0.001) forage intake, daily carcass and live weight gains, final live weight and carcass weight. Increasing maize silage feed value tended to increase (P = 0.07) daily carcass gain. Increasing concentrate feed level increased total food and ME intakes, and live weight and carcass gains. There was a significant interaction between silage feed value and the response to concentrate feed level. Relative to the HFV grass silage, the positive linear response to increasing concentrate feed level was greater with lambs offered the MFV grass silage for daily live weight gain (P < 0.001), daily carcass gain (P < 0.01) and final carcass weight (P < 0.01). Relative to the HFV maize silage, there was a greater response to increasing concentrate feed level from lambs offered the MFV maize silage in terms of daily carcass gain (P < 0.05) and daily live weight gain (P = 0.06). Forage type had no significant effect on the response to increased concentrate feed level. Relative to the MFV grass silage supplemented with 0.2 kg concentrate, the potential concentrate-sparing effect of the HFV grass silage, and the MFV and HFV maize silages was 0.41, 0.09 and 0.25 kg daily per lamb, respectively. It is concluded that increasing forage feed value increased forage intake and animal performance, and maize silage can replace MFV grass silage in the diet of finishing lambs as performance was equal to or better (depending on maturity of maize at harvest) than that for MFV grass silage.

A pro-asthmatic culture milieu and β2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single-nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing P-values <0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5' of the thyroid hormone receptor-β gene was associated with BDR in the childhood population and two adult populations (P-value=0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.

This paper concerns the likely origin of three mutations with large effects on ovulation rate identified in the Belclare and Cambridge sheep breeds; two in the BMP15 gene (FecX(G) and FecX(B)) and the third (FecG(H)) in GDF9. All three mutations segregate in Belclare sheep while one, FecX(B), has not been found in the Cambridge. Both Belclare and Cambridge breeds are relatively recently developed composites that have common ancestry through the use of genetic material from the Finnish Landrace and Lleyn breeds. The development of both composites also involved major contributions from exceptionally prolific ewes screened from flocks in Ireland (Belclare) and Britain (Cambridge) during the 1960s. The objective of the current study was to establish the likely origin of the mutations (FecX(G), FecX(B) and FecG(H)) through analysis of DNA from Finnish Landrace and Lleyn sheep, and Galway and Texel breeds which contributed to the development of the Belclare breed. Ewes with exceptionally high prolificacy (hyper-prolific ewes) in current flocks on Irish farms were identified to simulate the screening of ewes from Irish flocks in the 1960s. DNA was obtained from: prolific ewes in extant flocks of Lleyn sheep (n = 44) on the Lleyn peninsula in Wales; hyper-prolific ewes (n = 41); prolific Galway (n = 41) ewes; Finnish Landrace (n = 124) and Texel (n = 19) ewes. The FecX(G) mutation was identified in Lleyn but not in Finnish Landrace, Galway or Texel sheep; FecX(B) was only found among the hyper-prolific ewes. The FecG(H) mutation was identified in the sample of Lleyn sheep. It was concluded from these findings that the Lleyn breed was the most likely source of the FecX(G) and FecG(H) mutations in Belclare and Cambridge sheep and that the FecX(B) mutation came from the High Fertility line that was developed using prolific ewes selected from commercial flocks in Ireland in the 1960's and subsequently used in the genesis of the Belclare.

Anthelmintic resistance has been reported in most sheep producing countries. Prior to the mid 1990s, reports of anthelmintic resistance in Ireland were sparse and focused on benzimidazole, one of the three classes of anthelmintic available during this period. This evidence for efficacy issues on Irish farms combined with awareness that anthelmintic resistance was increasingly being reported in other countries prompted the need for more comprehensive investigations on Irish farms. Faecal egg count reduction and micro-agar larval development tests were employed to investigate resistance to benzimidazole, levamisole and macrocyclic lactone. There is compelling evidence for resistance to both benzimidazole (>88% of flocks) and levamisole (>39% of flocks). Resistance of nematode populations to macrocyclic lactone was suspected on a small number of farms (11%) but needs to be confirmed. The recent introduction of two new classes of anthelmintics, after over a 25 year interval, together with the evidence that anthelmintic resistance is reported within a relatively short time following the introduction of a new anthelmintic compound means that the challenge to the industry is immediate. Actions are urgently required to manage anthelmintic resistance so as to prolong the lifespan of anthelmintics.

Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting β(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a β(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β(2)-agonists through GWAS., Competing Interests: The authors have declared that no competing interests exist.

The widespread use of artificial insemination (AI) in sheep is currently prevented due to the lack of a cost effective insemination technique utilising frozen-thawed semen. The objective of the present study was to determine if the deposition of frozen-thawed semen in the vaginal fornix would result in a pregnancy rate comparable to that achieved following cervical insemination. Multiparous ewes of various breeds were synchronised and inseminated into either the vaginal fornix (n=78) or the cervix (n=79), at 57 h post sponge removal, with frozen-thawed semen. Information on mucus secretion and the depth to which it was possible to penetrate the cervix at insemination (cervically inseminated ewes only) was recorded at the time of AI. Pregnancy rate was subsequently determined either by return to service (oestrus) or after slaughter 30 days post insemination. Insemination site did not significantly influence pregnancy rate using frozen-thawed semen (36.2% compared to 27.6% for cervical and vaginal fornix insemination, respectively; P=0.26). Whilst depth of cervical penetration was positively associated with pregnancy rate (P<0.05), this association needs to be interpreted with caution as none of the ewes where the cervix could not be penetrated (score=0) was pregnant. In conclusion, pregnancy rate following insemination of frozen-thawed semen into the vaginal fornix was within 10% points of that obtained following cervical AI of frozen-thawed semen. As insemination into the vaginal fornix is technically easier than cervical insemination, it may be more practical for use in large scale applications., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The objective of this study was to examine sperm penetration through cervical mucus and associated physicochemical properties of cervical mucus from Belclare and Suffolk ewes - two breeds with divergent pregnancy rate following cervical AI using frozen-thawed semen. In Experiment 1, sperm penetration through cervical mucus was assessed in 15 Belclare and 15 Suffolk ewes at 30, 48 and 57h post sponge removal. In Experiment 2, rheological properties of mucus from 17 Belclare and 19 Suffolk ewes at 48 and 57h post sponge removal were determined. In Experiment 3, 20 Belclare and 20 Suffolk ewes were used to assess mucus ferning and pH collected at 42, 48, 57 and 65h post sponge removal. In Experiment 1, a higher number of sperm penetrated cervical mucus from Belclare ewes at 48h, reflected by a breed by time interaction (P=0.05). In Experiment 2, mucus from Suffolk ewes tended to have higher elastic and complex moduli than that from Belclare ewes (P=0.06) regardless of time of collection. There was no effect of ewe breed on the viscous modulus. In Experiment 3, there was a significant effect of time post sponge removal on ferning (P<0.01), but there was no effect of breed. There was no effect of time or breed on mucus pH. It is concluded that breed differences in the rheological properties of cervical mucus affect the ability of sperm to swim through cervical mucus and this may explain breed differences in fertility observed after cervical AI using frozen-thawed semen., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: Short-acting β(2) -agonists (SABAs) are recommended for treating acute pediatric asthma. The long-acting β(2) -agonist (LABA) arformoterol is approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Arformoterol acts rapidly, is delivered via nebulization, and, as such, raises concerns from the FDA over possible off-label use in acute asthma in children. As a step to investigate this issue, this study evaluated the safety and tolerability of three consecutive doses of arformoterol administered over 1 hr in children with stable asthma., Methods: This study consisted of a double-blind, crossover period in which subjects (ages 2-11 years) with stable asthma were randomized to three consecutive nebulized doses of arformoterol (7.5 µg/dose) or levalbuterol (0.63 mg/dose) administered over 1-hr (0, 30, and 60 min) followed by an open-label period with three consecutive doses of arformoterol (15 µg/dose) administered over 1 hr. Endpoints were change in heart rate, blood pressure, and serum potassium and glucose levels. Other endpoints included adverse events and pulmonary function., Results: There were no clinically important mean changes from pre-dose in heart rate, blood pressure, or serum glucose levels, across treatment groups. Substantial declines in serum potassium levels were observed both 2 and 6 hr post-dosing. Two subjects had declines to 2.8 mEq/L and 2.9 mEq/L 2-hr post-dosing. Adverse events were infrequent and differences in forced expiratory volume in 1 sec and peak expiratory flow across treatment groups were not clinically meaningful., Conclusion: In this study, in children with stable asthma, three consecutive doses of arformoterol (7.5 and 15 µg) and levalbuterol were overall well tolerated. Nonetheless, serum potassium levels demonstrated substantial mean declines after dosing. These findings do not address or support the safety and tolerability of arformoterol use in acute exacerbations of asthma in children., (Copyright © 2011 Wiley-Liss, Inc.)