Pharmacokinetic profiles of the active metamizole metabolites in healthy horses

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among other secondary metabolites, 4-aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 9 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (Cmax), time to maximum concentration (Tmax) and AUMC0-last of MAA were statistically different between the i.v. and i.m. groups. The AUCIM/AUCIV ratio of MAA was 1.06. In contrast, AUC0-last of AA was statistically different between the groups (P < 0.05) with an AUCIM/AUCIV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug

Positioning Eye Fixation and Vehicle Movement: Visual-motor Coordination Assessment in Naturalistic Driving

In recent years, many driving studies in the traffic safety literature have undertaken error assessments of driver behaviour. However, few studies have been able to analyse the detailed individual vision and motor behaviours of drivers, due to the lack of reliable data and available technologies. Therefore, little is currently known about drivers' visual-motor coordination involving the use of visual information to regulate their physical movements. This research sets-up a technical framework to investigate on-road drivers' visual-motor coordination via vision tracking and vehicle positioning. The driving behaviour and performance were recorded and analysed using Eye Movement Tracking, Global Navigation Satellite System (GNSS) and Geographic Information Systems (GIS). The eye tracker recorded eye fixations and duration on video images to analyse the visual pattern of individual drivers. Real-time kinematic (RTK) post-processing of multi-GNSS generated vehicle movement trajectory at centimetre-level accuracy horizontally, which encompasses precise lateral positioning, speed and acceleration parameters of driving behaviours. The eye fixation data was then geocoded and synchronised with the vehicle movement trajectory in order to investigate the visual-motor coordination of the drivers. A prototype of implementation of the framework focusing on complex U-turn manoeuvre at a roundabout in five older drivers was presented in this paper. The visualisation of spatial-temporal patterns of visual-motor coordination for individual drivers allows for a greater insight to behaviour assessment. The on-road driving test in this study has also demonstrated a discriminant and ecologically valid approach in driving behaviour assessment, which can be used in studies with other cohort population

Multi-Mission Automated Task Invocation Subsystem

Multi-Mission Automated Task Invocation Subsystem (MATIS) is software that establishes a distributed data-processing framework for automated generation of instrument data products from a spacecraft mission. Each mission may set up a set of MATIS servers for processing its data products. MATIS embodies lessons learned in experience with prior instrument- data-product-generation software. MATIS is an event-driven workflow manager that interprets project-specific, user-defined rules for managing processes. It executes programs in response to specific events under specific conditions according to the rules. Because requirements of different missions are too diverse to be satisfied by one program, MATIS accommodates plug-in programs. MATIS is flexible in that users can control such processing parameters as how many pipelines to run and on which computing machines to run them. MATIS has a fail-safe capability. At each step, MATIS captures and retains pertinent information needed to complete the step and start the next step. In the event of a restart, this information is retrieved so that processing can be resumed appropriately. At this writing, it is planned to develop a graphical user interface (GUI) for monitoring and controlling a product generation engine in MATIS. The GUI would enable users to schedule multiple processes and manage the data products produced in the processes. Although MATIS was initially designed for instrument data product generation

Glaucoma Patients' Trust in the Physician

Objectives. To describe glaucoma patients' trust in the physician and to test the hypothesis that increased interpersonal trust is associated with increased medication adherence. Methods. One hundred ninety-five subjects with open-angle glaucoma seen by multiple glaucoma subspecialists participated in a cross-sectional patient survey and concomitant chart review which included a test of health literacy and the Trust in Physician Scale (TPS), a scale from 1–100, with 100 indicating greatest trust. Charts were reviewed for visual acuity and visual field results. Subjects' pharmacies were contacted to ascertain medication refill rates over the preceding six months. Results. TPS scores ranged from 57.5 to 100, 78.7 ± 8.4 (mean ± SD,) median 75.0. When age, race, gender, baseline visual acuity and visual field status, education level, and literacy status were considered, only race was associated with TPS. Caucasians expressed slightly higher levels of trust (n = 108; TPS 80.1 ± 8.2) than non-Caucasians, (n = 87 (82 Africans Americans); TPS 77.1 ± 8.4; P = .012). TPS score was not associated with refill rates (P = .190). Conclusions. Trust in physician is generally high in this group of glaucoma patients but varies slightly by race. Trust in physician was not associated with glaucoma medication adherence in this tertiary care population

Roles for a Lipid Phosphatase in the Activation of its Opposing Lipid Kinase

Fig4 is a phosphoinositide phosphatase that converts PI3,5P2 to PI3P. Paradoxically, mutation of Fig4 results in lower PI3,5P2, indicating that Fig4 is also required for PI3,5P2 production. Fig4 promotes elevation of PI3,5P2, in part, through stabilization of a protein complex that includes its opposing lipid kinase, Fab1, and the scaffold protein Vac14. Here we show that multiple regions of Fig4 contribute to its roles in the elevation of PI3,5P2: Its catalytic site, an N-terminal disease-related surface, and a C-terminal region. We show that mutation of the Fig4 catalytic site enhances the formation of the Fab1-Vac14-Fig4 complex, and reduces the ability to elevate PI3,5P2. This suggests that independent of its lipid phosphatase function, the active site plays a role in the Fab1-Vac14-Fig4 complex. We also show that the N-terminal disease-related surface contributes to the elevation of PI3,5P2 and promotes Fig4 association with Vac14 in a manner that requires the Fig4 C-terminus. We find that the Fig4 C-terminus alone interacts with Vac14 in vivo and retains some functions of full-length Fig4. Thus, a subset of Fig4 functions are independent of its phosphatase domain and at least three regions of Fig4 play roles in the function of the Fab1-Vac14-Fig4 complex

