An improved algorithm of white matter hyperintensity detection in elderly adults.

Automated segmentation of the aging brain raises significant challenges because of the prevalence, extent, and heterogeneity of white matter hyperintensities. White matter hyperintensities can be frequently identified in magnetic resonance imaging (MRI) scans of older individuals and among those who have Alzheimer's disease. We propose OASIS-AD, a method for automatic segmentation of white matter hyperintensities in older adults using structural brain MRIs. OASIS-AD is an approach evolved from OASIS, which was developed for automatic lesion segmentation in multiple sclerosis. OASIS-AD is a major refinement of OASIS that takes into account the specific challenges raised by white matter hyperintensities in Alzheimer's disease. In particular, OASIS-AD combines three processing steps: 1) using an eroding procedure on the skull stripped mask; 2) adding a nearest neighbor feature construction approach; and 3) applying a Gaussian filter to refine segmentation results, creating a novel process for WMH detection in aging population. We show that OASIS-AD performs better than existing automatic white matter hyperintensity segmentation approaches.

Genomic prediction of residual feed intake in US Holstein dairy cattle.

Genomic selection is an important tool to introduce feed efficiency into dairy cattle breeding. The goals of the current research are to estimate genomic breeding values of residual feed intake (RFI) and to assess the prediction reliability for RFI in the US Holstein population. The RFI data were collected from 4,823 lactations of 3,947 Holstein cows in 9 research herds in the United States, and were pre-adjusted to remove phenotypic correlations with milk energy, metabolic body weight, body weight change, and for several environmental effects. In the current analyses, genomic predicted transmitting abilities of milk energy and of body weight composite were included into the RFI model to further remove the genetic correlations that remained between RFI and these energy sinks. In the first part of the analyses, a national genomic evaluation for RFI was conducted for all the Holsteins in the national database using a standard multi-step genomic evaluation method and 60,671 SNP list. In the second part of the study, a single-step genomic prediction method was applied to estimate genomic breeding values of RFI for all cows with phenotypes, 5,252 elite young bulls, 4,029 young heifers, as well as their ancestors in the pedigree, using a high-density genotype chip. Theoretical prediction reliabilities were calculated for all the studied animals in the single-step genomic prediction by direct inversion of the mixed model equations. In the results, breeding values were estimated for 1.6 million genotyped Holsteins and 60 million ungenotyped Holsteins, The genomic predicted transmitting ability correlations between RFI and other traits in the index (e.g., fertility) are generally low, indicating minor correlated responses on other index traits when selecting for RFI. Genomic prediction reliabilities for RFI averaged 34% for all phenotyped animals and 13% for all 1.6 million genotyped animals. Including genomic information increased the prediction reliabilities for RFI compared with using only pedigree information. All bulls had low reliabilities, and averaged to only 16% for the top 100 net merit progeny-tested bulls. Analyses using single-step genomic prediction and high-density genotypes gave similar results to those obtained from the national evaluation. The average theoretical reliability for RFI was 18% among the elite young bulls under 5 yr old, being lower in the younger generations of elite bulls compared with older bulls. To conclude, the size of the reference population and its relationship to the predicted population remain as the limiting factors in the genomic prediction for RFI. Continued collection of feed intake data is necessary so that reliabilities can be maintained due to close relationships of phenotyped animals with breeding stock. Considering the currently low prediction reliability and high cost of data collection, focusing RFI data collection on relatives of elite bulls that will have the greatest genetic contribution to the next generation will give more gains and profit.

High-density genome-wide association study for residual feed intake in Holstein dairy cattle.

Improving feed efficiency (FE) of dairy cattle may boost farm profitability and reduce the environmental footprint of the dairy industry. Residual feed intake (RFI), a candidate FE trait in dairy cattle, can be defined to be genetically uncorrelated with major energy sink traits (e.g., milk production, body weight) by including genomic predicted transmitting ability of such traits in genetic analyses for RFI. We examined the genetic basis of RFI through genome-wide association (GWA) analyses and post-GWA enrichment analyses and identified candidate genes and biological pathways associated with RFI in dairy cattle. Data were collected from 4,823 lactations of 3,947 Holstein cows in 9 research herds in the United States. Of these cows, 3,555 were genotyped and were imputed to a high-density list of 312,614 SNP. We used a single-step GWA method to combine information from genotyped and nongenotyped animals with phenotypes as well as their ancestors' information. The estimated genomic breeding values from a single-step genomic BLUP were back-solved to obtain the individual SNP effects for RFI. The proportion of genetic variance explained by each 5-SNP sliding window was also calculated for RFI. Our GWA analyses suggested that RFI is a highly polygenic trait regulated by many genes with small effects. The closest genes to the top SNP and sliding windows were associated with dry matter intake (DMI), RFI, energy homeostasis and energy balance regulation, digestion and metabolism of carbohydrates and proteins, immune regulation, leptin signaling, mitochondrial ATP activities, rumen development, skeletal muscle development, and spermatogenesis. The region of 40.7 to 41.5 Mb on BTA25 (UMD3.1 reference genome) was the top associated region for RFI. The closest genes to this region, CARD11 and EIF3B, were previously shown to be related to RFI of dairy cattle and FE of broilers, respectively. Another candidate region, 57.7 to 58.2 Mb on BTA18, which is associated with DMI and leptin signaling, was also associated with RFI in this study. Post-GWA enrichment analyses used a sum-based marker-set test based on 4 public annotation databases: Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Reactome pathways, and medical subject heading (MeSH) terms. Results of these analyses were consistent with those from the top GWA signals. Across the 4 databases, GWA signals for RFI were highly enriched in the biosynthesis and metabolism of amino acids and proteins, digestion and metabolism of carbohydrates, skeletal development, mitochondrial electron transport, immunity, rumen bacteria activities, and sperm motility. Our findings offer novel insight into the genetic basis of RFI and identify candidate regions and biological pathways associated with RFI in dairy cattle.

Defining the optimal period length and stage of growth or lactation to estimate residual feed intake in dairy cows.

Residual feed intake (RFI) is an estimate of animal feed efficiency, calculated as the difference between observed and expected feed intake. Expected intake typically is derived from a multiple regression model of dry matter intake on energy sinks, including maintenance and growth in growing animals, or maintenance, gain in body reserves, and milk production in lactating animals. The best period during the production cycle of a dairy cow to estimate RFI is not clear. Here, we characterized RFI in growing Holstein heifers (RFIGrowth; ∼10 to 14 mo of age; n = 226) and cows throughout a 305-d lactation (RFILac-Full; n = 118). The goals were to characterize relationships between RFI estimated at different production stages of the dairy cow; determine effects of selection for efficiency during growth on subsequent lactation and feed efficiency; and identify the most desirable testing scheme for RFILac-Full. For RFIGrowth, intake was predicted from multiple linear regression of metabolizable energy (ME) intake on mid-test body weight (BW)0.75 and average daily gain (ADG). For RFILac-Full, predicted intake was based on regression of BW0.75, ADG, and energy-corrected milk yield. Mean energy intake of the least and most efficient growing heifers (±0.5 standard deviations from mean RFIGrowth of 0) differed by 3.01 Mcal of ME/d, but the groups showed no difference in mid-test BW or ADG. Phenotypic correlation between RFIGrowth and RFI of heifers estimated in the first 100 d in milk (RFILac100DIM; n = 130) was 0.37. Ranking of these heifers as least (mean + 0.5 standard deviations), middle, or most efficient (mean - 0.5 standard deviations) based on RFIGrowth resulted in 43% maintaining the same ranking by RFILac100DIM. On average, the most efficient heifers ate 3.27 Mcal of ME/d less during the first 100 DIM than the least efficient heifers, but exhibited no differences in average energy-corrected milk yield, ADG, or BW. The correlation between RFILac100DIM and RFILac-Full was 0.72. Thus, RFIGrowth may serve as an indicator trait for RFI during lactation, and selection for heifers exhibiting low RFIGrowth should improve overall herd feed efficiency during lactation. Correlation analysis between RFILac-Full (10 to 305 DIM) and subperiod estimates of RFI during lactation indicated a test period of 64 to 70 d in duration occurring between 150 to 220 DIM provided a reliable approximation (r ≥ 0.90) of RFILac-Full among the test periods evaluated.

The effects of feeding mixed tocopherol oil on whole-blood respiratory burst and neutrophil immunometabolic-related gene expression in lactating dairy cows.

The 4 major tocopherol isoforms differ in their biochemical reactivity and cellular effects due to basic chemical structural differences. Alpha-tocopherol has been well studied regarding effects on bovine polymorphonuclear leukocyte (PMN) function and its involvement in respiratory burst. However, no studies to date have identified the effects of supplementing a mixed tocopherol oil (Tmix) particularly enriched in non-α tocopherol isoforms (i.e., γ- and δ-isoforms) on fundamental immunometabolic changes in dairy cows. Therefore, the objectives of this study were to determine whether short-term feeding of vegetable oil-derived Tmix alters specific biomarkers of metabolism, whole-blood leukocyte populations, respiratory burst, immunometabolic-related gene expression of PMN, or gene expression of isolated PMN when challenged with lipopolysaccharides (LPS). Clinically healthy multiparous lactating Holstein cows (n = 12; 179 ± 17 d in milk, 40.65 ± 3.68 kg of milk yield) were fed Tmix (620 g/d) for 7 consecutive days. Jugular blood (EDTA anticoagulant) was collected from all cows on d 0 before treatment initiation and again on d 7 after Tmix feeding. Total stimulated respiratory burst activity (RBA) and leukocyte populations were assessed in whole blood, and tocopherol isoform concentrations, metabolites, and hormones were measured in plasma. For gene expression analysis, isolated PMN from cows before and after Tmix feeding were incubated with LPS at a final concentration of either 0.0 or 1.5 µg/mL. Feeding of Tmix for 7 d increased the concentrations of α- and γ-tocopherol. The Tmix did not alter plasma insulin but decreased cholesterol. The Tmix did not alter whole-blood RBA or the leukocyte populations. The LPS challenge increased the expression of proinflammatory genes TNFA and IL6. However, Tmix treatment did not alter the patterns of LPS-affected expression of genes (e.g., TNFA, ITGB2, PPARA, and RXRA) associated with the immune or metabolic response. In conclusion, short-term feeding of Tmix may have no negative effect on animal health as Tmix increased α- and γ-tocopherol concentrations in blood and did not impair whole-blood RBA or alter leukocyte populations. The data provide further support that the α- and γ-tocopherol isoforms do not interfere with normal immune or metabolic function.

Genome-wide association analyses based on a multiple-trait approach for modeling feed efficiency.

Genome-wide association (GWA) of feed efficiency (FE) could help target important genomic regions influencing FE. Data provided by an international dairy FE research consortium consisted of phenotypic records on dry matter intakes (DMI), milk energy (MILKE), and metabolic body weight (MBW) on 6,937 cows from 16 stations in 4 counties. Of these cows, 4,916 had genotypes on 57,347 single nucleotide polymorphism (SNP) markers. We compared a GWA analysis based on the more classical residual feed intake (RFI) model with one based on a previously proposed multiple trait (MT) approach for modeling FE using an alternative measure (DMI|MILKE,MBW). Both models were based on a single-step genomic BLUP procedure that allowed the use of phenotypes from both genotyped and nongenotyped cows. Estimated effects for single SNP markers were small and not statistically important but virtually identical for either FE measure (RFI vs. DMI|MILKE,MBW). However, upon further refining this analysis to develop joint tests within nonoverlapping 1-Mb windows, significant associations were detected between either measure of FE with a window on each of Bos taurus autosomes BTA12 and BTA26. There was, as expected, no overlap between detected genomic regions for DMI|MILKE,MBW and genomic regions influencing the energy sink traits (i.e., MILKE and MBW) because of orthogonal relationships clearly defined between the various traits. Conversely, GWA inferences on DMI can be demonstrated to be partly driven by genetic associations between DMI with these same energy sink traits, thereby having clear implications when comparing GWA studies on DMI to GWA studies on FE-like measures such as RFI.

Brain Structural Changes following HIV Infection: Meta-Analysis.

BACKGROUND: Numerous studies have used structural neuroimaging to measure HIV effects on brain macroarchitecture. While many have reported changes in total brain volume, gray matter volume, white matter volume, CSF volume, and basal ganglia volume following HIV infection, quantitative inconsistencies observed across studies are large. PURPOSE: Our aim was to evaluate the consistency and temporal stability of serostatus effects on a range of structural neuroimaging measures. DATA SOURCES: PubMed, reference lists, and corresponding authors. STUDY SELECTION: The meta-analysis included 19 cross-sectional studies reporting HIV effects on cortical and subcortical volume from 1993 to 2016. DATA ANALYSIS: Random-effects meta-analysis was used to estimate individual study standardized mean differences and study heterogeneity. Meta-regression was used to examine the effects of the study publication year. DATA SYNTHESIS: Meta-analysis revealed standardized mean differences related to the serostatus of -0.65 (P = .002) for total brain volume, -0.28 for gray matter volume (P = .008), -0.24 (P = .076) for white matter volume, and 0.56 (P = .001) for CSF volume. Basal ganglia volume differences related to serostatus were not significant. Nevertheless, estimates of between-study heterogeneity suggested that much of the observed variance was between studies. Publication year was associated with recent reductions in many neurostructural effects. LIMITATIONS: Many studies pooled participants with varying durations of treatment, disease, and comorbidities. Image-acquisition methods changed with time. CONCLUSIONS: While published studies of HIV effects on brain structure had substantial variations that are likely to result from changes in HIV treatment practice during the study period, quantitative neurostructural measures can reliably detect the effects of HIV infection during treatment, serving as reliable biomarkers.

The genetic and biological basis of feed efficiency in mid-lactation Holstein dairy cows.

The objective of this study was to identify genomic regions and candidate genes associated with feed efficiency in lactating Holstein cows. In total, 4,916 cows with actual or imputed genotypes for 60,671 single nucleotide polymorphisms having individual feed intake, milk yield, milk composition, and body weight records were used in this study. Cows were from research herds located in the United States, Canada, the Netherlands, and the United Kingdom. Feed efficiency, defined as residual feed intake (RFI), was calculated within location as the residual of the regression of dry matter intake (DMI) on milk energy (MilkE), metabolic body weight (MBW), change in body weight, and systematic effects. For RFI, DMI, MilkE, and MBW, bivariate analyses were performed considering each trait as a separate trait within parity group to estimate variance components and genetic correlations between them. Animal relationships were established using a genomic relationship matrix. Genome-wide association studies were performed separately by parity group for RFI, DMI, MilkE, and MBW using the Bayes B method with a prior assumption that 1% of single nucleotide polymorphisms have a nonzero effect. One-megabase windows with greatest percentage of the total genetic variation explained by the markers (TGVM) were identified, and adjacent windows with large proportion of the TGVM were combined and reanalyzed. Heritability estimates for RFI were 0.14 (±0.03; ±SE) in primiparous cows and 0.13 (±0.03) in multiparous cows. Genetic correlations between primiparous and multiparous cows were 0.76 for RFI, 0.78 for DMI, 0.92 for MBW, and 0.61 for MilkE. No single 1-Mb window explained a significant proportion of the TGVM for RFI; however, after combining windows, significance was met on Bos taurus autosome 27 in primiparous cows, and nearly reached on Bos taurus autosome 4 in multiparous cows. Among other genes, these regions contain ß-3 adrenergic receptor and the physiological candidate gene, leptin, respectively. Between the 2 parity groups, 3 of the 10 windows with the largest effects on DMI neighbored windows affecting RFI, but were not in the top 10 regions for MilkE or MBW. This result suggests a genetic basis for feed intake that is unrelated to energy consumption required for milk production or expected maintenance as determined by MBW. In conclusion, feed efficiency measured as RFI is a polygenic trait exhibiting a dynamic genetic basis and genetic variation distinct from that underlying expected maintenance requirements and milk energy output.

Reliability of White Matter Microstructural Changes in HIV Infection: Meta-Analysis and Confirmation.

BACKGROUND: Diffusion tensor imaging has been widely used to measure HIV effects on white matter microarchitecture. While many authors have reported reduced fractional anisotropy and increased mean diffusivity in HIV, quantitative inconsistencies across studies are numerous. PURPOSE: Our aim was to evaluate the consistency across studies of HIV effects on DTI measures and then examine the DTI reliability in a longitudinal seropositive cohort. DATA SOURCES: Published studies and investigators. STUDY SELECTION: The meta-analysis included 16 cross-sectional studies reporting fractional anisotropy and 12 studies reporting mean diffusivity in the corpus callosum. DATA ANALYSIS: Random-effects meta-analysis was used to estimate study standardized mean differences and heterogeneity. DTI longitudinal reliability was estimated in seropositive participants studied before and 3 and 6 months after beginning treatment. DATA SYNTHESIS: Meta-analysis revealed lower fractional anisotropy (standardized mean difference, -0.43; P < .001) and higher mean diffusivity (standardized mean difference, 0.44; P < .003) in seropositive participants. Nevertheless, between-study heterogeneity accounted for 58% and 66% of the observed variance (P < .01). In contrast, the longitudinal cohort fractional anisotropy was higher and mean diffusivity was lower in seropositive participants (both, P < .001), and fractional anisotropy and mean diffusivity measures were very stable during 6 months, with intraclass correlation coefficients all >0.96. LIMITATIONS: Many studies pooled participants with varying treatments, ages, and disease durations. CONCLUSIONS: HIV effects on WM microstructure had substantial variations that could result from acquisition, processing, or cohort-selection differences. When acquisition parameters and processing were carefully controlled, the resulting DTI measures did not show high temporal variation. HIV effects on WM microstructure may be age-dependent. The high longitudinal reliability of DTI WM microstructure measures makes them promising disease-activity markers.

Reducing gut effects from Cryptosporidium parvum infection in dairy calves through prophylactic glucagon-like peptide 2 therapy or feeding of an artificial sweetener.

Glucagon-like peptide 2 (GLP-2) therapy was shown previously to reduce inflammation-related gut damage from coccidiosis in dairy calves, and feeding of artificial sweetener stimulates GLP-2 secretion from intestinal L cells. The purpose of this study was to determine whether GLP-2 treatment or artificial sweetener feeding beginning 1 wk before an experimental inoculation with the coccidian parasite Cryptosporidium parvum can reduce infection-related intestinal damage in Holstein bull calves. Newborn calves were assigned to 1 of 4 treatment groups of 6 calves each, including noninfected control calves injected s.c. every 12 h with control buffer (CON), infected control calves injected s.c. every 12 h with control buffer (INF), infected calves injected s.c. every 12 h with 50 µg/kg of body weight of GLP-2 (GLP2), and infected calves injected s.c. every 12 h with control buffer and supplemented in the diet with Sucram (Pancosma, Geneva, Switzerland) at 400 mg/kg of dry matter of milk replacer (SUC). Treatments were initiated on d 1, and calves in INF, GLP2, and SUC were orally dosed on d 8 with 12,500 C. parvum oocysts. Fecal scores were recorded daily, plasma was collected on d 1, 8, 12, 15, and 18 to evaluate markers of inflammation, and fecal samples were collected on d 1, 8, and every other day thereafter to determine the presence of oocysts. Calves were euthanized on d 18 for collection of intestinal tissues and histological and gene expression analyses. Relative to CON, calves in INF exhibited an increase in diarrhea severity, increased plasma serum amyloid A concentration on d 15 and 18, reduced intestinal villus height, increased villus apoptosis and crypt cell proliferation, and increased intestinal mRNA expression of MARVELD2 and GPX2. However, calves in SUC and GLP2 had reduced diarrhea severity and fecal C. parvum oocyst shedding, reduced plasma serum amyloid A concentration on d 15 and 18, and, depending on the intestinal segment, increased villus height, reduced crypt cell proliferation, and reduced mRNA expression of MARVELD2, GPX2, and other tight junction proteins relative to INF. Lastly, GLP2 and SUC exhibited increased intestinal mass-to-length ratio and decreased length-to-empty body weight ratio relative to INF. Our findings suggest that GLP-2 and Sucram treatments administered before a low-level C. parvum exposure may contribute to fewer effects on intestinal integrity, morphology, and inflammation in response to infection, and shorter, denser intestines.

Use of genotype × environment interaction model to accommodate genetic heterogeneity for residual feed intake, dry matter intake, net energy in milk, and metabolic body weight in dairy cattle.

Feed efficiency in dairy cattle has gained much attention recently. Due to the cost-prohibitive measurement of individual feed intakes, combining data from multiple countries is often necessary to ensure an adequate reference population. It may then be essential to model genetic heterogeneity when making inferences about feed efficiency or selecting efficient cattle using genomic information. In this study, we constructed a marker × environment interaction model that decomposed marker effects into main effects and interaction components that were specific to each environment. We compared environment-specific variance component estimates and prediction accuracies from the interaction model analyses, an across-environment analyses ignoring population stratification, and a within-environment analyses using an international feed efficiency data set. Phenotypes included residual feed intake, dry matter intake, net energy in milk, and metabolic body weight from 3,656 cows measured in 3 broadly defined environments: North America (NAM), the Netherlands (NLD), and Scotland (SAC). Genotypic data included 57,574 single nucleotide polymorphisms per animal. The interaction model gave the highest prediction accuracy for metabolic body weight, which had the largest estimated heritabilities ranging from 0.37 to 0.55. The within-environment model performed the best when predicting residual feed intake, which had the lowest estimated heritabilities ranging from 0.13 to 0.41. For traits (dry matter intake and net energy in milk) with intermediate estimated heritabilities (0.21 to 0.50 and 0.17 to 0.53, respectively), performance of the 3 models was comparable. Genomic correlations between environments also were computed using variance component estimates from the interaction model. Averaged across all traits, genomic correlations were highest between NAM and NLD, and lowest between NAM and SAC. In conclusion, the interaction model provided a novel way to evaluate traits measured in multiple environments in which genetic heterogeneity may exist. This model allowed estimation of environment-specific parameters and provided genomic predictions that approached or exceeded the accuracy of competing within- or across-environment models.

Efficacy of Double-Blind Peer Review in an Imaging Subspecialty Journal.

BACKGROUND AND PURPOSE: Many scientific journals use double-blind peer review to minimize potential reviewer bias concerning publication recommendations. However, because neuroradiology is a relatively small subspecialty, this process may be limited by prior knowledge of the authors' work or associated institutions. We sought to investigate the efficacy of reviewer blinding and determine the impact that unblinding may have on manuscript acceptance. MATERIALS AND METHODS: For manuscripts submitted to the American Journal of Neuroradiology (AJNR) from January through June 2015, reviewers completed a brief anonymous questionnaire after submitting their evaluations, assessing whether they were familiar with the research or had knowledge of the authors or institutions from which the work originated. RESULTS: The response rate for 1079 questionnaires was 98.8%; 12.9% of reviewers knew or suspected that they knew authors, and 15.3% knew or suspected that they knew the associated institutions. Reviewers correctly identified the authors in 90.3% of cases and correctly stated the institutions in 86.8% of cases. Unblinding resulted from self-citation in 34.1% for both authorship and institutions. The acceptance rate when reviewers knew or suspected that they knew the authors was 57/137 (41.6%) and 262/929 (28.2%) when reviewers did not. The acceptance rate when reviewers knew or suspected that they knew the institutions was 60/163 (36.8%) and 259/903 (28.7%) when they did not. The Fisher exact test showed that author (P < .038) and institution (P < .039) familiarity was associated with greater manuscript acceptance. CONCLUSIONS: While the AJNR process of double-blind peer review minimizes reviewer bias, perceived knowledge of the author and institution is associated with a higher rate of manuscript acceptance.

Modeling genetic and nongenetic variation of feed efficiency and its partial relationships between component traits as a function of management and environmental factors.

Feed efficiency (FE), characterized as the fraction of feed nutrients converted into salable milk or meat, is of increasing economic importance in the dairy industry. We conjecture that FE is a complex trait whose variation and relationships or partial efficiencies (PE) involving the conversion of dry matter intake to milk energy and metabolic body weight may be highly heterogeneous across environments or management scenarios. In this study, a hierarchical Bayesian multivariate mixed model was proposed to jointly infer upon such heterogeneity at both genetic and nongenetic levels on PE and variance components (VC). The heterogeneity was modeled by embedding mixed effects specifications on PE and VC in addition to those directly specified on the component traits. We validated the model by simulation and applied it to a joint analysis of a dairy FE consortium data set with 5,088 Holstein cows from 13 research stations in Canada, the Netherlands, the United Kingdom, and the United States. Although no differences were detected among research stations for PE at the genetic level, some evidence was found of heterogeneity in residual PE. Furthermore, substantial heterogeneity in VC across stations, parities, and ration was observed with heritability estimates of FE ranging from 0.16 to 0.46 across stations.

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals.

Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections.

An alternative approach to modeling genetic merit of feed efficiency in dairy cattle.

Genetic improvement of feed efficiency (FE) in dairy cattle requires greater attention given increasingly important resource constraint issues. A widely accepted yet occasionally contested measure of FE in dairy cattle is residual feed intake (RFI). The use of RFI is limiting for several reasons, including interpretation, differences in recording frequencies between the various component traits that define RFI, and potential differences in genetic versus nongenetic relationships between dry matter intake (DMI) and FE component traits. Hence, analyses focusing on DMI as the response are often preferred. We propose an alternative multiple-trait (MT) modeling strategy that exploits the Cholesky decomposition to provide a potentially more robust measure of FE. We demonstrate that our proposed FE measure is identical to RFI provided that genetic and nongenetic relationships between DMI and component traits of FE are identical. We assessed both approaches (MT and RFI) by simulation as well as by application to 26,383 weekly records from 50 to 200 d in milk on 2,470 cows from a dairy FE consortium study involving 7 institutions. Although the proposed MT model fared better than the RFI model when simulated genetic and nongenetic associations between DMI and FE component traits were substantially different from each other, no meaningful differences were found in predictive performance between the 2 models when applied to the consortium data.

COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of glucagon-like peptide-2: Implications and applications for production and health of ruminants.

Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L cells. Studies conducted in humans, in rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in the intestinal lumen, including fatty acids, carbohydrates, amino acids, and bile acids, which are detected by luminal chemosensors. The physiological actions of GLP-2 are mediated by its G protein-coupled receptor expressed primarily in the intestinal tract on enteric neurons, enteroendocrine cells, and myofibroblasts. The biological activity of GLP-2 is further regulated by dipeptidyl peptidase IV, which rapidly cleaves the N-terminus of GLP-2 that is responsible for GLP-2 receptor activation. Within the gut, GLP-2 increases nutrient absorption, crypt cell proliferation, and mesenteric blood flow and decreases gut permeability and motility, epithelial cell apoptosis, and inflammation. Outside the gut, GLP-2 reduces bone resorption, can suppress appetite, and is cytoprotective in the lung. Thus, GLP-2 has been studied intensively as a therapeutic to improve intestinal function of humans during parenteral nutrition and following small bowel resection and, more recently, as a treatment for osteoporosis and obesity-related disorders and to reduce cellular damage associated with inflammation of the gut and lungs. Recent studies demonstrate that many biological actions and properties of GLP-2 in ruminants are similar to those in nonruminants, including the potential to reduce intestinal nitro-oxidative stress in calves caused by parasitic diseases such as coccidiosis. Because of its beneficial impacts on nutrient absorption, gut healing, and normal gut development, GLP-2 therapy offers significant opportunities to improve calf health and production efficiency. However, GLP-2 therapies require an extended time course to achieve desired physiological responses, as well as daily administration because of the hormone's short half-life. Thus, practical means of administration and alternative strategies to enhance basal GLP-2 secretion (e.g., through specific feed additives), which are more likely to achieve consumer acceptance, are needed. Opportunities to address these challenges are discussed.

Short communication: Glucagon-like peptide-2 and coccidiosis alter tight junction gene expression in the gastrointestinal tract of dairy calves.

Tight junction (TJ) proteins are integral factors involved in gut barrier function, and therapy with glucagon-like peptide-2 (GLP-2) enhances gut integrity. Our aim was to assess effects of GLP-2 treatment on mRNA expression of 8 TJ complex proteins in the intestine of dairy calves not infected or infected with Eimeria bovis at 11±3d of age. Mucosal epithelium from jejunum, ileum, and cecum was collected at slaughter from Holstein bull calves assigned to 4 groups: noninfected, buffer-treated (n=5); noninfected, GLP-2 treated (n=4); E. bovis-infected, buffer-treated (n=5); and E. bovis-infected, GLP-2-treated (n=4). Infected calves were orally dosed with 100,000 to 200,000 sporulated E. bovis oocysts on d 0; GLP-2-treated calves received 50 µg of GLP-2/kg of body weight subcutaneously twice daily for 10d beginning on d 18; and buffer-treated calves received an equal injection volume of 0.01 M Na bicarbonate buffer. All calves were killed on d 28. The mRNA expression of coxsackie and adenovirus receptor (CXADR), claudins 1, 2, and 4 (CLDN1, CLDN2, and CLDN4), F11 receptor (F11R), junction adhesion molecule 2 (JAM2), occludin (OCLN), and tight junction protein ZO-1 (TJP1) was determined by real-time quantitative PCR. In jejunum and ileum, an interaction of E. bovis infection and GLP-2 treatment on gene expression was noted. In jejunum of noninfected calves, GLP-2 increased CXADR, CLDN2, OCLN, and TJP1 mRNA expression but had no effect on mRNA expression in infected calves. Treatment with GLP-2 also increased tight junction protein ZO-1 protein expression in jejunum of noninfected calves as determined by immunohistochemistry. In ileum, E. bovis decreased expression of JAM2, OCLN, and TJP1 in buffer-treated calves, and GLP-2 increased TJP1 expression in infected calves. In cecum, E. bovis infection reduced expression of CXADR, CLDN4, F11R, and OCLN, and GLP-2 therapy increased expression of CLDN4, F11R, OCLN, and TJP1. Results are consistent with studies in nonruminants showing decreased expression of TJ complex proteins in the intestinal tract during pathogen-induced diarrhea and increased TJ protein expression in intestinal tissues in response to GLP-2 treatment. In conclusion, E. bovis reduces gene expression of TJ proteins primarily in cecum of calves 28d postinfection, and GLP-2 increases expression of selected TJ genes in intestinal tissues. Use of GLP-2 to improve gut barrier function in ruminants during pathogen-induced diarrhea warrants additional study.

