Retrospective study of the presentation, diagnosis and management of 16 cats with otitis media not due to nasopharyngeal polyp

Objectives The aim of this study was to analyse retrospectively cats diagnosed with otitis media (OM) not due to nasopharyngeal polyp, and to review the clinical outcome with surgical and medical management. Methods Patient records were searched for cats diagnosed with OM. The diagnosis of OM was based on the presence of clinical signs, including neurological signs, respiratory signs and signs of otitis externa, and on the basis of evidence of thickened or irregular bullae walls, or the presence of fluid within the tympanic cavity in those that had diagnostic imaging. In those that did not have imaging, the diagnosis was made on the basis of the presence of fluid in the bulla or organisms cultured using myringotomy. These records were analysed retrospectively. Results Of 16 cats, one had a total ear canal ablation, five had ventral bulla osteotomy surgery and 11 were medically managed. Of the cats that were medically managed, using either topical products, systemic antimicrobials or a combination of both, eight had complete resolution of clinical signs. Conclusions and relevance This small cohort shows that some cats with OM can be successfully managed medically. Surgery is invasive and may not necessarily be required if appropriate medical management is undertaken. This is the first study of OM treatment in cats and provides the basis for further studies, which should aim to establish specific infectious causes of OM and how they can potentially be managed with medical therapies. </jats:sec

Promoting engagement in physical activity in early rheumatoid arthritis: A proof‐of‐concept intervention study

Objective(s): The aim of this study is to test the feasibility and acceptability of promoting engagement in physical activity in early rheumatoid arthritis (PEPA-RA) to inform a future trial.Design: A ‘proof of concept’ study was carried out.Setting: This study was conducted in community hospitals delivered by musculoskeletal primary care physiotherapists.Participants: Participants were 12 adults with rheumatoid arthritis (RA) diagnosed 6–24 months previously (nine females, three males; mean age 58 years, range 23–79).Intervention: The intervention consisted of five sessions, that is, four group sessions and one individual session facilitated by a physiotherapist over 12 weeks including patient education and support for behaviour change as well as supervised practical exercise.Main outcomes: The main outcomes were attendance, completion of outcome measures, adverse events, and participant and physiotherapist feedback views relating to the intervention.Results: Overall attendance was 85%, with sessions missed due to illness or RA flare. Outcome measure completion ranged from 83% to 100%. There were no clinically meaningful changes in pain or function at 12 weeks, but mean 6-min walk distance improved from 394 to 440m. No serious adverse events were reported, and participantswere generally positive about the intervention. Suggested minor modifications for the group sessions included venue accessibility and ensuring that physical activity time was protected. Several participants indicated that they would have liked to receive the intervention earlier following diagnosis.Conclusions: PEPA-RA and the outcomes appear feasible and acceptable. Overall, small beneficial effects were noted at 12 weeks for most outcomes. Challenges to recruitment resulted in a smaller than anticipated sample size, and the majority of participants were active at baseline indicating that future recruitment needs to targetless active individuals

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (&gt;6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress

Aims Circulating endogenous, dietary and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene program in the vasculature.Methods and Results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells and blood vessels including human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C and glutathione-S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR null mice stimulated in vivo or in rat aortic smooth muscle cells expressing dominant negative PXR. Activation of aortic PXR by classical agonists had several protective effects; increased xenobiotic metabolism demonstrated by bio-activation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death.Conclusions PXR co-ordinately up-regulates drug metabolism, transport and anti-oxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence