Clinical Risk Factors Associated with Anti-Epileptic Drug Responsiveness in Canine Epilepsy

The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs’ owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy

Histone H3K56 Acetylation, CAF1, and Rtt106 Coordinate Nucleosome Assembly and Stability of Advancing Replication Forks

Chromatin assembly mutants accumulate recombinogenic DNA damage and are sensitive to genotoxic agents. Here we have analyzed why impairment of the H3K56 acetylation-dependent CAF1 and Rtt106 chromatin assembly pathways, which have redundant roles in H3/H4 deposition during DNA replication, leads to genetic instability. We show that the absence of H3K56 acetylation or the simultaneous knock out of CAF1 and Rtt106 increases homologous recombination by affecting the integrity of advancing replication forks, while they have a minor effect on stalled replication fork stability in response to the replication inhibitor hydroxyurea. This defect in replication fork integrity is not due to defective checkpoints. In contrast, H3K56 acetylation protects against replicative DNA damaging agents by DNA repair/tolerance mechanisms that do not require CAF1/Rtt106 and are likely subsequent to the process of replication-coupled nucleosome deposition. We propose that the tight connection between DNA synthesis and histone deposition during DNA replication mediated by H3K56ac/CAF1/Rtt106 provides a mechanism for the stabilization of advancing replication forks and the maintenance of genome integrity, while H3K56 acetylation has an additional, CAF1/Rtt106-independent function in the response to replicative DNA damage

An economic model of long-term use of celecoxib in patients with osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Previous evaluations of the cost-effectiveness of the cyclooxygenase-2 selective inhibitor celecoxib (Celebrex, Pfizer Inc, USA) have produced conflicting results. The recent controversy over the cardiovascular (CV) risks of rofecoxib and other coxibs has renewed interest in the economic profile of celecoxib, the only coxib now available in the United States. The objective of our study was to evaluate the long-term cost-effectiveness of celecoxib compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in a population of 60-year-old osteoarthritis (OA) patients with average risks of upper gastrointestinal (UGI) complications who require chronic daily NSAID therapy.</p> <p>Methods</p> <p>We used decision analysis based on data from the literature to evaluate cost-effectiveness from a modified societal perspective over patients' lifetimes, with outcomes expressed as incremental costs per quality-adjusted life-year (QALY) gained. Sensitivity tests were performed to evaluate the impacts of advancing age, CV thromboembolic event risk, different analytic horizons and alternate treatment strategies after UGI adverse events.</p> <p>Results</p> <p>Our main findings were: 1) the base model incremental cost-effectiveness ratio (ICER) for celecoxib versus nsNSAIDs was $31,097 per QALY; 2) the ICER per QALY was$19,309 for a model in which UGI ulcer and ulcer complication event risks increased with advancing age; 3) the ICER per QALY was $17,120 in sensitivity analyses combining serious CV thromboembolic event (myocardial infarction, stroke, CV death) risks with base model assumptions.</p> <p>Conclusion</p> <p>Our model suggests that chronic celecoxib is cost-effective versus nsNSAIDs in a population of 60-year-old OA patients with average risks of UGI events.</p

A protocol for a randomised controlled trial of prefabricated versus customised foot orthoses for people with rheumatoid arthritis: the FOCOS RA trial [Foot Orthoses – Customised v Off-the-Shelf in Rheumatoid Arthritis]

Background Foot pain is common in rheumatoid arthritis and appears to persist despite modern day medical management. Several clinical practice guidelines currently recommend the use of foot orthoses for the treatment of foot pain in people with rheumatoid arthritis. However, an evidence gap currently exists concerning the comparative clinical- and cost-effectiveness of prefabricated and customised foot orthoses in people with early rheumatoid arthritis. Early intervention with orthotics may offer the best opportunity for positive therapeutic outcomes. The primary aim of this study is to evaluate the comparative clinical- and cost-effectiveness of prefabricated versus customised orthoses for reducing foot pain over 12 months. Methods/design This is a multi-centre two-arm parallel randomised controlled trial comparing prefabricated versus customised orthoses in participants with early rheumatoid arthritis (< 2 years disease duration). A total of 160 (a minimum of 80 randomised to each arm) eligible participants will be recruited from United Kingdom National Health Service Rheumatology Outpatient Clinics. The primary outcome will be foot pain measured via the Foot Function Index pain subscale at 12 months. Secondary outcomes will include foot related impairments and disability via the Foot Impact Scale for rheumatoid arthritis, global functional status via the Stanford Health Assessment Questionnaire, foot disease activity via the Rheumatoid Arthritis Foot Disease Activity Index, and health-related quality of life at baseline, 6 and 12 months. Process outcomes will include recruitment/retention rates, data completion rates, intervention adherence rates, and participant intervention and trial participation satisfaction. Cost-utility and cost-effectiveness analyses will be undertaken. Discussion Outcome measures collected at baseline, 6 and 12 months will be used to evaluate the comparative clinical- and cost- effectiveness of customised versus prefabricated orthoses for this treatment of early rheumatoid arthritis foot conditions. This trial will help to guide orthotic prescription recommendations for the management of foot pain for people with early rheumatoid arthritis in future. Trial registration ISRCTN13654421. Registered 09 February 2016

Osteoporosis in psoriatic arthritis: is there any?

AIMS: Although considered as a feature of inflammatory rheumatic diseases, there is a lot of controversy around low bone mass in patients with psoriatic arthritis. The aim of this cross-sectional study was to analyze bone mineral density in patients with psoriatic arthritis, as well as to investigate its possible association with some measures of disease activity and functional capacity. ----- SUBJECTS AND METHODS: Sixty-nine patients with established psoriatic arthritis (mean age 56.20 ± 12.23 years) and who have not been treated with specific antiosteoporotic drugs were recruited from the out-patient clinic database. Bone mineral density was measured by dual-energy X-ray absorptiometry at the lumbar spine and at the left hip. Disease activity measures included: duration of morning stiffness, tender and swollen joint count, patient's and physician's global assessment, presence of dactylitis and enthesitis, ESR, CRP and Disease Activity Score 28. Health Assessment Questionnaire was used to assess functional status. ----- RESULTS: According to WHO definition, spinal osteoporosis was found in 7.2% of patients, total hip osteoporosis in 1.4% of patients and femoral neck osteoporosis in 2.9% of patients. There was no significant association of any of the measures of disease activity with BMD at any site. Higher HAQ scores were associated with lower total hip BMD. ----- CONCLUSIONS: In our sample of patients with psoriatic arthritis we did not find increased prevalence of osteoporosis. There was no association of BMD with indices of disease activity, while negative correlation was found between HAQ and total hip BMD