Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis.

BackgroundIndividuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA. The purpose of this study was to determine whether B-cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow-mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients.Methods and resultsRA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P<0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B-cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study.ConclusionsDepletion of B-cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA.Clinical trial registrationURL http://ClinicalTrials.gov. Unique identifier: NCT00844714

Carotid Intima-Media Thickness Progression in HIV-Infected Adults Occurs Preferentially at the Carotid Bifurcation and Is Predicted by Inflammation.

BackgroundShear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.Methods and resultsWe measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.ConclusionsAtherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)Clinical trial registrationURL: http://clinicaltrials.gov. Unique identifier: NCT01519141

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors

Purpose The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.Methods This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks.Results Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2 and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug-drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease.Conclusions The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2 (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed

Adenovirus vector delivery stimulates natural killer cell recognition

We report that delivery of first-generation replication-deficient adenovirus (RDAd) vectors into primary human fibroblasts is associated with the induction of natural killer (NK) cell-mediated cytolysis in vitro. RDAd vector delivery induced cytolysis by a range of NK cell populations including the NK cell clone NKL, primary polyclonal NK lines and a proportion of NK clones (36 %) in autologous HLA-matched assays. Adenovirus-induced cytolysis was inhibited by antibody blocking of the NK-activating receptor NKG2D, implicating this receptor in this function. NKG2D is ubiquitously expressed on NK cells and CD8+ T cells. Significantly, γ-irradiation of the vector eliminated the effect, suggesting that breakthrough expression from the vector induces at least some of the pro-inflammatory responses of unknown aetiology following the application of RDAd vectors during in vivo gene delivery

A Machine learning approach to violin bow technique classification: a comparison between IMU and MOCAP systems

Comunicació presentada a: 5th international Workshop on Sensor-based Activity Recognition and Interaction celebrat el 20 i 21 de setembre de 2018 a Berlin, Alemanya.Motion Capture (MOCAP) Systems have been used to analyze body motion and postures in biomedicine, sports, rehabilitation, and music. With the aim to compare the precision of low-cost devices for motion tracking (e.g. Myo) with the precision of MOCAP systems in the context of music performance, we recorded MOCAP and Myo data of a top professional violinist executing four fundamental bowing techniques (i.e. Détaché, Martelé, Spiccato and Ricochet). Using the recorded data we applied machine learning techniques to train models to classify the four bowing techniques. Despite intrinsic differences between the MOCAP and low-cost data, the Myo-based classifier resulted in slightly higher accuracy than the MOCAP-based classifier. This result shows that it is possible to develop music-gesture learning applications based on low-cost technology which can be used in home environments for self-learning practitioners.This work has been partly sponsored by the Spanish TIN project TIMUL (TIN 2013-48152-C2-2-R), the European Union Horizon 2020 research and innovation programme under grant agreement No. 688269 (TELMI project), and the Spanish Ministry of Economy and Competitiveness under the Maria de Maeztu Units of Excellence Programme (MDM-2015-0502)

Replication Data for: 'Food Deserts and the Causes of Nutritional Inequality'

The programs replicate tables and figures from "Food Deserts and the Causes of Nutritional Inequality", by Allcott, Diamond, Dube, Handbury, Rahkovsky, and Schnell. Please see the file Replication Instructions for additional details

Use of Zwitterionic Ligands in Uranyl Hybrid Materials: Explorations on the Structural Features that Control Water Ordering and Mobility

Development of novel materials for water purification and storage is reliant on our understanding of the interaction of water within solid-state materials and inspired by the high selectivity present in certain biological systems. The present study investigates the influence of zwitterionic ligands on water properties within hybrid materials through the synthesis and characterization of four novel coordination polymers built from the uranyl unit and an imidazolium dicarboxylate (Imd) linker. One of the compounds (<b>UIM-5</b>) hosts an infinite water chain of edge sharing hexamers and octamers of hydrogen bonded water molecules. The other three compounds (<b>UIM-2A</b>, <b>2B</b>, <b>2C</b>) make up a polymorphic system in which the guest water molecules are found in varying degrees of isolation. We further explore the expansive literature on uranyl hybrid materials to identify common water nets and possible structural features that may control water structure and properties