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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]

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.)

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.

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.)

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.

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.

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.

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.

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 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.

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.

Gastrointestinal parasitism is a widely recognised problem in sheep production, particularly for lambs. While anthelmintics have a pivotal role in controlling the effects of parasites, there is a paucity of data on how farmers use anthelmintics. A representative sample of Irish lowland farmers were surveyed regarding their parasite control practices and risk factors that may contribute to the development of anthelmintic resistance. Questionnaires were distributed to 166 lowland Irish sheep producers. The vast majority of respondents treated their sheep with anthelmintics. Lambs were the cohort treated most frequently, the majority of farmers followed a set programme as opposed to treating at sign of disease. A substantial proportion (61%) administered four or more treatments to lambs in a 'normal' year. Departures from best practice in anthelmintic administration that would encourage the development of anthelmintic resistance were observed. In conclusion, in the light of anthelmintic resistance, there is a need for a greater awareness of the principles that underpin the sustainable use of anthelmintics and practices that preserve anthelmintic efficacy should be given a very high priority in the design of helminth control programmes on each farm. To this end, given that veterinary practitioners and agricultural advisors were considered to be the farmer's most popular information resource, the capacity of these professions to communicate information relating to best practice in parasite control should be targeted.

Suffolk sheep carrying the DRB1*1101 (previously referred to as-DRB1*0203 or G2) allele have been reported to show increased resistance to natural Teladorsagia circumcincta infection compared to non-carriers. The objective of this study was to compare the biochemical and physiological responses of DRB1*1101 carrier and non-carrier twin lambs to an experimental infection with 3 × 10(4) L3 Teladorsagia circumcincta. The variables studied included worm burden, faecal egg count, abomasal mast cells, IgA, IgE, IgG1 plus IgG2 and haematological parameters at 0, 3, 7, 21 and 35 days post infection (dpi), and duodenal smooth muscle contractility at 0 and 35 dpi. DRB1*1101 carrier lambs had significantly lower worm burden, higher mast cell and plasma platelet counts than the DRB1*1101 non-carriers (P < 0.05). Before infection, the non-carrier lambs exhibited significantly higher mucosal levels of all antibody isotypes measured compared to the carriers; these levels remained relatively stable over the course of infection in the non-carriers while there was a slow build up of these antibodies in the carriers up to day 21 post infection (pi). The DRB1*1101 non-carrier lambs had a significantly higher plasma lymphocyte count, and produced greater duodenal contractile force relative to the carrier lambs (P < 0.05). There was no significant difference between genotypes in the level of plasma eosinophils, monocytes, neutrophils or FEC. This evidence suggests that resistance conferred by DRB1*1101 is acquired rather than innate, depends on worm expulsion rather than fecundity and is dependent on mucosal mast cell proliferation, platelet activation, and IgA and IgE antibody responses.

Substantial debate exists on whether the immune response between sheep resistant and susceptible to gastrointestinal nematodes can be differentiated into a Th1 and Th2 phenotype. The present study addresses the hypothesis that variation in resistance to Teladorsagia circumcincta between DRB1*1101 (associated with reduced faecal egg count and worm burden) carriers and non-carriers is due to a differential interplay in the expression of Th1/Th2 and regulatory T (Treg) related cytokine genes. Lambs from each genotype were either slaughtered at day 0 (un-infected control) or infected with 3 × 10(4) Teladorsagia circumcincta L3 and slaughtered at 3, 7, 21, and 35 days later. Lambs carrying the DRB1*1101 allele had a significantly lower worm burden (P < 0.05) compared to the non-carriers. Abomasal mucosal cytokine gene expression was evaluated by quantitative real-time PCR and comparison made for time and genotype effects. The response generated varied through the course of infection and was affected by genotype. DRB1*1101 carriers had an up-regulated expression of the Th1-related cytokine genes (IL-1β, TNFα, and IFN-γ) at day 3, but this was replaced by an up-regulated expression of Th2-related cytokine genes (IL-10 and IL-13) and Treg-related cytokine genes (IL-2RA-CD25, TGFα, TGFβ, Arg2, MIF and FOXP3) by day 7. Conversely, in the non-carriers these changes in gene expression were delayed until days 7 and 21 post infection (pi), respectively. It is concluded that resistance to Teladorsagia circumcincta in animals carrying the DRB1*1101 allele is influenced by an earlier interplay between Th1, Th2 and T regulatory immune response genes.

Rationale: β₂-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with β₂-agonist bronchodilator response (BDR)., Objectives: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro., Methods: We resequenced ARG1 in 96 individuals and identified three common, 5' haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression., Measurements and Main Results: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03-1.71) and 2.18 (95% confidence interval, 1.34-2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3., Conclusions: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to β(2)-agonists for optimal asthma management. Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).

Aluminium-based water treatment residual (Al-WTR) is the most widely generated residual from water treatment facilities worldwide. It is regarded as a by-product of no reuse potential and landfilled. This study assessed Al-WTR as potential phosphate-removing substrate in engineered wetlands. Results indicate specific surface area ranged from 28.0 m(2) g(-1) to 41.4 m(2) g(-1). X-ray Diffraction, Fourier transform infrared and energy-dispersive X-ray spectroscopes all indicate Al-WTR is mainly composed of amorphous aluminium which influences its phosphorus (P) adsorption capacity. The pH and electrical conductivity ranged from 5.9 to 6.0 and 0.104 dS m(-1) to 0.140 dS m(-1) respectively, showing that it should support plant growth. Batch tests showed adsorption maxima of 31.9 mg P g(-1) and significant P removal was achieved in column tests. Overall, results showed that Al-WTR can be used for P removal in engineered wetlands and it carries the benefits of reuse of a by-product that promotes sustainability.

The effects of (i) herbage allowance, (ii) frequency of allocation and (iii) grass silage feed value on ewe and lamb performance were studied in mid-gestation ewes. Furthermore, the effects of (i) herbage allowance, (ii) frequency of allocation and (iii) grazing date and their interactions on subsequent herbage yield and feed value were also evaluated. Swards, which had a cut of silage removed on 6 September, received fertiliser nitrogen (34 kg/ha) for extended (deferred) grazing between 6 December and 1 February. Two grass silages differing in feed value were ensiled either precision chopped or in big bales from predominantly perennial ryegrass swards, respectively. In experiment 1, a completely randomised study involving 120 crossbred mid-gestation ewes (Belclare × Scottish Blackface) that had been mated in October was undertaken to evaluate the effects of extended grazed herbage allowance (1.0 and 1.8 kg dry matter (DM)/day), frequency of herbage allocation (daily and twice weekly) and grass silage feed value (low and medium) on ewe and subsequent lamb performance. The six diets were offered from days 63 to 120 of gestation. From day 120 of gestation to parturition all ewes were housed and offered the medium feed value silage ad libitum. All ewes received 19 kg concentrate prior to lambing. Increasing herbage allowance increased forage intake (P < 0.05), lamb birth weight (P < 0.01), weaning weight (P < 0.05) and growth rate from birth to weaning (P < 0.05), decreased herbage utilisation (P < 0.05) and tended to increase ewe condition score at lambing (P = 0.06). Frequency of herbage allocation or grass silage feed value did not alter (P > 0.05) ewe or subsequent lamb performance. In experiment 2, the effect of extended grazed herbage allowance (1.0 and 1.8 kg DM/ewe daily), frequency of allocation (daily and twice weekly) and grazing date (6 to 12 December, 27 December to 3 January and 17 to 23 January) on herbage yield at two harvest dates (27 April and 25 May) was examined in a split plot design study consisting of 72 plots. Delaying grazing date decreased herbage yield (P < 0.01) whilst delaying harvest date increased herbage yield (P < 0.05). Frequency of herbage allocation did not alter (P > 0.05) subsequent herbage yield. It is concluded that for ewes in mid-gestation 1.0 kg of low feed value silage DM had the same feed value, as determined by weaned lamb weight, as 1.3 kg herbage DM allowance. Each 1-day delay in grazing date reduced herbage DM yield by 54.2 kg/ha.

Purpose: Current guidelines support using in combination more than one class of long-acting bronchodilator for COPD patients whose symptoms are not controlled by mono-therapy. This 2-week, multi-center (34 sites), randomized, modified-blind, parallel group study evaluated the efficacy and safety of concomitant treatment with nebulized arformoterol (the formoterol(R,R)-isomer) BID and tiotropium DPI QD., Methods: COPD patients (mean FEV(1) 1.37L, 45.4% predicted) were randomized to receive mono-therapy (either arformoterol 15microg BID [n=76] or tiotropium 18microg QD [n=80]), or combined therapy (sequential dosing of arformoterol 15microg BID and tiotropium 18microg QD [n=78]). Changes in pulmonary function, dyspnea, and rescue levalbuterol use were evaluated, as were safety outcomes., Results: Mean FEV(1)AUC(0-24) (the primary endpoint) improved similarly from baseline for arformoterol (0.10L) and tiotropium (0.08L) treatment groups and greater for the combined therapy group (0.22L; all p-values <0.005). Peak FEV(1), peak FVC, 24-h trough FEV(1), and inspiratory capacity also improved similarly for the mono-therapies and greatest for the combined therapy. Dyspnea (mean transition dyspnea index) improved similarly for arformoterol (+2.3) and tiotropium (+1.8) and greatest with combined therapy (+3.1; p-values <0.05). Levalbuterol use decreased for all treatment groups (range -1.8 to -2.5 actuations/day). All treatments had similar frequency of adverse events., Conclusion: In this study, the combination of nebulized arformoterol 15microg BID plus tiotropium 18microg DPI QD was the most effective in improving pulmonary function and disease symptoms. Mono-therapy improvement with arformoterol or tiotropium was similar. All three treatments were well tolerated.

The study involved 120 crossbred ewes (sixty 1.5 years old animals and sixty 2.5 years old animals; initial liveweight 67.6 kg, condition score 3.7), that were mated in October. They were assigned to six treatments (two shearing treatments (shorn and unshorn) × two silage feed values (low and medium) and two extended grazed herbage allowances (1.0 and 1.8 kg dry matter (DM)/day)) designed to evaluate the effects of shearing at housing, grass silage feed value and extended-grazed herbage allowance on their performance and the performance of their progeny. Swards, which had silage harvested on 6 September, received fertiliser N (34 kg/ha) for extended (deferred) grazing between 19 December and lambing in mid-March. The herbage was allocated at DM allowances of 1.0 or 1.8 kg/ewe daily until 1 February. For the final 6 weeks of pregnancy, daily herbage DM allowances were 1.5, 1.6, 2.0, 2.0 and 2.0 kg for weeks 6, 5, 4, 3 and 2 to parturition, respectively. Two grass silages (low and medium feed value) were offered from housing on 19 December to lambing in mid-March. At housing, half the ewes were shorn whilst the remainder remained unshorn. Each ewe received 23.4 kg concentrate prior to lambing. For the extended-grazed herbage and the low and medium feed-value silages, DM concentrations were 132, 225 and 265 g/kg, and metabolisable energy (ME) concentrations were 10.0, 10.0 and 10.7 MJ/kg DM, respectively. Treatment did not alter (P > 0.05) litter size or number reared. Grass silage feed value did not significantly alter silage DM intake, or ewe and subsequent lamb performance. Increasing herbage allowance in mid-pregnancy decreased herbage utilisation (P < 0.05) and increased herbage intake (P < 0.05). Shearing increased silage intake (P < 0.05), lamb birth weight (P < 0.01) and tended to increase lamb weaning weight (P = 0.07). Relative to the housed shorn ewes, extended grazing did not alter (P > 0.05) ewe or subsequent lamb performance. It is concluded that shearing ewes at housing increased lamb birth weight due to increased silage intake probably associated with cold stress immediately post shearing and reduced heat stress in late pregnancy. Based on differences in lamb weight at weaning 0.8 kg of grass silage DM intake had the same feed value as a daily extended herbage DM allowance of 1.8 kg per ewe throughout the study. Neither silage feed value nor herbage allowance in mid-pregnancy affected lamb birth weight or subsequent growth rate.

Rationale: Inhaled beta-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients., Objectives: To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists., Methods: We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled beta-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts., Measurements and Main Results: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047)., Conclusions: These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.

The EU Commission issued a regulation in 2003, which requires all member states to implement a breeding programme for resistance to transmissible spongiform encephalopathies in sheep by selecting for specific alleles of the prion protein (PrP) gene. A key concern with regard to this regulation was that the intensive selection programmes, designed to increase resistance to scrapie, may have a negative impact on a range of other economically important production, reproduction, and disease traits in sheep. Such problems could arise for a number of reasons. Firstly, a number of breeds have a low frequency of the resistant PrP allele. Secondly, there may be a negative association between the resistant allele and animal performance. Thirdly, selection for scrapie resistance may reduce the rate of improvement towards current breeding goals. The evidence concerning the relationship between PrP genotype and reproduction, production, and disease traits is the subject of this review. We conclude that there is no evidence for a negative association between PrP genotype and reproduction traits (e.g. litter size), lamb performance traits (e.g. growth rate, conformation, carcass composition) or milk production. There is, however, a distinct paucity of information on the relationship between the PrP gene and disease traits. In this context it is noted that there are a number of genes located on chromosome 13, in close proximity to the PrP gene, that are involved in intracellular cell signalling, apoptosis, phagocytosis, and immune function. Thus further direct studies of key disease traits associated with sheep production systems are warranted.

Genetic mutations with major effects on ovulation rate in sheep were recently identified in two genes of the transforming growth factor (TGFbeta) superfamily and a TGFbeta receptor, namely bone morphogenetic protein 15 (BMP15), otherwise known as the growth differentiation factor 9b (GDF9b), GDF9 and activin-like kinase 6 (ALK6) otherwise known as the BMP receptor type IB (BMPRIB). Animals homozygous for the BMP15 or GDF9 mutations are anovulatory whereas animals heterozygous for BMP15 or GDF9 or heterozygous or homozygous for ALK6 have higher than normal ovulation rates. Immunisation of ewes against BMP15 or GDF9 shows that both are essential for normal follicular development and control of ovulation rate. Common features of fertile animals with the BMP15, ALK6 (and possibly GDF9) mutations are changes in oocyte development during early preantral follicular growth, earlier maturation of granulosa cells and ovulation of mature follicles at smaller diameters. In summary, these findings have led to a new paradigm in reproductive biology, namely that the oocyte plays a key role in regulating the ovulation rate.

