Antibody-drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin.

INTRODUCTION: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. AREAS COVERED: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. EXPERT OPINION: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

Genome-wide association study to identify genetic loci associated with gastrointestinal nematode resistance in Katahdin sheep.

Resistance to gastrointestinal nematodes has previously been shown to be a moderately heritable trait in some breeds of sheep, but the mechanisms of resistance are not well understood. Selection for resistance currently relies upon faecal egg counts (FEC), blood packed cell volumes and FAMACHA visual indicator scores of anaemia. Identifying genomic markers associated with disease resistance would potentially improve the selection process and provide a more reliable means of classifying and understanding the biology behind resistant and susceptible sheep. A GWAS was conducted to identify possible genetic loci associated with resistance to Haemonchus contortus in Katahdin sheep. Forty animals were selected from the top and bottom 10% of estimated breeding values for FEC from a total pool of 641 sires and ram lambs. Samples were genotyped using Applied Biosystems™ Axiom™ Ovine Genotyping Array (50K) consisting of 51 572 SNPs. Following quality control, 46 268 SNPs were included in subsequent analyses. Analyses were conducted using a linear regression model in plink v1.90 and a single-locus mixed model in snp and variation suite. Genome-wide significance was determined by a Bonferroni correction for multiple testing. Using linear regression, loci on chromosomes 2, 3, 16, 23 and 24 were significantly associated at the genome level with FEC estimated breeding values, and we identified a region on chromosome 2 that was significant using both statistical analyses. We suggest a potential role for the gene DIS3L2 for gastrointestinal nematode resistance in Katahdin sheep, although further research is needed to validate these findings.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Genetic parameters for fecal egg counts and their relationship with body weights in Katahdin lambs.

Reliance on anthelmintic drugs to control internal parasites in sheep is no longer sustainable because of the development of resistance to these drugs in parasite populations. Genetic selection may offer an alternative long-term solution, as differences in parasite resistance exist both within and among sheep breeds. However, selection for parasite resistance may have correlated effects on other production traits. The objectives of this study were to estimate genetic parameters for weaning (WFEC) and postweaning (PWFEC) fecal egg counts (FEC) and assess their relationship with birth (BWT), weaning (WWT), and postweaning (PWWT) BW in Katahdin lambs. The study used WFEC (n = 2,537), PWFEC (n = 3.421), BWT (n = 12,869), WWT (n = 10,961), and PWWT (n = 7,812) from 12,869 lambs measured between 2003 and 2015 in 13 flocks enrolled in the U.S. National Sheep Improvement Program. Animal and sire models were fitted to the data using the ASReml statistical package. Records were corrected for fixed effects of dam age, joint effect of type of birth and rearing, and management group (defined by joint effects of flock, sex, and birth year and season); lamb age in days at each measurement time was fitted as a covariate. Maternal additive and maternal permanent environmental effects were not significant (P > 0.05), but litter effects influenced (P < 0.01) both WFEC and PWFEC. Heritability estimates ranged from 0.18 to 0.26 for WFEC and 0.23 to 0.46 for PWFEC, depending on the model used. Heritability estimates from sire models were higher than estimates from animal models. Direct additive, litter, residual, and phenotypic correlations between WFEC and PWFEC were 0.82, 0.25, 0.15, and 0.29, respectively. Bivariate analyses revealed low to moderate correlations between BW and FEC. Moderate heritabilities for FEC in this study indicated that genetic progress for this trait can be achieved in Katahdin lambs and that selection for low FEC should have little or no effect on BW.

Variance components for direct and maternal effects on body weights of Katahdin lambs.

The aim of this study was to estimate genetic parameters for BW in Katahdin lambs. Six animal models were used to study direct and maternal effects on birth weight (BWT), weaning weight (WWT), and postweaning weight (PWWT) using 41,066 BWT, 33,980 WWT, and 22,793 PWWT records collected over 17 yr in 100 flocks. Models included fixed effects of management group, dam age, type of birth (for BWT) or birth and rearing (for WWT and PWWT), and lamb age at weighing (fitted as a covariate for WWT and PWWT; all < 0.05). Variance components for random effects were estimated in sequentially more complex models and tested for significance with likelihood-ratio tests. A model that fitted only an additive animal effect overestimated additive variance for all BW, resulting in larger estimates of direct heritability than models that included maternal effects. Maternal effects explained variation ( < 0.05) in all BW. Heritability estimates for optimal models were 0.15 ± 0.01 for BWT, 0.18 ± 0.02 for WWT, and 0.20 ± 0.02 for PWWT. Estimates of maternal heritabilities were 0.14 for BWT, 0.10 for WWT, and 0.06 for PWWT, with SE = 0.01. Permanent environmental maternal effects explained 4 to 6% (±1%) of total phenotypic variances for these BW. Litter effects included temporary environmental effects common to littermates and a proportion of the dominance genetic variance and accounted for 16 to 19% (±1%) of phenotypic variance. Correlations between additive direct and maternal genetic effects were -0.14 for BWT, -0.23 for WWT, and -0.04 for PWWT but differed from 0 ( < 0.05) only for WWT. The total heritability predicted the total response in direct and maternal genetic effects from mass selection and was 0.23 for BWT, 0.20 for WWT, and 0.23 for PWWT. Direct and maternal additive, maternal permanent environmental, residual, and phenotypic correlations between BWT and WWT were 0.53 ± 0.05, 0.58 ± 0.06, 0.51 ± 0.06, 0.39 ± 0.01, and 0.44 ± 0.01, respectively; those between BWT and PWWT were 0.45 ± 0.06, 0.58 ± 0.08, 0.36 ± 0.08, 0.33 ± 0.01, and 0.37 ± 0.01 respectively; and those between WWT and PWWT were 0.85, 0.99, 0.92, 0.77, and 0.81, respectively, with SE ≤ 0.02. Therefore, both direct and maternal effects had an important impact on BW in Katahdin lambs. Models that included both additive and permanent environmental maternal effects as well as a temporary environmental litter effect should result in more accurate estimates of breeding values and better selection decisions.

High-resolution anorectal manometry: A comparison of solid-state and water-perfused catheters.

BACKGROUND: Anorectal manometry is the most commonly performed investigation for assessment of anorectal dysfunction. Findings from previous studies comparing water-perfused (WP) and solid-state (SS) techniques in the anorectum are conflicting. We compared anal sphincter pressure at rest and during dynamic maneuvers (squeezing and coughing) in healthy volunteers using SS and WP high-resolution anorectal manometry (HR-ARM) employing equivalent catheter configurations, a standardized protocol, and identical data acquisition and analysis software. METHODS: Sixty healthy volunteers (40F; median age: 40; range: 18-74) underwent WP and SS HR-ARM in randomized order. Anal resting pressure, and squeeze and cough increments were measured. Median pressure and 5th and 95th percentiles were calculated for each maneuver and compared using Wilcoxon signed-rank test. Bland and Altman plots were used to assess agreement between the systems. The impact of gender and parity was also explored. KEY RESULTS: Anal sphincter pressure measurements during squeeze (P<.001) and cough (P<.001) were significantly higher using SS HR-ARM than WP HR-ARM. No differences were seen at rest between the two types of catheter (nulliparous: P=.304; parous: P=.390; males: P=.167). Normal ranges for SS and WP manometry from this small group of healthy volunteers are presented. CONCLUSIONS & INFERENCES: Greater sensitivity to rapid pressure change is one of the advantages associated with SS HR-ARM. This is reflected in the differences observed during dynamic maneuvers performed during this study. Catheter type should be taken into consideration when selecting normal ranges for comparison to disease states.

Association between FAMACHA scores and fecal egg counts in Katahdin lambs.

The FAMACHA system was introduced to the U.S. just over 10 yr ago to allow selective deworming of lambs with anemia associated with and retard the development of anthelmintic resistance. The FAMACHA system was initially developed as a predictor of packed cell volume (PCV), but correlations between FAMACHA and fecal egg counts (FEC) have also been reported. It is important to understand factors that influence FAMACHA scores among farms to improve management of gastrointestinal nematodes. The objectives of this study were therefore to quantify associations between FAMACHA scores, FEC, BW, and age in Katahdin lambs at 2 different measurement times in 8 flocks in the eastern U.S., and to assess consistency of relationships between FAMACHA and FEC among flocks. Data came from 1,644 Katahdin lambs from 7 flocks sampled at approximately 90 d of age, and 1,295 lambs from 6 flocks sampled at approximately 120 d of age over a 5 yr period. Residual correlations among log-transformed FEC (LFEC), FAMACHA scores, BW, and lamb ages at each measurement time were determined. Repeatability of each variable was also determined as residual correlations among repeated measures. At both 90 and 120 d of age, correlations of FAMACHA scores with LFEC and BW were significant ( < 0.001), but numerically modest (0.25 and -0.16, respectively at 90 d; 0.31 and -0.16, respectively at 120 d), demonstrating that higher FAMACHA scores were associated with higher FEC and more likely to be observed in lighter lambs. A small negative correlation was observed between FAMACHA score and lamb age ( = -0.05, = 0.05, 90 d; = -0.11, < 0.001, 120 d) indicating that younger lambs were more likely to have elevated FAMACHA scores. Thus, younger and lighter lambs will likely be more susceptible to parasitism and may need to be managed more diligently than older or heavier lambs. In addition, FAMACHA scores have potential to improve breeding value estimates in programs designed to genetically improve parasite resistance.

Factors affecting fecal egg counts in periparturient Katahdin ewes and their lambs.

Selection for low fecal egg counts (FEC) can be used to genetically enhance resistance to gastrointestinal nematode parasites in growing lambs, thereby reducing the frequency of use of anthelmintics, facilitating marketing of organic lamb, and reducing the risk of development of anthelmintic resistance by the parasite. Recording of FEC in lambs has, therefore, been incorporated into several national sheep genetic evaluation programs. Ewes in late gestation and early lactation are also vulnerable to parasite infection and commonly experience a periparturient rise in FEC. This study was designed to assess factors associated with the periparturient rise in FEC in Katahdin ewes and associated changes in FEC in their lambs. Data came from 1,487 lambings by 931 Katahdin ewes from 11 farms in the Eastern United States. Fecal egg counts were measured in ewes at approximately 0, 30, and 60 d postpartum and in their lambs at approximately 60, 90, and 120 d of age. Approximately 1,400 lambs were evaluated at each measurement age. Data were analyzed separately for ewes and lambs and also initially analyzed separately for each measurement time. Repeated-measures analyses were then used to evaluate responses across measurement times. In ewes, FEC peaked at approximately 28 d postpartum, and we concluded that informative periparturient FEC could be obtained from 1 wk before until approximately 5 wk after lambing. Yearling ewes had higher FEC than adult ewes ( < 0.01), and ewes that nursed twin or triplet lambs had higher FEC than ewes that nursed single lambs ( < 0.01). In lambs, FEC increased through approximately 120 d of age. Lambs from yearling ewes and lambs nursed in larger litters were, like their dams, at greater risk of parasitism ( < 0.05). Ewes and lambs in these groups would benefit from enhanced monitoring of parasite loads at lambing and in early lactation. Correlations () between FEC in lambs at 90 d of age and FEC in ewes at 0, 30, and 60 d postpartum of 0.05 to 0.09 ( ≤ 0.05) support the presence of a genetic relationship between these 2 indicators of parasite resistance.

Nitroxide free radicals protect macular carotenoids against chemical destruction (bleaching) during lipid peroxidation.

Macular xanthophylls (MXs) lutein and zeaxanthin are dietary carotenoids that are selectively concentrated in the human eye retina, where they are thought to protect against age-related macular degeneration (AMD) by multiple mechanisms, including filtration of phototoxic blue light and quenching of singlet oxygen and triplet states of photosensitizers. These physical protective mechanisms require that MXs be in their intact structure. Here, we investigated the protection of the intact structure of zeaxanthin incorporated into model membranes subjected to oxidative modification by water- and/or membrane-soluble small nitroxide free radicals. Model membranes were formed from saturated, monounsaturated, and polyunsaturated phosphatidylcholines (PCs). Oxidative modification involved autoxidation, iron-mediated, and singlet oxygen-mediated lipid peroxidation. The extent of chemical destruction (bleaching) of zeaxanthin was evaluated from its absorption spectra and compared with the extent of lipid peroxidation evaluated using the thiobarbituric acid assay. Nitroxide free radicals with different polarity (membrane/water partition coefficients) were used. The extent of zeaxanthin bleaching increased with membrane unsaturation and correlated with the rate of PC oxidation. Protection of the intact structure of zeaxanthin by membrane-soluble nitroxides was much stronger than that by water-soluble nitroxides. The combination of zeaxanthin and lipid-soluble nitroxides exerted strong synergistic protection against singlet oxygen-induced lipid peroxidation. The synergistic effect may be explained in terms of protection of the intact zeaxanthin structure by effective scavenging of free radicals by nitroxides, therefore allowing zeaxanthin to quench the primary oxidant, singlet oxygen, effectively by the physical protective mechanism. The redox state of nitroxides was monitored using electron paramagnetic resonance spectroscopy. Both nitroxide free radicals and their reduced form, hydroxylamines, were equally effective. Obtained data were compared with the protective effects of α-tocopherol, which is the natural antioxidant and protector of MXs within the retina. The new strategies employed here to maintain the intact structure of MXs may enhance their protective potential against AMD.

Changes in concentrations of trace minerals in lambs fed sericea lespedeza leaf meal pellets with or without dietary sodium molybdate.

Prolonged feeding of sericea lespedeza (SL) previously led to reduced serum concentrations of Mo, a cofactor in an enzyme complex that may be involved in weight gain. The current objective was to determine the effect of Mo supplementation on changes in serum, fecal, urine, and liver concentrations of trace minerals in lambs fed SL leaf meal pellets. Thirty ram lambs weaned in May (84 ± 1.5 d of age and 27 ± 1.1 kg; D 0) were blocked by BW, breed type (full or three-fourths Katahdin), and EBV of parasite resistance and randomly assigned to be fed 900 g/d of an alfalfa-based supplement (CON; = 10) or a SL-based supplement ( = 20) for 103 d. Supplements were formulated to be isonitrogenous and isocaloric and to meet trace mineral requirements. Within the SL group, individual lambs were administered either 5 mL water or 5 mL of water with 163.3 mg of sodium molybdate (SLMO). Serum was collected on d 28, 56, and 104; a liver sample was collected by biopsy on d 104 to determine concentrations of trace minerals. Data were analyzed using a mixed model and orthogonal contrasts. Serum concentrations of Mo increased in response to the drench and were greatest in SLMO lambs and then CON lambs and lowest in SL lambs ( < 0.001). Concentrations of Mo in the liver ( < 0.001) were similar between CON and SLMO lambs and were lower in SL lambs than other groups. Serum ( < 0.001) and liver ( = 0.013) concentrations of zinc (Zn) were reduced in both SL and SLMO lambs compared with CON lambs. Serum concentrations of cobalt (Co) increased in CON lambs compared with SL and SLMO lambs between d 0 and 56 but were similar on d 104 (diet × day, < 0.005) as with concentrations in the liver. Serum and liver concentrations of copper (Cu) were greatest ( < 0.001 and < 0.001, respectively) in CON lambs followed by SL lambs and then SLMO lambs. Serum concentrations of selenium (Se) tended ( = 0.10) to be reduced in SL lambs compared with CON and SLMO lambs, but concentrations in the liver were reduced in SL lambs compared with CON lambs and even more so in SLMO lambs ( < 0.003). Although the dietary Mo did increase stores of Mo in the animal and reduced copper, trace minerals associated with metalloproteins-Mo, copper, selenium, and zinc-were reduced in the liver of SL- and/or SLMO-fed lambs. These reductions could be associated with the lower weight gains previously observed after prolonged feeding of SL.

Heterosis and direct effects for Charolais-sired calf weight and growth, cow weight and weight change, and ratios of cow and calf weights and weight changes across warm season lactation in Romosinuano, Angus, and F cows in Arkansas.

The use of Brahman in cow-calf production offers some adaptation to the harsh characteristics of endophyte-infected tall fescue. Criollo breeds, such as the Romosinuano, may have similar adaptation. The objectives were to estimate genetic effects in Romosinuano, Angus, and crossbred cows for their weights, weights of their calves, and ratios (calf weight:cow weight and cow weight change:calf weight gain) across lactation and to assess the influence of forage on traits and estimates. Cows ( = 91) were bred to Charolais bulls after their second parity. Calves ( = 214) were born from 2006 to 2009. Cows and calves were weighed in early (April and June), mid- (July), and late lactation (August and October). Animal was a random effect in analyses of calf data; sire was random in analyses of cow records and ratios. Fixed effects investigated included calf age, calf sex, cow age-year combinations, sire breed of cow, dam breed of cow, and interactions. Subsequent analyses evaluated the effect of forage grazed: endophyte-free or endophyte-infected tall fescue. Estimates of maternal heterosis for calf weight ranged from 9.3 ± 4.3 to 15.4 ± 5.7 kg from mid-lactation through weaning ( < 0.05). Romosinuano direct effects (of the cow) were -6.8 ± 3.0 and -8.9 ± 4.2 kg for weights recorded in April and June. Calf weights and weight gains from birth were greater ( < 0.05) for calves of cows grazing endophyte-free tall fescue except in mid-summer. Cow weight change from April to each time was negative for Angus cows and lower ( < 0.05) than other groups. Cows grazing endophyte-free tall fescue were heavier ( < 0.05) at all times but had more weight loss in late lactation. Angus cows had the lowest ( < 0.05) ratios (negative) of cow weight change:calf weight gain, indicating an energy-deficit condition. Cows grazing endophyte-free tall fescue had more negative ( < 0.05) values for this trait but not in early lactation ( < 0.05). Estimates of heterosis ranged from 12.8 ± 9.5 to 28.6 ± 9.4 kg for cow weight, 7.9 ± 3.0 to 15.8 ± 5.0 kg for cow weight change, and 0.07 ± 0.03 to 0.27 ± 0.1 for cow weight change:calf weight gain. Direct Romosinuano effects ranged from 14.8 ± 4.2 to 49.8 ± 7.7 kg for cow weight change and 0.2 ± 0.04 to 0.51 ± 0.14 for cow weight change:calf weight gain. The adaptive ability of Romosinuano in temperate fescue regions may be favorable with respect to relative cow and calf weight but may be a consequence of lower milk-producing ability.

Examination of commercially available copper oxide wire particles in combination with albendazole for control of gastrointestinal nematodes in lambs.

Control of gastrointestinal nematodes (GIN) remains a critical issue due to the prevalence of anthelmintic resistance. The objective of the experiment was to determine the efficacy of copper oxide wire particles (COWP) from three commercial sources and a combination of COWP and albendazole to control GIN and/or Haemonchus contortus in lambs. Naturally infected Katahdin lambs in early June 2014 and 2015 were randomly assigned to receive no COWP (CON; n=9 and 12) or 2g COWP in a gel capsule as Copasure(®) (COP; n=4 and 17; Animax Ltd.), copper oxide-wire form (AUS; n=7 in 2014 only; Pharmplex), Ultracruz™ (ULT; n=8 and 15; Santa Cruz Animal Health™), no COWP and albendazole (CON+alb; n=10 in 2015 only; 15mg/kg BW; Valbazen(®); Zoetis Animal Health), or COWP+alb (n=7 and 11; in 2014, lambs were administered alb on day 3). Lambs grazed grass pastures as a group and were supplemented with 227g/lamb daily of a commercial grain mix (15% crude protein) and the same amount of alfalfa pellets. Feces were collected on days 0 (day of COWP treatment), 7, and 14 for determination of fecal egg counts (FEC). Pooled (2014) or pooled treatment group feces were cultured on days 0, 7, and 14 (2015 only) to determine GIN genera. Data were analyzed using repeated measures in a mixed model, and FEC were log transformed. The predominant GIN on day 0 was H. contortus (87%) in 2014, and there was a mixed population in 2015. The mean FEC was reduced by day 7 in AUS and ULT lambs (treatment×day, P=0.001), and all of the COWP products were similar. By day 14, the AUS FEC were lower than the CON and COP groups. When examining the combination of COWP and synthetic anthelmintic, the FEC of COWP+alb were reduced to nearly 0eggs/g (back-transformed) and lower than the other groups (treatment×day, P=0.001). The percentage of H. contortus in cultured feces was reduced to a greater extent in the COWP than CON or CON+alb groups of lambs. In a mixed GIN population, the COWP products appeared to be similar in efficacy and using a combination of COWP+alb increased the efficacy not only against H. contortus, but all GIN genera present, offering options in the face of resistance to benzimidazoles.

Changes in hematology, serum biochemistry, and gastrointestinal nematode infection in lambs fed sericea lespedeza with or without dietary sodium molybdate.

Sericea lespedeza (SL; Lespedeza cuneata) is a legume rich in condensed tannins that can be grazed or fed to small ruminants for parasite control. Condensed tannins, a secondary plant compound in SL, may lead to unintended consequences such as changes in production. In our preliminary research, there was consistently a reduction in serum and liver concentrations of Mo. The objective of this study was to determine the effect of SL with or without Mo supplementation on changes in BW, hematology, and serum biochemistry in lambs. Thirty ram lambs weaned in May (84 ± 1.5 d of age; 27 ± 1.1 kg) were blocked by BW, breed type (full or three-fourths Katahdin), and EBV of parasite resistance and randomly assigned to be fed 900 g of alfalfa-based supplement (CON; n = 10) or SL-based supplement (n = 20) for 103 d. Supplements were formulated to be isonitrogenous and isocaloric and to meet trace mineral requirements. Within the SL diet, half of the lambs received 490 mg sodium molybdate weekly (SLMO). Body condition scores and BW were determined every 14 d and blood and feces collected to determine hematological and serum biochemical profiles and fecal egg counts (FEC). Data were analyzed using a mixed model with repeated measures and orthogonal contrasts. The white blood cell counts tended to be reduced in SL- and SLMO-fed lambs compared with CON-fed lambs (P < 0.06), which was associated with a reduction in neutrophils (P < 0.001). Red blood cell counts were also reduced in SL but not SLMO lambs compared with CON lambs (P < 0.04). There was a reduction in blood packed cell volume (P < 0.04) and serum concentrations of albumin (P < 0.001) and creatinine (P < 0.02) in both SL and SLMO lambs compared with CON lambs. Similarly, concentrations of blood urea nitrogen were reduced in both SL and SLMO lambs, but differences among dietary treatments disappeared after 42 d of feeding (treatment × day, P < 0.004). Serum concentrations of total proteins were reduced only in SLMO lambs compared with other lambs (P < 0.001). Body weight and FEC were similar among dietary treatments. Means of all measurements were within a normal range, even though there were subtle but significant differences between dietary groups. Feeding a diet high in condensed tannin-rich SL did not lead to serious effects on hematology or serum biochemistry in lambs.

Effect of sericea lespedeza leaf meal pellets on adult female Haemonchus contortus in goats.

Sericea lespedeza (SL; Lespedeza cuneata) is a perennial warm-season forage rich in condensed tannins (CT) that has been reported to have anthelmintic activity against small ruminant gastrointestinal nematodes (GIN), particularly Haemonchus contortus, a highly pathogenic blood-feeder, but the mechanism of action of CT against H. contortus is not clearly understood. An experiment with young goats was designed to study the effect of SL leaf meal pellets on (1) a mature H. contortus infection, and (2) the surface appearance of adult H. contortus female worms. Thirty-six female and castrated male Boer crossbred goats artificially infected with H. contortus larvae were fed 75% SL leaf meal pellets or alfalfa pellets (18 goats/treatment group) in a 28-day confinement feeding trial. Fecal and blood samples were collected weekly for fecal egg count (FEC) and packed cell volume (PCV) determination, respectively, and all goats were slaughtered at the end of the trial for adult GIN recovery and counting. Five adult female H. contortus were recovered from the abomasum of two goats from each treatment group and from a prior study in which 75% and 95% SL leaf meal pellets or a commercial feed pellet were group-fed to grazing goats (270 days old, Spanish males, 10/treatment group) at 0.91 kg/head/d for 11 weeks. Adult GIN collected were fixed and examined for evidence of surface damage using scanning electron microscopy. Feeding 75% SL pellets to young goats in confinement reduced (P<0.05) FEC compared with control animals, while total worm numbers and PCV were not influenced by treatment. Three out of the 5 adult H. contortus recovered from SL treatment goats in the confinement feeding trial had cuticular surface damage, while no damage was observed on worms from the control group. All five worms observed from both SL treatments in the grazing study showed a shrunken, disheveled cuticular surface, whereas this was not observed on worms from control animals. Overall, this work suggests that a possible mechanism of action of SL against female H. contortus in the animal's abomasum is a direct action of CT on the cuticle of the worm.

Effect of fall-grazed sericea lespedeza (Lespedeza cuneata) on gastrointestinal nematode infections of growing goats.

High prevalence of anthelmintic-resistant gastrointestinal nematodes (GIN) in goats has increased pressure to find effective, alternative non-synthetic control methods, one of which is adding forage of the high condensed tannin (CT) legume sericea lespedeza (SL; Lespedeza cuneata) to the animal's diet. Previous work has demonstrated good efficacy of dried SL (hay, pellets) against small ruminant GIN, but information is lacking on consumption of fresh SL, particularly during the late summer-autumn period in the southern USA when perennial warm-season grass pastures are often low in quality. A study was designed to determine the effects of autumn (September-November) consumption of fresh SL forage, grass pasture (predominantly bermudagrass, BG; Cynodon dactylon), or a combination of SL+BG forage by young goats [intact male Spanish kids, 9 months old (20.7 ± 1.1 kg), n = 10/treatment group] on their GIN infection status. Three forage paddocks (0.40 ha) were set up at the Fort Valley State University Agricultural Research Station (Fort Valley, GA) for an 8-week trial. The goats in each paddock were supplemented with a commercial feed pellet at 0.45 kg/head/d for the first 4 weeks of the trial, and 0.27 kg/head/d for the final 4 weeks. Forage samples taken at the start of the trial were analyzed for crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) content, and a separate set of SL samples was analyzed for CT in leaves, stems, and whole plant using the benzyl mercaptan thiolysis method. Animal weights were taken at the start and end of the trial, and fecal and blood samples were collected weekly for determination of fecal egg counts (FEC) and packed cell volume (PCV), respectively. Adult GIN was recovered from the abomasum and small intestines of all goats at the end of the experiment for counting and speciation. The CP levels were highest for SL forage, intermediate for SL+BG, and lowest for BG forage samples, while NDF and ADF values were the opposite, with highest levels in BG and lowest in SL forage samples. Sericea lespedeza leaves had more CT than stems (16.0 g vs. 3.3g/100g dry weight), a slightly higher percentage of PDs (98% vs. 94%, respectively) and polymers of larger mean degrees of polymerization (42 vs. 18, respectively). There were no differences in average daily gain or blood PCV between the treatment groups, but SL goats had lower FEC (P < 0.05) than the BG or SL+BG forage goats throughout most of the trial. The SL+BG goats had lower FEC than the BG forage animals by the end of the trial (week 8, P < 0.05). The SL goats had lower numbers (P < 0.05) of male Haemonchus contortus and tended to have fewer female (P < 0.10) and total (P < 0.07) H. contortus compared with the BG goats. The predominant GIN in all the goats was Trichostrongylus colubriformis (73% of total GIN). As a low-input forage with activity against pathogenic GIN (H. contortus), SL has a potential to reduce producers' dependence upon synthetic anthelmintics and also to fill the autumn 'window' in good-quality fresh forages for goat grazing in the southern USA.

Use of pelleted sericea lespedeza (Lespedeza cuneata) for natural control of coccidia and gastrointestinal nematodes in weaned goats.

Infection with Eimeria spp. (coccidia) can be devastating in goats, particularly for young, recently-weaned kids, resulting in diarrhea, dehydration, and even death. Feeding dried sericea lespedeza [SL; Lespedeza cuneata (Dum.-Cours.) G. Don.] to young goats has been reported to reduce the effects of internal parasites, including gastrointestinal nematodes (GIN) but there have been no reports of the effects of feeding this forage on Eimeria spp. in goats. Two confinement feeding experiments were completed on recently-weaned intact bucks (24 Kiko-cross, Exp. 1; 20 Spanish, Exp. 2) to determine effects of SL pellets on an established infection of GIN and coccidia. The bucks were assigned to 1 of 2 (Exp. 1) or 3 (Exp. 2) treatment groups based upon the number of Eimeria spp. oocysts per gram (OPG) of feces. In Exp. 1, the kids were fed 1 of 2 pelleted rations ad libitum; 90% SL leaf meal+10% of a liquid molasses/lignin binder mix and a commercial pellet with 12% crude protein (CP) and 24% acid detergent fiber (n=12/treatment group, 2 animals/pen). For Exp. 2, treatment groups were fed (1) 90% SL leaf meal pellets from leaves stored 3 years (n=7), (2) 90% SL pellets from leaf meal stored less than 6 months, (n=7), and the commercial pellets (n=6) ad libitum. For both trials, fecal and blood samples were taken from individual animals every 7 days for 28 days to determine OPG and GIN eggs per gram (EPG) and packed cell volume (PCV), respectively. In Exp. 2, feces were scored for consistency (1=solid pellets, 5=slurry) as an indicator of coccidiosis. In Exp. 1, EPG (P<0.001) and OPG (P<0.01) were reduced by 78.7% and 96.9%, respectively, 7 days after initiation of feeding in goats on the SL pellet diet compared with animals fed the control pellets. The OPG and EPG remained lower in treatment than control animals until the end of the trial. In Exp. 2, goats fed new and old SL leaf meal pellets had 66.2% and 79.2% lower (P<0.05) EPG and 92.2% and 91.2% lower (P<0.05) OPG, respectively, than control animals within 7 days, and these differences were maintained or increased throughout the trial. After 4 weeks of pellet feeding in Exp. 2, fecal scores were lower (P<0.01) in both SL-fed groups compared with control animals, indicating fewer signs of coccidiosis. There was no effect of diet on PCV values throughout either experiment. Dried, pelleted SL has excellent potential as a natural anti-coccidial feed for weaned goats.

Impact of integrated gastrointestinal nematode management training for U.S. goat and sheep producers.

The objective of this study was to determine the impact of integrated parasite management (IPM) training, including FAMACHA(©) eyelid color scoring, on the ability of U.S. sheep and goat producers to control gastrointestinal nematodes (GIN) on their farms. A survey was developed and provided to over 2000 producers trained from 2004 to 2008 in IPM with questions involving farm size (number of sheep/goats), location (U.S. state), impact of training on parasite control efforts and parasite problems on farm, and IPM practices used. Responses were divided into U.S. Census regions of the U.S. Descriptive statistics and logistic regression were used to describe results. Most of the 729 respondents were from the southern region of the U.S. (54.3%) and were small-scale producers (50 or less animals; 64.8%). Nearly all of the respondents (95.1%) agreed that IPM workshop attendance made a difference in their ability to control and monitor parasitism in their herd or flock and employed IPM practices to control GIN (96.3%). The most popular practices respondents used were rotational grazing (71.2%), genetic selection (choosing a parasite resistant breed and/or culling susceptible animals; 52.7%), grain supplementation on pasture to improve nutrition (44.0%), and increased height of plants being grazed (41.8%). Although reporting using a practice decreased (P<0.05) the likelihood of reporting fewer problems, for each 1-point increase in the number of practices which producers employed to control internal parasitism in their herd or flock, they were 16% more likely to report fewer GIN problems (P<0.05). Approximately 75% of respondents indicated an economic benefit of IPM on their farm (P<0.05), and those reporting savings of over $80 were more likely to report fewer problems (P<0.05) with parasites after the training while those reporting no economic benefit were less likely to report fewer problems with GIN (P<0.001). Overall, IPM training resulted in positive impacts for producers responding to the survey and should continue.

Genomic islands of divergence are not affected by geography of speciation in sunflowers.

Genomic studies of speciation often report the presence of highly differentiated genomic regions interspersed within a milieu of weakly diverged loci. The formation of these speciation islands is generally attributed to reduced inter-population gene flow near loci under divergent selection, but few studies have critically evaluated this hypothesis. Here, we report on transcriptome scans among four recently diverged pairs of sunflower (Helianthus) species that vary in the geographical context of speciation. We find that genetic divergence is lower in sympatric and parapatric comparisons, consistent with a role for gene flow in eroding neutral differences. However, genomic islands of divergence are numerous and small in all comparisons, and contrary to expectations, island number and size are not significantly affected by levels of interspecific gene flow. Rather, island formation is strongly associated with reduced recombination rates. Overall, our results indicate that the functional architecture of genomes plays a larger role in shaping genomic divergence than does the geography of speciation.

Sericea lespdeza as an aid in the control of Emeria spp. in lambs.

The objective was to examine the effects of feeding sericea lespedeza leaf meal (SL) on control of coccidiosis in lambs. In Exp. 1, naturally infected lambs (n=76) were weaned (102.7±1.4 d of age) in May (spring) and randomly assigned in a 2×2 factorial design to receive 2% of BW/d of alfalfa pellets (control) or SL with or without amprolium added to drinking water (n=38/level or 19/treatment). Fecal oocyst counts (FOC), egg counts (FEC), and fecal score (1=solid pellets; 5=slurry) were determined every 7d between weaning and 21 d post-weaning. In Exp. 2, twin rearing ewes were randomly assigned to two groups, and their naturally infected lambs were fed a control creep supplement (16% CP; n=40) or SL pellets (14% CP; n=32) 30 d before weaning. Intake of SL was initially low (100g/lamb daily) and increased to 454 g/lamb daily after weaning. Lambs were weaned at 103.6±0.9 d of age and moved to semi-confinement. The FEC, FOC, packed cell volume (PCV), fecal score, and dag score (soiling around rear of lamb; 1=no soiling; 5=heavy soiling) were determined at d -14, 0 (weaning), 7, 14, and 21. In Exp. 3, lambs were randomly assigned to a control or SL diet (n=12/diet) fed at 1.4 kg/d for 22d and inoculated with 50,000 sporulated oocysts on d 8, 11, and 13. The FEC, FOC, and fecal score were determined every 2 to 3d between d 1 and 29 (d 0=first day of dietary treatment). Data on all experiments were analyzed using mixed models. The FOC and FEC data were log transformed. Chi squared analysis was used to determine differences in incidence of treatment (sulfadimethoxine) for coccidiosis in Exp. 1 and 2. In Exp. 1, FOC and FEC were similar between dietary groups, and FOC declined more rapidly in amprolium treated lambs following weaning (P<0.001). Fecal score was higher in the control compared with the SL fed lambs (P=0.05), suggesting more signs of coccidiosis in control lambs. In Exp. 2, FOC was similar initially but was reduced in SL fed lambs by weaning and remained lower thereafter (P=0.004). Dag (P=0.01) and fecal (P=0.001) scores were similar before weaning, but lower in SL fed lambs by weaning and remained lower thereafter. No SL lambs required treatment for coccidiosis, whereas 33% of control lambs required treatment (P<0.001). Fecal egg counts were similar before weaning but were reduced in SL compared with control fed lambs after weaning (P<0.001). In Exp. 3, FOC (P<0.001) and FEC (P<0.001) were reduced in SL compared with control fed lambs. Sericea lespedeza was effective in the prevention and control of coccidiosis as well as in reducing GIN infection. Use of SL could reduce lamb loss post-weaning, reduce the need to treat for coccidiosis, and create a significant economic benefit to livestock producers.