Heterogeneity in genetic and nongenetic variation and energy sink relationships for residual feed intake across research stations and countries.

Our long-term objective is to develop breeding strategies for improving feed efficiency in dairy cattle. In this study, phenotypic data were pooled across multiple research stations to facilitate investigation of the genetic and nongenetic components of feed efficiency in Holstein cattle. Specifically, the heritability of residual feed intake (RFI) was estimated and heterogeneous relationships between RFI and traits relating to energy utilization were characterized across research stations. Milk, fat, protein, and lactose production converted to megacalories (milk energy; MilkE), dry matter intakes (DMI), and body weights (BW) were collected on 6,824 lactations from 4,893 Holstein cows from research stations in Scotland, the Netherlands, and the United States. Weekly DMI, recorded between 50 to 200 d in milk, was fitted as a linear function of MilkE, BW0.75, and change in BW (ΔBW), along with parity, a fifth-order polynomial on days in milk (DIM), and the interaction between this polynomial and parity in a first-stage model. The residuals from this analysis were considered to be a phenotypic measure of RFI. Estimated partial regression coefficients of DMI on MilkE and on BW0.75 ranged from 0.29 to 0.47 kg/Mcal for MilkE across research stations, whereas estimated partial regression coefficients on BW0.75 ranged from 0.06 to 0.16 kg/kg0.75. Estimated partial regression coefficients on ΔBW ranged from 0.06 to 0.39 across stations. Heritabilities for country-specific RFI were based on fitting second-stage random regression models and ranged from 0.06 to 0.24 depending on DIM. The overall heritability estimate across all research stations and all DIM was 0.15±0.02, whereas an alternative analysis based on combining the first- and second-stage model as 1 model led to an overall heritability estimate of 0.18±0.02. Hence future genomic selection programs on feed efficiency appear to be promising; nevertheless, care should be taken to allow for potentially heterogeneous variance components and partial relationships between DMI and other energy sink traits across environments when determining RFI.

Depression in Childhood and Early Adolescence: Parental Expressed Emotion and Family Functioning.

Across development depression is associated with impairments in interpersonal and family functioning. In turn, these impairments may predict a more negative depression course and outcome. This study examined family functioning and parental Expressed Emotion (EE) among depressed youth during middle childhood and early adolescence and their relationship to demographic and clinical factors. Data were drawn from pretreatment evaluations of 132 depressed youth ages 7-14 and their families enrolled in a randomized clinical trial comparing family to individual treatment for youth depressive disorders. Families completed semi-structured diagnostic interviews, self-report measures of family functioning, and the Five Minute Speech Sample EE measure. High parental EE was more common in one-parent, as opposed to two-parent families, and early adolescent youth were more likely than pre-adolescent youth to have high critical EE parents. Severity and chronicity of child depression, child comorbidity, functional impairment, and maternal depressive symptoms were not associated with parental EE. Parental high EE overall and critical EE in particular were associated with reports of higher conflict and lower cohesion by both parents and children when compared to low parental EE. Similar patterns of associations were evident for youth across pre-adolescent and early adolescent developmental periods. Single parent status may be an indicator of greater family stress; and higher levels of critical EE may reflect the higher levels of parent-child conflict characteristic of the transition from late childhood to early adolescence. Among youth with depression parental EE appears to reflect potentially important impairments in family functioning.

Invited review: improving feed efficiency in dairy production: challenges and possibilities.

Despite substantial advances in milk production efficiency of dairy cattle over the last 50 years, rising feed costs remain a significant threat to producer profitability. There also is a greater emphasis being placed on reducing the negative impacts of dairy production on the environment; thus means to lower greenhouse gas (GHG) emissions and nutrient losses to the environment associated with cattle production are being sought. Improving feed efficiency among dairy cattle herds offers an opportunity to address both of these issues for the dairy industry. However, the best means to assess feed efficiency and make genetic progress in efficiency-related traits among lactating cows without negatively impacting other economically important traits is not entirely obvious. In this review, multiple measurements of feed efficiency for lactating cows are described, as well as the heritability of the traits and their genetic and phenotypic correlations with other production traits. The measure of feed efficiency, residual feed intake is discussed in detail in terms of the benefits for its selection, how it could be assessed in large commercial populations, as well as biological mechanisms contributing to its variation among cows, as it has become a commonly used method to estimate efficiency in the recent scientific literature.