Mesenchymal stromal cells suppress microglial activation and tumor necrosis factor production.

BACKGROUND AIMS: White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear. METHODS: In this study, we utilized numerous assays of varying complexity to model different aspects of white matter disease. These assays ranged from an in vivo spinal cord acute demyelination model to a simple microglial cell line activation assay. Our goal was to investigate the influence of human umbilical cord tissue MSCs on the activation of microglia. RESULTS: MSCs reduced the production of tumor necrosis factor (TNF) by microglia and decreased demyelinated lesions in the spinal cord after acute focal injury. To determine if MSCs could directly suppress the activation of microglia and to develop an efficient potency assay, we utilized isolated primary microglia from mouse brains and the Immortalized MicroGlial Cell Line (IMG). MSCs suppressed the activation of microglia and the release of TNF after stimulation with lipopolysaccharide, a toll-like receptor agonist. CONCLUSIONS: In this study, we demonstrated that MSCs altered the immune response after acute injury in the spinal cord. In numerous assays, MSCs suppressed activation of microglia and release of the pro-inflammatory cytokine TNF. Of these assays, IMG could be standardized and used as an effective potency assay to determine the efficacy of MSCs for treating white matter disease or other neuroinflammatory conditions associated with microglial activation.

Improving the Documentation of Penicillin Allergy Labels Among Pediatric Inpatients.

BACKGROUND AND OBJECTIVES: Penicillin allergy is the most common medication allergy, and the penicillin allergy label is commonly over-applied without adequate reaction history inquiry or documentation. Because penicillin allergy labels are often applied in childhood and carried into adulthood, we sought to increase the completeness of reaction history documentation from 20% to 70% for pediatric hospital medicine patients and from 20% to 50% for all other pediatric inpatients within 12 months. As a secondary outcome, we also aimed to increase the proportion of delabeling unnecessary penicillin labels to 20% for all pediatric inpatients. METHODS: To address our aims, our quality improvement initiative included education for pediatric faculty and staff, development and implementation of a clinical pathway for allergy risk stratification, and electronic health record optimizations. Statistical process control charts were used to track the impact of the interventions facilitated by an automated dashboard. RESULTS: Within 12 months of interventions, the completeness of allergy labels improved from 20% to 64% among patients admitted to the pediatric hospital medicine service and improved from 20% to 45% for all other pediatric inpatients. The frequency of penicillin allergy delabeling remained unchanged; however, 98 patients were risk stratified and 34 received outpatient allergy referrals for further testing. The number of adverse drug reactions to penicillin, a balancing measure, did not change during the study period. CONCLUSIONS: We increased the completeness of penicillin allergy documentation using a standardized workflow facilitated by a multidisciplinary clinical pathway. With ongoing efforts, more penicillin delabeling in low-risk patients is anticipated.

A cord blood monocyte-derived cell therapy product accelerates brain remyelination.

Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding-mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.

Measuring the impact of different brands of computer systems on the clinical consultation: a pilot study.

BACKGROUND: UK general practitioners largely conduct computer-mediated consultations. Although historically there were many small general practice (GP) computer suppliers there are now around five widely used electronic patient record (EPR) systems. A new method has been developed for assessing the impact of the computer on doctor-patient interaction through detailed observation of the consultation and computer use. OBJECTIVE: To pilot the latest version of a method to measure the difference in coding and prescribing times on two different brands of general practice EPR system. METHOD: We compared two GP EPR systems by observing use in real life consultations. Three video cameras recorded the consultation and screen capture software recorded computer activity. We piloted semi-automated user action recording (UAR) software to record mouse and keyboard use, to overcome limitations in manual measurement. Six trained raters analysed the videos using data capture software to measure the doctor-patient-computer interactions; we used interclass correlation coefficients (ICC) to measure reliability. RESULTS: Raters demonstrated high inter-rater reliability for verbal interactions and prescribing (ICC 0.74 to 0.99), but for measures of computer use they were not reliable. We used UAR to capture computer use and found it more reliable. Coded data entry time varied between the systems: 6.8 compared with 11.5 seconds (P = 0.006). However, the EPR with the shortest coding time had a longer prescribing time: 27.5 compared with 23.7 seconds (P = 0.64). CONCLUSION: This methodological development improves the reliability of our method for measuring the impact of different computer systems on the GP consultation. UAR added more objectivity to the observation of doctor-computer interactions. If larger studies were to reproduce the differences between computer systems demonstrated in this pilot it might be possible to make objective comparisons between systems.