Role of the major histocompatibility complex in immune responsiveness in a Holstein Charolais cattle cross population

Infectious disease is a major issue facing the livestock industry. Further understanding of the role of genetic factors in the observed phenotypic variability of the immune response to pathogens and vaccination could assist in designing improved preventative measures such as more efficacious vaccines and targeted breeding strategies to select for disease resistance. Major candidate genes for controlling immune responsiveness are located within the major histocompatibility complex (MHC). The highly polymorphic classical MHC genes are key determinants in the strength and type of immune response. However, it has proved difficult to establish genotyping approaches to define functionally relevant allelic variations for outbred species such as cattle, not least because the peptide binding clefts (PBC) of classical MHC molecules are highly polymorphic, and the genes within the MHC complex are closely linked. The overall aim of this project was to investigate the role of MHC genes in immune responsiveness in approximately 200 F2 and backcross Holstein-Charolais cattle. These animals were generated as part of the Roslin Bovine Genome (RoBoGen) herd, established through a quantitative trait loci (QTL) project, in which a number of phenotypic traits including immune traits were measured. The immune traits included responses to a Foot-and-mouth disease virus (FMDV) peptide, and vaccines against bovine respiratory syncytial virus (BRSV), para-influenza virus 3 (PIV-3) and bovine herpes virus-1 (BHV-1), as well as T cell response to Staphylococcus aureus. The immune phenotypes measured included IgG and interferon- (IFN- ) levels and T cell proliferation. The cattle MHC region, known as bovine leukocyte antigens (BoLA), resides on bovine chromosome 23. The BoLA region contains approximately 200 genes most of which are immune-related. Class II gene polymorphisms were considered to be the most likely to influence the immune traits measured, and the project primarily focused on the best defined gene, BoLA-DRB3. A sequence-based typing technique was successfully improved to facilitate genotyping of the PBC of BoLA-DRB3 in all generations of the RoBoGen herd (approximately 400 animals) and identified 24 distinct alleles. The sequence information obtained also enabled further analysis of the role of defined ‘pockets’ within the PBC, which directly determine peptide binding affinity. All datasets were statistically analysed using a residual maximum likelihood (REML) model and it was shown that several of the DRB3 alleles within the RoBoGen herd had highly significant (p<0.05) associations with the immune response to the FMDV peptide. In addition DRB3 alleles were identified which had significant associations with the response to the respiratory pathogen vaccinations and exposure to S. aureus. The pocket analysis also enabled the identification of several amino acid positions within the PBC which were significantly associated with the immune response traits. In order to explore whether DQ Class II gene polymorphisms also played a role in the variability of responses and whether BoLA Class I-Class II haplotypes could be discerned, microarrays which utilized allele specific oligonucleotides for BoLA Class I and Class II DQ genes were employed. In addition, to investigate whether the number of DQ gene pairs per chromosome influenced the responses, a quantitative polymerase chain reaction (qPCR) assay to determine DQA gene dosage was developed. However, due to the extremely complex nature of the BoLA region both, techniques would require improving to be used for large-scale studies. Nonetheless, information about haplotypes was determined from the microarray results and the qPCR technique lays the foundations for future development to investigate DQ gene dosage. The MHC region in cattle is very complex due the high level of polymorphisms and gene duplications. It is likely that many genes play a role in the immune response to both pathogens and vaccines. However, from the evidence presented here, polymorphisms in the PBC of BoLA-DRB3, particularly within the pockets, are significantly associated with variation in immune response to many different antigens and this information could be exploited in the design of vaccines or breeding cattle for improved disease resistance

Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol.

