Structure-Activity Relationships, Deuteration, and Fluorination of Synthetic Cannabinoid Receptor Agonists Related to AKB48, 5F-AKB-48, and AFUBIATA.

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.

Generation and reaction of alanyl radicals in open flasks.

The generation and Giese-type reaction of alanyl radicals under metal-free reaction conditions is described. The procedure is operationally simple, occurring at ambient temperature in an open reaction vessel, and requiring short reaction times (≤5 min). The reaction occurs without epimerization and provides ready access to non-proteinogenic amino acids and peptides. Importantly, the process is tolerant of light absorbing groups including commonly used fluorescent tags.

Assessing the environmental impact of resource recovery from dairy manure.

Manure management is a major contributor to environmental impacts from large-scale dairy production. In this study, technologies for recovering energy, nutrients, and water from dairy manure were evaluated using life cycle assessment (LCA) and compared to conventional practices on California dairy farms. Six scenarios were evaluated: conventional manure management practices, anaerobic digestion (AD) for biogas recovery, and four scenarios for nutrients, energy, and water integrated recovery, called NEWIR. The NEWIR system consists of hydrothermal carbonization (HTC) for energy recovery via hydrochar, algae cultivation in the HTC aqueous product for nutrient recovery and production of protein-rich cattle feed, and water recovery from algae pond effluent via membrane distillation. Four NEWIR scenarios were evaluated, each with a different species of algae. Based on the results of the LCA, AD improves GHG emissions relative to conventional practices by 82%, but has similar eutrophication impacts, posing similar concerns for nutrient management as current practices. Results for the NEWIR system are highly dependent on the algae species used. Three of the four species evaluated (Chlamydomonas reinhardtii, Chlorella vulgaris, and Scenedesmus obliquus) improve GHG emissions by 420-500 kg CO2-eq. per functional unit, while net water consumption is increased by approximately 75% over AD and conventional practices Spirulina maxima requires more water and chemical inputs for cultivation than the other species, resulting in higher water use (21 times higher than baseline), though GHG emissions are still reduced by 85 kg CO2-eq. per functional unit relative to conventional practices. All NEWIR scenarios improve eutrophication impacts relative to AD and conventional practices by 16-46% for marine eutrophication and 18-99% for freshwater eutrophication, depending on the algae species used. The results suggest integrated resource recovery through NEWIR is a promising treatment method for manure to mitigate GHG emissions and improve nutrient management on large-scale farms. In addition, carbon and nutrient trading policies are discussed in relation to resource recovery technologies and their potential to incentivize producers to recover products from dairy manure.

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA.

Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole- (e.g., CUMYL-CPrMICA, CUMYL-CPMICA) and cumyl-indazole-carboxamides (e.g., CUMYL-CPrMINACA, CUMYL-CPMINACA), encompassing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl tails. Comprehensive pharmacological characterization was performed with three assay formats, monitoring the recruitment of either wild-type or C-terminally truncated (ßarr2d366) ß-arrestin2 to the activated cannabinoid 1 receptor (CB1) or monitoring Gßγ-mediated membrane hyperpolarization. Altered compound characterization was observed when comparing derived potency (EC50) and efficacy (Emax) values from both assays monitoring the same or a different signaling event, whereas ranges and ranking orders were similar. Structure-activity relationships (SAR) were assessed in threefold, resulting in the identification of the pendant tail as a critical pharmacophore, with the optimal chain length for CB1 activation approximating an n-pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activity of the SCRAs encompassing cyclic tails decreased with decreasing number of carbons forming the cyclic moiety, with CUMYL-CPrMICA showing the least CB1 activity in all assay formats. The SARs were rationalized via molecular docking, demonstrating the importance of the optimal steric contribution of the hydrophobic tail. While SAR conclusions remained largely unchanged, the differential compound characterization by both similar and different assay designs emphasizes the importance of detailing specific assay characteristics to allow adequate interpretation of potencies and efficacies.

Defining Steric Requirements at CB1 and CB2 Cannabinoid Receptors Using Synthetic Cannabinoid Receptor Agonists 5F-AB-PINACA, 5F-ADB-PINACA, PX-1, PX-2, NNL-1, and Their Analogues.

