A serological investigation of caseous lymphadenitis in four flocks of sheep

A double antibody sandwich ELISA developed by ID-DLO, Lelystad to detect Corynebocterium pseudotuberculosis infection was used on 329 sheep from four pedigree Suffolk flocks in which clinical cases of caseous lymphadenitis (CLA) had occurred. At subsequent necropsy, typical CLA lesions were seen in 133 sheep, and the diagnosis was confirmed on culture. Lesions were most commonly seen in lungs (n = 46), parotid lymph nodes (n = 44), prescapular lymph nodes (n = 38) and mediastinal lymph nodes (n = 31). The sensitivity of the ELISA test for detecting culture-positive sheep was 0.88, while the specificity of the test was 0.55. The antibody ELISA detected 87.5 per cent of sheep that had CLA lesions restricted to internal organs only. It was concluded that the ELISA test has a valuable role in detecting sheep with both clinical and subclinical CLA

The Anisakis Transcriptome Provides a Resource for Fundamental and Applied Studies on Allergy-Causing Parasites.

BACKGROUND: Food-borne nematodes of the genus Anisakis are responsible for a wide range of illnesses (= anisakiasis), from self-limiting gastrointestinal forms to severe systemic allergic reactions, which are often misdiagnosed and under-reported. In order to enhance and refine current diagnostic tools for anisakiasis, knowledge of the whole spectrum of parasite molecules transcribed and expressed by this parasite, including those acting as potential allergens, is necessary. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we employ high-throughput (Illumina) sequencing and bioinformatics to characterise the transcriptomes of two Anisakis species, A. simplex and A. pegreffii, and utilize this resource to compile lists of potential allergens from these parasites. A total of ~65,000,000 reads were generated from cDNA libraries for each species, and assembled into ~34,000 transcripts (= Unigenes); ~18,000 peptides were predicted from each cDNA library and classified based on homology searches, protein motifs and gene ontology and biological pathway mapping. Using comparative analyses with sequence data available in public databases, 36 (A. simplex) and 29 (A. pegreffii) putative allergens were identified, including sequences encoding 'novel' Anisakis allergenic proteins (i.e. cyclophilins and ABA-1 domain containing proteins). CONCLUSIONS/SIGNIFICANCE: This study represents a first step towards providing the research community with a curated dataset to use as a molecular resource for future investigations of the biology of Anisakis, including molecules putatively acting as allergens, using functional genomics, proteomics and immunological tools. Ultimately, an improved knowledge of the biological functions of these molecules in the parasite, as well as of their immunogenic properties, will assist the development of comprehensive, reliable and robust diagnostic tools.This work was supported by a ‘Collaborations Across Boundaries’ grant and a seed grant from the Centre of Biodiscovery and Molecular Development of Therapeutics, James Cook University (FJB and CC). ALL is an Australian Research Council (ARC) Future Fellow and his laboratory is supported by grants from the National Health and Medical Research Council of Australia (NHMRC). Research in the CC laboratory is supported by grants from the Isaac Newton Trust/Wellcome Trust/University of Cambridge (grant number PNVM/GAAB) and the Royal Society (grant number PNAG/428)

Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X-Ray Absorptiometry–Derived Hip Shape in a Population-Based Cohort of Perimenopausal Women

This publication is the work of the authors and does not necessarily reflect the views of any funders. Supported by the UK Medical Research Council (grant G1001357 for collection of hip shape), and the Wellcome Trust (grants WT092830M for collection of hip shape and WT088806 for genotyping). Core support for the Avon Longitudinal Study of Parents and Children is provided by the UK Medical Research Council, the Wellcome Trust (102215/2/13/2), and the University of Bristol. Dr. Baird's work was supported by Arthritis Research UK (grant 20244). Mr. Faber's work was supported by an Elizabeth Blackwell Institute Clinical Research Primer Scheme.Peer reviewedPostprin

Impact of noncardiac findings in patients undergoing CT coronary angiography:a substudy of the Scottish computed tomography of the heart (SCOT-HEART) trial

