220 results on '"T. Velasco"'
Search Results
2. Philippine Eagle Optimization Algorithm.
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Erika Antonette T. Enriquez, Renier G. Mendoza, and Arrianne Crystal T. Velasco
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- 2022
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3. COVID-19 Mass Vaccination Resource Calculator.
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Grace E. Pryor, Kelsea Marble, Ferdinand T. Velasco, Christoph U. Lehmann, and Mujeeb A. Basit
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- 2021
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4. Philippine Eagle Optimization Algorithm.
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Erika Antonette T. Enriquez, Renier G. Mendoza, and Arrianne Crystal T. Velasco
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- 2021
5. Mortality and other outcomes of patients with coronavirus disease pneumonia admitted to the emergency department: A prospective observational Brazilian study.
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Rodrigo A Brandão Neto, Julio F Marchini, Lucas O Marino, Julio C G Alencar, Felippe Lazar Neto, Sabrina Ribeiro, Fernando V Salvetti, Hassan Rahhal, Luz Marina Gomez Gomez, Caue G Bueno, Carine C Faria, Victor P da Cunha, Eduardo Padrão, Irineu T Velasco, Heraldo Possolo de Souza, and Emergencia USP Covid group
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Medicine ,Science - Abstract
BackgroundThe first cases of coronavirus disease (COVID-19) in Brazil were diagnosed in February 2020. Our Emergency Department (ED) was designated as a COVID-19 exclusive service. We report our first 500 confirmed COVID-19 pneumonia patients.MethodsFrom 14 March to 16 May 2020, we enrolled all patients admitted to our ED that had a diagnosis of COVID-19 pneumonia. Infection was confirmed via nasopharyngeal swabs or tracheal aspirate PCR. The outcomes included hospital discharge, invasive mechanical ventilation, and in-hospital death, among others.ResultsFrom 2219 patients received in the ED, we included 506 with confirmed COVID-19 pneumonia. We found that 333 patients were discharged home (65.9%), 153 died (30.2%), and 20 (3.9%) remained in the hospital. A total of 300 patients (59.3%) required ICU admission, and 227 (44.9%) needed invasive ventilation. The multivariate analysis found age, number of comorbidities, extension of ground glass opacities on chest CT and troponin with a direct relationship with all-cause mortality, whereas dysgeusia, use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker and number of lymphocytes with an inverse relationship with all-cause mortality.ConclusionsThis was a sample of severe patients with COVID-19, with 59.2% admitted to the ICU and 41.5% requiring mechanical ventilator support. We were able to ascertain the outcome in majority (96%) of patients. While the overall mortality was 30.2%, mortality for intubated patients was 55.9%. Multivariate analysis agreed with data found in other studies although the use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker as a protective factor could be promising but would need further studies.Trial registrationThe study was registered in the Brazilian registry of clinical trials: RBR-5d4dj5.
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- 2021
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6. Correction: Mortality and other outcomes of patients with coronavirus disease pneumonia admitted to the emergency department: A prospective observational Brazilian study.
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Rodrigo A Brandão Neto, Julio F Marchini, Lucas O Marino, Julio C G Alencar, Felippe Lazar Neto, Sabrina Ribeiro, Fernando S Valente, Hassan Rahhal, Luz Marina Gomez Gomez, Caue G Bueno, Carine C Faria, Victor P da Cunha, Eduardo Padrão, Irineu T Velasco, Heraldo Possolo de Souza, and Emergencia USP Covid group
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0244532.].
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- 2021
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7. The Mars Environmental Dynamics Analyzer, MEDA. A Suite of Environmental Sensors for the Mars 2020 Mission
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J. A. Rodriguez-Manfredi, M. de la Torre Juárez, A. Alonso, V. Apéstigue, I. Arruego, T. Atienza, D. Banfield, J. Boland, M. A. Carrera, L. Castañer, J. Ceballos, H. Chen-Chen, A. Cobos, P. G. Conrad, E. Cordoba, T. del Río-Gaztelurrutia, A. de Vicente-Retortillo, M. Domínguez-Pumar, S. Espejo, A. G. Fairen, A. Fernández-Palma, R. Ferrándiz, F. Ferri, E. Fischer, A. García-Manchado, M. García-Villadangos, M. Genzer, S. Giménez, J. Gómez-Elvira, F. Gómez, S. D. Guzewich, A.-M. Harri, C. D. Hernández, M. Hieta, R. Hueso, I. Jaakonaho, J. J. Jiménez, V. Jiménez, A. Larman, R. Leiter, A. Lepinette, M. T. Lemmon, G. López, S. N. Madsen, T. Mäkinen, M. Marín, J. Martín-Soler, G. Martínez, A. Molina, L. Mora-Sotomayor, J. F. Moreno-Álvarez, S. Navarro, C. E. Newman, C. Ortega, M. C. Parrondo, V. Peinado, A. Peña, I. Pérez-Grande, S. Pérez-Hoyos, J. Pla-García, J. Polkko, M. Postigo, O. Prieto-Ballesteros, S. C. R. Rafkin, M. Ramos, M. I. Richardson, J. Romeral, C. Romero, K. D. Runyon, A. Saiz-Lopez, A. Sánchez-Lavega, I. Sard, J. T. Schofield, E. Sebastian, M. D. Smith, R. J. Sullivan, L. K. Tamppari, A. D. Thompson, D. Toledo, F. Torrero, J. Torres, R. Urquí, T. Velasco, D. Viúdez-Moreiras, and S. Zurita
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Space Sciences (General) - Abstract
NASA’s Mars 2020 (M2020) rover mission includes a suite of sensors to monitor current environmental conditions near the surface of Mars and to constrain bulk aerosol properties from changes in atmospheric radiation at the surface. The Mars Environmental Dynamics Analyzer (MEDA) consists of a set of meteorological sensors including wind sensor, a barometer, a relative humidity sensor, a set of 5 thermocouples to measure atmospheric temperature at ∼1.5 m and ∼0.5 m above the surface, a set of thermopiles to characterize the thermal IR brightness temperatures of the surface and the lower atmosphere. MEDA adds a radiation and dust sensor to monitor the optical atmospheric properties that can be used to infer bulk aerosol physical properties such as particle size distribution, non-sphericity, and concentration. The MEDA package and its scientific purpose are described in this document as well as how it responded to the calibration tests and how it helps prepare for the human exploration of Mars. A comparison is also presented to previous environmental monitoring payloads landed on Mars on the Viking, Pathfinder, Phoenix, MSL, and InSight spacecraft.
