Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

The impact of Box-Cox transformation on phenotypic and genomic characteristics of litter size variability in Landrace pigs.

The genetic background of variability remains of interest especially in traits of high economic importance, e.g. litter size in pigs. It has been indicated that the data transformation can affect the variability phenotype. This study aims to evaluate the phenotypic and genomic background of variability of litter size obtained from data before and after the Box-Cox transformation. In total, 67 500 records on the total number born (TNB) in Landrace pig population were used. Since the data presented skewness, the decision was made to perform Box-Cox transformation on TNB and obtain bcTNB. Next, the phenotypic variability was estimated as log-transformed variance of residuals (LnVar) for both TNB (LnVar_TNB) and bcTNB (LnVar_bcTNB). The variability traits were further used in the genome-wide association study (GWAS) performed on 10 688 sows genotyped with Axiom porcine 660 K or imputed to 660 K SNP-chip. The substantial difference in skewness was observed after data transformation, represented as a change from -0.46 to -0.02. Heritability for TNB was 0.118 vs 0.125 for bcTNB. The heritability for LnVar_TNB was 0.0025 vs 0.0037 for LnVar_bcTNB. The change in the genetic variance was confirmed when genetic coefficients on SD level were compared: 2% for LnVar_TNB vs 4% for LnVar_bcTNB. In bivariate analysis, the genetic correlation between the additive genetic effects of the mean TNB and its variability changed from 0.38 to 0.63. The observed positive genetic correlations indicated that selection focused on increasing the litter size will simultaneously cause an increase in litter size variability. Based on GWAS, 14 SNPs were detected for LnVar_TNB and eight for LnVar_bcTNB, with two of them indicating the most promising candidate genes. First candidate gene located on Sus scrofa chromosome (SSC) 3 is STAG3, which plays an essential role in gametogenesis. Second gene located on SSC 10 is ESRRG, which affects placenta development. The additional post-GWAS analysis indicated even more candidate genes for LnVar_TNB and LnVar_bcTNB. The most promising candidate gene was located on SSC 13 - MFN1, which is involved in embryonic development. The results of this study indicated a substantial change in variance components for variability when the Box-Cox transformation was applied to data presenting skewness. Moreover, the data transformation changed the phenotype substantially enough that only part of SNP overlapped between two variability traits. Our investigation shows that it is essential to perform Box-Cox transformation for skewed data in order to properly describe phenotypic and genomic properties of litter size variability in Landrace pigs.

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses.

A multi-suckling system combined with an enriched housing environment during the growing period promotes resilience to various challenges in pigs.

Little is known about the impact of social and environmental enrichment on improving livestock resilience, i.e. the ability to quickly recover from perturbations. We evaluated the effect of an alternative housing system (AHS) on resilience of pigs, as compared to conventional housing (CONV). The AHS consisted of multi-litter housing during lactation, delayed weaning, extra space allowance and environmental enrichment at all times. We assessed recovery to a 2 h-transport challenge, an LPS injection, 2 h-heat stress and a biopsy wound in 96 pigs. Additionally, indicators of long-term "wear and tear" on the body were determined. AHS pigs had better physiological recoveries with quicker returns to baseline in the transport and LPS challenges, showed lower cortisol accumulation in hairs and lower variance in weight gain over the experimental period compared to conventionally-housed (CONV) pigs. They also had higher levels of natural antibodies binding KLH than CONV pigs. Their response to heat stress revealed a different strategy compared to CONV pigs. Taken together, AHS pigs appear to be more resilient and experience less chronic stress. Enhancing welfare by provision of social and environmental enrichment that better meets the behavioural needs of pigs seems to be a promising approach to improve their resilience.

Influence of the metabolic state during lactation on milk production in modern sows.

Selection for prolificacy in sows has resulted in higher metabolic demands during lactation. In addition, modern sows have an increased genetic merit for leanness. Consequently, sow metabolism during lactation has changed, possibly affecting milk production and litter weight gain. The aim of this study was to investigate the effect of lactational feed intake on milk production and relations between mobilization of body tissues (adipose tissue or skeletal muscle) and milk production in modern sows with a different lactational feed intake. A total of 36 primiparous sows were used, which were either full-fed (6.5 kg/day) or restricted-fed (3.25 kg/day) during the last 2 weeks of a 24-day lactation. Restricted-fed sows had a lower milk fat percentage at weaning and a lower litter weight gain and estimated milk fat and protein production in the last week of lactation. Next, several relations between sow body condition (loss) and milk production variables were identified. Sow BW, loin muscle depth and backfat depth at parturition were positively related to milk fat production in the last week of lactation. In addition, milk fat production was related to the backfat depth loss while milk protein production was related to the loin muscle depth loss during lactation. Backfat depth and loin muscle depth at parturition were positively related to lactational backfat depth loss or muscle depth loss, respectively. Together, results suggest that sows which have more available resources during lactation, either from a higher amount of body tissues at parturition or from an increased feed intake during lactation, direct more energy toward milk production to support a higher litter weight gain. In addition, results show that the type of milk nutrients that sows produce (i.e. milk fat or milk protein) is highly related to the type of body tissues that are mobilized during lactation. Interestingly, relations between sow body condition and milk production were all independent of feed level during lactation. Sow management strategies to increase milk production and litter growth in modern sows may focus on improving sow body condition at the start of lactation or increasing feed intake during lactation.

Follicular development of sows at weaning in relation to estimated breeding value for within-litter variation in piglet birth weight.

In this study we aimed to identify possible causes of within-litter variation in piglet birth weight (birth weight variation) by studying follicular development of sows at weaning in relation to their estimated breeding value (EBV) for birth weight variation. In total, 29 multiparous sows (parity 3 to 5) were selected on their EBV for birth weight variation (SD in grams; High-EBV: 15.8±1.6, N=14 and Low-EBV: -24.7±1.5, N=15). The two groups of sows had similar litter sizes (15.7 v. 16.9). Within 24 h after parturition, piglets were cross-fostered to ensure 13 suckling piglets per sow. Sows weaned 12.8±1.0 and 12.7±1.0 piglets, respectively, at days 26.1±0.2 of lactation. Blood and ovaries were collected within 2 h after weaning. The right ovary was immediately frozen to assess average follicle size and percentage healthy follicles of the 15 largest follicles. The left ovary was used to assess the percentage morphologically healthy cumulus-oocyte complexes (COCs) of the 15 largest follicles. To assess the metabolic state of the sows, body condition and the circulating metabolic markers insulin, IGF1, non-esterified fatty acid, creatinine, leptin, urea and fibroblast growth factor 21 were analysed at weaning. No significant differences were found in any of the measured follicular or metabolic parameters between High-EBV and Low-EBV. A higher weight loss during lactation was related to a lower percentage healthy COCs (ß= -0.65, P=0.02). Serum creatinine, a marker for protein breakdown, was negatively related to average follicle size (ß= -0.60, P=0.05). Backfat loss during lactation was related to a higher backfat thickness at parturition and to a higher average follicle size (ß=0.36, P<0.001) at weaning. In conclusion, we hypothesise that modern hybrid sows with more backfat at the start of lactation are able to mobilise more energy from backfat during lactation and could thereby spare protein reserves to support follicular development.

2S protein Ara h 7.0201 has unique epitopes compared to other Ara h 7 isoforms and is comparable to 2S proteins Ara h 2 and 6 in basophil degranulation capacity.

BACKGROUND: Screening for specific IgE against 2S albumin proteins Ara h 2 and 6 has good positive predictive value in diagnosing peanut allergy. From the third 2S member Ara h 7, 3 isoforms have been identified. Their allergenicity has not been elucidated. OBJECTIVE: This study investigated the allergenicity of Ara h 7 isoforms compared to Ara h 2 and 6. METHODS: Sensitization of 15 DBPCFC-confirmed peanut-allergic patients to recombinant Ara h 2.0201, Ara h 6.01 and isoforms of recombinant Ara h 7 was determined by IgE immunoblotting strips. A basophil activation test (BAT) was performed in 9 patients to determine IgE-cross-linking capacities of the allergens. Sensitivity to the allergens was tested in 5 patients who were sensitized to at least 1 Ara h 7 isoform, by a concentration range in the BAT. 3D prediction models and sequence alignments were used to visualize differences between isoforms and to predict allergenic epitope regions. RESULTS: Sensitization to Ara h 7.0201 was most frequent (80%) and showed to be equally potent as Ara h 2.0201 and 6.01 in inducing basophil degranulation. Sensitization to Ara h 7.0201 together with Ara h 2.0201 and/or 6.01 was observed, indicating the presence of unique epitopes compared to the other 2 isoforms. Differences between the 3 Ara h 7 isoforms were observed in C-terminal cysteine residues, pepsin and trypsin cleavage sites and 3 single amino acid substitutions. CONCLUSION & CLINICAL RELEVANCE: The majority of peanut-allergic patients are sensitized to isoform Ara h 7.0201, which is functionally as active as Ara h 2.0201 and 6.01. Unique epitopes are most likely located in the C-terminus or an allergenic loop region which is a known allergenic epitope region for Ara h 2.0201 and 6.01. Due to its unique epitopes and allergenicity, it is an interesting candidate to improve the diagnostic accuracy for peanut allergy.

Treatment for moderate to severe atopic dermatitis in alpine and moderate maritime climates differentially affects helper T cells and memory B cells in children.

BACKGROUND: Treatment of atopic dermatitis (AD) is focused on topical anti-inflammatory therapy, epidermal barrier repair and trigger avoidance. Multidisciplinary treatment in both moderate maritime and alpine climates can successfully reduce disease activity in children with AD. However, it remains unclear whether abnormalities in B cell and T cell memory normalize and whether this differs between treatment strategies. OBJECTIVE: To determine whether successful treatment in maritime and alpine climates normalizes B- and T lymphocytes in children with moderate to severe AD. METHODS: The study was performed in the context of a trial (DAVOS trial, registered at Current Controlled Trials ISCRTN88136485) in which eighty-eight children with moderate to severe AD were randomized to 6 weeks of treatment in moderate maritime climate (outpatient setting) or in the alpine climate (inpatient setting). Before and directly after treatment, disease activity was determined with SA-EASI and serum TARC, and T cell and B cell subsets were quantified in blood. RESULTS: Both treatment protocols achieved a significant decrease in disease activity, which was accompanied by a reduction in circulating memory Treg, transitional B cell and plasmablast numbers. Alpine climate treatment had a significantly greater effect on disease activity and was accompanied by a reduction in blood eosinophils and increases in memory B cells, CD8+ TemRO, CD4+ Tcm and CCR7+ Th2 subsets. CONCLUSIONS AND CLINICAL RELEVANCE: Clinically successful treatment of AD induces changes in blood B- and T cell subsets reflecting reduced chronic inflammation. In addition, multidisciplinary inpatient treatment in the alpine climate specifically affects memory B cells, CD8+ T cells and Th2 cells. These cell types could represent good markers for treatment efficacy.

Genetic correlations between feed efficiency traits, and growth performance and carcass traits in purebred and crossbred pigs.

Selection for feed efficiency (FE) is a strategy to reduce the production costs per unit of animal product, which is one of the major objectives of current animal breeding programs. In pig breeding, selection for FE and other traits traditionally takes place based on purebred pig (PB) performance at the nucleus level, while pork production typically makes use of crossbred animals (CB). The success of this selection, therefore, depends on the genetic correlation between the performance of PB and CB (rpc) and on the genetic correlation (rg) between FE and the other traits that are currently under selection. Different traits are being used to account for FE, but the rpc has been reported only for feed conversion rate. Therefore, this study aimed 1) to estimate the rpc for growth performance, carcass, and FE traits; 2) to estimate rg between traits within PB and CB populations; and 3) to compare three different traits representing FE: feed conversion rate, residual energy intake (REI), and residual feed intake (RFI). Phenotypes of 194,445 PB animals from 23 nucleus farms, and 46,328 CB animals from three farms where research is conducted under near commercial production conditions were available for this study. From these, 22,984 PB and 8,657 CB presented records for feed intake. The PB population consisted of five sire and four dam lines, and the CB population consisted of terminal cross-progeny generated by crossing sires from one of the five PB sire lines with commercially available two-way maternal sow crosses. Estimates of rpc ranged from 0.61 to 0.71 for growth performance traits, from 0.75 to 0.82 for carcass traits, and from 0.62 to 0.67 for FE traits. Estimates of rg between growth performance, carcass, and FE traits differed within PB and CB. REI and RFI showed substantial positive rg estimates in PB (0.84) and CB (0.90) populations. The magnitudes of rpc estimates indicate that genetic progress is being realized in CB at the production level from selection on PB performance at nucleus level. However, including CB phenotypes recorded on production farms, when predicting breeding values, has the potential to increase genetic progress for these traits in CB. Given the genetic correlations with growth performance traits and the genetic correlation between the performance of PB and CB, REI is an attractive FE parameter for a breeding program.

Specific IgE to peanut 2S albumin Ara h 7 has a discriminative ability comparable to Ara h 2 and 6.

BACKGROUND: Little is known on the clinical relevance of peanut 2S albumin Ara h 7. OBJECTIVE: To investigate the discriminative ability of Ara h 7 in peanut allergy and assess the role of cross-reactivity between Ara h 2, 6 and Ara h 7 isoforms. METHODS: Sensitization to recombinant peanut storage proteins Ara h 1, 2, 3, 6, and 7 was assessed using a line blot in sera from 40 peanut-tolerant and 40 peanut-allergic patients, based on food challenge outcome. A dose-dependent ELISA inhibition experiment was performed with recombinant Ara h 2, 6 and Ara h 7 isoforms. RESULTS: For Ara h 7.0201, an area under the ROC curve was found of 0.83, comparable to Ara h 2 (AUC 0.81) and Ara h 6 (AUC 0.85). Ara h 7 intensity values strongly correlated with those from Ara h 2 and 6 (rs = 0.81). Of all patients sensitized to 2S albumins Ara h 2, 6, or 7, the majority was co-sensitized to all three (n = 24, 68%), although mono-sensitization to either 2S albumin was also observed in selected patients (Ara h 2: n = 6, 17%; Ara h 6: n = 2, 6%; Ara h 7: n = 2, 6%). Binding to Ara h 7.0101 could be strongly inhibited by Ara h 7.0201, but not the other way around. CONCLUSIONS AND CLINICAL RELEVANCE: Specific IgE against Ara h 7.0201 has a predictive ability for peanut allergy similar to Ara h 2 and 6 and possesses unique IgE epitopes as well as epitopes shared between the other Ara h 7 isoform and Ara h 2 and 6. While co-sensitization to all three 2S albumins is most common, mono-sensitization to either Ara h 2, 6, or 7 occurs in selected patients, leading to a risk of misdiagnosis when testing for a single 2S albumin.

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

Genetic parameters for semen quality and quantity traits in five pig lines.

We aimed to estimate genetic parameters for semen quality and quantity traits as well as for within-boar variation of these traits to evaluate their inclusion in breeding goals. Genetic parameters were estimated within line using a multiple-trait (4 × 4) repeatability animal model fitted for 5 pig lines, considering 4 semen traits: sperm motility (MOT), sperm progressive motility (PROMOT), log-transformed number of sperm cells per ejaculate (lnN), and total morphological abnormalities (ABN). The within-boar variation of these traits was analyzed based on a multiple-trait (2 × 2) approach for SD and average (AVG) and a single-trait analysis for CV. The average heritabilities across the 5 lines estimated by multiple-trait analysis were 0.18 ± 0.07 (MOT), 0.22 ± 0.08 (PROMOT), 0.16 ± 0.04 (lnN), and 0.20 ± 0.04 (ABN). The average genetic correlations were favorable between MOT and PROMOT (0.86 ± 0.10), between MOT and ABN (-0.66 ± 0.25), and between PROMOT and ABN (-0.65 ± 0.25). As determined by within-boar variation analysis, AVG exhibited the greatest heritabilities followed by SD and CV, respectively, for the traits MOT and ABN. For PROMOT, average SD heritability was lower than CV heritability, whereas for lnN, they were the same. The average genetic correlations between AVG and SD were favorable for MOT (-0.60 ± 0.13), PROMOT (-0.79 ± 0.14), and ABN (0.78 ± 0.17). The moderate heritabilities indicate the possibility of effective selection of boars based on semen traits. Average and SD are proposed as appropriate traits for selection regarding uniformity.

A major gene for host response to porcine reproductive and respiratory syndrome is not unfavorably associated with overall performance under nonchallenging conditions in commercial pig lines.

A QTL for host response to porcine reproductive and respiratory syndrome (PRRS) was identified in a previous study. The SNP WUR10000125 (WUR) is used as a tag SNP for this QTL. The favorable (B) allele at this SNP is in low frequency in commercial populations, possibly because this allele is unfavorably associated with an important trait under nonchallenging conditions and, therefore, may have been selected against. Therefore, objectives of this study were to estimate the effect of WUR on traits under selection in commercial lines under nonchallenging conditions and to estimate the effect of WUR genotype of parents on performance of crossbred progeny in a commercial-like environment. Data were collected on 4 purebred lines: a Landrace dam line (D1), a Large White dam line (D2), a synthetic sire line (S1), and a Pietrain sire line (S2). Traits analyzed included total number born, number stillborn, farrowing survival, lactation survival, litter mortality, daily feed intake (DFI), backfat, average test daily gain (TGR), average lifetime daily gain (LGR), and Topigs Norsvin selection index (TSI) value, indicative of overall economic value. Deregressed EBV were calculated for each trait (except TSI) and analyzed within line. In the S1 line, AB and BB pigs had significantly lower TGR ( = 0.002) and LGR ( = 0.001) than AA pigs but also lower DFI ( = 0.004). Conversely, AB and BB pigs had significantly higher DFI ( < 0.001) and AB pigs had significantly higher TGR ( = 0.03) than AA pigs in the S2 line. The effect of WUR on TSI was not significant for any line ( ≥ 0.15). Analyses of phenotypic records collected on crossbred progeny of S1 sires and D1 × D2 F females showed no significant effect of parent WUR genotype on DFI, backfat, TGR, or LGR ( ≥ 0.07). In conclusion, the effect of WUR was nonsignificant for most traits but the magnitude and direction of the effect differed by trait and by line. The favorable allele for host response to PRRS was associated with greater DFI and a tendency for greater TGR in the S2 line, but the opposite direction of effect was detected for the S1 line. Regardless of the effect on individual traits, no significant effect of WUR on TSI was detected for any line. Therefore, selecting for the B allele is expected to result in progeny with increased resistance to PRRS without compromising overall economic value under normal, nonchallenging conditions.

Relationship between ovulation rate and embryonic characteristics in gilts at 35 d of pregnancy.

This study investigated the relationship between ovulation rate (OR) and embryonic characteristics in gilts. Landrace ( = 86) and Yorkshire x Landrace ( = 212) gilts were inseminated with semen stored for 3 to 5 d (SS1, = 59), 6 to7 d (SS2, = 133), or 8 to 10 d (SS3, = 106), and slaughtered at 35 d of pregnancy. Ovulation rate was assessed by dissection of the corpora lutea on both ovaries. Embryos were classified as vital (VE) by visual appearance and individually weighed (VEg) and the SD of the weight calculated (SDVEg). Early embryonic mortality (EM) was estimated as the difference between OR and the number of vital plus nonvital embryos. Embryonic characteristics were analyzed with a model that included linear and quadratic terms of OR and fixed class effects of semen storage duration (SS) and genetic line (GL). Landrace gilts had a higher OR than Yorkshire x Landrace gilts (22.1 ± 0.4 vs. 20.3 ± 0.2, ≤ 0.05) and also a higher EM (6.1 ± 0.4 vs. 3.5 ± 0.3, ≤ 0.05). EM was also higher in gilts inseminated with semen stored for more than 8 d. Also, Yorkshire x Landrace gilts had a higher number of VE (16.9 ± 0.7) than the Landrace gilts (13.3 ± 0.8) when inseminations were done with semen stored for up to 5 d. Yorkshire x Landrace gilts had the highest VEg when inseminated with semen stored for 3 to 5 d (SS1: 4.9 ± 0.2 g, SS2: 4.1 ± 0.1 g, and SS3: 4.0 ± 0.2 g; ≤ 0.05). VE and VEg did not differ within Landrace gilts between different SS classes. A quadratic relationship of OR ( ≤ 0.05) was found with VE: a maximum of 16.8 VE was observed at 26 ovulations [(2.5 (± 0.6)*OR- 0.05 (± 0.01)*OR]. A quadratic relationship of OR ( ≤ 0.05) was also found for EM: a minimum of 3.33 EM was observed at 15 ovulations [(-1.1 (± 0.6)*OR -0.03 (± 0.01)*OR]. VEg was not related with OR, but SDVEg had a positive linear relationship with OR [0.01 (± 0.003)*OR, ≤ 0.05]. Results show that Yorkshire x Landrace gilts perform better than Landrace when inseminated with fresh semen, but not with semen stored for longer time. Also, the VE increases with an increase in OR up to 26, but at a lower level at higher OR, which is likely related with the increase in EM. The higher EM at higher OR might arise from a higher variation in follicular/oocyte quality leading to a higher variation in embryonic quality and development, increasing mortality before uterine implantation and the variation in embryonic weight already at 35 d of pregnancy.

Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.

BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD: The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS: All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS: It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.

Using markers with large effect in genetic and genomic predictions.

The first attempts of applying marker-assisted selection (MAS) in animal breeding were not very successful because the identification of markers closely linked to QTL using low-density microsatellite panels was difficult. More recently, the use of high-density SNP panels in genome-wide association studies (GWAS) have increased the power and precision of identifying markers linked to QTL, which offer new possibilities for MAS. However, when GWAS started to be performed, the focus of many breeders had already shifted from the use of MAS to the application of genomic selection (using all available markers without any preselection of markers linked to QTL). In this study, we aimed to evaluate the prediction accuracy of a MAS approach that accounts for GWAS findings in the prediction models by including the most significant SNP from GWAS as a fixed effect in the marker-assisted BLUP (MA-BLUP) and marker-assisted genomic BLUP (MA-GBLUP) prediction models. A second aim was to compare the prediction accuracies from the marker-assisted models with those obtained from a Bayesian variable selection (BVS) model. To compare the prediction accuracies of traditional BLUP, MA-BLUP, genomic BLUP (GBLUP), MA-GBLUP, and BVS, we applied these models to the trait "number of teats" in 4 distinct pig populations, for validation of the results. The most significant SNP in each population was located at approximately 103.50 Mb on chromosome 7. Applying MAS by accounting for the most significant SNP in the prediction models resulted in improved prediction accuracy for number of teats in all evaluated populations compared with BLUP and GBLUP. Using MA-BLUP instead of BLUP, the increase in prediction accuracy ranged from 0.021 to 0.124, whereas using MA-GBLUP instead of GBLUP, the increase in prediction accuracy ranged from 0.003 to 0.043. The BVS model resulted in similar or higher prediction accuracies than MA-GBLUP. For the trait number of teats, BLUP resulted in the lowest prediction accuracies whereas the highest were observed when applying MA-GBLUP or BVS. In the same data set, MA-BLUP can yield similar or superior accuracies compared with GBLUP. The superiority of MA-GBLUP over traditional GBLUP is more pronounced when training populations are smaller and when relationships between training and validation populations are smaller. Marker-assisted GBLUP did not outperform BVS but does have implementation advantages in large-scale evaluations.

Validation of transrectal ultrasonography for assessment of corpora lutea characteristics in pregnant sows and its relationship with litter characteristics at birth.

In experiment 1 we investigated the accuracy of transrectal ultrasonography (TUS) to assess the number (OR) and diameter of corpora lutea (CL) in 45 and 25 sows, respectively, at 23.4 ± 2.9 d of pregnancy. The diameter was calculated as the average diameter of 10 biggest CL. Sows were subsequently slaughtered and OR was assessed by dissection of CL from both ovaries (n = 45) and average diameter of the 10 biggest CL was also calculated after measurement of CL with the caliper rule (n = 25). There was a weak relationship between OR counted after dissection of the ovaries and OR counted with TUS (ß = 0.28 ± 0.01 CL/CL, P = 0.01), but there was a strong relationship between the average CL diameter measured with the caliper rule after dissection and the average CL diameter based on TUS (ß = 1.0 ± 0.1 mm/mm, P < 0.0001). This shows that TUS is not a valid method to assess OR in pregnant sows but it is a valid method to assess average CL diameter. In experiment 2, we investigated the relationship between the average CL diameter assessed by TUS (n = 100) at 23.8 ± 2.4 d of pregnancy and average piglet birth weight (BW) and observed an increase of 37.6 ± 17.8 g in piglet BW per mm increase in average CL diameter measured by TUS (P = 0.04). This relationship is probably because larger CL develop from bigger follicles at ovulation, which might have ovulated oocytes of higher quality that developed into embryos with higher growth potential and thus higher birth weight.