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1.  Bovine congenital erythropoietic protoporphyria in a crossbred limousin heifer in Ireland 
Irish Veterinary Journal  2015;68(1):15.
An unusual case of an 11-month-old, black Limousin-cross heifer, with an 8-month history of episodic seizures and photosensitisation, was referred by a veterinary practitioner to the Farm Animal Section of the UCD Veterinary Hospital, School of Veterinary Medicine, University College Dublin, Ireland, in August 2014. Following an investigation, a diagnosis of Bovine Congenital Erythropoietic Protoporphyria (BCEPP) was made. To the authors’ knowledge this is the first report of such a case in Ireland. BCEPP should be considered as a differential diagnosis in young animals displaying periodic seizures and/or photosensitisation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13620-015-0044-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13620-015-0044-3
PMCID: PMC4489402  PMID: 26140209
Protoporphyria; Photosensitisation; Seizures; Convulsions; Cattle
2.  The effect of Lameness before and during the breeding season on fertility in 10 pasture-based Irish dairy herds 
Irish Veterinary Journal  2015;68(1):14.
Background
The effects of lameness on fertility have been documented frequently but few data are available from seasonally breeding, pasture-based herds (such as those used in Ireland) where cows are housed during the winter months but managed at pasture for the remainder of the year. This study determined the prevalence of lameness in a group of 786 cows in 10 pasture-based Irish dairy herds before, during and after the breeding season and assessed the relationship between lameness and the reproductive performance in these herds through serial locomotion scoring during the grazing period.
Results
Lameness prevalences of 11.6 % before, 14.6 % during and 11.6 % after the breeding season were found and these compared favourably to results from housed cattle and are similar to other studies carried out in grazing herds. A Cox proportional hazards model with locomotion score as time varying covariate was used. After controlling for the effect of farm, month of calving, body condition score at calving, body condition score loss after calving and economic breeding index, cows identified as lame during the study were less likely to become pregnant. Cows lame before the earliest serve date but no longer lame during the breeding season, cows becoming lame after the earliest serve date and cows identified lame both before and after this date were respectively 12 %, 35 % and 38 % less likely to become pregnant compared to cows never observed lame during the study. However, these findings were only significant for cows becoming lame after the earliest serve date and cows lame both before and after the start of breeding.
Conclusions
This study found that the reproductive efficiency was significantly (p < 0.05) lower in cows becoming lame during the breeding season and cows lame before and during the breeding season compared to non-lame cows. Cows no longer lame during the breeding season had a lower Submission Rate to first serve within 3 weeks of earliest serve date. However, the Pregnancy Rate was not significantly (p > 0.05) lower in these animals compared to cows never diagnosed as lame. In addition to lameness status, nutritional status and genetics were found to influence the reproductive performance in pasture-based Irish dairy herds.
doi:10.1186/s13620-015-0043-4
PMCID: PMC4476086  PMID: 26101586
Lameness; Dairy; Cows; Pasture; Fertility; Locomotion score; Breeding season; Pregnancy rate
3.  Nematode control in suckler beef cattle over their first two grazing seasons using a targeted selective treatment approach 
Irish Veterinary Journal  2015;68(1):13.
Background
With concerns over the development of anthelmintic resistance in cattle nematode populations, we must re-examine our approach to nematode control in cattle. Targeted selective treatments (TST), whereby individual animals are treated instead of entire groups, are being investigated as an alternative. The study objective was to determine if anthelmintic usage could be reduced using a TST-based approach to nematode control in spring-born suckler beef cattle over their first and second grazing seasons (SGS) without affecting performance. In the first grazing season (FGS), 99 calves with an initial mean (s.d.) calf age and live weight on day 0 (June 28th 2012) of 107 (23.1) days and 160 (32.5) kg, respectively, were used. The study commenced on day 0 when calves were randomised and allocated to one of two treatments; 1), standard treatment (control) and 2), TST. Control calves were treated subcutaneously with ivermectin on days 0, 41 and 82 in the FGS. All calves were treated with ivermectin on day 124 and housed on day 133. In the SGS, only heifer calves from the FGS were used and control heifers were treated with ivermectin on day 393. Animals were weighed, blood and faecal sampled every three weeks. The TST animals were treated with ivermectin if thresholds based on a combination of plasma pepsinogen concentrations, faecal egg count and/or the presence of Dictyocaulus viviparus larvae in faeces (FGS only) were reached.
Results
No TST calves reached the treatment threshold criteria in the FGS. The FGS average daily live weight gain (ADG ± s.e.m.) for control and TST group calves was 0.89 ± 0.02 kg and 0.94 ± 0.02 kg day−1, respectively (P = 0.17). In the SGS, all heifers were treated with ivermectin on day 431 due to clinical signs of respiratory disease. The ADG for control and TST heifers from turnout on day 321 to day 431 was 0.90 ± 0.04 and 0.80 ± 0.04 kg day−1, respectively (P = 0.03).
