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Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: Results A total of 1338 patients with AAV were included: 66% had disease onset at Conclusion Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

The authors are investigating self-complementary adeno-associated virus (scAAV) as a vector for intra-articular gene-delivery of interleukin-1 receptor antagonist (IL-1Ra), and its therapeutic capacity in the treatment of osteoarthritis (OA). To model gene transfer on a scale proportional to the human knee, a frequent site of OA incidence, studies were focused on the joints of the equine forelimb. Using AAV2.5 capsid and equine IL-1Ra as a homologous transgene, a functional ceiling dose of ∼5 × 10(12) viral genomes was previously identified, which elevated the steady state levels of eqIL-1Ra in synovial fluids by >40-fold over endogenous production for at least 6 months. Here, using an osteochondral fragmentation model of early OA, the functional capacity of scAAV.IL-1Ra gene-delivery was examined in equine joints over a period of 12 weeks. In the disease model, transgenic eqIL-1Ra expression was several fold higher than seen previously in healthy joints, and correlated directly with the severity of joint pathology at the time of treatment. Despite wide variation in expression, the steady-state eqIL-1Ra in synovial fluids exceeded that of IL-1 by >400-fold in all animals, and a consistent treatment effect was observed. This included a 30–40% reduction in lameness and ∼25% improvement in total joint pathology by both magnetic resonance imaging and arthroscopic assessments, which included reduced joint effusion and synovitis, and improved repair of the osteochondral lesion. No vector-related increase in eqIL-1Ra levels in blood or urine was noted. Cumulatively, these studies in the equine model indicate scAAV.IL-1Ra administration is reasonably safe and capable of sustained therapeutic IL-1Ra production intra-articularly in joints of human scale. This profile supports consideration for human testing in OA.

Toward the treatment of osteoarthritis (OA), the authors have been investigating self-complementary adeno-associated virus (scAAV) for intra-articular delivery of therapeutic gene products. As OA frequently affects weight-bearing joints, pharmacokinetic studies of scAAV gene delivery were performed in the joints of the equine forelimb to identify parameters relevant to clinical translation in humans. Using interleukin-1 receptor antagonist (IL-1Ra) as a secreted therapeutic reporter, scAAV vector plasmids containing codon-optimized cDNA for equine IL-1Ra (eqIL-1Ra) were generated, which produced eqIL-1Ra at levels 30- to 50-fold higher than the native sequence. The most efficient cDNA was packaged in AAV2.5 capsid, and following characterization in vitro, the virus was injected into the carpal and metacarpophalangeal joints of horses over a 100-fold dose range. A putative ceiling dose of 5 × 10(12) viral genomes was identified that elevated the steady-state eqIL-1Ra in the synovial fluids of injected joints by >40-fold over endogenous levels and was sustained for at least 6 months. No adverse effects were seen, and eqIL-1Ra in serum and urine remained at background levels throughout. Using the 5 × 10(12) viral genome dose of scAAV, and green fluorescent protein as a cytologic marker, the local and systemic distribution of vector and transduced cells following intra-articular injection scAAV.GFP were compared in healthy equine joints and in those with late-stage, naturally occurring OA. In both cases, 99.7% of the vector remained within the injected joint. Strikingly, the pathologies characteristic of OA (synovitis, osteophyte formation, and cartilage erosion) were associated with a substantial increase in transgenic expression relative to tissues in healthy joints. This was most notable in regions of articular cartilage with visible damage, where foci of brilliantly fluorescent chondrocytes were observed. Overall, these data suggest that AAV-mediated gene transfer can provide relatively safe, sustained protein drug delivery to joints of human proportions.

PubMedID: 28864648 Objective. To arrive at consensus for candidate outcomes for disease activity assessment in largevessel vasculitis (LVV) in clinical trials. Methods.A Delphi survey including 99 items was circulated among international experts for 3 rounds. Results. Fifty-seven items were accepted for both giant cell arteritis and Takayasu arteritis. Sixty-seven percent of experts voted to have a common approach for both diseases with additional disease-specific items such as weight loss, scalp tenderness/necrosis, morning stiffness, dizziness, visual symptoms, and imaging. Conclusion. This study highlights similarities and differences in experts' perspectives for assessing clinical activity in LVV and may guide a consensus-driven core set of validated outcomes. Copyright © 2017. All rights reserved. National Institute of Arthritis and Musculoskeletal and Skin Diseases: U01 AR51874 04, U54 AR057319 National Center for Research Resources: U54 RR019497 Sponsored by the Vasculitis Clinical Research Consortium, which has received support from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874 04), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research. Additional support for the work of the OMERACT Vasculitis Working Group was received through a Patient-Centered Outcomes Research Institute Pilot Project Grant. S.Z. Aydin, MD, Associate Professor, Division of Rheumatology, The Ottawa Hospital Research Institute, University of Ottawa; H. Direskeneli, MD, Professor of Rheumatology, Division of Rheumatology, Marmara University Faculty of Medicine; P.A. Merkel, MD, MPH, Professor of Medicine and Epidemiology, Division of Rheumatology, and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania. Address correspondence to Dr. P.A. Merkel, Section of Rheumatology, University of Pennsylvania, White Building, 5th Floor Penn, 3400 Spruce St., Philadelphia, Pennsylvania 19104, USA. E-mail: pmerkel@upenn.edu Accepted for publication June 3, 2017.

With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for adeno-associated virus (AAV)-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1-receptor antagonist (hIL-1Ra) or green fluorescent protein was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 × 10(11) vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.

Summary Reasons for performing study: Sildenafil, a phosphodiesterase-5 inhibitor vasodilator, increases cGMP concentrations by inhibiting enzymatic degradation. Marketed to treat erectile dysfunction in men, it also reduces pulmonary arterial pressure (PAP). Because it reduces PAP, sildenafil may enhance performance and/or prevent exercise induced-pulmonary haemorrhage (EIPH). Objective: To determine if sildenafil citrate administration altered commonly measured indices of performance or reduced EIPH in exercised horses. Methods: Thirteen athletically conditioned Thoroughbred horses (2 mares and 11 geldings, age 3–12 years) were administered sildenafil citrate or placebo in 2 crossover design exercise testing studies. In a step-wise test to exhaustion, inspired/expired gas analysis, blood lactate, heart rate, runtime and bronchoalveolar lavage (BAL) cytology were measured. In a 13 m/s test to exhaustion, blood lactate, heart rate, runtime, BAL cytology and pulmonary arterial pressure were measured. Data were analysed with paired and unpaired t tests, one-way ANOVA and Tukey's pair-wise multiple comparison and Friedman repeated measure analysis of variance on ranks. Results: The administration of sildenafil did not alter mean inspired/expired gas measurements, plasma lactate concentrations or acute pulmonary haemorrhage in either exercise test or pulmonary arterial pressure measurement in the 13 m/s trial. Heart rates in both stress tests were significantly different at submaximal speeds and during the early recovery period. Run time was not affected by sildenafil administration in the step-wise trial (P = 0.622) or in the 13 m/s trial (P = 0.059). Conclusions: Sildenafil did not alleviate pulmonary haemorrhage or enhance performance-related indices in these trials. Sildenafil administration altered cardiovascular adaptation to intense exercise as evidenced by altered heart rates at submaximal speeds and post exercise. The effect of these alterations on other performance perimeters was not evident.

Partial hospitalization is a service modality that some have suggested is incompatible with both evidence-based and recovery-oriented treatment. The purpose of this study was to examine the accuracy of this assumption. Toward this end, a specific partial hospitalization program was examined using administrative data, self-reports regarding recovery orientation, and fidelity ratings from independent assessors. Findings support that the partial hospitalization program studied has reasonable lengths of stay, provides recovery-oriented services, and has implemented evidence-based practices. We conclude that partial hospitalization programs have the potential to become part of an evidence-based and recovery-oriented system.

Adrenergic activity accompanies intense exercise and mediates physiological and metabolic responses to exercise. Guanabenz, an antihypertensive drug marketed for human usage, depresses brain vasomotor and cardioaccelerator centres, blocks peripherally adrenergic neurons and is reportedly used as a calming agent in horses but little is known of its effects in the species.To determine if guanabenz induces measurable signs of adrenergic suppression on fit Thoroughbred horses undergoing intense exercise.In a random crossover design, 12 exercise conditioned Thoroughbred horses each received guanabenz (0.08 mg/kg bwt i.v.) and placebo at 3-week intervals. An incremental exercise test to exhaustion on a treadmill followed treatment by 1 h. Heart rate, oxygen consumption, carbon dioxide production, plasma lactate, catecholamines, adrenocorticotropic hormone (ACTH) and cortisol, and time to fatigue were monitored. Statistical analysis was performed using mixed-effects linear modelling.Mean heart rate during the exercise period was lower in guanabenz-treated horses (P = 0.04). Mean concentrations of plasma cortisol (P = 0.02) and adrenaline (P = 0.03) were lower for guanabenz-treated horses during the exercise period. Mean run time was slightly but not significantly longer for guanabenz-treated horses, (P = 0.053). No significant effects of guanabenz administration were found for oxygen consumption, carbon dioxide production nor for plasma lactate, noradrenaline and ACTH concentrations.Guanabenz administration induced signs of adrenergic suppression including plasma cortisol and adrenaline concentrations and heart rate and may enhance endurance, but did not eliminate increases in hormone concentrations induced by exercise. Clear determination of a positive performance effect of adrenaline, but not noradrenaline, suppression is needed before clinical significance can be determined.

Objective—To determine effects of leukotriene (LT) C4 on ion transport across equine tracheal epithelium. Sample—Tracheal epithelium from cadavers of 24 horses considered free of respiratory tract disease. Procedures—Mucosae were mounted into Ussing chambers, and short-circuit current (Isc) was monitored over time. Effects of LTC4 were examined for various conditions, including addition of amiloride (10μM) to the mucosal bath solution, addition of bumetanide (10μM) to the serosal bath solution, addition of barium (1mM) to the serosal bath solution, and substitution of gluconate for chloride and HEPES for bicarbonate in bath solutions. Electrolyte transport was assessed via 22Na and 36Cl isotope fluxes. Results—Addition of LTC4 (50nM) to the serosal bath solution caused an increase in Isc for basal conditions and a larger increase after pretreatment with amiloride. The increase was negated in part by the addition of bumetanide to the serosal bath solution and further reduced by substitution of HEPES for bicarbonate in bath solutions. Remaining current was reduced to values less than those before treatment with LTC4 by the addition of barium to the serosal solution. There was a small increase in Isc after the addition of amiloride and substitution of gluconate for chloride. Radioisotope flux indicated that addition of LTC4 to the serosal bath solution increased chloride secretion and reduced sodium absorption. Conclusions and Clinical Relevance—LTC4 stimulated chloride secretion through a predominately bumetanide-sensitive pathway, with a smaller contribution from a bicarbonate-dependent pathway. Thus, LTC4 appears to be a potential mediator of airway hypersecretion in horses.

Despite ongoing controversy, there has never been a large-scale, prospective study of the cognitive effects of electroconvulsive therapy (ECT). We conducted a prospective, naturalistic, longitudinal study of clinical and cognitive outcomes in patients with major depression treated at seven facilities in the New York City metropolitan area. Of 751 patients referred for ECT with a provisional diagnosis of a depressive disorder, 347 patients were eligible and participated in at least one post-ECT outcome evaluation. The primary outcome measures, Modified Mini-Mental State exam scores, delayed recall scores from the Buschke Selective Reminding Test, and retrograde amnesia scores from the Columbia University Autobiographical Memory Interview-SF (AMI-SF), were evaluated shortly following the ECT course and 6 months later. A substantial number of secondary cognitive measures were also administered. The seven sites differed significantly in cognitive outcomes both immediately and 6 months following ECT, even when controlling for patient characteristics. Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.

Background Clinical trials indicate that electroconvulsive therapy (ECT) is the most effective treatment for major depression, but its effectiveness in community settings has not been examined. Methods In a prospective, naturalistic study involving 347 patients at seven hospitals, clinical outcomes immediately after ECT and over a 24-week follow-up period were examined in relation to patient characteristics and treatment variables. Results The sites differed markedly in patient features and ECT administration but did not differ in clinical outcomes. In contrast to the 70%–90% remission rates expected with ECT, remission rates, depending on criteria, were 30.3%–46.7%. Longer episode duration, comorbid personality disorder, and schizoaffective disorder were associated with poorer outcome. Among remitters, the relapse rate during follow-up was 64.3%. Relapse was more frequent in patients with psychotic depression or comorbid Axis I or Axis II disorders. Only 23.4% of ECT nonremitters had sustained remission during follow-up. Conclusions The remission rate with ECT in community settings is substantially less than that in clinical trials. Providers frequently end the ECT course with the view that patients have benefited fully, yet formal assessment shows significant residual symptoms. Patients who do not remit with ECT have a poor prognosis; this underscores the need to achieve maximal improvement with this modality.

Bronchoalveolar lavage (BAL) was performed at weekly intervals in 10 Thoroughbred horses in race training (group 1) and in 4 rested horses (group 2) for 10 weeks. Lavages were continued on a weekly basis in 4 group 1 horses for an additional 9 weeks (group 3). Cytological analysis of samples included leukocyte counts, erythrocyte counts, differential leukocyte counts, and haemosiderophage score. The mean leukocyte concentration was significantly lower in group 1 (92.1 +/- 4.6 cells/microL) when compared with group 2 (133.5 +/- 8.2 cells/microL), P = 0.037. The differential leukocyte data were not significantly different between groups. There was a large amount of variability in the percentage of macrophages and lymphocytes in the differential counts over time with no obvious trends. The proportion of neutrophils demonstrated a tendency to decrease over time for both groups 1 and 2. Erythrocyte counts and haemosiderin scores were significantly higher in the exercising group than the rested horses. Neither exercise nor the technique itself evoked an inflammatory response in the BAL fluid.