Objectives Noncardiac findings are common on coronary computed tomography angiography (CCTA). We assessed the clinical impact of noncardiac findings, and potential changes to surveillance scans with the application of new lung nodule guidelines. Methods This substudy of the SCOT-HEART randomized controlled trial assessed noncardiac findings identified on CCTA. Clinically significant noncardiac findings were those causing symptoms or requiring further investigation, follow-up or treatment. Lung nodule follow-up was undertaken following the 2005 Fleischner guidelines. The potential impact of the 2015 British Thoracic Society (BTS) and the 2017 Fleischner guidelines was assessed. Results CCTA was performed in 1,778 patients and noncardiac findings were identified in 677 (38%). In 173 patients (10%) the abnormal findings were clinically significant and in 55 patients (3%) the findings were the cause of symptoms. Follow-up imaging was recommended in 136 patients (7.6%) and additional clinic consultations were organized in 46 patients (2.6%). Malignancy was diagnosed in 7 patients (0.4%). Application of the new lung nodule guidelines would have reduced the number of patients undergoing a follow-up CT scan: 68 fewer with the 2015 BTS guidelines and 78 fewer with the 2017 Fleischner guidelines; none of these patients subsequently developed malignancy. Conclusions Clinically significant noncardiac findings are identified in 10% of patients undergoing CCTA. Application of new lung nodule guidelines will reduce the cost of surveillance, without the risk of missing malignancy

The catalytic subunit of the system L1 amino acid transporter (S<i>lc7a5</i>) facilitates nutrient signalling in mouse skeletal muscle

The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass

Hyperpolarized 13C-MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer

Purpose: To compare hyperpolarized carbon-13 (13C)-MRI with dynamic contrast-enhanced MRI (DCE-MRI) for detecting early treatment response in breast cancer. Materials and Methods: In this institutional review board-approved prospective study, one woman with triple-negative breast cancer (age 49) underwent 13C-MRI following injection of hyperpolarized [1-13C]pyruvate and DCE-MRI at 3 T at baseline and after a single cycle of neoadjuvant therapy. The 13C-lactate/13C-pyruvate ratio derived from hyperpolarized 13C-MRI and the pharmacokinetic parameters Ktrans and kep derived from DCE-MRI were compared, before and after treatment. Results: Exchange of the 13C-label between injected hyperpolarized [1-13C]pyruvate and the endogenous lactate pool was demonstrated, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the 13C-lactate/13C-pyruvate ratio was shown to correctly identify the patient as a responder to therapy, which was subsequently confirmed by a complete pathologic response. However, DCE-MRI showed an increase in the pharmacokinetic parameters Ktrans (132%) and kep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion: Hyperpolarized 13C-MRI successfully identified response in breast cancer after a single cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.This work was supported by a Wellcome Trust Strategic Award, Cancer Research UK (CRUK; Grants C8742/A18097, C19212/ A16628, C19212/A911376, and C197/A16465), the Austrian Science Fund (Grant J4025-B26), the CRUK Cambridge Centre, the CRUK & Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and Manchester, the Mark Foundation for Cancer Research and Cancer Research UK Cambridge Centre (Grant C9685/A25177), CRUK National Cancer Imaging Translational Accelerator Award, Addenbrooke’s Charitable Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, and Cambridge University Hospitals National Health Service Foundation Trust

Does routine child health surveillance contribute to the early detection of children with pervasive developmental disorders? – An epidemiological study in Kent, U.K.

BACKGROUND: Recently changed guidelines for child health surveillance in the United Kingdom (U.K.) suggest targeted checks only, instead of the previously conducted routine or universal screening at 2 years and 3.5 years. There are concerns that these changes could lead to a delay in the detection of children with autism and other pervasive developmental disorders (PDD). Recent U.K. studies have suggested that the prevalence of PDD is much higher than previously estimated. This study establishes to which extent the routine checks contributed to the early detection and assessment of cases of PDD. Simultaneously we have evaluated the process involved and estimate the prevalence of PDD in our district. METHODS: Retrospective study design utilising community medical files. Headteachers of schools (n = 75) within Maidstone district (Kent) were asked to report all children with an established diagnosis of autism or PDD attending year 4 (born '91 and '92 / n = 2536) in October 2000 based on educational records. RESULTS: 59 schools (78.7%) took part in the study. A total of 33 children were reported. 21 fulfilled the inclusion criteria (12 falsely reported). The prevalences were (per 10,000): PDD 82.8 (male to female ratio 6:1), childhood autism 23.7, Asperger's syndrome 11.8 and autistic spectrum disorder 47.3. Co-existing medical conditions were noted in 14.3%; 52.4% were attending mainstream schools. In 63.2% of cases concerns – mainly in the area of speech and language development (SLD) – had been documented at the 2 year check. At the 3.5 year check concerns were noted in 94.1% – the main area was again SLD (76.5%), although behavioural abnormalities were becoming more frequent (47.1%). A total of 13 children (68.4%) were referred for further assessment as a direct result of the checks. CONCLUSIONS: The prevalences for different types of PDD were similar to figures published recently, but much higher than reported a few years ago. Analysis of our data suggests that routine surveillance is a valuable contributing factor for the early detection of PDD and thereby facilitates early intervention. Thus, if routine surveillance ceases, then an alternative method of early detection should be put in place

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia

Identification of novel loci associated with hip shape:a meta-analysis of genome-wide association studies

This study was funded by Arthritis Research UK project grant 20244, which also provided salary funding for DB and CVG. LP works in the MRC Integrative Epidemiology Unit, a UK MRC‐funded unit (MC_ UU_ 12013/4 & MC_UU_12013/5). ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. ALSPAC data collection was supported by the Wellcome Trust (grants WT092830M; WT088806; WT102215/2/13/2), UK Medical Research Council (G1001357), and University of Bristol. The UK Medical Research Council and the Wellcome Trust (102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Framingham Heart Study: The Framingham Osteoporosis Study is supported by grants from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute on Aging (R01 AR41398, R01 AR 061162, R01 AR050066, and R01 AR061445). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01‐HC‐25195) and its contract with Affymetrix, Inc., for genotyping services (N02‐HL‐6‐4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. DK was also supported by Israel Science Foundation grant #1283/14. TDC and DR thank Dr Claire Reardon and the entire Harvard University Bauer Core facility for assistance with ATAC‐seq next generation sequencing. This work was funded in part by the Harvard University Milton Fund, NSF (BCS‐1518596), and NIH NIAMS (1R01AR070139‐01A1) to TDC. MrOS: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under the grant number R01 AR051124. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2 AR058973. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. TwinsUK: The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007‐2013). The study also receives support from the National Institute for Health Research (NIHR)‐funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. This study was also supported by the Australian National Health and Medical Research Council (project grants 1048216 and 1127156), the Sir Charles Gairdner Hospital RAC (SGW), and the iVEC/Pawsey Supercomputing Centre (project grants Pawsey0162 and Director2025 [SGW]). The salary of BHM was supported by a Raine Medical Research Foundation Priming Grant. The Umeå Fracture and Osteoporosis Study (UFO) is supported by the Swedish Research Council (K20006‐72X‐20155013), the Swedish Sports Research Council (87/06), the Swedish Society of Medicine, the Kempe‐Foundation (JCK‐1021), and by grants from the Medical Faculty of Umeå Unviersity (ALFVLL:968:22‐2005, ALFVL:‐937‐2006, ALFVLL:223:11‐2007, and ALFVLL:78151‐2009) and from the county council of Västerbotten (Spjutspetsanslag VLL:159:33‐2007). This publication is the work of the authors and does not necessarily reflect the views of any funders. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper. DB will serve as the guarantor of the paper. Authors’ roles: Study conception and design: DAB, JSG, RMA, LP, DK, and JHT. Data collection: DJ, DPK, ESO, SRC, NEL, BHM, FMKW, JBR, SGW, TDC, BGF, DAL, CO, and UP‐L. Data analysis: DAB, DSE, FKK, JSG, FRS, CVG, RJB, RMA, SGW, EG, TDC, DR, and TB. Data interpretation: JSG, RMA, TDC, DR, DME, LP, DK, and JHT. Drafting manuscript: DAB and JHT. Revising manuscript content: JHT. All authors approved the final version of manuscript. DAB takes responsibility for the integrity of the data analysis.Peer reviewedPublisher PD

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy