Effect of concomitant Renal DeNervation and cardiac ablation on Atrial Fibrillation recurrence - RDN+AF study.

BACKGROUND: Renal denervation (RDN) can reduce cardiac sympathetic activity maintained by arterial hypertension (aHT). Its potential antiarrhythmic effect on rhythm outcome in patients with multi-drug resistant aHT undergoing catheter ablation for atrial fibrillation (AF) is unclear. METHODS: The RDN+AF study was a prospective, randomized, two-center trial. Patients with paroxysmal or persistent AF and uncontrolled aHT (mean systolic 24-h ambulatory BP > 135 mmHg) despite taking at least three antihypertensive drugs were enrolled. Patients were 1:2 randomized to either RDN+AF ablation or AF-only ablation. Primary endpoint was freedom from any AF episode > 2 min at 12 months assessed by implantable loop recorder (ILR) or 7d-holter electrocardiogram. Secondary endpoints included rhythm outcome at 24 months, blood pressure control, periprocedural complications, and renovascular safety. RESULTS: The study randomized 61 patients (mean age 65 ± 9 years, 53% men). At 12 months, RDN+AF patients tended to have a greater decrease in ambulatory BPs but did not reach statistical significance. No differences in rhythm outcome were observed. Freedom from AF recurrence in the RDN+AF and AF-only group measured 61% versus 53% p = .622 at 12 months and 39% versus 47% p = .927 at 24 months, respectively. Periprocedural complications occurred in 9/61 patients (15%). No patient died. CONCLUSION: Among patients with multidrug-resistant aHT and paroxysmal or persistent AF, concomitant RDN+AF ablation was not associated with better blood pressure control or rhythm outcome in comparison to AF-only ablation and medical therapy.

Alternative activation of human macrophages enhances tissue factor expression and production of extracellular vesicles.

Macrophages are versatile cells that can be polarized by the tissue environment to fulfill required needs. Proinflammatory polarization is associated with increased tissue degradation and propagation of inflammation whereas alternative polarization within a Th2 cytokine environment is associated with wound healing and angiogenesis. To understand if polarization of macrophages can lead to a procoagulant macrophage subset we polarized human monocyte derived macrophages to a proinflammatory and an alternative activation state. Alternative polarization with interleukin-4 and IL-13 led to a macrophage phenotype characterized by increased tissue factor (TF) production and release and by an increase in extracellular vesicle production. In addition, also TF activity was enhanced in extracellular vesicles of alternatively polarized macrophages. This TF induction was dependent on signal transducer and activator of transcription-6 signaling and poly ADP ribose polymerase activity. In contrast to monocytes, human macrophages did not show increased tissue factor expression upon stimulation with lipopolysaccharide and interferon-γ. Previous polarization to either a proinflammatory or an alternative activation subset does not change the subsequent stimulation of TF. The inability of proinflammatory activated macrophages to respond to lipopolysaccharide and interferon-γ with an increase in TF production seems to be due to an increase in TF promoter methylation and was reversible when treating these macrophages with a demethylation agent. In conclusion, we provide evidence that proinflammatory polarization of macrophages does not lead to enhanced procoagulatory function, whereas alternative polarization of macrophages leads to an increased expression of TF and increased production of TF bearing extracellular vesicles by these cells suggesting a procoagulatory phenotype of alternatively polarized macrophages.

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets.

OBJECTIVE: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden. CONCLUSIONS: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.

Electrophysiological findings during atrial fibrillation reablation: Extending from pulmonary vein reconnection to sequential bipolar voltage map information.