Validation of the Total Visual Acuity Extraction Algorithm (TOVA) for Automated Extraction of Visual Acuity Data From Free Text, Unstructured Clinical Records

Citation: Baughman DM, Su GL, Tsui I, Lee CS, Lee AY. Validation of the total visual acuity extraction algorithm (TOVA) for automated extraction of visual acuity data from free text, unstructured clinical records. Trans Vis Sci Tech. 2017;6(2):2, doi: 10.1167/tvst.6.2.2 Copyright 2017 The Authors Purpose: With increasing volumes of electronic health record data, algorithm-driven extraction may aid manual extraction. Visual acuity often is extracted manually in vision research. The total visual acuity extraction algorithm (TOVA) is presented and validated for automated extraction of visual acuity from free text, unstructured clinical notes. Methods: Consecutive inpatient ophthalmology notes over an 8-year period from the University of Washington healthcare system in Seattle, WA were used for validation of TOVA. The total visual acuity extraction algorithm applied natural language processing to recognize Snellen visual acuity in free text notes and assign laterality. The best corrected measurement was determined for each eye and converted to logMAR. The algorithm was validated against manual extraction of a subset of notes. Conclusions: The total visual acuity extraction algorithm is a novel tool for extraction of visual acuity from free text, unstructured clinical notes and provides an open source method of data extraction. Translational Relevance: Automated visual acuity extraction through natural language processing can be a valuable tool for data extraction from free text ophthalmology notes

64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist

© 2020 by the Society of Nuclear Medicine and Molecular Imaging. Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models

Reaction products and the X-ray structure of AmpDh2, a virulence determinant of Pseudomonas aeruginosa

4 pags, 4 figs. -- Supporting Information is available at the Publisher web.The zinc protease AmpDh2 is a virulence determinant of Pseudomonas aeruginosa, a problematic human pathogen. The mechanism of how the protease manifests virulence is not known, but it is known that it turns over the bacterial cell wall. The reaction of AmpDh2 with the cell wall was investigated, and nine distinct turnover products were characterized by LC/MS/MS. The enzyme turns over both the cross-linked and noncross-linked cell wall. Three high-resolution X-ray structures, the apo enzyme and two complexes with turnover products, were solved. The X-ray structures show how the dimeric protein interacts with the inner leaflet of the bacterial outer membrane and that the two monomers provide a more expansive surface for recognition of the cell wall. This binding surface can accommodate the 3D solution structure of the cross-linked cell wall. © 2013 American Chemical Society.This work was supported by a grant from the NIH (GM61629) and by grants BFU2011-25326 (the Spanish Ministry of Economy and Competitiveness) and S2010/BMD-2457 (the Government of Community of Madrid). The Mass Spectrometry & Proteomics Facility of the University of Notre Dame is supported by grant CHE0741793 from the NSF

Immunology and Microbiology Paucibacterial Microbiome and Resident DNA Virome of the Healthy Conjunctiva

Citation: Doan T, Akileswaran L, Andersen D, et al. Paucibacterial microbiome and resident DNA virome of the healthy conjunctiva. Invest Ophthalmol Vis Sci. 2016;57:5116-5126. DOI:10.1167/iovs.16-19803 PURPOSE. To characterize the ocular surface microbiome of healthy volunteers using a combination of microbial culture and high-throughput DNA sequencing techniques. METHODS. Conjunctival swab samples from 107 healthy volunteers were analyzed by bacterial culture, 16S rDNA gene deep sequencing (n ¼ 89), and biome representational in silico karyotyping (BRiSK; n ¼ 80). Swab samples of the facial skin (n ¼ 42), buccal mucosa (n ¼ 50), and environmental controls (n ¼ 27) were processed in parallel. 16S rDNA gene quantitative PCR was used to calculate the bacterial load in each site. Bacteria were characterized by site using principal coordinate analysis of metagenomics data. BRiSK data were analyzed for presence of fungi and viruses. RESULTS. Corynebacteria, Propionibacteria, and coagulase-negative Staphylococci were the predominant organisms identified by all three techniques. Quantitative 16S PCR demonstrated approximately 0.1 bacterial 16S rDNA/human actin copy on the ocular surface compared with greater than 10 16S rDNA/human actin copy for facial skin or the buccal mucosa. The conjunctival bacterial community structure is distinct compared with the facial skin (R ¼ 0.474, analysis of similarities P ¼ 0.0001), the buccal mucosa (R ¼ 0.893, P ¼ 0.0001), and environmental control samples (R ¼ 0.536, P ¼ 0.0001). 16S metagenomics revealed substantially more bacterial diversity on the ocular surface than other techniques, which appears to be artifactual. BRiSK revealed presence of torque teno virus (TTV) on the healthy ocular surface, which was confirmed by direct PCR to be present in 65% of all conjunctiva samples tested. CONCLUSIONS. Relative to adjacent skin or other mucosa, healthy ocular surface microbiome is paucibacterial. Its flora are distinct from adjacent skin. Torque teno virus is a frequent constituent of the ocular surface microbiome. (ClinicalTrials.gov number, NCT02298881.