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- 2021
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8. Peri-Implant Fractures Around Hindfoot Fusion Nails: A Systematic Literature Review and Classification System
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Brian T. Velasco BA, Jorge Briceno MD, Christopher Miller MD, Michael Y. Ye BSE, Ian Savage-Elliott MD, J. Kent Ellington MD, and John Y. Kwon MD
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Orthopedic surgery ,RD701-811 - Abstract
Category: Hindfoot Introduction/Purpose: Tibio-talo calcaneal (TTC) arthrodesis is increasingly performed for hindfoot arthrosis and other indications. Peri-implant fracture around hindfoot fusion nails has been previously reported and can be problematic to treat given multiple surgical considerations including the status of hind foot arthrodesis at time of fracture. We present a systematic review of the literature regarding peri-implant fractures around hindfoot fusion nails and propose a classification system to help guide treatment based on findings from the current literature as well as the collective experience of the senior authors. Methods: A review of the literature was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to identify clinical investigations in which peri-implant fractures or other hardware failures were observed as complications following TTC arthrodesis using hindfoot nails by two research assistants. The electronic database of PubMed / Medline was explored using specific search terms, Boolean operators, and field tags. The same query without field tags and under “Search All Text” was used to explore the electronic database of the Cochrane Library. Inclusion criteria was any clinical investigation that reported on outcomes after TTC arthrodesis using a hindfoot nail in at least one patient. Cadaveric and non-clinical investigations were excluded. Manuscript language for both databases was restricted to the English literature. Results: A total of 36 studies were identified which met inclusion criteria and reported clinical outcomes after TTC arthrodesis using a hindfoot fusion nail. Of the 36 studies, there was a total of 13 intraoperative fractures, 43 tibial stress fractures and 24 peri-implant fractures recorded in 12 of the 36 studies. Conclusion: Peri-implant fracture following tibio-talo calcaneal arthrodesis using a hindfoot intramedullary nail is an uncommon but problematic condition to treat. General heterogeneity of patients and indications as well as a lack of descriptive detail in the current literature makes meta-analysis difficult. Given the lack of consensus on treatment, a classification system may be helpful to guide clinical practice.
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- 2019
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9. Online Ratings and Reviews of American Orthopedic Foot and Ankle Surgeons
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Brian T. Velasco BA, Bonnie Chien MD, John Y. Kwon MD, and Christopher P. Miller MD, MHS
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Orthopedic surgery ,RD701-811 - Abstract
Category: Practice Management Introduction/Purpose: Utilization by patients of physician rating websites continues to expand. There is limited information on how these websites function and influence patient perception and physicians’ practices. No study has specifically investigated online ratings and comments of orthopedic foot and ankle surgeons. In this study, we identified what factors impact online ratings and comments for this subset of surgeons. Methods: A total of 210 orthopedic foot and ankle surgeons in or near metropolitan areas were randomly selected from the American Orthopaedic of Foot & Ankle Society (AOFAS) website. Demographic information, ratings (number of stars), and comments were reviewed on the three most visited public domain physician ratings websites: HealthGrades.com (HealthGrades), Vitals.com (Vitals), and Ratemds.com (Ratemds). Content differences between positive and negative comments were evaluated. Results: Orthopedic foot and ankle surgeons had a mean rating of 4.03 ± 0.57 out of 5 stars. A high percentage (84%) of the total number of ratings were either 1-star (17%) or 5-stars (67%). Most positive comments related to outcome, physician personality, and communication while most negative comments related to outcome, bedside manner, and waiting time. Chi-square analysis revealed statistically significant proportions of positive comments pertaining to surgeon-dependent factors (eg, physician personality, knowledge, skills) and of negative comments concerning surgeon-independent factors (eg, waiting time, logistics). Conclusion: This is the first study examining online ratings and written comments of orthopedic foot and ankle surgeons. Surgeons had a generally favorable rating and were likely to have positive comments. Patients were likely to write positive comments about surgeon personality and communication, and negative comments pertaining to bedside manner and waiting time. Knowledge and management of online content may allow surgeons to improve patient satisfaction and online ratings.
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- 2019
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10. A single-cell expression atlas of human AML-LScs unravels the contribution of HIF pathway and its therapeutic potential
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T Velasco-Hernandez, JL Trincado, M Vinyoles, A Closa, O Molina, L Velten, C Bueno, E Eyras, H Heyn, and P Menendez
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- 2022
11. Effects of terlipressin and naloxone compared with epinephrine in a rat model of asphyxia-induced cardiac arrest
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Herlon S. Martins, Marcia K. Koike, and Irineu T. Velasco
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Cardiopulmonary Resuscitation ,Cardiac Arrest ,Naloxone ,Lypressin/Analogs and Derivatives ,Asphyxia ,Medicine (General) ,R5-920 - Abstract
OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine.
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- 2013
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12. lasR/rhlR Expression Linked to Quorum Sensing-Mediated Biofilm Formation in Pseudomonas aeruginosa Using Gold Nanoparticles Synthesized with Ethnobotanical Extracts
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Somar Israel D. Fernando, Alexander T. Velasco, and Khristina G. Judan Cruz
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0301 basic medicine ,biology ,Chemistry ,Pseudomonas aeruginosa ,030106 microbiology ,Biomedical Engineering ,Biofilm ,Virulence ,Bioengineering ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Antimicrobial ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,Quorum sensing ,030104 developmental biology ,Gene expression ,medicine ,Antibacterial activity ,Bacteria - Abstract
The rapid emergence of multidrug-resistant bacteria endangers the efficacy of antibiotics, which leads to the search for novel anti-infective measures that do not rely on antibiotics. Quorum sensing inhibition (QSI) presents potential in making straightforward approach in disrupting cell-to-cell communication in bacteria, thereby decreasing virulence factors such as biofilm formation. To assess QSI of gold nanoparticles conjugated with ethnobotanical extracts (AuNPs + CEs) against Pseudomonas aeruginosa, antibacterial activity was assessed as a preliminary test and AuNPs + CEs that exhibited antibacterial activity were not used in the biofilm formation assay to rule out antimicrobial decrease in biofilm formation. RNA of bacterial sample treated with AuNPs + CEs with biofilm formation inhibitory activity was subjected to gene expression analysis. The results revealed that all AuNPs + CEs used in the microtiter biofilm formation assay showed a significant decrease in biofilm formation in P. aeruginosa. Gene expression analysis of lasR and rhlR revealed that AuNPs + CEs that exhibited decrease in biofilm formation also have downregulated expression of lasR and rhlR, an indication of quorum sensing–mediated decrease in virulence. Furthermore, samples treated with AuNPs + CEs, showed lower expression of lasR compared to samples treated with only CEs. This result presents the role of gold nanoparticles in enhancing the delivery of bioactive compounds present in the ethnobotanicals, with QSI activity against P. aeruginosa. Hence, the result offers the potential of AuNPs + CEs in QSI of disease-causing human pathogens.
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- 2020
13. An Automated Model to Identify Adult Medicine Patients at Risk for 30-Day Readmission Using Electronic Medical Record Data.
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Ruben Amarasingham, Ferdinand T. Velasco, Christopher A. Clark, Song Zhang 0001, Brian Lucena, Bin Xie, Ying Ma, and Ethan A. Halm
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- 2013
14. Enabling Cross-Platform Clinical Decision Support through Web-Based Decision Support in Commercial Electronic Health Record Systems: Proposal and Evaluation of Initial Prototype Implementations.
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Mingyuan Zhang, Ferdinand T. Velasco, Robert Clayton Musser, and Kensaku Kawamoto
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- 2013
15. Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated Aβ Oligomers.
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Kyle C Wilcox, Matthew R Marunde, Aditi Das, Pauline T Velasco, Benjamin D Kuhns, Michael T Marty, Haoming Jiang, Chi-Hao Luan, Stephen G Sligar, and William L Klein
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Medicine ,Science - Abstract
Despite their value as sources of therapeutic drug targets, membrane proteomes are largely inaccessible to high-throughput screening (HTS) tools designed for soluble proteins. An important example comprises the membrane proteins that bind amyloid β oligomers (AβOs). AβOs are neurotoxic ligands thought to instigate the synapse damage that leads to Alzheimer's dementia. At present, the identities of initial AβO binding sites are highly uncertain, largely because of extensive protein-protein interactions that occur following attachment of AβOs to surface membranes. Here, we show that AβO binding sites can be obtained in a state suitable for unbiased HTS by encapsulating the solubilized synaptic membrane proteome into nanoscale lipid bilayers (Nanodiscs). This method gives a soluble membrane protein library (SMPL)--a collection of individualized synaptic proteins in a soluble state. Proteins within SMPL Nanodiscs showed enzymatic and ligand binding activity consistent with conformational integrity. AβOs were found to bind SMPL Nanodiscs with high affinity and specificity, with binding dependent on intact synaptic membrane proteins, and selective for the higher molecular weight oligomers known to accumulate at synapses. Combining SMPL Nanodiscs with a mix-incubate-read chemiluminescence assay provided a solution-based HTS platform to discover antagonists of AβO binding. Screening a library of 2700 drug-like compounds and natural products yielded one compound that potently reduced AβO binding to SMPL Nanodiscs, synaptosomes, and synapses in nerve cell cultures. Although not a therapeutic candidate, this small molecule inhibitor of synaptic AβO binding will provide a useful experimental antagonist for future mechanistic studies of AβOs in Alzheimer's model systems. Overall, results provide proof of concept for using SMPLs in high throughput screening for AβO binding antagonists, and illustrate in general how a SMPL Nanodisc system can facilitate drug discovery for membrane protein targets.
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- 2015
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16. Impact of a computerized alert during physician order entry on medication dosing in patients with renal impairment.
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Michael I. Oppenheim, Cristina Vidal, Ferdinand T. Velasco, Aurelia Boyer, Mary Reich Cooper, Joseph G. Hayes, and William W. Frayer
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- 2002
17. Electronic medical record-based multicondition models to predict the risk of 30 day readmission or death among adult medicine patients: validation and comparison to existing models.
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Ruben Amarasingham, Ferdinand T. Velasco, Bin Xie, Christopher A. Clark, Ying Ma, Song Zhang 0001, Deepa Bhat, Brian Lucena, Marco D. Huesch, and Ethan A. Halm
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- 2015
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18. Dynamic constriction and fission of endoplasmic reticulum membranes by reticulon
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Espadas J., Pendin D., Bocanegra R., Escalada A., Misticoni G., Trevisan T., Velasco del Olmo A., Montagna A., Bova S., Ibarra B., Kuzmin P.I., Bashkirov P.V., Shnyrova A.V., Frolov V.A., Daga A. and This work was partially supported by NIH R01GM121725 to V.A.F., a 5×1000 grant from the Italian Ministry of Health and Telethon GGP11189 to A.D., Spanish Ministry of Science, Innovation and Universities grants BFU2015-70552-P to V.A.F. and A.V.S., and BFU2015-63714-R and PGC2018-099341-B-I00 to B.I., Basque Government grant IT1196-19, Russian Science Foundation Grant No. 17-75-30064 and Ministry of Science and Higher Education of the Russian Federation.