BACKGROUND: Left atrial substrate modification targeting low voltage zones (LVZ) is an ablation strategy that-in addition to pulmonary vein (PV) isolation-tries to eliminate arrhythmogenic mechanisms harbored in such tissue. Electrophysiological findings at reablation include (a) PV reconnection, (b) reconnection over previous substrate ablation, and (c) de-novo LVZ. OBJECTIVE: To study, prevalence and contribution of these arrhythmogenic electrophysiological entities in patients with atrial fibrillation (AF) recurrences. METHODS: Consecutive patients with highly symptomatic AF undergoing index and reablation were included (n = 113). In all patients' PV reconnection, reconnection over previous substrate ablation and spontaneous de-novo LVZ were quantitatively assessed and integrated into an individual reablation strategy. Follow-up was based on continuous device monitoring. RESULTS: At re-do procedure, 45 out of 113 (39.8%) patients showed PV reconnection as the only electrophysiological abnormality. Reconduction over previous lines was the only electrophysiological abnormality in 8 out of 113 (7.1%) patients. Spontaneous de-novo LVZ was the only electrophysiological abnormality in 12 out of 113 (10.6%) patients. Combined findings of PV reconnection, line reconduction, and/or spontaneous de-novo LVZ were seen in 40 out of 113 (35.4%) patients. No detectable electrophysiological abnormality was observed in 8 out of 113 (7.1%) patients. In univariate analysis, none of the tested electrophysiological characteristics independently predicted the outcome after re-do. CONCLUSIONS: In patients undergoing reablation, we could show that reconduction over previous substrate ablation as well as the development of new low voltage areas are frequent findings besides classical PV reconnection-without a clear leading cause for recurrences. These findings impact reablation strategies as well as the strategic focus during index procedures.

Left atrial fibrosis predicts left ventricular ejection fraction response after atrial fibrillation ablation in heart failure patients: the Fibrosis-HF Study.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often coexist. Catheter ablation has been reported to restore left ventricular (LV) function but patients benefit differently. This study investigated the correlation between left atrial (LA) fibrosis extent and LV ejection fraction (LVEF) recovery after AF ablation. METHODS AND RESULTS: In this study, 103 patients [64 years, 69% men, 79% persistent AF, LVEF 33% interquartile range (IQR) (25-38)] undergoing first time AF ablation were investigated. Identification of LA fibrosis and selection of ablation strategy were based on sinus rhythm voltage mapping. Continuous rhythm monitoring was used to assess ablation success. Improvement in post-ablation LVEF was measured as primary study endpoint. An absolute increase in post-ablation LVEF ≥10% was defined as 'Super Response'. Left atrial fibrosis was present in 38% of patients. After ablation LVEF increased by absolute 15% (IQR 6-25) (P < 0.001). Left ventricular ejection fraction improvement was higher in patients without LA fibrosis [15% (IQR 10-25) vs. 10% (IQR 0-20), P < 0.001]. An inverse correlation between LVEF improvement and the extent of LA fibrosis was found (R2 = 0.931). In multivariate analysis, the presence of LA fibrosis was the only independent predictor for failing LVEF improvement [odds ratio 7.2 (95% confidence interval 2.2-23.4), P < 0.001]. Echocardiographic 'Super Response' was observed in 55/64 (86%) patients without and 21/39 (54%) patients with LA fibrosis, respectively (P < 0.001). CONCLUSION: Presence and extent of LA fibrosis predict LVEF response in HF patients undergoing AF ablation. The assessment of LA fibrosis may impact prognostic stratification and clinical management in HF patients with AF.

[Erratum to: Strategy for university emergency room management at the beginning of an epidemic using COVID-19 as an example]. / Erratum zu: Strategie einer universitären Notaufnahme für das COVID-19-Management im Rahmen einer beginnenden Epidemie.

[This corrects the article DOI: 10.1007/s10049-020-00759-8.].

[Strategy for university emergency room management at the beginning of an epidemic using COVID-19 as an example]. / Strategie einer universitären Notaufnahme für das COVID-19-Management im Rahmen einer beginnenden Epidemie.

Due to the increasing number of COVID-19 infections worldwide, all hospitals are faced with the challenge associated with the pandemic. In particular, emergency rooms must prepare and implement completely new workflows. This applies in particular to patient screening and selection (triage). Close cooperation with other specialist areas such as hygiene, infectiology or virology is also necessary in order to implement appropriate treatment concepts before, during and after the diagnosis is completed. In addition, communication and quality and risk management are highly relevant in addition to the clinical aspects. This article uses COVID-19 as an example to describe how emergency rooms can prepare for a pandemic.