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS). They commonly comprise N-alkylated indole, indazole, or 7-azaindole scaffolds with amide-linked pendant amino acid groups. To explore the contribution of the amino acid side chain to the cannabinoid pharmacology of SCRA NPS, a systematic library of side chain-modified SCRAs was prepared based on the recent detections of amino acid derivatives 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), and 20 (NNL-1). In vitro binding affinities and functional activities at cannabinoid type 1 and 2 receptors (CB1 and CB2, respectively) were determined for all the library members using radioligand competition experiments and a fluorescence-based membrane potential assay. Binding affinities and functional activities varied widely across compounds (Ki = 0.32 to >10 000 nM, EC50 = 0.24-1259 nM), with several clear structure-activity relationships (SARs) emerging. Affinity and potency at CB1 changed as a function of the heterocyclic core (indazole > indole > 7-azaindole) and the pendant amino acid side chain (tert-butyl > iso-propyl > iso-butyl > benzyl > ethyl > methyl > hydrogen). Ensemble docking at CB1 revealed a clear steric basis for observed SAR trends. Interestingly, although 15 (PX-1) and 19 (PX-2) have been detected in recreational drug markets, they failed to induce centrally CB1-mediated effects (e.g., hypothermia) in mice using radiobiotelemetry. Together, these data provide insights regarding structural contributions to the cannabimimetic profiles of 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), 20 (NNL-1), and other SCRA NPS.

Immunotherapy toxicity: identification and management.

The widespread adoption of immunotherapy has revolutionized the treatment of various cancer types, including metastatic triple-negative breast cancer (TNBC), which has long been associated with poor prognostic outcomes. In particular, immune checkpoint inhibitors (ICIs) that target and inhibit programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), have shown promising results in the treatment of patients with metastatic TNBC. However, while manipulating the immune system to induce antitumor response, ICIs can also lead to a unique set of immune-related adverse events (IRAEs), which differ from standard chemotherapy toxicities due to their immune-based origin. These toxicities require highly specific management, including guidance from multidisciplinary specialists. The primary treatment strategy against IRAEs is systemic corticosteroid use, but additional treatment approaches may also involve supportive care, additional immunosuppression, and concurrent treatment delay or discontinuation. Given the rising prevalence of ICI therapy, it is essential to educate clinicians on the presentation and management of these potentially life-threatening events so that they are identified early and treated appropriately. Using data from recent clinical trials, this review will focus on known IRAEs, particularly those seen in patients with breast cancer, and will summarize their prevalence, severity, and outcomes. We will discuss optimal strategies for early recognition and management, as well as approaches toward cautious retreatment following resolution of IRAEs.

Parent and Teacher Perspectives on Factors Decreasing Participation in School-Based Vision Programs.

Purpose: To examine factors decreasing participation in school-based vision programs from parent and teacher perspectives.Methods: We conducted 41 semi-structured focus groups (20 parent groups, 21 teacher/staff groups), at 10 Baltimore and 11 Chicago public elementary and middle schools offering school-based vision programs. School-based vision programs provided vision screening, eye exams, and eyeglasses if needed. Focus groups ranged in size from 2-9 participants (median = 5). Sessions were recorded, transcribed, and coded through an iterative process to develop themes using inductive analysis.Results: Ninety parents and 117 teachers/staff participated. Participants identified five major factors decreasing participation in school-based vision programs: (1) challenges with the consent form, including distribution, collection, and literacy and language barriers; (2) having existing eye care; (3) misunderstandings about the program, especially related to cost and insurance; (4) difficulty raising parental awareness of the program; and (5) certain attitudes towards vision, eye care, and school-based programs, including low prioritization of eye care, mistrust of the program, fear of sharing private information, not believing their child needs glasses, and reluctance accepting 'subsidized' services.Conclusion: Parents and teachers identified important structural barriers to participation (i.e., consent form challenges and low parental awareness) and specific reasons for non-participation (i.e., attitudes, misunderstanding of the program, existing eye care) in school-based vision programs. Effective strategies are needed to facilitate return of consent forms and promote awareness of school-based vision programs among parents. Programs should also target services towards those currently without access to eye care and increase awareness about paediatric vision needs.

A versatile, stimulus-responsive nanoparticle-based platform for use in both sonodynamic and photodynamic cancer therapy.