Ovulation rate in mammals is determined by a complex exchange of hormonal signals between the pituitary gland and the ovary and by a localised exchange of hormones within ovarian follicles between the oocyte and its adjacent somatic cells. From examination of inherited patterns of ovulation rate in sheep, point mutations have been identified in two oocyte-expressed genes, BMP15 (GDF9B) and GDF9. Animals heterozygous for any of these mutations have higher ovulation rates (that is, + 0.8-3) than wild-type contemporaries, whereas those homozygous for each of these mutations are sterile with ovarian follicular development disrupted during the preantral growth stages. Both GDF9 and BMP15 proteins are present in follicular fluid, indicating that they are secreted products. In vitro studies show that granulosa and/or cumulus cells are an important target for both growth factors. Multiple immunisations of sheep with BMP15 or GDF9 peptide protein conjugates show that both growth factors are essential for normal follicular growth and the maturation of preovulatory follicles. Short-term (that is, primary and booster) immunisation with a GDF9 or BMP15 peptide-protein conjugate has been shown to enhance ovulation rate and lamb production. In summary, recent studies of genetic mutations in sheep highlight the importance of oocyte-secreted factors in regulating ovulation rate, and these discoveries may help to explain why some mammals have a predisposition to produce two or more offspring rather than one.

Belclare and Cambridge are prolific sheep breeds, the origins of which involved selecting ewes with exceptionally high litter size records from commercial flocks. The variation in ovulation rate in both breeds is consistent with segregation of a gene (or genes) with a large effect on this trait. Sterile ewes, due to a failure of normal ovarian follicle development, occur in both breeds. New naturally occurring mutations in genes for the oocyte-derived growth factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are described. These mutations are associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers in both breeds. This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF9 is essential for normal folliculogenesis in sheep. Furthermore, it is shown, for the first time in any species, that individuals with mutations in both GDF9 and BMP15 have a greater ovulation rate than sheep with either of the mutations separately.

Recent discoveries that high prolificacy in sheep carrying the Booroola gene (FecB) is the result of a mutation in the BMPIB receptor and high prolificacy in Inverdale sheep (FecX(I)) is the result of a mutation in the BMP15 oocyte-derived growth factor gene have allowed direct marker tests to be developed for FecB and FecX(I). These tests were carried out in seven strains of sheep (Javanese, Thoka, Woodlands, Olkuska, Lacaune, Belclare, and Cambridge) in which inheritance patterns have suggested the presence of major genes affecting prolificacy and in the prolific Garole sheep of India, which have been proposed as the ancestor of Australian Booroola Merinos. The FecB mutation was found in the Garole and Javanese sheep but not in Thoka, Woodlands, Olkuska, Lacaune, Belclare, and Cambridge sheep. None of the sheep tested had the FecX(I) mutation. These findings present strong evidence to support historical records that the Booroola gene was introduced into Australian flocks from Garole (Bengal) sheep in the late 18th century. It is unknown whether Javanese Thin-tailed sheep acquired the Booroola gene directly from Garole sheep from India or via Merinos from Australia. The DNA mutation test for FecB will enable breeding plans to be developed that allow the most effective use of this gene in Garole and Javanese Thin-tailed sheep and their crosses.

Measurements of maximal flow at functional residual capacity (Vmax(FRC)) from partial forced expiratory maneuvers remain the most popular method for assessing small airway function in infants and young children. However, the lack of appropriate reference data that are both applicable outside the centers that developed them and reflect the normal variability between healthy subjects has limited interpretation of Vmax(FRC) results in both clinical practice and research. To address this problem, we collated Vmax(FRC) data from 459 healthy infants (226 boys) tested on 654 occasions during the first 20 months of life from three collaborating centers. Multiple linear regression analysis indicated that sex, age, and length were important predictors of Vmax (FRC), which was, on average, 20% higher in girls than in boys during the first 9 months of life. (Vmax(FRC))0.5 (ml x second(-1)) = 4.22 + 0.00210 x length2 (cm) for boys (RSD = 3.01; R2 = 0.48), and -1.23 + 0.242 x length for girls (RSD = 2.72; R2 = 0.49). Alternative models incorporating both age and length z scores are also described. Failure to use sex-specific prediction equations for Vmax(FRC) may preclude detection of clinically significant changes in girls and lead to false reports of diminished airway function in boys. Appropriate use of z scores, which indicate a "normal" range (z scores of 0 +/- 2) for Vmax(FRC), during infancy should also improve interpretation of both clinical and research studies.