Upregulated epithelial junction expression represents a novel parameter of the epithelial radiation response to fractionated irradiation in oral mucosa.

PURPOSE: During head and neck cancer treatment, the radiation response of the oral mucosa represents a frequent early side effect. Besides radiation-induced inhibition of proliferation, various other cellular responses occur. The radiation response of adherens and tight junction proteins was so far mostly investigated with large single-dose irradiation protocols, in vivo and in vitro. Therefore, the current study was initiated to investigate the impact of daily fractionated irradiation on the expression of adherens and tight junction proteins in vivo. MATERIALS AND METHODS: Fractionation with 5â€¯× 3 Gy/week (days 0-4, 7-11) was given to the snouts of mice. Groups of 5 animals per day were euthanized every second day between day 0 (unirradiated controls) and day 14, and their tongues subjected to histological processing. Adherens junction marker (ß-catenin and E­cadherin) and tight junction marker (claudin-1 and occludin) expression was analysed in the oral mucosa of unirradiated controls and during two weeks of fractionated irradiation. RESULTS: Adherens as well as tight junction marker proteins were rapidly and consistently upregulated in both the germinal as well as the functional layer of the oral mucosa. This represents a previously unknown parameter of the epithelial radiation response to clinically relevant fractionation protocols. CONCLUSION: Fractionated irradiation significantly enhanced the expression of all proteins investigated. This study revealed a new parameter of the epithelial radiation response to fractionated irradiation.

Prevalence and predictors of low voltage zones in the left atrium in patients with atrial fibrillation.

Aims: To describe the extent and distribution of low voltage zones (LVZ) in a large cohort of patients undergoing ablation for paroxysmal and persistent atrial fibrillation (AF), and to explore baseline predictors of LVZ in these patients. Methods and results: Consecutive patients who underwent a bipolar voltage map guided AF ablation, were enrolled. Voltage maps were conducted for each patient using 3-dimensional electroanatomical mapping system and LVZ were defined as areas of bipolar voltage < 0.5 mV. A total of 539 patients (309 male, age 65 ± 10 years) were included. Low voltage zones was present in 58 out of 292 patients with paroxysmal and 134 out of 247 persistent AF (P < 0.001). The area of LVZ was larger in patients with persistent as compare to paroxysmal AF, 5 cm2 (IQR 3-18.6) vs. 12.1 cm2 (IQR 3.6-28.5), P = 0.026, respectively. In the multivariate analysis age (OR 1.07, 95%CI 1.05-1.10, P < 0.001), female gender (OR 2.18, 95%CI 1.38-3.43, P = 0.001), sinoatrial node dysfunction (OR 3.90, 95%CI 1.24-12.21, P = 0.020), larger surface area of left atrium pr. cm2 (OR 1.01, 95%CI 1.00-1.02, P = 0.016), and persistent AF (OR 5.03, 95%CI 3.20-7.90, P<0.001) were associated with presence of LVZ. Conclusion: In a large cohort of patients undergoing ablation for AF, the prevalence of LVZ was higher and LVZ areas larger in patients with persistent as compared with paroxysmal AF. The most frequent localization of LVZ was anterior wall, septum and posterior wall. Presence of LVZ was associated with higher age, female gender, larger LA surface area, and sinoatrial node dysfunction.

Continuous monitoring after atrial fibrillation ablation: the LINQ AF study.