BACKGROUND: Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. METHODS/DESIGN: The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. DISCUSSION: Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01120028 and ISRCTN88894088.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Post-Heroic Leadership, Tempered Radicalism and Senior Leaders as Change Agents for Gender Equality

Micro change agents for gender equality in organisations are often considered to be tempered radicals who work within an existing structure to change the status quo. However for gender equality to happen, it is often claimed that heroic leadership of top leaders, or macro change agents, is required. The aim of this article is to show how CEOs as macro change agents for gender equality can be conceptualised. Drawing on interviews with 20 global CEOs and a literature review, the article develops a framework to conceptualise how CEOs are fostering gender equality around accountability, building ownership, communicating, leading by example, initiating and driving culture change. The article questions the conceptualisation of change agents of gender equality as either tempered radicals, for micro change agents, or heroic leaders, for macro change agents, and argues instead that to be macro change agents for gender equality, CEOs need to display post‐heroic leadership and tempered radicalism to foster change in regard to gender relations

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms

Exercise and bone health across the lifespan

With ageing, bone tissue undergoes significant compositional, architectural and metabolic alterations potentially leading to osteoporosis. Osteoporosis is the most prevalent bone disorder, which is characterised by progressive bone weakening and an increased risk of fragility fractures. Although this metabolic disease is conventionally associated with ageing and menopause, the predisposing factors are thought to be established during childhood and adolescence. In light of this, exercise interventions implemented during maturation are likely to be highly beneficial as part of a long-term strategy to maximise peak bone mass and hence delay the onset of age- or menopause-related osteoporosis. This notion is supported by data on exercise interventions implemented during childhood and adolescence, which confirmed that weight-bearing activity, particularly if undertaken during peripubertal development, is capable of generating a significant osteogenic response leading to bone anabolism. Recent work on human ageing and epigenetics suggests that undertaking exercise after the fourth decade of life is still important, given the anti-ageing effect and health benefits provided, potentially occurring via a delay in telomere shortening and modification of DNA methylation patterns associated with ageing. Exercise is among the primary modifiable factors capable of influencing bone health by preserving bone mass and strength, preventing the death of bone cells and anti-ageing action provided

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

A multi-center prospective study of plant-based nutritional support in adult community-based patients at risk of disease-related malnutrition

IntroductionThere is an emerging need for plant-based, vegan options for patients requiring nutritional support.MethodsTwenty-four adults at risk of malnutrition (age: 59 years (SD 18); Sex: 18 female, 6 male; BMI: 19.0 kg/m2 (SD 3.3); multiple diagnoses) requiring plant-based nutritional support participated in a multi-center, prospective study of a (vegan suitable) multi-nutrient, ready-to-drink, oral nutritional supplement (ONS) [1.5 kcal/mL; 300 kcal, 12 g protein/200 mL bottle, mean prescription 275 mL/day (SD 115)] alongside dietary advice for 28 days. Compliance, anthropometry, malnutrition risk, dietary intake, appetite, acceptability, gastrointestinal (GI) tolerance, nutritional goal(s), and safety were assessed.ResultsPatients required a plant-based ONS due to personal preference/variety (33%), religious/cultural reasons (28%), veganism/reduce animal-derived consumption (17%), environmental/sustainability reasons (17%), and health reasons (5%). Compliance was 94% (SD 16). High risk of malnutrition (‘MUST’ score ≥ 2) reduced from 20 to 16 patients (p = 0.046). Body weight (+0.6 kg (SD 1.2), p = 0.02), BMI (+0.2 kg/m2 (SD 0.5), p = 0.03), total mean energy (+387 kcal/day (SD 416), p &lt; 0.0001) and protein intake (+14 g/day (SD 39), p = 0.03), and the number of micronutrients meeting the UK reference nutrient intake (RNI) (7 vs. 14, p = 0.008) significantly increased. Appetite (Simplified Nutritional Appetite Questionnaire (SNAQ) score; p = 0.13) was maintained. Most GI symptoms were stable throughout the study (p &gt; 0.06) with no serious adverse events related.DiscussionThis study highlights that plant-based nutrition support using a vegan-suitable plant-based ONS is highly complied with, improving the nutritional outcomes of patients at risk of malnutrition

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication