A validation study of loci associated with mastitis resistance in two French dairy sheep breeds

The identification of loci associated with resistance to mastitis or of the causative mutations may be helpful in breeding programs for dairy sheep as it is for cattle worldwide. Seven genomic regions that control milk somatic cell counts, an indirect indicator of udder infection, have already been identified in sheep (Spanish Churra, French Lacaune and Italian Sardinian-Lacaune backcross populations). In this study, we used a 960 custom-designed ovine single nucleotide polymorphism (SNP) chip in Lacaune and Manech Tete Rousse dairy sheep to validate these seven genomic regions associated with mastitis. The most significant SNP (rs868996547) on Ovis aries chromosome (OAR) 3 was a previously described mutation in the suppressor of cytokine signalling 2 (SOCS2) gene. An antagonist effect of this causal candidate between health and growth in Lacaune sheep was confirmed. Effects of the mutation on the infectious status of the udder, i.e. increases in milk somatic cell counts and bacteria shedding, were also identified. This SNP was not present in the data available on Manech Tete Rousse. Three other regions associated with mastitis were also confirmed on OAR16 (Manech Tete Rousse), 19 (Lacaune) and 2 (both breeds). For the OAR2 region, we validated previously detected SNPs in several other breeds (Sarda, Churra, and Chios). For significant SNPs in the four mastitis regions, the effect varied from 0.24 to 0.67 phenotypic standard deviation of the traits. Two of the mastitis quantitative trait loci (QTL) regions (OAR2 and 16) that we validated here were also associated in opposite ways with milk production traits in both populations. These results indicate, at least in part, a genomic basis for the trade-off between milk production and mastitis resistance. Four of the seven mastitis QTL regions that were previously identified in independent populations, were confirmed in this study, which demonstrates partial sharing of mastitis-related genetic mechanisms between different distant dairy sheep populations

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

"Forget to whom you have told this proverb": directed forgetting of destination memory in Alzheimer's disease

Destination memory is the ability to remember the receiver of transmitted information. By means of a destination memory directed forgetting task, we investigated whether participants with Alzheimer's Disease (AD) were able to suppress irrelevant information in destination memory. Twenty-six AD participants and 30 healthy elderly subjects were asked to tell 10 different proverbs to 10 different celebrities (List 1). Afterwards, half of the participants were instructed to forget the destinations (i.e., the celebrities) whereas the other half were asked to keep them in mind. After telling 10 other proverbs to 10 other celebrities (List 2), participants were asked to read numbers aloud. Subsequently, all the participants were asked to remember the destinations of List 1 and List 2, regardless of the forget or remember instructions. The results show similar destination memory in AD participants who were asked to forget the destinations of List 1 and those who were asked to retain them. These findings are attributed to inhibitory deficits, by which AD participants have difficulties to suppress irrelevant information in destination memory

Prevalence and Impact of Malnutrition in Patients Surgically Treated for Chronic Mesenteric Ischemia

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Fine mapping of 7 QTL regions in dairy sheep confirms pleiotropic effect of the R96C mutation in the Socs2 gene on SCC, bacterial infection, size and milk production

The aim of this study was to investigate the pleiotropic effects of a Socs2 gene point mutation associated to lower resistance to mastitis, an inflammation of the mammary gland, mostly due to bacterial infection by Staphylococci in dairy sheep. GWAS were performed on SCC (Somatic Cell Count), bacterial infection, animal size and milk production using a 960 custom-designed ovine SNP chip and a data set of 504 Lacaune dairy ewes. The resultsconfirmed the strong effect of this mutation on the inflammatory response (p-value of LSCS_L1 = 3.03e-07 and p-value of abscess = 2.83e-03), a slighter effect on animal size (pvalue of W_ DAY_250 = 3.71e-04) and also showed for the first time an effect of this mutation on intramammary infections (p-value of STAPH_L1 = 6.80e-04). In contrast, no effect on milk production could be confirmed (p-value of MILK_L1 = 2.01e-01), suggesting an indirect role of SOCS-2 protein on milk production. Then pleiotropy tests (CLIP test) proved pleiotropic effects of the mutation on SCC, bacterial infection, size and more indirectly on milk production

Defining Success in the Commons: Addressing Problem Orientations, Multidimensionality, Norms, and Tradeoffs

Commons and social-ecological systems research examines institutional arrangements for governing natural resources to improve social and ecological outcomes. However, no universal definition of success exists. We examine the CPR and SES synthesis literature to identify trends, gaps and challenges for examining success. We address: (1) gaps in the literature, (2) multidimensionality and tradeoffs, and (3) and the link between problem orientation and definitions of success. To do this we conduct a comprehensive review of Large-N studies, meta-analyses and systematic reviews of CPR and SES governance (n = 45). We found seven dimensions of success, corresponding to collective choice, constitutional and operational levels, temporal dimensions, and socio-economic outcomes. Most studies did not address power and tradeoffs, or specify the social groups to whom success would apply. The majority of studies defined success in one dimension, most often demand-side provisioning (e.g., productivity or biodiversity). A regression analysis suggests that studies on rangelands or grasslands, correlative studies, and/or studies of state property systems (i.e., protected areas) were more likely to use fewer dimensions of success. Problem orientations often did not correlate with dimensions of success considered in a study, suggesting that measures of success often cannot adequately address the full suite of problems recognized in synthesis research. This presents a significant challenge for collective action among scholars who aim to develop general knowledge on SES and CPR governance. We discuss exemplary studies that measure success as multidimensional, address power and tradeoffs, and conclude with four recommendations for advancing the analysis of success

A Nonsense Variant in CCDC65 Gene Causes Respiratory Failure Associated with Increased Lamb Mortality in French Lacaune Dairy Sheep

We recently demonstrated that the Lacaune deficient homozygous haplotype 6 (LDHH6) potentially hosts a recessive perinatal lethal mutation in Lacaune dairy sheep mapped on OAR3. In the present study, we have analyzed the whole-genome sequences of two Lacaune ram heterozygous carriers of LDHH6. After variant calling and filtering against the variants of 86 non-carrier rams, we have identified a single nucleotide variant (SNV) in the two LDHH6 carriers whose variant allele induced a premature stop codon (p.Glu111*) in the Coiled-Coil Domain Containing 65 (CCDC65) gene. CCDC65 is involved in the assembly of the nexin-dynein regulatory complex for the formation of microtubules in ciliated cells. In order to identify the phenotype in homozygous sheep, we generated at-risk matings (n = 17) between rams and ewes heterozygous for the candidate variant in CCDC65. A total of 16 lambs were born alive with five genotyped as homozygous carriers. The homozygous lambs suffered from respiratory problems, and four of them died within the first month of life. At necropsy, we observed a broad hepatization of lung lobes possibly induced by infectious pneumonia. The management of this lethal recessive allele (frequency of 0.06) through reasoned mating in the Lacaune sheep selection schemes could reduce lamb mortality by 2%

Genetic parameters for milk flow and relationships with bacterial infection, SCC and production traits in Lacaune dairy sheep

Improving milking ability is a major issue for consideration in dairy species. Milk flow is not yet recorded in dairy sheep flocks and so far recorded only in the INRA experimental sheep flock of La Fage. The objective of our study was thus to estimate heritability estimates for milk flow traits and genetic correlations with milk production and with udder health traits in dairy Lacaune sheep. Genetic parameters were estimated by multivariate REML with an animal model on first - lactation field data of 377,945 Lacaune ewes for milk production and somatic cell count traits, on additional experimental data of 1,641 ewes for milk flow and 518 ewes for intra-mammary bacterial infection. Heritability estimates were high for annual milk flow traits (ranging from 0.36 to 0.64) and moderate for subclinical intra-mammary infections (0.18). A low to moderate (from -0.13 to +0.53) genetic correlations were found between milk yield and milk flow traits and indicated that the current selection in Lacaune sheep based on yield is associated to an increase of both parameters, milk flow and milking time. Lactation somatic cell score was positively correlated with subclinical intra-mammary infections (+0.72) and unfavourably associated with milk yield (+0.12). These results reinforce the interest of including LSCS in the breeding objectives of dairy sheep in order to balance the negative effect of selecting for increased production on udder health. The genetic correlation of intra-mammary infections with latency time was unfavourable and moderate (-0.33). The hypothesis was that ewes with high milk flow rate may have a lower sphincter tone facilitating pathogen entry