Aims: To study device performance, arrhythmia recurrence characteristics, and methods of outcome assessment using a novel implantable cardiac monitor (ICM) in patients undergoing ablation for atrial fibrillation (AF). Methods and results: In 419 consecutive patients undergoing first-time catheter ablation for symptomatic paroxysmal (n = 224) or persistent (n = 195) AF an ICM was injected at the end of the procedure. Telemedicine staff ensured full episode transmission coverage and manually evaluated all automatic arrhythmia episodes. Device detection metrics were calculated for ≥2, ≥6, and ≥10 min AF detection durations. Four methods of outcome assessment were studied: continuous recurrence analysis, discontinuous recurrence analysis, AF-burden analysis, and analysis of individual rhythm profiles. A total of 43 673 automatic AF episodes were transmitted over a follow-up of 15 ± 6 months. Episode-based positive predictive values changed significantly with longer AF detection durations (70.5% for ≥2 min, 81.8% for ≥6 min, and 85.9% for ≥10 min). Patients with exclusive short episode recurrences (≥2 to <6 min) were rare and their arrhythmia detection was clinically irrelevant. Different methods of outcome assessment showed a large variation (46-79%) in ablation success. Individual rhythm characteristics and subclinical AF added to this inconsistency. Analysis of AF-burden and individual rhythm profiles were least influenced and showed successful treatment in 60-70% of the patients. Conclusion: We suggest AF detection duration >6 min and AF burden >0.1% as a standardized outcome definition for AF studies to come in the future.

Technical note: Evaluation of a triaxial accelerometer for monitoring selected behaviors in dairy calves.

The objectives of this study were (1) to develop an algorithm for the acceleration sensor of the Smartbow Eartag (Smartbow GmbH, Weibern, Austria) to distinguish between postures (lying and standing or locomotion) and to detect 6 kinds of activities (milk intake, water intake, solid feed intake, ruminating, licking or sucking without milk intake, and other activities) in dairy calves and (2) to evaluate this sensor for identifying these behaviors in dairy calves compared with observations from video. Accelerometers were applied to the left ears of 15 preweaned Holstein dairy calves. Calves were kept in a group pen and received milk replacer from an automatic calf feeder. Based on 38 h of acceleration data and video observation, an algorithm was established to detect the predefined behaviors. Using cross-validation, video recordings were used to analyze whether a behavior was detected correctly by the developed algorithm. For posture, sensitivity (94.4%), specificity (94.3%), precision (95.8%), and accuracy (94.3%) were high. Cohen's kappa was calculated as 0.88. For the 6 defined activities, overall (i.e., aggregated for all activities) accuracy was 70.8% and kappa was calculated as 0.58. Some activities (e.g., ruminating, feed intake, other activities) were identified better than others. In conclusion, the developed algorithm based on the acceleration data of the Smartbow Eartag was successful in detecting lying behavior, rumination, feed intake, and other activities in calves, but further development of the underlying algorithm will be necessary to produce reliable results for milk and water intake.

[European Collaboration in Medical Device Assessment: One Step Towards Cross-Border Health Care]. / Europäische Zusammenarbeit in der Bewertung von Medizinprodukten ­ ein Schritt zur grenzüberschreitenden Gesundheitsversorgung.

AIM: The aim of this paper was to present the legal framework as well as previous experience in transnational collaboration regarding the assessment of medical devices for reimbursement decisions. Furthermore, the possible benefit of transnational collaboration for various stakeholders will be discussed. METHODS: Experiences gathered with the compilation of overall 6 joint rapid assessments of medical devices within the completed European Network for Health Technology Assessment (EUnetHTA) Joint Action 2 (JA2) are summarised and discussed. Benefits, aims and opportunities of the ongoing EUnetHTA Joint Action 3 (JA3) are described. RESULTS: Challenges in joint European assessment of medical devices encompass the choice of topics and the time point of assessments, the non-transparency of the medical devices market as well as the lack of European standards for systematic patient involvement. Characteristics of medical devices such as incremental changes and learning curves call for monitoring of medical devices through their whole lifecycle. The concrete benefit of European collaboration for stakeholders is manifold: uncertainties with regard to the actual added value of a technology, caused by a lack of evidence, may be reduced by Early Dialogues; harmonized and transparent assessment processes throughout Europe increase the reproducibility and quality of reports; the division of work among the health technology assessment (HTA) organisations allows a resource efficient assessment of a larger amount of technologies; patient involvement facilitates consideration of patient-relevant endpoints. The importance of cross-border collaboration in the field of HTA is shown in the continuation of the EUnetHTA project, which aims to further strengthen international collaboration even after expiration of EU funding. CONCLUSION: A sustainable transnational collaboration in the assessment of medical devices can ensure cross-border health care as well as efficient collaboration of national health systems. The focus should be on a wide implementation of jointly established methods and quality standards. The European collaboration can lead to a concrete benefit for patients, physicians, HTA organisations and national decision makers.

Radioprotective Effects of Dermatan Sulfate in a Preclinical Model of Oral Mucositis-Targeting Inflammation, Hypoxia and Junction Proteins without Stimulating Proliferation.

Oral mucositis is the most frequently occurring early side effect of head-and-neck cancer radiotherapy. Systemic dermatan sulfate (DS) treatment revealed a significant radioprotective potential in a preclinical model of oral mucositis. This study was initiated to elucidate the mechanistic effects of DS in the same model. Irradiation comprised daily fractionated irradiation (5 × 3 Gy/week) over two weeks, either alone (IR) or in combination with daily dermatan sulfate treatment of 4 mg/kg (IR + DS). Groups of mice (n = 5) were sacrificed every second day over the course of 14 days in both experimental arms, their tongues excised and evaluated. The response to irradiation with and without DS was analyzed on a morphological (cell numbers, epithelial thickness) as well as on a functional (proliferation and expression of inflammation, hypoxia and epithelial junction markers) level. The mucoprotective activity of DS can be attributed to a combination of various effects, comprising increased expression of epithelial junctions, reduced inflammation and reduced hypoxia. No DS-mediated effect on proliferation was observed. DS demonstrated a significant mucositis-ameliorating activity and could provide a promising strategy for mucositis treatment, based on targeting specific, radiation-induced, mucositis-associated signaling without stimulating proliferation.

Performance of an Implantable Cardiac Monitor to Detect Atrial Fibrillation: Results of the DETECT AF Study.

INTRODUCTION: Reliable detection and monitoring of atrial fibrillation (AF) is essential for accurate clinical decision making, which can now be done continuously with the introduction of implantable cardiac monitors (ICM) The DETECT AF study evaluated the performance of the Confirm DM2102 ICM (St. Jude Medical, St. Paul, MN, USA) to accurately detect and monitor AF. METHODS: Ninety patients previously implanted with the ICM and with either suspected or known paroxysmal AF were enrolled at 12 centers in Germany and The Netherlands. At least 2 weeks after ICM implant, patients wore a Holter monitor for 4 days, while the ICM monitored for AF episodes lasting at least 2 minutes. Holter monitor data was analyzed by a blinded, independent core laboratory and compared to the ICM AF detections. Patient and episode sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive (NPV) were calculated using standard analysis and a generalized estimation equation method where appropriate. RESULTS: A total of 79/90 subjects (61% male, 65.7 ± 9.6 years old) were included in the analysis, totaling 6,894 hours of Holter monitoring. Using a per patient analysis SE was 100%, PPV was 64.0%, SP was 85.7%, and NPV was 100%. Using a per episode analysis, SE was 94.0% and PPV was 64.0%. With an AF duration analysis, the SE was 83.9%, PPV was 97.3%, SP was 99.4% with an NPV of 98.5%. CONCLUSION: The SJM Confirm DM2102 can accurately and repeatedly detect paroxysmal AF episodes of at least 2 minutes in length.

[Overtreatment: Initiatives to identify ineffective and inappropriate medical interventions]. / Überversorgung: Initiativen zur Identifikation ineffektiver oder nicht bedarfsgerechter Leistungen.

A growing number of international initiatives rise to the challenge of reduction of medical overuse. Increasingly, these activities are promoted by physicians and clinicians, and aim to identify and avoid inappropriate health interventions. This article places the Choosing Wisely initiative within the context of less well-known activities, 13 all together, and briefly describes their characteristics; in addition, similarities and differences regarding their methods are elaborated.

Fluoroscopy integrated 3D mapping significantly reduces radiation exposure during ablation for a wide spectrum of cardiac arrhythmias.

AIMS: Despite the use of established 3D-mapping systems, invasive electrophysiological studies and catheter ablation require high radiation exposure of patients and medical staff. This study investigated whether electroanatomic catheter tracking in prerecorded X-ray images on top of an existing 3D-mapping system has any impact on radiation exposure. METHODS AND RESULTS: Two hundred and ninety-five consecutive patients were either ablated with the guidance of the traditional CARTO-3 system (c3) or with help of the CARTO-UNIVU system (cU): [typical atrial flutter (AFL) n = 58, drug refractory atrial fibrillation (AF) n = 81, ectopic atrial tachycardia (EAT) n = 37, accessory pathways (APs) n = 22, symptomatic, idiopathic premature ventricular complexes (PVCs) n = 56, ventricular tachycardias (VTs) n = 41]. The CARTO-UNIVU allowed a reduction in radiation exposure: fluoroscopy time: AFL c3: 8.6 ± 0.8 min vs. cU: 2.9 ± 0.3 min, P < 0.001; AF c3: 16.0 ± 1.3 min vs. cU: 6.4 ± 0.9 min, P < 0.001; EAT c3: 23.4 ± 3.1 min vs. cU: 9.7 ± 1.7 min, P < 0.001; AP c3: 7.1 ± 1.2 min vs. cU: 6.0 ± 1.5 min, P = 0.59; PVCs c3: 17.6 ± 2.3 min vs. cU: 15.2 ± 2.8 min, P = 0.52; VT c3: 31.4 ± 3.4 min vs. cU: 17.5 ± 2.4 min, P = 0.003. Corresponding to the fluoroscopy time the fluoroscopy dose was also reduced significantly. These advantages were not at the cost of increased procedure times, periprocedural complications, or decreased acute ablation success rates. CONCLUSION: In a wide spectrum of cardiac arrhythmias, and especially in AF and VT ablation, fluoroscopy integrated 3D mapping contributed to a dramatic reduction in radiation exposure without prolonging procedure times and compromising patient's safety. That effect, however, could not be maintained in patients with APs and PVCs.

DISINVESTING FROM INEFFECTIVE TECHNOLOGIES: LESSONS LEARNED FROM CURRENT PROGRAMS.

OBJECTIVES: Many of the currently used health technologies have never been systematically assessed or are misused, overused or superseded. Therefore, they may be ineffective. Active identification of ineffectiveness in health care is gaining importance to facilitate best care for patients and optimal use of limited resources. The present research analyzed processes and experiences of programs for identifying ineffective health technologies. The goal of this study was to elucidate factors that facilitate implementation. METHODS: Based on an overview article, a systematic literature search and unsystematic hand-search were conducted. Further information was gained from international experts. RESULTS: Seven programs were identified that include identification, prioritization and assessment of ineffective health technologies and dissemination of recommendations. The programs are quite similar regarding their goals, target groups and criteria for identification and prioritization. Outputs, mainly HTA reports or lists, are mostly disseminated by means of the internet. Top-down and bottom-up programs both have benefits in terms of implementation of recommendations, either as binding guidelines and decisions or as nonbinding information for physicians and other stakeholders. Crucial facilitators of implementation are political will, transparent processes and broad stakeholder involvement focusing on physicians. CONCLUSIONS: All programs can improve the quality of health care and enable cost reduction in supportive surrounding conditions. Physicians and patients must be continuously involved in the process of evaluating health technologies. Additionally, decision makers must support programs and translate recommendations into concrete actions.

Redox-dependent plasticity of oxMIF facilitates its interaction with CD74 and therapeutic antibodies.

MIF is a ubiquitous protein involved in proinflammatory processes, which undergoes an oxidation-driven conformational change to oxidized (ox)MIF. We demonstrate that hypochlorous acid, produced by neutrophil-released myeloperoxidase (MPO) under inflammatory conditions, effectively oxidizes MIF into the oxMIF isoform, which is specifically recognized by the anti-oxMIF therapeutic antibody, ON104. NMR investigation of MIF oxidized by the MPO system revealed increased flexibility throughout the MIF structure, including at several catalytic and allosteric sites. Mass spectrometry of MPO-oxMIF revealed methionines as the primary site of oxidation, whereas Pro2 and Tyr99/100 remained almost unmodified. ELISA, SPR and cell-based assays demonstrated that structural changes caused by MPO-driven oxidation promoted binding of oxMIF to its receptor, CD74, which does not occur with native MIF. These data reveal the environment and modifications that facilitate interactions between MIF and its pro-inflammatory receptor, and a route for therapeutic intervention targeting the oxMIF isoform.

The newly engineered monoclonal antibody ON104, targeting the oxidized Macrophage Migration Inhibitory Factor (oxMIF), ameliorates clinical and histopathological signs of collagen-induced arthritis.

Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine that emerged as a pivotal regulator in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA). MIF occurs in two immunologically distinct conformational isoforms, indicated as reduced (redMIF) and oxidized MIF (oxMIF) where the latter exerts disease-related activities. In this study we demonstrate the presence of circulating oxMIF in RA patients and investigate the in vivo effects of an oxMIF-neutralizing antibody in a murine model of RA. By advanced antibody engineering we generated the fully human anti-oxMIF antibody ON104 with abolished effector functions. The therapeutic potential of ON104 was tested in a model of Collagen-Induced Arthritis (CIA) in DBA/1j mice. At disease onset, the mice received ON104 twice a week for three weeks. Clinical symptoms were assessed daily, and histological examinations of the joints were performed at the end of the study. Antibody ON104, specifically targeting human and murine oxMIF, is highly affine and does not elicit effector functions in vitro. The treatment of CIA mice with ON104 profoundly modulated disease progression with marked amelioration of clinical signs of arthritis that was associated with reduced synovial and cartilage damage and reduced F4/80-positive macrophages in the joints. These data prove that oxMIF is a relevant target in a well-known model of human RA and its specific neutralization by the antibody ON104 ameliorates clinical and histological signs of the disease in the so-treated mice. Thus, ON104 represents a new and promising treatment option for RA and possibly other autoimmune diseases.

Dog assisted education in children with rheumatic diseases and adolescents with chronic pain in Germany.

Objectives: Animal assisted intervention is an increasingly accepted tool to improve human well-being. The present study was performed to assess whether dog assisted education has a positive effect on children suffering from rheumatic disorders with pain and adolescents with chronic pain syndrome. Design: Two groups of juvenile patients were recruited: 7-17-year-old children in children with rheumatic diseases and adolescents with chronic pain syndromes. Overall, n=26 participated in the intervention, and n=29 in the control group. Setting: The intervention group met once a month, 12 times overall, for working with man trailing dogs in various locations. Main outcome measures: The influence of dog assisted education on quality of life (PedsQLTM Scoring Algorithm), pain intensity, perception, coping (Paediatric Pain Coping Inventory-Revised), and state anxiety (State Trait Anxiety Inventory) was assessed. Results: The quality of life increased significantly in the investigated period, but for both, the intervention and the control group. The state anxiety of children was lower after the dog assisted education than before. After the dog training sessions, state anxiety was 18% to 30% lower than before the intervention. Some participants noted subjectively improved pain coping and changes in pain perception, which were not found in the data. Conclusion: Our results indicate that for children with rheumatic diseases and adolescents with chronic pain syndromes dog assisted education (1) might lead to an increase of the quality of life, (2) leads to decreased state anxiety from pre to post intervention and (3) does not influence pain perception, frequency and intensity.