A PLGA-based multifunctional biodegradable nanoparticle platform co-harboring hematoporphyrin and indocyanine green has been developed. In vitro studies demonstrate ultrasound and light stimulated generation of cytotoxic reactive oxygen species. In vivo studies show that the ICG component facilitates nIR fluorescence imaging that demonstrates accumulation of IV- administered nanoparticles in tumours. In vivo studies also demonstrate ultrasound- and light-mediated inhibition of tumour growth in animals treated with the platform. Since the platform consists entirely of clinically-approved agents it could find use in sonodynamic- and photodynamic-based therapies for cancer. STATEMENT OF SIGNIFICANCE: We describe a biocompatible and biodegradable nanoparticle-based platform for use in sonodynamic and photodynamic therapeutic approaches for the treatment of cancer. The non-toxic nanoparticles produce cytotoxic reactive oxygen species when exposed to ultrasound and/or light at levels that have no impact on tissues. The system is unique in that it is accumulated by tumours within six hours and has the ability to release its sensitising capability while retaining its imaging capability within a therapeutic time frame. The former could enhance dispersion and sensitising capabilities in less permeable tumour tissues and the latter permits the design of therapeutic approaches that minimize collateral damage to normal tissues.

ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents.

OBJECTIVES: This European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position statement provides a comprehensive guide for health care providers to manage percutaneous endoscopic gastrostomy tubes in a safe, effective, and appropriate way. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of evidence, recommendations reflect the expert opinion of the authors. Final consensus was obtained by multiple e-mail exchange and during 3 face-to-face meetings of the gastroenterology committee of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. RESULTS: Endoscopically placed gastrostomy devices are essential in the management of children with feeding and nutritional problems. The article focuses on practical issues such as indications and contraindications. CONCLUSIONS: The decision to place an endoscopic gastrostomy has to be made by an appropriate multidisciplinary team, which then provides active follow-up and care for the child and the device.

Modification of selected bacteria and markers of protein fermentation in the distal gastrointestinal tract of pigs upon consumption of chitosan is accompanied by heightened manure odor emissions.

Previous studies have indicated that reducing dietary CP may improve N utilization and effectively diminish manure ammonia emissions; however, the response of manure odor emissions to such dietary modifications has been inconsistent. The objective of the current experiment was to induce decreased lactobacilli (DL) numbers in the distal gastrointestinal tract (dGIT; cecum + colon) of finishing pigs offered both high- and low-CP diets through consumption of chitosan, and examine the influence of this model on manure ammonia and odor emissions when compared with a positive control diet. It was hypothesized that an DL population would be accompanied by an increase in markers of protein fermentation. When compared with normal lactobacilli populations in the dGIT, generation of an DL population would result in increased manure odor emissions from pigs offered both dietary CP concentrations. A 2 × 2 factorial arrangement of treatments was conducted to investigate the effect of including chitosan [0 (positive control) vs. 20 g/kg of feed] and high or low dietary CP concentration (200 vs. 150 g/kg of feed) on nutrient digestibility, N utilization, selected bacterial populations, and metabolite composition of the dGIT and manure emissions from finisher pigs (60.3 kg). Consumption of chitosan had no influence (P > 0.05) on nutrient digestibility or N utilization. In both high- and low-CP diets, consumption of chitosan decreased the lactobacilli-to-Enterobacteriaceae ratio (P < 0.01), generating an DL population, and increased pH (P < 0.01) in the dGIT and ammonia (P = 0.02) in the cecum compared with diets that supported normal lactobacilli populations. Consumption of chitosan decreased molar proportions of butyric acid (P < 0.01) and increased valeric acid (P < 0.01) in the dGIT compared with unsupplemented diets. Furthermore, consumption of chitosan increased manure odor emissions (P = 0.05) compared with unsupplemented diets. There was no effect (P > 0.05) of chitosan consumption on manure ammonia emissions from 0 to 240 h. The current study demonstrates that dietary chitosan suppressed populations of lactobacilli in the dGIT. In response, a considerable increase in Enterobacteriaceae, markers of protein fermentation, and manure odor emissions was observed compared with the positive control diet. These effects were observed in pigs offered both high-and low-CP diets. The current study indicates a possible role for lactic-acid bacteria in modulating manure odor emissions relatively independent of the proportions of dietary CP available for fermentation in the dGIT.

Comparison of a wheat-based diet supplemented with purified {beta}-glucans, with an oat-based diet on nutrient digestibility, nitrogen utilization, distal gastrointestinal tract composition, and manure odor and ammonia emissions from finishing pigs.

It was hypothesized that supplementation of an oat-extracted mixed-linkage (1 → 3), (1 → 4)-ß-d-glucan (ß-glucans) to a wheat-based diet may beneficially mitigate manure odor and ammonia emissions associated with intensive pig production, without depressing nutrient digestibility as has been observed with oat-based diets. An experiment was conducted to investigate the effect of dietary ß-glucan source and the inclusion of an enzyme composite containing ß-glucanase on energy and nutrient digestibility, N utilization, distal gastrointestinal tract (GIT) fermentation, and manure emissions from finisher boars. Twenty-eight boars (BW = 74.2 ± 3.6 kg) were assigned to 1 of 4 dietary treatments (n = 7/treatment): 1) an oat-based diet (oat), 2) an oat diet + enzyme composite (OE), 3) a wheat-based diet + purified ß-glucans (WG), and 4) a wheat-based diet + purified ß-glucans + enzyme composite. The wheat-based diets containing purified ß-glucans were formulated to contain concentrations of total ß-glucans comparable with the oat-based diet. Consumption of the WG diet resulted in a greater digestibility of GE (P = 0.001) and an increase in the urine:feces N excretion ratio (P = 0.049) compared with the oat diet. In the distal GIT, pigs offered the WG diet contained fewer bifidobacteria (P = 0.027) and lactobacilli (P = 0.050) compared with the oat diet. Pigs offered the WG diet had increased manure odor emissions compared with the oat diet (P = 0.023). In conclusion, although supplementing wheat-based diets with extracted oat-ß-glucan did not reduce nutrient digestibility, there was a negligible effect in beneficially influencing manure emissions from pigs when compared with a conventional oat formulation.

A comparison between Holstein-Friesian and Jersey dairy cows and their F(1) hybrid on milk fatty acid composition under grazing conditions.

The objective of this study was to investigate the effect of 2 breeds, Holstein and Jersey, and their F(1) hybrid (Jersey x Holstein) on milk fatty acid (FA) concentrations under grazing conditions, especially conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids because of their importance to human health. Eighty-one cows (27 per breed grouping) were allocated a predominantly perennial ryegrass pasture. Samples were collected over 2 periods (June and July). Breed affected dry matter intake and milk production and composition. Holstein cows had the highest dry matter intake (18.4+/-0.40kg of DM/d) and milk production (21.1+/-0.53kg of DM/d). Holstein and Jersey x Holstein cows had similar 4% fat corrected milk, fat yield, and protein yield; with the exception of fat yield, these were all higher than for Jersey cows. Milk fat concentration was highest for Jersey cows and lowest for Holstein cows, with the hybrid cows intermediate. Total FA and linolenic acid intake (1.09+/-0.023 and 0.58+/-0.012 kg/d, respectively) were highest for Holstein cows. In terms of milk FA, Holstein cows had higher contents of C14:1, cis-9 C18:1 and linoleic acid. In turn, Jersey and Jersey x Holstein cows had higher content of C16:0. Milk concentrations of neither the cis-9,trans-11 isomer of CLA nor its precursor, vaccenic acid, were affected by breed. Nevertheless, large variation between individual animals within breed grouping was observed for CLA and estimated Delta(9)-desaturase activity. There was some evidence for a negative heterotic effect on milk concentration of CLA, with the F(1) hybrid cows having lower concentrations compared with the mid parent average. Plasma FA profile did not accurately reflect differences in milk FA composition. In conclusion, there was little evidence for either breed or beneficial heterotic effects on milk FA content with human health-promoting potential, though significant within-breed, interanimal variation was observed.

Effects of phytase and 25-hydroxyvitamin D3 inclusions on the performance, mineral balance and bone parameters of grower-finisher pigs fed low-phosphorus diets.

Two experiments, a performance experiment and a mineral balance study, were conducted on grower-finisher pigs (42 to 101 kg live weight) to investigate the effects of Peniophora lycii phytase enzyme and 25-hydroxyvitamin D3 (25-OHD3) on growth performance, carcass characteristics, nutrient retention and excretion, and bone and blood parameters. The two experiments were designed as a 2 × 2 factorial (two levels of phytase and two levels of 25-OHD3). The four diets were T1, low-phosphorous diet; T2, T1 + phytase; T3, T1 + 25-OHD3 and T4, T1 + phytase + 25-OHD3 diet. In all, 25 µg of 25-OHD3 was used to replace 1000 IU of vitamin D3 in diets T3 and T4. Diets were pelleted (70°C) and formulated to contain similar concentrations of energy (13.8 MJ DE/kg), lysine (9.5 g/kg) and digestible phosphorus (P; 1.8 g/kg). Neither the inclusion of phytase nor 25-OHD3 in the diet had any effect on pig performance. There was an interaction between phytase and 25-OHD3 on calcium (Ca) and P retention (P < 0.01) and on the apparent digestibility of ash (P < 0.01), P (P < 0.001) and Ca (P < 0.001). Pigs offered phytase diets only, had a higher retention of Ca and P and digestibility of ash (P < 0.01), P (P < 0.001) and Ca (P < 0.01) compared with pigs offered unsupplemented diets. However, when the combination of phytase and 25-OHD3 were offered, no effects were detected compared with 25-OHD3 diets only. Pigs fed phytase diets had higher bone ash (P < 0.01), bone P (P < 0.01) and bone Ca (P < 0.05) concentrations compared with pigs offered non-phytase diets. In conclusion, pigs offered phytase diets had a significantly increased bone ash, Ca and P than pigs offered unsupplemented phytase diets. However, there was no advantage to offering a combination of phytase and 25-OHD3 on either bone strength or mineral status compared to offering these feed additives separately.

Effect of beta-glucans contained in barley- and oat-based diets and exogenous enzyme supplementation on gastrointestinal fermentation of finisher pigs and subsequent manure odor and ammonia emissions.

The objective of the current experiment was to evaluate the influence of dietary cereal sources of beta(1,3)(1,4)-d-glucan (beta-glucan) and enzyme supplementation on indices of environmental pollution from finisher pigs. An experiment with a 2 x 2 factorial arrangement of treatments was initiated to investigate the effect of dietary source of beta-glucan (barley vs. oats) and enzyme supplementation (no vs. yes) on nutrient digestibility, N utilization, intestinal fermentation, and manure odor and ammonia emissions from finisher boars (n = 4; BW = 73.9 kg; SD = 4.7). Sixteen boars were assigned to 1 of 4 dietary treatments (n = 4/treatment): 1) barley-based diet, 2) barley-based diet + exogenous enzyme, 3) oat-based diet, and 4) oat-based diet + enzyme. The enzyme supplement used contained endo-1,3(4)-beta-glucanase and endo-1,4-beta-xylanase. Experimental diets were formulated to contain similar concentrations of DE (13.5 MJ/kg) and digestible lysine (8.8 g/kg). Pigs offered oat-based diets had reduced digestibility of DM (0.795 vs. 0.849; SEM 0.007; P = 0.001), OM (0.808 vs. 0.865; SEM 0.007; P = 0.001), GE (0.806 vs. 0.845; SEM 0.006; P = 0.002), and NDF (0.233 vs. 0.423; SEM 0.033; P < 0.003) compared with those offered barley-based diets. Oat-based diets increased populations of Bifidobacterium spp. (7.26 vs. 6.38 log cfu/g of digesta; SEM 0.201; P = 0.005) and Lactobacillus spp. (6.99 vs. 6.18 log cfu/g of digesta; SEM 0.234; P = 0.022) in the proximal colon and decreased manure odor emissions [2,179.6 vs. 4,984.6 Ou(E)/m(3) (where Ou(E) refers to European odor units); SEM 653.7; P < 0.011] compared with barley-based diets. There was an interaction between cereal type and enzyme inclusion on manure ammonia emissions from 0 to 96 h (P = 0.050). Pigs offered barley-based diets containing an enzyme supplement had increased manure ammonia emissions compared with those offered unsupplemented barley-based diets. However, there was no effect of enzyme inclusion on oat-based diets. In conclusion, pigs offered oat-based diets harbored increased Bifidobacterium spp. and Lactobacillus spp. populations in the proximal colon and had decreased manure odor emissions compared with those offered barley-based diets. Enzyme inclusion had no effect on manure ammonia emissions from pigs offered oat-based diets.

Fatty acid intake and milk fatty acid composition of Holstein dairy cows under different grazing strategies: herbage mass and daily herbage allowance.

The objective of this study was to investigate the effect of level of 1) pregrazing herbage mass (HM) and 2) level of daily herbage allowance (DHA) on the performance and fatty acid (FA) composition of milk from grazing dairy cows. Sixty-eight Holstein-Friesian dairy cows were allocated to either a high or low pregrazing HM (1,700 vs. 2,400 kg of DM/ha; >40 mm), and within HM treatment, cows were further allocated to either a high or low DHA (16 vs. 20 kg of DM/d per cow; >40 mm) in a 2 x 2 factorial design. Pregrazing HM did not affect dry matter intake (17.5 +/- 0.75 kg/d), milk production (22.1 +/- 0.99 kg/d), milk composition (milk fat, 3.88 +/- 0.114%; milk protein, 3.28 +/- 0.051%), body weight (525 +/- 16 kg), or body condition score (2.65 +/- 0.064). Increasing DHA increased dry matter intake (+1.5 kg/d) but did not affect any other variable measured. Cows grazing the low HM or high DHA had a higher daily intake of total FA (+0.12 and +0.09 kg/d, respectively, for the low HM and high DHA), alpha-linolenic acid (LNA; +0.08 and +0.05 kg/d, respectively, for the low HM and high DHA), and linoleic acid (+0.01 for both the low HM and high DHA) compared with either the high HM or low DHA. Milk conjugated linoleic acid (cis-9, trans-11 isomer) was not affected by treatment (13.0 +/- 0.77 g/kg of total FA); however, large variation was recorded between individual animals (range from 5.9 to 20.6 g/kg of total FA). Milk concentrations of LNA were higher for animals offered the low HM (5.3 g/kg of total FA), but across treatments, milk concentrations of LNA were low (4.9 +/- 0.33 g/kg of total FA). The present study indicates that changes in HM and DHA do not have a great effect on the milk FA composition of grazing dairy cows. Further enhancement of the beneficial FA content in milk purely from changes in grazing strategy may be difficult when pasture quality is already high.

Effect of DL-malic acid supplementation on feed intake, methane emissions, and performance of lactating dairy cows at pasture.

The objective of this study was to determine the effect of dietary dl-malic acid (MA) supplementation on feed intake, methane (CH(4)) emissions, and performance of mid lactation Holstein-Friesian cows at pasture. Twenty-four (6 primiparous and 18 multiparous) mid- to late-lactation cows (206 +/- 65 d in milk) grazing a mixed-species grass sward were blocked on parity, days in milk, and pretrial milk yield, and randomly allocated within block to 1 of 2 dietary treatments offered twice daily at milking in 2 equal portions (6 kg/d in total): a control concentrate (0 g/d of MA) and a concentrate supplemented with MA (480 g/d of MA) over a 6-wk period. Cows were allowed a 3-wk acclimation period followed by a 5-d CH(4) measurement period. Enteric CH(4) emissions were estimated using the sulfur hexafluoride tracer gas technique, and herbage intake was measured using the n-alkane technique. Dietary supplementation with MA did not affect voluntary intake of herbage or total dry matter intake, body weight gain, milk yield, fat-corrected milk yield, or daily CH(4) production. These results suggest that there is little benefit to be gained from the dietary supplementation of dairy cows at pasture with MA at least within the inclusion rates used in this study.

Effect of DL-malic acid supplementation on feed intake, methane emission, and rumen fermentation in beef cattle.

The objective of this study was to determine the effect of dietary concentration of dl-malic acid (MA) on DMI, CH(4) emission, and rumen fermentation in beef cattle. Two Latin square experiments were conducted. In Exp. 1, six beef heifers (19 +/- 1 mo old) were assigned in a duplicated Latin square to 1 of 3 dietary concentrations of MA on a DMI basis (0%, MA-0; 3.75%, MA-3.75; or 7.5%, MA-7.5) over 3 periods. In Exp. 2, four rumen-fistulated steers (48 +/- 1 mo old) were assigned to 1 of 4 dietary concentrations of MA (0%, MA-0; 2.5%, MA-2.5; 5.0%, MA-5.0; or 7.5%, MA-7.5) on a DMI basis, over 4 periods. Both experimental diets consisted of grass silage and pelleted concentrate (containing MA). Silage was fed ad libitum once daily (a.m.), whereas concentrate was fed twice daily (a.m. and p.m.) with the aim of achieving a total DMI of 40:60 silage:concentrate. In both Exp. 1 and 2, experimental periods consisted of 28 d, incorporating a 13-d acclimatization, a 5-d measurement period, and a 10-d washout period. In Exp. 1, enteric CH(4), feed apparent digestibility, and feed intake were measured over the 5-d measurement period. In Exp. 2, rumen fluid was collected on d 16 to 18, immediately before (a.m.) feeding and 2, 4, 6, and 8 h thereafter. Rumen pH was determined and samples were taken for protozoa count, VFA, and ammonia analysis. Enteric CH(4) emissions were estimated by using the sulfur hexafluoride tracer technique and feed apparent digestibility was estimated by using chromic oxide as an external marker for fecal output. In Exp. 1, increasing dietary MA led to a linear decrease in total DMI (P < 0.001) and total daily CH(4) emissions (P < 0.001). Compared with the control diet, the greatest concentration of MA decreased total daily CH(4) emissions by 16%, which corresponded to a 9% reduction per unit of DMI. Similarly, in Exp. 2, inclusion of MA reduced DMI in a linear (P = 0.002) and quadratic (P < 0.001) fashion. Increasing dietary MA led to a linear decrease in molar proportion of acetic (P = 0.004) and butyric acids (P < 0.001) and an increase in propionic acid (P < 0.001). Ruminal pH tended to increase (P = 0.10) with increasing dietary MA. Dietary inclusion of MA led to a linear (P = 0.01) decrease in protozoa numbers. Increasing supplementation with MA decreased CH(4) emissions, but DMI was also decreased, which could have potentially negative effects on animal performance.

Performance of weanling piglets offered low-, medium- or high-lactose diets supplemented with a seaweed extract from Laminaria spp.

An experiment (3 × 4 factorial arrangement) was conducted to investigate the interaction between different levels of lactose (60 v. 150 v. 250 g/kg) and seaweed extract (0 v. 1 v. 2 v. 4 g/kg) containing both laminarin and fucoidan derived from Laminaria spp. on growth performance and nutrient digestibility of weanling pigs. In all, 384 piglets (24 days of age, 7.5 kg (s.d. 1 kg) live weight) were blocked on the basis of live weight and were assigned to one of 12 dietary treatments (eight replicates per treatment). Piglets were offered diets containing either low (60 g/kg), medium (150 g/kg) or high (250 g/kg) lactose levels with one of the following levels of seaweed extract additive: (1) 0 g/kg, (2) 1 g/kg, (3) 2 g/kg or (4) 4 g/kg seaweed extract. The pigs were offered the diets ad libitum for 21 days post weaning. There was a significant lactose × seaweed extract interaction (P < 0.05) in average daily gain (ADG) during the experimental period (days 0 to 21). At the low and medium levels of lactose, there was an increase in ADG as the level of seaweed extract increased to 2 g/kg (P < 0.05). However, at the high level of lactose there was no further response in ADG as the level of seaweed extract increased above 1 g/kg. There was a significant lactose × seaweed extract interaction during the experimental period (days 0 to 21) (P < 0.05) on the food conversion ratio (FCR). At the low level of lactose, there was a significant improvement in FCR as the levels of seaweed extract increased to 4 g/kg (P < 0.01). At the medium level of lactose, there was a significant improvement in FCR as seaweed extract increased to 2 g/kg. However, there was no significant effect of seaweed extract on FCR at the high levels of lactose (P > 0.05). There was a linear increase in average daily feed intake (ADFI) during the experimental period (days 0 to 21) (P < 0.05) as levels of seaweed extract increased. There was a linear increase in ash digestibility (P < 0.01) during the experimental period (days 0 to 21) as the level of lactose increased. There was a quadratic decrease (P < 0.01) in nitrogen (N) and neutral detergent fibre digestibility as the levels of lactose increased. In conclusion, pigs responded differently to the inclusion levels of seaweed extract at each level of lactose supplementation. The inclusion of a laminarin-fucoidan extract in piglet diets may alleviate the use for high-lactose diets (>60 g/kg) and would also alleviate some of the common problems that occur post weaning.

The effects of seaweed extract inclusion on gut morphology, selected intestinal microbiota, nutrient digestibility, volatile fatty acid concentrations and the immune status of the weaned pig.

An experiment (complete randomised design) was conducted to investigate the effects of Laminaria hyperborea and Laminaria digitata seaweed extract inclusion on gut morphology, selected intestinal microbiota populations, volatile fatty acid concentrations and the immune status of the weaned pig. Twenty-eight piglets (24 days of age, 6.5 ± 1.4 kg live weight) were assigned to one of four dietary treatments for 7 days and then sacrificed: (T1) basal diet (control); (T2) basal diet and 1.5 g/kg L. hyperborea seaweed extract; (T3) basal diet and 1.5 g/kg L. digitata seaweed extract; and (T4) basal diet and 1.5 g/kg of a combination of L. hyperborea and L. digitata seaweed extract. The seaweed extract contained both laminarin and fucoidan. Digesta samples were taken from the caecum and colon to measure the enterobacteria, bifidobacteria and lactobacilli populations and for volatile fatty acid analysis. Tissue samples were taken from the duodenum, jejunum and ileum for morphological examination. Blood samples were taken to determine the cytokine gene expression profile and to measure the phagocytotic capacity of the blood. Pigs offered diets containing L. hyperborea seaweed extract had less bifidobacteria in the colon (P < 0.05) and lactobacilli in the caecum (P < 0.05) and colon (P < 0.001). The inclusion of L. digitata seaweed extract resulted in lower populations of enterobacteria in the caecum and colon (P < 0.01), bifidobacteria in the caecum (P < 0.05), and lactobacilli in the caecum (P < 0.05) and colon (P < 0.001). Pigs offered the combination of L. hyperborea and L. digitata seaweed extracts had less enterobacteria (P < 0.05) and lactobacilli (P < 0.01) in the caecum and colon. Pigs offered the L. digitata-supplemented diet had a reduced villous height in the duodenum and jejunum (P < 0.05). The inclusion of the L. digitata seaweed extract increased the molar proportion of butyric acid in the colon (P < 0.05). There was a significant reduction in the ammonia concentration in the colon with the inclusion of L. hyperborea (P < 0.01) and L. digitata (P < 0.05) seaweed extracts. An increase in the expression of the Interleukin-8 mRNA was observed on day 6 with the supplementation of the combination of L. hyperborea and L. digitata seaweed extract (P < 0.05). The inclusion of L. hyperborea seaweed extract resulted in an increase in total monocyte number (P < 0.05). In conclusion, the supplementation of L. hyperborea and L. digitata seaweed extract alone and in combination reduced the enterobacteria, bifidobacteria and lactobacilli populations in the caecum and colon, while only marginal effects on the immune response was observed.

The effects of cobalt and iodine supplementation of the pregnant ewe diet on immunoglobulin G, vitamin E, T3 and T4 levels in the progeny.

Sixty twin-bearing ewes were allocated to one of four dietary treatments investigating the effects of supplementary iodine or cobalt during late pregnancy on lamb serum immunoglobulin G (IgG), triiodothyronine (T3), thyroxine (T4) and vitamin E concentrations, and lamb IgG absorption efficiency. Ewes were offered grass silage ad libitum supplemented with 800 g per ewe per day of a 190 g/kg crude protein (CP) concentrate from day 126 of gestation until parturition plus one of the following supplements (n = 15 per treatment); no supplement (C); 26.6 mg iodine per day for final 3 weeks pre partum (I-3); 26.6 mg iodine/day for final week pre partum (I-1); 20 mg cobalt/day for final 3 weeks pre partum (Co-3). Lambs were blood sampled at 24 and 72 h post partum for serum IgG and vitamin E concentrations. Ten lambs from C and I-3 were blood sampled at 1 h post partum for serum IgG, vitamin E, T3 and T4 concentrations. There were no differences in serum IgG, vitamin E or T4 values (P > 0.05) at 1 h post partum between lambs born to the C and I-3 ewes. T3 levels were lower in I-3 compared with C progeny (P < 0.05). Supplemental iodine reduced colostral IgG absorption efficiency (P < 0.001) and lamb serum IgG concentrations at 24 and 72 h post partum (P < 0.001). Serum vitamin E concentration in I-3 and I-1 lambs was lower than in Co-3 lambs at 24 h post partum, while at 72 h post partum I-3, I-1 and Co-3 lambs had significantly lower concentrations than C lambs (P < 0.001). Supplementing the ewe's diet with 26.6 mg/day of iodine for the final week of pregnancy reduced lamb serum IgG concentration at 24 and 72 h post partum. The lower total and free T3 values in the progeny of I-3-treated ewes suggest interference in the synthesis and metabolism of thyroid hormones when ewes receive excessive dietary iodine for 3 weeks immediately pre partum. Based on these findings, the indications are that the toxicity level for iodine in the diet of the pregnant ewe should be lowered to 20 mg per ewe per day, equivalent to 40% of its current level. The finding that high-level cobalt supplementation during the final 3 weeks of pregnancy will have a negative effect on serum vitamin E concentration at 72 h post partum is a new and significant finding and previously has not been reported in the literature.