Conclusions
Spring-born FGS suckler beef calves require minimal anthelmintic treatment to maintain performance. In contrast, clinical parasitic disease may develop in the SGS unless appropriate anthelmintic treatment is provided.
doi:10.1186/s13620-015-0038-1
PMCID: PMC4511250  PMID: 26203352
Anthelmintics; Gastrointestinal nematodes; Lungworm; Suckler beef cattle; Targeted selective treatments
4.  False Discovery Rates in PET and CT Studies with Texture Features: A Systematic Review 
PLoS ONE  2015;10(5):e0124165.
Purpose
A number of recent publications have proposed that a family of image-derived indices, called texture features, can predict clinical outcome in patients with cancer. However, the investigation of multiple indices on a single data set can lead to significant inflation of type-I errors. We report a systematic review of the type-I error inflation in such studies and review the evidence regarding associations between patient outcome and texture features derived from positron emission tomography (PET) or computed tomography (CT) images.
Methods
For study identification PubMed and Scopus were searched (1/2000–9/2013) using combinations of the keywords texture, prognostic, predictive and cancer. Studies were divided into three categories according to the sources of the type-I error inflation and the use or not of an independent validation dataset. For each study, the true type-I error probability and the adjusted level of significance were estimated using the optimum cut-off approach correction, and the Benjamini-Hochberg method. To demonstrate explicitly the variable selection bias in these studies, we re-analyzed data from one of the published studies, but using 100 random variables substituted for the original image-derived indices. The significance of the random variables as potential predictors of outcome was examined using the analysis methods used in the identified studies.
Results
Fifteen studies were identified. After applying appropriate statistical corrections, an average type-I error probability of 76% (range: 34–99%) was estimated with the majority of published results not reaching statistical significance. Only 3/15 studies used a validation dataset. For the 100 random variables examined, 10% proved to be significant predictors of survival when subjected to ROC and multiple hypothesis testing analysis.
Conclusions
We found insufficient evidence to support a relationship between PET or CT texture features and patient survival. Further fit for purpose validation of these image-derived biomarkers should be supported by appropriate biological and statistical evidence before their association with patient outcome is investigated in prospective studies.
doi:10.1371/journal.pone.0124165
PMCID: PMC4418696  PMID: 25938522
5.  PATTERNS OF OPIOID UTILIZATION IN PREGNANCY IN A LARGE COHORT OF COMMERCIAL INSURANCE BENEFICIARIES IN THE UNITED STATES 
Anesthesiology  2014;120(5):1216-1224.
Background
There are few data regarding the utilization of opioids during pregnancy. The objective of this study was to define the prevalence and patterns of opioid use in a large cohort of pregnant women who were commercial insurance beneficiaries.
Methods
Data for the study were derived from a de-identified research database of women from across the United States who had both medical and prescription benefits. Using diagnostic codes we defined a cohort of 534,500 women with completed pregnancies who were enrolled in a commercial insurance plan from 6 months prior to pregnancy through delivery.
Results
Overall, 76,742 (14.4%) women were dispensed an opioid at some point during pregnancy. There were 30,566 (5.7%) women dispensed an opioid during the first trimester, 30,434 (5.7%) women during the second trimester, and 34,906 (6.5%) women during the third trimester. Of these, 11,747 (2.2%) women were dispensed opioids 3 or more times during pregnancy. The most commonly dispensed opioids during pregnancy were hydrocodone (6.8%), codeine (6.1%), and oxycodone (2.0%). The prevalence of exposure at anytime during pregnancy decreased slightly during the study period from 14.9% for pregnancies that delivered in 2005 to 12.9% in 2011. The prevalence of exposure varied significantly by region, and was lowest in the Northeast and highest in the South.
Conclusions
This study demonstrated that opioids are very common exposures during pregnancy. Given the small and inconsistent body of literature on their safety in pregnancy, these findings suggest a need for research in this area.
doi:10.1097/ALN.0000000000000172
PMCID: PMC3999216  PMID: 24525628
6.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
doi:10.1002/art.24524
PMCID: PMC4412885  PMID: 19479880
7.  Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study 
Annals of the Rheumatic Diseases  2014;74(4):661-667.
Objectives
To describe trends in the epidemiology of gout and patterns of urate-lowering treatment (ULT) in the UK general population from 1997 to 2012.
Methods
We used the Clinical Practice Research Datalink to estimate the prevalence and incidence of gout for each calendar year from 1997 to 2012. We also investigated the pattern of gout management for both prevalent and incident gout patients.
Results
In 2012, the prevalence of gout was 2.49% (95% CI 2.48% to 2.51%) and the incidence was 1.77 (95% CI 1.73 to 1.81) per 1000 person-years. Prevalence and incidence both were significantly higher in 2012 than in 1997, with a 63.9% increase in prevalence and 29.6% increase in incidence over this period. Regions with highest prevalence and incidence were the North East and Wales. Among prevalent gout patients in 2012, only 48.48% (95% CI 48.08% to 48.89%) were being consulted specifically for gout or treated with ULT and of these 37.63% (95% CI 37.28% to 38.99%) received ULT. In addition, only 18.6% (95% CI 17.6% to 19.6%) of incident gout patients received ULT within 6 months and 27.3% (95% CI 26.1% to 28.5%) within 12 months of diagnosis. The management of prevalent and incident gout patients remained essentially the same during the study period, although the percentage of adherent patients improved from 28.28% (95% CI 27.33% to 29.26%) in 1997 to 39.66% (95% CI 39.11% to 40.22%) in 2012.
Conclusions
In recent years, both the prevalence and incidence of gout have increased significantly in the UK. Suboptimal use of ULT has not changed between 1997 and 2012. Patient adherence has improved during the study period, but it remains poor.
doi:10.1136/annrheumdis-2013-204463
PMCID: PMC4392307  PMID: 24431399
8.  Prevalence, risk factors and associations of primary Raynaud's phenomenon: systematic review and meta-analysis of observational studies 
BMJ Open  2015;5(3):e006389.
Objective
To systematically review the literature with regard to the prevalence, incidence, risk factors and associations of primary Raynaud's phenomenon (PRP).
Method
A systematic review of the literature of observational studies for PRP was undertaken using five electronic databases. Any studies reporting prevalence, incidence and risk factors of PRP were collected. Relative risk or OR and 95% CI were extracted or calculated to present the association between risk factors and PRP. Random effects model was used to pool the results.
Results
33 articles assessing a total of 33 733 participants were included in this analysis (2 cohort, 17 cross-sectional and 14 case–control studies). The pooled prevalence of PRP was 4.85% (95% CI 2.08% to 8.71%) in the general population. The pooled annual incidence of PRP was 0.25% (95% CI 0.19% to 0.32%). Risk factors and associations for PRP included female gender (OR=1.65, 95% CI 1.42 to 1.91), family history (OR=16.6, 95% CI 7.44 to 36.8), smoking (OR=1.27, 95% CI 1.06 to 1.53), manual occupation (OR=2.66 95% CI 1.73 to 4.08), migraine (OR=4.02, 95% CI 2.62 to 6.17), cardiovascular disease (OR=1.69, 95% CI 1.22 to 2.34) and marital status (married, OR=0.60, 95% CI 0.43 to 0.83). The definition of PRP varied considerably between studies.
Conclusions
This is the first systematic review of the prevalence, incidence, risk factors and associations of PRP. Further study using uniform strict criteria for the condition is required to confirm these findings, particularly the possible association with cardiovascular disease.
doi:10.1136/bmjopen-2014-006389
PMCID: PMC4368987  PMID: 25776043
RHEUMATOLOGY; EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS
9.  Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial 
Trials  2015;16:77.
Background
Osteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain.
Methods/Design
Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.
Discussion
The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.
Trial registration
Current Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).
doi:10.1186/s13063-015-0602-8
PMCID: PMC4351849  PMID: 25872649
Double-blind; Knee osteoarthritis; Methotrexate; Placebo-controlled; Randomized
10.  CXCL13 antibody for the treatment of autoimmune disorders 
BMC Immunology  2015;16(1):6.
Background
Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.
Results
We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).
Conclusions
We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.
doi:10.1186/s12865-015-0068-1
PMCID: PMC4329654  PMID: 25879435
CXCL13; Chemokine; Monoclonal antibody; Collagen-induced arthritis; Experimental autoimmune encephalomyelitis
11.  Beer and wine consumption and risk of knee or hip osteoarthritis: a case control study 
Introduction
The aim of this study was to investigate the association between alcoholic and non-alcoholic beverages and knee or hip osteoarthritis (OA).
Methods
We conducted a case–control study of Caucasian men and women aged 45 to 86 years of age from Nottingham, UK. Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee or hip OA. Exposure information was sought using interview-based questionnaires and a semi-quantitative food frequency questionnaire to assess beverage consumption at ages 21 to 50 years. Odds ratios (ORs), adjusted ORs (aORs), 95% confidence intervals (CI) and P values were estimated using logistic regression models.
Results
A total of 1,001 knee OA, 993 hip OA and 933 control participants were included in the study. Increasing beer consumption was associated with an increasing risk of OA (P for trend ≤0.001). Compared to those who did not consume beer, aORs for people who consumed 20 or more servings of beer were 1.93 (95% CI 1.26 to 2.94) and 2.15 (95% CI 1.45 to 3.19) for knee OA and hip OA, respectively. In contrast, increasing levels of wine consumption were associated with decreased likelihood of knee OA (P for trend <0.001). Compared to those who did not consume wine, aOR for knee OA among those who consumed 4 to 6 glasses of wine per week and ≥7 glasses of wine per week was 0.55 (95% CI 0.34 to 0.87) and 0.48 (95% CI 0.29 to 0.80), respectively. No association was identified between non-alcoholic beverages and knee or hip OA.
Conclusions
Beer consumption appears to be a risk factor for knee and hip OA whereas consumption of wine has a negative association with knee OA. The mechanism behind these findings is speculative but warrants further study.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0534-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0534-4
PMCID: PMC4355424  PMID: 25652201
12.  Epidemiology and management of gout in Taiwan: a nationwide population study 
Introduction
Gout is the most common inflammatory arthritis worldwide and is the only type of chronic arthritis that potentially can be ‘cured’. However, data on gout incidence, prevalence and management, assessed at multiple time points in the same population, are sparse, particularly in Asian populations. The aim of this study was to describe trends in the epidemiology of gout in the general population of Taiwan.
Methods
The National Health Insurance Research Database was used to identify patients with gout and to estimate the prevalence and incidence of gout for each calendar year from 2005 to 2010. The pattern of gout management was also examined.
Results
Of 23,371,362 beneficiaries in 2010, there were 1,458,569 prevalent and 56,595 incident cases of gout, giving a prevalence of 6.24% (95% confidence interval (CI), 6.23% to 6.25%) and an incidence of 2.74 (95% CI, 2.72 to 2.76) per 1,000 person-years. The annual percentage change (APC) of the standardised prevalence was −0.7% (95% CI, −1.7% to 0.3%; P = 0.14), suggesting that the prevalence of gout was essentially the same throughout the study period. However, The APC of incidence was −13.4 (95% CI, −16.1 to −10.6) between 2005 and 2007 and −2.1 (95% CI, −10.4 to 7.1) between 2007 and 2010. Regions with the highest prevalence and incidence were eastern coastal counties and offshore islets, where indigenous people are clustered. Among prevalent gout cases in 2010, only 22.93% (95% CI, 22.87% to 23.00%) were prescribed urate-lowering treatment (ULT), which remained unchanged between 2005 and 2010 at an APC of 0.0 (95% CI, −3.8 to 4.0). Uricosuric agents were more commonly prescribed than xanthine oxidase inhibitors in Taiwan.
Conclusions
In Taiwan, 1 in 16 people have gout. Whereas the incidence has decreased recently, the prevalence remains unchanged. Management of gout in Taiwan is poor, with only one in five affected people being treated with ULT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0522-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0522-8
PMCID: PMC4342824  PMID: 25612613
13.  Disease screening profiles and colostrum management practices on 16 Irish suckler beef farms 
Irish Veterinary Journal  2015;68(1):1.
Background
Calf output is a key element in determining the profitability of a suckler beef enterprise. Infectious agents such as Bovine Virus Diarrhoea (BVD) virus, colostrum management and parasitic challenge can all affect calf output. Prior to the national BVD eradication programme, there was little published information on either the prevalence or effect of BVD in Irish beef herds. There is little published information on colostrum management practices in Irish commercial beef herds and there have also been few studies published on the prevalence of liver fluke or rumen fluke infection in Irish beef herds. Sixteen farms participating in the Teagasc/Farmers Journal BETTER farm beef programme were used in this study. Fourteen herds were screened for the presence of BVD virus in 2010 using RT-PCR. In 13 herds, blood samples were collected from calves (2–14 days of age) in November 2011 - April 2012 to determine their passive immune status using the zinc sulphate turbidity (ZST) test, while in 12 herds, blood and faecal samples were taken in order to determine the level of exposure to gastrointestinal and hepatic helminths.
Results
The overall prevalence of BVD virus-positive cattle was 0.98% (range 0 - 3% per herd, range 0.6 - 3.0% per positive herd). Eighteen of the 82 calves (22%) sampled had ZST values less than 20 units (herd mean range 17.0 – 38.5 units) indicating a failure of passive transfer. The overall animal-level (herd-level) prevalence of liver fluke and rumen fluke infection in these herds was 40.5% (100%) and 20.8% (75%), respectively.
Conclusions
The potential costs associated with the presence of animals persistently infected with BVD virus through the increased use of antibiotics; the rate of failure of passive transfer of colostral immunoglobulins and the high prevalence of liver fluke infection in these herds highlight that some Irish suckler beef farms may not be realizing their economic potential due to a range of herd health issues. The use of farm-specific herd health plans should be further encouraged on Irish suckler beef farms.
doi:10.1186/s13620-014-0029-7
PMCID: PMC4311419  PMID: 25642324
Beef; BVD; Colostrum; Herd health; Liver fluke; Rumen fluke; Suckler
14.  Imaging Inflammation in Asthma: Real Time, Differential Tracking of Human Neutrophil and Eosinophil Migration in Allergen Challenged, Atopic Asthmatics in Vivo 
EBioMedicine  2014;1(2-3):173-180.
Background
It is important to study differential inflammatory cellular migration, particularly of eosinophils and neutrophils, in asthma and how this is influenced by environmental stimuli such as allergen exposure and the effects of anti asthma therapy.
Methods
We isolated blood neutrophils and eosinophils from 12 atopic asthmatic human volunteers (Group 1 — four Early Allergic Responders unchallenged (EAR); Group 2 — four Early and Late Allergic Responders (LAR) challenged; Group 3 — four EAR and LAR challenged and treated with systemic corticosteroids) using cGMP CD16 CliniMACS. Cells were isolated prior to allergen challenge where applicable, labelled with 99mTc-HMPAO and then re-infused intravenously. The kinetics of cellular influx/efflux into the lungs and other organs were imaged via scintigraphy over 4 h, starting at 5 to 6 h following allergen challenge where applicable.
Results
Neutrophils and eosinophils were isolated to a mean (SD) purity of 98.36% (1.09) and 96.31% (3.0), respectively. Asthmatic neutrophils were activated at baseline, mean (SD) CD11bHigh cells 46 (10.50) %. Isolation and radiolabelling significantly increased their activation to > 98%. Eosinophils were not activated at baseline, CD69+ cells 1.9 (0.6) %, increasing to 38 (3.46) % following isolation and labelling. Analysis of the kinetics of net eosinophil and neutrophil lung influx/efflux conformed to a net exponential clearance with respective mean half times of clearance 6.98 (2.18) and 14.01 (2.63) minutes for Group 1, 6.03 (0.72) and 16.04 (2.0) minutes for Group 2 and 5.63 (1.20) and 14.56 (3.36) minutes for Group 3. These did not significantly differ between the three asthma groups (p > 0.05).
Conclusions
Isolation and radiolabelling significantly increased activation of eosinophils (CD69) and completely activated neutrophils (CD11bHigh) in all asthma groups. Net lung neutrophil efflux was significantly slower than that of eosinophils in all asthma study groups. There was a trend for pre-treatment with systemic corticosteroids to reduce lung retention of eosinophils following allergen challenge.
Highlights
•Isolation and radiolabelling of eosinophils or neutrophils from asthmatics significantly activates them.•Corticosteroids alter eosinophil, but not neutrophil 99mTc-HMPAO radiolabelling efficiency.•Leukocyte activation as a result of manipulation ex vivo does not measurably alter lung sequestration.•Eosinophil migration through the lungs of asthmatic patients is slower than in healthy volunteers.
doi:10.1016/j.ebiom.2014.10.014
PMCID: PMC4457433  PMID: 26137523
Asthma; Eosinophils; Neutrophils; Migration kinetics; Radioisotope; Allergen challenge
15.  Creatine phosphokinase elevation exacerbated by levetiracetam therapy 
A 19-year-old muscular male with a history of epilepsy presented following two convulsive events. Levetiracetam (LEV) was given as an additional therapy, resulting in a marked boost in creatine phosphokinase (CPK) that could not easily be explained by renal dysfunction or rhabdomyolysis alone. Levetiracetam discontinuation caused CPK levels to quickly normalize and should be considered in patients with persisting CPK elevations postconvulsive seizure.
doi:10.1016/j.ebcr.2014.09.008
PMCID: PMC4308055  PMID: 25667904
Epilepsy; Toxicity; Rhabdomyolysis; Renal; Sarcolemma; Muscle
16.  Self-reported adult footwear and the risks of lower limb osteoarthritis: the GOAL case control study 
Background
Biomechanical factors may play a role in osteoarthritis (OA) development and progression. Previous biomechanical studies have indicated that types of footwear may modulate forces across the knee joint, and high heeled womens’ shoes in particular are hypothesised to be detrimental to lower limb joint health. This analysis of data from a case control study investigated persistent users of different adult footwear for risks of knee and hip OA. Our underlying hypotheses were that high heeled, narrow heeled, and hard soled shoe types were putative risk factors for lower limb OA.
Methods
Data on footwear were initially obtained from participants during the Genetics of Osteoarthritis and Lifestyle (GOAL) hospital-based, case control study using standardised interview-delivered questionnaires. An additional questionnaire was later sent to GOAL study participants to verify findings and to further investigate specific shoe use per decade of life. Persistent users of footwear types (high or narrow heel; sole thickness or hardness) were identified from early adulthood. Participants were grouped into single sex knee OA, hip OA or control groups. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were calculated.
Results
Univariate analysis of persistent users of women’s high heeled and narrow heeled shoes during early adulthood showed negative associations with knee OA and hip OA. After logistic regression, persistent narrow heel users were associated with less risk of OA (knee OA aOR 0.59, 95% CI 0.35 – 1.00 and hip aOR: 0.50, 95% CI 0.30 – 0.85), and other analyses were not statistically significant. Further analysis suggested that women with hip OA may have stopped wearing high and narrow heeled footwear to attenuate hip pain in early adulthood. Consistent associations between shoe soles and OA were not found.
Conclusions
In general, persistent users of high and narrow heeled shoes during early adulthood had a negative association with knee or hip OA. This does not necessarily imply a causal relationship, as changing footwear during early adulthood to modulate index joint pain may provide a possible explanation. Despite the findings of previous biomechanical studies of high heels, we did not find a positive association between women’s shoes and lower limb osteoarthritis.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-308) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2474-15-308
PMCID: PMC4190490  PMID: 25240981
Footwear; Osteoarthritis; Hip; Knee; Shoe
17.  Aspects of bovine herpesvirus 1 and bovine viral diarrhoea virus herd-level seroprevalence and vaccination in dairy and beef herds in Northern Ireland 
Irish Veterinary Journal  2014;67(1):18.
Background
Infections with bovine herpesvirus 1 (BoHV-1) and bovine viral diarrhoea (BVD) virus cause diseases of cattle with a worldwide distribution. The primary objective of the present study was to describe aspects of herd-level BoHV-1 and BVDV seroprevalence (based on testing of pooled sera) and control on farms in Northern Ireland, including vaccine usage.
An indirect antibody ELISA test (SVANOVA, Biotech AB, Uppsala, Sweden) was applied to serum pools which were constructed from serum samples taken for a cross-sectional study of a convenience sample of 500 Northern Irish dairy and beef cow herds in 2010, for which vaccination status was determined by telephone survey. The herd-level seroprevalence of BoHV-1 and BVDV in Northern Ireland was estimated in non-vaccinating herds and associations between possible risk factors (herd type and herd size (quartiles)) and herd-level prevalence were determined using chi-squared analysis.
Results
The herd-level seroprevalence (of BoHV-1 and BVDV) in non-vaccinating herds was 77.3% (95% CI: 73.6–80.9%) and 98.4% (95% CI: 97.3–99.5%) respectively in the cross-sectional study. A significant difference existed in BoHV-1 herd-level seroprevalence between dairy and beef herds (74.7% vs 86.5% respectively; p < 0.02) though not for BVDV seroprevalence (98.5% vs 98.3% respectively; p > 0.91). A significant association was found between herd size (quartiles) and herd-level classification for BoHV-1 herd-level seroprevalence based on cut-off percentage positivity (COPP) (p < 0.01) while no such association was found for BVDV (p = 0.22).
15.5% and 23.8% of farmers used BoHV-1 and BVDV vaccines, respectively. BoHV-1 vaccine was used in 30% of dairy herds and in 11% of beef herds, while BVDV vaccine was used in 46% and 16% of dairy and beef herds, respectively.
Conclusions
The results from this study indicate that the true herd-level seroprevalences to bovine herpesvirus 1 and bovine virus diarrhoea virus in non-vaccinating herds in Northern Northern Ireland are 77.3% (95% CI: 73.6–80.9%) and 98.4% (95% CI: 97.3–99.5%), respectively. The present study will assist in guiding regional policy development and establish a baseline against which the progress of current and future control and eradication programmes can be measured.
doi:10.1186/2046-0481-67-18
PMCID: PMC4141657  PMID: 25152811
18.  Proteomic Analysis Reveals CACN-1 Is a Component of the Spliceosome in Caenorhabditis elegans 
G3: Genes|Genomes|Genetics  2014;4(8):1555-1564.
Cell migration is essential for embryonic development and tissue formation in all animals. cacn-1 is a conserved gene of unknown molecular function identified in a genome-wide screen for genes that regulate distal tip cell migration in the nematode worm Caenorhabditis elegans. In this study we take a proteomics approach to understand CACN-1 function. To isolate CACN-1−interacting proteins, we used an in vivo tandem-affinity purification strategy. Tandem-affinity purification−tagged CACN-1 complexes were isolated from C. elegans lysate, analyzed by mass spectrometry, and characterized bioinformatically. Results suggest significant interaction of CACN-1 with the C. elegans spliceosome. All of the identified interactors were screened for distal tip cell migration phenotypes using RNAi. Depletion of many of these factors led to distal tip cell migration defects, particularly a failure to stop migrating, a phenotype commonly seen in cacn-1 deficient animals. The results of this screen identify eight novel regulators of cell migration and suggest CACN-1 may participate in a protein network dedicated to high-fidelity gonad development. The composition of proteins comprising the CACN-1 network suggests that this critical developmental module may exert its influence through alternative splicing or other post-transcriptional gene regulation.
doi:10.1534/g3.114.012013
PMCID: PMC4132184  PMID: 24948787
proteomics; cell migration; C. elegans; spliceosome
19.  Irish Veterinary Journal reviewer acknowledgement 2013 
Irish Veterinary Journal  2014;67(1):3.
Contributing reviewers
The Irish Veterinary Journal editorial team would like to thank the following colleagues who contributed to peer review for the journal in 2013.
doi:10.1186/2046-0481-67-3
PMCID: PMC3923565  PMID: 24524550
20.  The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case–control study 
Introduction
Chondrocalcinosis (CC) most commonly results from calcium pyrophosphate crystal deposition (CPPD). The objective of this study is to examine the association between candidate single-nucleotide polymorphisms (SNPs) and radiographic CC.
Methods
SNPs in ankylosis human (ANKH), high ferritin (HFE), tissue non-specific alkaline phosphatase (TNAP), ecto-neucleotide pyrophosphatase 1 (ENPP1), and transferrin (TE) genes were genotyped in participants of the Genetics of Osteoarthritis and Lifestyle (GOAL) and Nottingham Osteoarthritis Case-Control studies. Adjusted genotype odds ratio (aORGENOTYPE), the OR for association between one additional minor allele and CC, was calculated and adjusted for age, gender, body mass index (BMI), and osteoarthritis (OA) by using binary logistic regression. Statistical significance was set at P ≤0.003 after Bonferroni correction for multiple tests.
Results
The -4bpG > A polymorphism in the 5′ untranslated region (5′ UTR) of ANKH associated with CC after Bonferroni correction. This was independent of age, gender, OA, and BMI; aORGENOTYPE (95% confidence interval, or CI) was 1.39 (1.14-1.69) (P = 0.001). rs3045 and rs875525, two other SNPs in ANKH, associated with CC; aORGENOTYPE (95% CI) values were 1.31 (1.09-1.58) (P = 0.005) and 1.18 (1.03-1.35) (P = 0.015), respectively; however, this was non-significant after Bonferroni correction.
Conclusions
This study validates the association between a functional polymorphism in the 5′ UTR of ANKH and CC and shows for the first time that this is independent of age and OA – the two key risk factors for CC. It shows that other SNPs in ANKH may also associate with CC. This supports the role of extracellular inorganic pyrophosphate in the pathogenesis of CC. The findings of this hospital-based study require replication in a community-based population.
doi:10.1186/ar4453
PMCID: PMC3978851  PMID: 24467728
21.  Herd health status and management practices on 16 Irish suckler beef farms 
Irish Veterinary Journal  2013;66(1):21.
Background
There have been few studies published internationally which document herd health management practices in suckler beef herds and no published Irish studies. The study objective was to document herd health status and management practices on sixteen Irish suckler beef herds over a two year period (2009–2010). The farms used in the study were part of the Teagasc BETTER farm beef programme. The mean (s.d.) herd size, stocking rate and farm size was 68 cows (27.6), 2.0 LU/ha (0.3) and 64.3 (21.6) adjusted hectares, respectively. Two questionnaires were designed; 1) a farmer questionnaire to collect information on farm background and current herd health control practices and 2) a veterinary questionnaire to collect information on the extent of animal health advice given by veterinarians to their clients and identification of any on-farm herd health issues.
Results
Dystocia, calf pneumonia, and calf diarrhoea, in that order, were identified as the primary herd health issues in these Irish suckler beef herds. In addition, substantial deficiencies in biosecurity practices were also identified on these farms.
Conclusions
The findings of this study may serve as the focus for future research in animal health management practices in Irish suckler beef herds.
doi:10.1186/2046-0481-66-21
PMCID: PMC3903451  PMID: 24195997
Herd health; Beef suckler; Management practices
22.  Performance of Global Assessments of Hip, Knee, and Back Symptom Change 
Clinical rheumatology  2010;30(3):331-338.
Objective
To compare patients’ global assessments of change in knee, hip, and back symptoms with actual changes over time in pain, function, and radiographic severity.
Methods
Participants (n=894, 80% female, mean age=66 years) completed two assessments (mean of 4 years apart) as part of a study on the genetics of generalized osteoarthritis. At both assessments, participants completed the Western Ontario and McMaster Universities OA Index (WOMAC), and radiographic severity was assessed for knees, hips, and low back. At the second assessment, participants described changes in knee, hip, and low back symptoms as Worse, Better, Same, or Never Had Symptoms. Analysis of covariance models examined mean changes in WOMAC scores and radiographic severity according to categories of the global assessment measures. Statistical significance was examined for linear trend.
Results
Mean WOMAC total, pain, and function scores decreased (indicating improvement) among participants who indicated joint symptoms were Better; showed little change among those who reported symptoms were the Same/Never Had Symptoms; and increased among those who reported symptoms were Worse. For all analyses except the comparison of WOMAC pain change according to global assessment of low back symptom change, there was a statistically significant linear trend (p<0.05). Patterns were similar for changes in radiographic severity, but the tests of linear trend were not statistically significant.
Conclusion
Results support the concordance of these global assessments of joint symptom change with actual changes in self-reported symptoms. These global assessments may be useful for assessing change over time when baseline data are unavailable.
doi:10.1007/s10067-010-1536-x
PMCID: PMC3731381  PMID: 20683742
Osteoarthritis; Knee; Hip; Back; Pain; Function; Psychometrics
23.  Bulk milk ELISA and the diagnosis of parasite infections in dairy herds: a review 
Irish Veterinary Journal  2013;66(1):14.
The bulk milk enzyme-linked immune sorbent assay (ELISA) is a rapid and inexpensive method of assessing herd exposure to pathogens that is increasingly being used for the diagnosis of parasite infections in dairy herds. In this paper, with the dairy herd health veterinarian in mind, we review the principles of the assay and the recent literature on the potential role of bulk milk ELISA for the diagnosis of ostertagiosis, fasciolosis, parasitic bronchitis due to cattle lung worm and neosporosis. It is generally accepted that assay results reflect exposure to the parasite rather than the presence of active infection. Bulk milk ELISA can be a useful tool for the veterinary practitioner as a component of a herd health monitoring programme or in the context of a herd health investigation. It can also play a role in regional or national surveillance programmes. However, the results need to be interpreted within the context of the herd-specific health management, the milk production pattern and the parasite life cycle.
doi:10.1186/2046-0481-66-14
PMCID: PMC3733751  PMID: 23883526
Bulk milk ELISA; Dairy herds; Parasite infections; Ostertagia; Fasciola; Dictyocaulus; Neospora
24.  Individual patient data meta-analysis of trials investigating the effectiveness of intra-articular glucocorticoid injections in patients with knee or hip osteoarthritis: an OA Trial Bank protocol for a systematic review 
Systematic Reviews  2013;2:54.
Background
Based on small to moderate effect sizes for the wide range of symptomatic treatments in osteoarthritis (OA), and on the heterogeneity of OA patients, treatment guidelines for OA have stressed the need for research on clinical predictors of response to different treatments. A meta-analysis to quantify the effect modified by the predictors using individual patient data (IPD) is suggested. The initiative to collect and analyze IPD in OA research is commenced by the OA Trial Bank. The study aims are therefore: to evaluate the efficacy of intra-articular glucocorticoids for knee or hip OA in specific subgroups of patients with severe pain and (mild) inflammatory signs, over both short-term and long-term follow-up, using IPD from existing studies; to reach consensus on the rules for cooperation in a consortium; and to develop and explore the methodological issues of meta-analysis with individual OA patient data.
Methods/Design
For the current IPD analysis we will collect and synthesize IPD from randomized trials studying the effect of intra-articular glucocorticoid injections in patients with hip or knee OA. Subgroup analyses will be performed for the primary outcome of pain at both short-term and long-term follow-up, in the subgroups of patients with and without severe pain and with and without inflammatory signs.
Discussion
This study protocol includes the first study of the OA Trial Bank, an international collaboration that initiates meta-analyses on predefined subgroups of OA patients from existing literature. This approach ensures a widely supported initiative and is therefore likely to be successful in data collection of existing trials. The collaboration developed (that is, the OA Trial Bank) may also lead to future IPD analyses on subgroups of patients with several intervention strategies applied in OA patients.
doi:10.1186/2046-4053-2-54
PMCID: PMC3707758  PMID: 23830482
Osteoarthritis; Individual patient data; Corticosteroid injection
25.  A Role for PACE4 in Osteoarthritis Pain: Evidence from Human Genetic Association and Null Mutant Phenotype 
Annals of the rheumatic diseases  2012;71(6):1042-1048.
Objectives
To assess if genetic variation in the PACE4 gene, PCSK6, influences the risk for symptomatic knee OA.
Methods
Ten PCSK6 single nucleotide polymorphisms (SNP) were tested for association in a discovery cohort of radiographic knee OA (n= 156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout (KO) mice and wildtype C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P; pain behaviours in response to intrathecal substance P; and pain behaviour in the abdominal constriction test.
Results
In the discovery cohort of radiographic knee OA, an intronic SNP at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an odds ratio =1.35 (95% CI 1.17, 1.56; p-value 4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout (KO) mice were significantly protected against pain in a battery of algesiometric assays.
Conclusions
These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.
doi:10.1136/annrheumdis-2011-200300
PMCID: PMC3603144  PMID: 22440827
Knee osteoarthritis; pain; PACE4; genetic association; SNP

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