- Published
- 2019
19. Multidisciplinary palliative care at the end of life of critically ill patient
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Á, Estella, T, Velasco, I, Saralegui, J M, Velasco Bueno, O, Rubio Sanchiz, M, Del Barrio, and M C, Martín Delgado
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Patient Care Team ,Terminal Care ,Critical Illness ,Palliative Care ,Humans - Published
- 2018
20. AB0390 Relationship between body mass index and personality in an early arthritis cohort of patients
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A. M. ortiz garcía, T. Velasco Ripoll, P. Moreno Fresneda, D. Martinez-Quintanilla Jimenez, I. González Álvaro, and N. García Castañeda
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education.field_of_study ,medicine.medical_specialty ,Multivariate analysis ,business.industry ,Population ,Arthritis ,Overweight ,medicine.disease ,Affect (psychology) ,Rheumatoid arthritis ,Internal medicine ,Cohort ,Medicine ,medicine.symptom ,business ,education ,Body mass index - Abstract
Background According to previously reported data from our early arthritis registry (PEARL, Princess Early Arthritis Register Longitudinal), patients with a higher BMI have higher scores in pain and disability scales. We also described some years ago that, in the same population, the structure of personality explored with the PANAS questionnaire (Positive and Negative Affect Scale) affects some outcomes in arthritis measures. Specifically, higher scores on the negative affect subscale associate higher scores in pain and disability scales. Objectives To analyse the relationship between BMI and the structure of the affect in the PEARL cohort. Methods PEARL registry includes patients with early arthritis (less than one year of duration), in whom, sociodemographic, disease related and treatment data are recorded in five protocolised visits. We analysed data from those patients in which the PANAS questionnaire data were available and whose classification, after 2 years of follow-up, were rheumatoid arthritis -according to the 1987 ACR classification criteria – or undifferntiated arthritis. The structure of the affect was evaluated with the PANAS questionnaire administered in one single occasion. This questionnaire is used to evaluate the components of positive (PA) and negative affect (NA). It consists of 20 questions and the score obtained from its administration ranges between 10 and 50 points for each affect. The WHO definition was used for low weight, normal weight, overweight and obesity (BMI Results We analysed the data of the 71 patients for whom PA values were available and of the 65 patients with NA values available. There was not a statistically significant relationship observed between PA and NA and BMI when analysed as a continuous variable (R=-0.12, p=0.25 and R=-0.1, p=0.36, respectively) or as a categorical variable. However, there was a non-significant trend to lower scores for both PA and NA in patients with a higher BMI (figure 1). The multivariate analyses, adjusted for sex, age and study level, also showed no statistically significant relationship between the BMI (analysed as continuous or categorical variable) and the PA and NA; but there was also a non-significant trend that sets a relationship between lower scores of both PA and NA and higher BMI values. Conclusions In our early arthritis registry there is no relationship between the BMI and the structure of the affect evaluated through the PANAS questionnaire. However, it is necessary to evaluate this relationship in a greater number of patients and in different populations before discarding this relationship definitely. Disclosure of Interest None declared
- Published
- 2018
21. Cuidados paliativos multidisciplinares al final de la vida del paciente crítico
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T. Velasco, M.C. Martín Delgado, J.M. Velasco Bueno, O. Rubio Sanchiz, Angel Estella, I. Saralegui, and M. del Barrio
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business.industry ,Medicine ,Critical Care and Intensive Care Medicine ,business ,Humanities - Published
- 2019
22. Multidisciplinary palliative care at the end of life of critically ill patient
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I. Saralegui, M.C. Martín Delgado, O. Rubio Sanchiz, Angel Estella, M. del Barrio, T. Velasco, and J.M. Velasco Bueno
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medicine.medical_specialty ,Palliative care ,Patient care team ,Multidisciplinary approach ,Critically ill ,business.industry ,Critical illness ,medicine ,MEDLINE ,Intensive care medicine ,business - Published
- 2019
23. Poster Session 3: Tuesday 5 May 2015, 08:30-12:30 * Room: Poster Area
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M. Ferreira, M. Robalo, T. Saraiva, M. Cunha, L. Goncalves, A. Albuquerque, D. Ramos, G. Costa, J. Lima, M. Pego, I. Peovska, J. Davceva Pavlovska, D. Pop Gorceva, M. Zdravkovska, M. Vavlukis, N. Kostova, D. S. Bulugahapitiya, A. Feben, M. Avison, J. Foley, J. Martin, M. A. De Graaf, I. Van Den Hoogen, A. Leen, A. Kharagjitsingh, L. Kroft, J. Jukema, J. Bax, A. Scholte, K. Patel, M. Mahan, K. Ananthasubramaniam, G. Durmus Altun, M. Alpay, A. Altun, D. Andreini, G. Pontone, S. Mushtaq, E. Bertella, E. Conte, C. Segurini, V. Volpato, M. Petulla, A. Baggiano, M. Pepi, J. Van Dijk, E. Huizing, P. Jager, C. Slump, J. Ottervanger, J. Van Dalen, E. Yambao, H. Calleja, A. Sibulo, A. Ramirez Moreno, J. Siles Rubio, M. Noureddine, J. Munoz-Bellido, R. Bravo, F. Martinez, A. Valle, A. Milan, L. Inigo-Garcia, T. Velasco, V. L. Ramaiah, J. S. Devanbu, S. K. Taywade, V. S. Hejjaji, N. Zafrir, T. Bental, A. Gutstein, A. Solodky, I. Mats, R. Kornowski, J. Lagan, J. Hasleton, M. Meah, J. Mcshane, R. Trent, S. Massalha, O. Israel, A. Koskosi, M. Kopelovich, I. Marai, S. Venuraju, A. Jeevarethinam, A. Dumo, S. Ruano, D. Darko, M. Cohen, D. Nair, M. Rosenthal, R. Rakhit, A. Lahiri, M. N. Pizzi, A. Roque, N. Fernandez-Hidalgo, H. Cuellar-Calabria, M. Gonzalez-Alujas, G. Oristrell, J. Rodriguez-Palomares, P. Tornos, S. Aguade-Bruix, O. Smettei, R. Abazid, W. M. K. Ahmed, W. Samy, N. Behairy, O. Tayeh, A. Hassan, A. Berezin, A. Kremzer, T. Samura, T. Berezina, G. Scrima, G. Bertuccio, N. Canseco Nadia, C. Cruz Raul, G. Gonzalez Cristian, S. Hernandez Salvador, E. Alexanderson Erick, B. Zerahn, Z. Shugushev, D. Maximkin, A. Chepurnoy, O. Volkova, A. Tsedenova, A. Faibushevich, V. Baranovich, H. Yoshida, A. Mizukami, A. Matsumura, M. Keller, S. Silber, A. Falcao, R. Imada, L. Azouri, M. Giorgi, R. Santos, S. Mello, R. Kalil Filho, J. Meneghetti, W. Chalela, L. Kanni, T. Ohrman, A. T. Nygren, R. Irabi, T. Parisotto, J. Soares, S. Burrell, C. Lo, K. Zavadovskyi, M. Gulya, Y. Lishmanov, A. Amin, A. Kandeel, M. Shaban, Z. Nawito, F. Caobelli, A. Soffientini, J. Thackeray, F. Bengel, C. Pizzocaro, U. Guerra, S. Hellberg, J. Silvola, M. Kiugel, H. Liljenback, N. Savisto, A. Thiele, V. Laine, J. Knuuti, A. Roivainen, A. Saraste, B. Ismail, T. Hadizad, R. Dekemp, R. Beanlands, J. N. Dasilva, F. Hyafil, E. Sorbets, V. Duchatelle, F. Rouzet, D. Le Guludec, L. Feldman, V. Martire, C. De Pierris, M. Martire, E. Pis Diez, V. Ramaiah, A. Lebasnier, D. Legallois, D. Peyronnet, C. Desmonts, G. Zalcman, B. Bienvenu, D. Agostini, A. Manrique, V. Solomyanyy, I. Mintale, M. Zabunova, I. Narbute, M. Ratniece, E. Jakobsons, K. Kaire, G. Kamzola, I. Briede, S. Jegere, A. Erglis, S. Mostafa, M. Abdelkader, H. Abdelkader, S. Abdelkhlek, E. Khairy, S. Huidu, A. Popescu, S. Lacau, A. Huidu, D. Dimulescu, S. Sayed, F. Al Harby, A. Habeeb, H. Saqqah, S. Merganiab, J. Selvanayagam, H. Harms, L. Tolbod, N. Hansson, T. Kero, L. Orndahl, W. Kim, K. Bouchelouche, H. Wiggers, J. Frokiaer, J. Sorensen, E. Hansen, and T. Zaremba
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Nuclear magnetic resonance ,Volume (thermodynamics) ,11c acetate ,medicine.diagnostic_test ,Positron emission tomography ,business.industry ,Head to head ,medicine ,Resonance ,Radiology, Nuclear Medicine and imaging ,General Medicine ,Cardiology and Cardiovascular Medicine ,business - Published
- 2015
24. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease
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Pauline T. Velasco, Vinayak P. Dravid, William L. Klein, Kirsten L. Viola, Jane Wang, James Sbarboro, Ruchi Sureka, Chang Lu, Joseph C. Phan, Hrushikesh M. Joshi, Mrinmoy De, Shaleen Vasavada, Pottumarthi V. Prasad, Pascale N. Lacor, Keith W. MacRenaris, E. Alex Waters, Summer Wu, Sreyesh Satpathy, and Maira A. Bicca
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magnetic nanoparticles ,Abeta Oligomers ,diagnostic imaging ,Biomedical Engineering ,Contrast Media ,Hippocampus ,Bioengineering ,Nanotechnology ,02 engineering and technology ,Hippocampal formation ,Sensitivity and Specificity ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Medical imaging ,Animals ,Humans ,antibodies ,General Materials Science ,Electrical and Electronic Engineering ,ADDLs ,Amyloid beta-Peptides ,medicine.diagnostic_test ,Molecular pathology ,Chemistry ,Reproducibility of Results ,Magnetic resonance imaging ,Human brain ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,Magnetic Resonance Imaging ,Atomic and Molecular Physics, and Optics ,3. Good health ,medicine.anatomical_structure ,Molecular Diagnostic Techniques ,Positron emission tomography ,Alzheimer's disease ,0210 nano-technology ,Alzheimer’s disease ,Neuroscience ,Biomarkers ,030217 neurology & neurosurgery ,MRI - Abstract
One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management. A magnetic resonance imaging probe that binds specifically to neurotoxic amyloid-beta oligomers can potentially be used for early detection of Alzheimer's disease.
- Published
- 2014
25. AB1231-HPR Living with rheumatoid arthritis in spain. a qualitative study
- Author
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J Zarco-Colon, N Sapena-Fortea, A Palmar-Santos, M Ramasco-Gutierrez, T Velasco-Ripoll, A Pedraz-Marcos, Claire Hale, and J Martín-Alarcόn
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medicine.medical_specialty ,biology ,Medical treatment ,business.industry ,Garcia ,Coding (therapy) ,Context (language use) ,Disease ,medicine.disease ,biology.organism_classification ,Rheumatoid arthritis ,Family medicine ,medicine ,Thematic analysis ,business ,Qualitative research - Abstract
Background The impact of rheumatoid arthritis (RA) on the lives of people is a constant in the studies explored. However, research shows the lack of impact that this has on clinical consultations, despite the influence it may have on the attitude of the person with RA towards treatment adherence. In the Spanish context, except for the study by Devillard & Otegui (1991), the experience of living with RA has scarcely been addressed. Objectives To explore the experience of living with RA in Spain. Methods In-depth interviews were conducted with a group of patients from two hospitals in the two main Spanish cities: Madrid and Barcelona. The interviews were conducted between April 2014 and February 2015. Thematic analysis was done, identifying the main themes and subthemes and organizing data in a coding framework that allows their interpretation Results Patients with disease activity moderate or severe (DAS28 >3.2), and already treated with DMARD, were aged 40–79, 15 were women and 4 men. Three main categories emerged from the discourses. (Table 1) Conclusions RA patients know well what is it like to get up in the morning, tired, stiff, sore and having to rethink their day. Prioritization and planning activities are key to the organization of the activity and rest. Families and external aid, in case they can afford it, are the most common supports on which the requested supports pivot. The constant development of new therapeutic strategies and outbreaks of the disease determine the use of an important therapeutic arsenal, with unpleasant side effects, and that should be administered in a hospital setting. This need to rely on medical treatment also extends to doctors, as part of the therapeutic strategy. Nurses are absent from the speeches of our participants RA patients in our study feel they are mainly on their own to cope with their disease. The new therapeutic strategies have improved the symptoms9 control, but they feel they need more than drugs to cope with their daily life. Contrary to the variety of professionals, institutions and organizations that try to empower patients to self manage their disease in other countries, the Spanish attention pivot mainly in rheumatologists. References Devillard, Marie Jose; Otegui, Rosario; Garcia, Pilar. La voz callada. Aproximaciones antropolόgico-social al enfermo de artritis reumatoide. Madrid: Comunidad de Madrid. Consejeria de Salud; 1991. Disclosure of Interest None declared
- Published
- 2017
26. A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers
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Lei A. Qin, Josette M. Kamel, Izolda A. Popova, Kirsten L. Viola, Kevin Luo, Anthea Weng, Milena A. Barcelos, Adrian M. Bebenek, William L. Klein, Erika N. Cline, Adriano Sebollela, Vanessa N. Bezerra, Pauline T. Velasco, Natalia M. Lyra e Silva, Nadia DiNunno, Jay Ahn, Pascale N. Lacor, Xiao-xia Sun, Jason Patel, Sergio T. Ferreira, and Nathalia R. Pinheiro
- Subjects
ANTICORPOS ,0301 basic medicine ,chemistry.chemical_classification ,biology ,Molecular mass ,Wild type ,Endogeny ,Peptide ,Hippocampal formation ,medicine.disease_cause ,Biochemistry ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,chemistry ,biology.protein ,medicine ,Antibody ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics.
- Published
- 2017
27. Ischnura Graellsii(Insecta: Odonata) A Water Pollution Biovulnerability Indicator-Probability Mapping Using Spatial Uncertainty
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Maria Teresa Durães Albuquerque, P. Casanueva, Isabel Margarida Horta Ribeiro Antunes, T. Velasco, G. Sanz, and F. Campos
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0106 biological sciences ,Hydrology ,Watershed ,biology ,Watershed area ,010501 environmental sciences ,Odonata ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Altitude ,Habitat ,Environmental Chemistry ,Environmental science ,Water quality ,Surface water ,Bioindicator ,0105 earth and related environmental sciences ,General Environmental Science ,Water Science and Technology - Abstract
Monitoring changes of anthropogenic impacts from a broad scope of species in biodiversity research require practical, easy-to-use and efficient assessment as well as monitoring methods. Odonates (Insecta: Odonata) are a valuable tool for assessing freshwater systems' quality and have been used as bioindicators of environmental variety. The Agueda watershed, located in the central west of the Iberian Peninsula, shows an exponential increase in the last 60 years of natural resource exploitation coupled with alterations in consumer habits, causing significant environmental changes and deferred direct effects on the natural habitats. Fourteen river sites, selected a priori, were sampled. Adult odonates were collected using standardized methods. Selected environmental variables and water quality parameters were evaluated in situ. Precipitation and altitude were the most important physical, environmental variables in explaining the assemblage structure. Meaningful abiotic–biotic as well as biotic–biotic relationships were set up. Furthermore, situations in the urbanized watershed area showed to be highly impacted and closely related with damselfly Ischnura graellsii, which should be targeted as a possible vulnerability indicator for polluted fresh waters. A probability map for Ischnura graellsii distribution was performed using indicator kriging with external drift and spatial uncertainty obtain through the calculation of two categorical maps (binary), corresponding to the mean (0.485) and the trimmed mean by discharging the 10% lower distribution tail (0.533). The subsequent overlapping of both categorical maps (binary) allowed the definition of the higher spatial uncertainty map for surface water contamination. Copyright © 2014 John Wiley & Sons, Ltd.
- Published
- 2014
28. Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice
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Kirsten L. Viola, Pascale N. Lacor, Chun Xiao, Balwantsinh C. Chauhan, Pauline T. Velasco, William L. Klein, Neelima B. Chauhan, and Francesca Davis
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Male ,Olfactory system ,Rostral migratory stream ,Central nervous system ,Mice, Transgenic ,Mucous membrane of nose ,Antibodies ,Article ,Mice ,Cognition ,Alzheimer Disease ,medicine ,Animals ,Humans ,Trigeminal Nerve ,Maze Learning ,Administration, Intranasal ,Amyloid beta-Peptides ,biology ,business.industry ,General Neuroscience ,Brain ,General Medicine ,medicine.disease ,Immunohistochemistry ,Bioavailability ,Psychiatry and Mental health ,Clinical Psychology ,medicine.anatomical_structure ,Immunology ,biology.protein ,Nasal administration ,Geriatrics and Gerontology ,Alzheimer's disease ,Antibody ,business - Abstract
Alzheimer’s disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice.
- Published
- 2013
29. REMS: The Environmental Sensor Suite for the Mars Science Laboratory Rover
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A. Pena, Ari-Matti Harri, Nilton O. Renno, Luis Castañer, Juan Moreno, María Paz Zorzano, I. McEwan, Henrik Kahanpää, Felipe Gómez, A. Lepinette, Miguel Ramos, F. Torrero, R. Urqui, Luis Vázquez, J. Romeral, Robert M. Haberle, Mark I. Richardson, Sara Navarro, Jesús Martínez-Frías, M. de la Torre Juárez, Lukasz Kowalski, M. A. de Pablo, Jouni Polkko, J. A. Rodríguez-Manfredi, J. Verdasca, J. Torres, Jacobo Martín, Carlos Armiens, J. Ricart, Maria Genzer, Eduardo Sebastián, V. Jiménez, Manuel Dominguez, L. Mora, Javier Martin-Torres, J. Serrano, Javier Gómez-Elvira, T. Velasco, V. Peinado, Universitat Politècnica de Catalunya. Departament d'Enginyeria Electrònica, and Universitat Politècnica de Catalunya. MNT - Grup de Recerca en Micro i Nanotecnologies
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Ultraviolet radiation ,Meteorology ,Atmosphere ,Mart (Planeta) -- Atmòsfera ,Habitability ,Temperature ,Mars ,Mars Science Laboratory ,Astronomy and Astrophysics ,Wind ,Mars Exploration Program ,Mars (Planet) -- Atmosphere ,Radiation assessment detector ,Pressure sensor ,Wind speed ,Relative Humidity ,Space and Planetary Science ,Martian surface ,Environmental monitoring ,Pressure ,Environmental science ,Enginyeria electrònica::Instrumentació i mesura [Àrees temàtiques de la UPC] ,Timekeeping on Mars ,Remote sensing - Abstract
The Rover Environmental Monitoring Station (REMS) will investigate environ- mental factors directly tied to current habitability at the Martian surface during the Mars Sci- ence Laboratory (MSL) mission. Three major habitability factors are addressed by REMS: the thermal environment, ultraviolet irradiation, and water cycling. The thermal environment is determined by a mixture of processes, chief amongst these being the meteorological. Ac- cordingly, the REMS sensors have been designed to record air and ground temperatures, pressure, relative humidity, wind speed in the horizontal and vertical directions, as well as ultraviolet radiation in different bands. These sensors are distributed over the rover in four places: two booms located on the MSL Remote Sensing Mast, the ultraviolet sensor on the rover deck, and the pressure sensor inside the rover body. Typical daily REMS observa- tions will collect 180 minutes of data from all sensors simultaneously (arranged in 5 minute hourly samples plus 60 additional minutes taken at times to be decided during the course of the mission). REMS will add significantly to the environmental record collected by prior missions through the range of simultaneous observations including water vapor; the ability to take measurements routinely through the night; the intended minimum of one Martian year of observations; and the first measurement of surface UV irradiation. In this paper, we describe the scientific potential of REMS measurements and describe in detail the sensors that constitute REMS and the calibration procedures
- Published
- 2012
30. Deleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5
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Anis Contractor, Pauline T. Velasco, Jian Xu, William L. Klein, Antoine Triller, Marianne Renner, and Pascale N. Lacor
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Receptor, Metabotropic Glutamate 5 ,Neuroscience(all) ,Plasma protein binding ,Hippocampal formation ,Biology ,Receptors, Metabotropic Glutamate ,Calcium in biology ,MOLNEURO ,Article ,Synapse ,Rats, Sprague-Dawley ,Mice ,Extracellular ,Animals ,Cells, Cultured ,Mice, Knockout ,Neurons ,Amyloid beta-Peptides ,Metabotropic glutamate receptor 5 ,Protein Stability ,General Neuroscience ,Glutamate receptor ,Extracellular Matrix ,Rats ,Biochemistry ,Metabotropic glutamate receptor ,SIGNALING ,Synapses ,Biophysics ,CELLBIO ,Protein Binding - Abstract
Soluble oligomers of amyloid beta (Abeta) play a role in the memory impairment characteristic of Alzheimer's disease. Acting as pathogenic ligands, Abeta oligomers bind to particular synapses and perturb their function, morphology, and maintenance. Events that occur shortly after oligomer binding have been investigated here in live hippocampal neurons by single particle tracking of quantum dot-labeled oligomers and synaptic proteins. Membrane-attached oligomers initially move freely, but their diffusion is hindered markedly upon accumulation at synapses. Concomitantly, individual metabotropic glutamate receptors (mGluR5) manifest strikingly reduced lateral diffusion as they become aberrantly clustered. This clustering of mGluR5 elevates intracellular calcium and causes synapse deterioration, responses prevented by an mGluR5 antagonist. As expected, clustering by artificial crosslinking also promotes synaptotoxicity. These results reveal a mechanism whereby Abeta oligomers induce the abnormal accumulation and overstabilization of a glutamate receptor, thus providing a mechanistic and molecular basis for Abeta oligomer-induced early synaptic failure.
- Published
- 2010
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31. Alzheimer's-associated Aβ oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal
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Pauline T. Velasco, William L. Klein, Matthew R. Blankenship, William Roth, Fernanda G. De Felice, Jason Pitt, Paul A. S. Breslin, Amos B. Smith, and Pascale N. Lacor
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Amyloid ,Protein Conformation ,Amyloid beta ,Immunoblotting ,Fluorescent Antibody Technique ,Peptide ,Toxicology ,Hippocampus ,Oligomer ,Article ,Antibodies ,Cyclopentane Monoterpenes ,Antigen-Antibody Reactions ,Synapse ,chemistry.chemical_compound ,Phenols ,Oleocanthal ,Animals ,Humans ,Neurotoxin ,Cells, Cultured ,Pharmacology ,chemistry.chemical_classification ,Aldehydes ,Amyloid beta-Peptides ,Microscopy, Confocal ,Dose-Response Relationship, Drug ,biology ,Neuropeptides ,Colocalization ,Peptide Fragments ,Molecular Weight ,Neuroprotective Agents ,chemistry ,Biochemistry ,Synapses ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Protein Multimerization - Abstract
It now appears likely that soluble oligomers of amyloid-beta1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Abeta oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Abeta species, when assayed with both sequence- and conformation-specific Abeta antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Abeta-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.
- Published
- 2009
32. Targeting Generation of Antibodies Specific to Conformational Epitopes of Amyloid β-Derived Neurotoxins
- Author
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William L. Klein, Kirsten L. Viola, Mary P. Lambert, and Pauline T. Velasco
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Pharmacology ,biology ,Mechanism (biology) ,General Neuroscience ,Neurodegeneration ,medicine.disease ,Epitope ,Pathogenesis ,Synapse ,Membrane protein ,medicine ,biology.protein ,Antibody ,Alzheimer's disease ,Neuroscience - Abstract
Individuals with early Alzheimers disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by toxic Aβ oligomers (also known as ADDLs). ADDLs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. The AD-like cellular pathologies induced by ADDLs suggest their impact could provide a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Discovery of these new toxins has provided an appealing target for disease-modifying immunotherapy. For optimal protection against these toxins, antibodies should bind to the pathological oligomers without being depleted by their monomeric subunits, which are rapidly generated by membrane protein turnover. A solution to this problem is likely to come from the continued development of conformation-specific antibodies, as described here. Prototype conformation-specific antibodies, not yet in the clinic, have been introduced and utilized in multiple applications for their ability to bind with high specificity and affinity to ADDLs. It can be anticipated that further development of such antibodies for use in clinical trials will come in the near future.
- Published
- 2009
33. Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers
- Author
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Kirsten L. Viola, Mary P. Lambert, Pauline T. Velasco, Wei Qin Zhao, Fernanda G. De Felice, Helena Decker, Theresa R. Bomfim, Marcelo N. N. Vieira, William L. Klein, and Sergio T. Ferreira
- Subjects
medicine.medical_specialty ,Multidisciplinary ,biology ,Amyloid beta ,Insulin ,medicine.medical_treatment ,Synapse ,Insulin receptor ,Endocrinology ,Downregulation and upregulation ,Internal medicine ,Ca2+/calmodulin-dependent protein kinase ,biology.protein ,medicine ,Casein kinase 2 ,Signal transduction - Abstract
Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Aβ) oligomers. Mechanistically, soluble Aβ oligomers, also referred to as Aβ-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.
- Published
- 2009
34. Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers
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Paul Acton, Sara J. Fernandez, Gene G. Kinney, Diana Wu, William L. Klein, Mary P. Lambert, Elizabeth Chen-Dodson, Paul J. Shughrue, Eileen H. Bigio, Jasna Jerecic, Fernanda G. De Felice, Pauline T. Velasco, and Pascale N. Lacor
- Subjects
Aging ,Hippocampus ,tau Proteins ,Hippocampal formation ,SRC Family Tyrosine Kinase ,Article ,chemistry.chemical_compound ,Alzheimer Disease ,medicine ,Extracellular ,Humans ,LY294002 ,Phosphorylation ,Cells, Cultured ,Neurons ,Amyloid beta-Peptides ,General Neuroscience ,medicine.disease ,Peptide Fragments ,Cell biology ,chemistry ,Biochemistry ,Neurology (clinical) ,Geriatrics and Gerontology ,Alzheimer's disease ,Developmental Biology ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar A beta in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble A beta oligomers (ADDLs). A major question is how these disparate facets of AD pathology are mechanistically related. Here we show that, independent of the presence of fibrils, ADDLs stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells at epitopes characteristically hyperphosphorylated in AD. A monoclonal antibody that targets ADDLs blocked their attachment to synaptic binding sites and prevented tau hyperphosphorylation. Tau phosphorylation was blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP1), and by the phosphatidylinositol-3-kinase inhibitor LY294002. Significantly, tau hyperphosphorylation was also induced by a soluble aqueous extract containing A beta oligomers from AD brains, but not by an extract from non-AD brains. A beta oligomers have been increasingly implicated as the main neurotoxins in AD, and the current results provide a unifying mechanism in which oligomer activity is directly linked to tau hyperphosphorylation in AD pathology.
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- 2008
35. Why Alzheimer’s is a disease of memory: The attack on synapses by Aß oligomers (ADDLs)
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Kirsten L. Viola, Pauline T. Velasco, and William L. Klein
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Pathology ,medicine.medical_specialty ,Memory Dysfunction ,Medicine (miscellaneous) ,Neuropathology ,Ligands ,Synapse ,Alzheimer Disease ,Memory ,Neural Pathways ,medicine ,Humans ,Senile plaques ,Aged ,Aged, 80 and over ,Brain Chemistry ,Neurons ,Amyloid beta-Peptides ,Nutrition and Dietetics ,Arc (protein) ,business.industry ,Long-term potentiation ,medicine.disease ,Synapses ,Geriatrics and Gerontology ,Alzheimer's disease ,business ,Neuroscience ,Immediate early gene - Abstract
Individuals with early-stage Alzheimer's disease (AD) suffer from profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active A beta oligomers (1). We have named these oligomers "ADDLs" (for pathogenic A beta-Derived Diffusible Ligands). ADDLs constitute metastable alternatives to the disease-defining A beta fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as A beta 12mers (2) (approximately 54 kDa) and can be found in dot-like clusters distinct from senile plaques (3). Oligomers of equal mass have been reported to occur in tgmouse AD models where they emerge concomitantly with memory failure (4), consistent with ADDL inhibition of LTP (1). In cell biology studies, ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors (5,6). Binding produces ectopic expression of the memory-linked immediate early gene Arc. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition (7) are predicted consequences of Arc overexpression, a pathology associated with memory dysfunction in tg-Arc mice. Significantly, the attack on synapses provides a plausible mechanism unifying memory dysfunction with major features of AD neuropathology; recent findings show that ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation. Acting as novel neurotoxins that putatively account for memory loss and neuropathology, ADDLs present significant targets for disease-modifying therapeutics in AD.
- Published
- 2008
36. Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine
- Author
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Fernanda G. De Felice, William L. Klein, Sara J. Fernandez, Kirsten L. Viola, Mary P. Lambert, Pauline T. Velasco, and Sergio T. Ferreira
- Subjects
Hippocampal formation ,medicine.disease_cause ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Antibodies ,Mice ,Memantine ,Calcium flux ,medicine ,Animals ,Receptor ,Molecular Biology ,Neurons ,chemistry.chemical_classification ,Reactive oxygen species ,Amyloid beta-Peptides ,Cell Differentiation ,Cell Biology ,medicine.disease ,Cell biology ,Oxidative Stress ,nervous system ,chemistry ,NMDA receptor ,Calcium ,Alzheimer's disease ,Reactive Oxygen Species ,Oxidative stress ,Protein Binding ,medicine.drug - Abstract
Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in brain tissue of AD patients and are considered centrally related to pathogenesis. Using hippocampal neuronal cultures, we found that ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-d-aspartate receptor (NMDA-R) activation. ADDL binding to neurons was reduced and ROS formation was completely blocked by an antibody to the extracellular domain of the NR1 subunit of NMDA-Rs. In harmony with a steric inhibition of ADDL binding by NR1 antibodies, ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits. The NR1 antibody did not affect ROS formation induced by NMDA, showing that NMDA-Rs themselves remained functional. Memantine, an open channel NMDA-R antagonist prescribed as a memory-preserving drug for AD patients, completely protected against ADDL-induced ROS formation, as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated ROS formation. These results show that ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux. This response provides a pathologically specific mechanism for the therapeutic action of memantine, indicates a role for ROS dysregulation in ADDL-induced cognitive impairment, and supports the unifying hypothesis that ADDLs play a central role in AD pathogenesis.
- Published
- 2007
37. Monoclonal antibodies that target pathological assemblies of Aβ
- Author
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Pauline T. Velasco, Daliya Khuon, Pascale N. Lacor, Eileen H. Bigio, Yuesong Gong, Pamela L Shaw, Grant A. Krafft, Fernanda G. De Felice, Lei Chang, Sara J. Fernandez, Kirsten L. Viola, Mary P. Lambert, and William L. Klein
- Subjects
Amyloid ,Amyloid beta ,medicine.drug_class ,medicine.medical_treatment ,Immunoblotting ,Tetrazolium Salts ,Monoclonal antibody ,Biochemistry ,Epitope ,Epitopes ,Mice ,Cellular and Molecular Neuroscience ,Antigen ,Alzheimer Disease ,Antibody Specificity ,Glial Fibrillary Acidic Protein ,mental disorders ,medicine ,Animals ,Humans ,Cells, Cultured ,Neurons ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,biology ,business.industry ,Antibodies, Monoclonal ,Brain ,Immunotherapy ,medicine.disease ,Immunohistochemistry ,Peptide Fragments ,Thiazoles ,Immunology ,biology.protein ,Calmodulin-Binding Proteins ,Rabbits ,Alzheimer's disease ,Antibody ,Reactive Oxygen Species ,business ,Protein Binding - Abstract
Amyloid beta (Abeta) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Abeta oligomers (amyloid beta-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Abeta oligomers and fibrils but not the physiologically prevalent Abeta monomer. Discrimination derived from an epitope found in assemblies of Abeta1-28 and ADDLs but not in other sequences, including Abeta1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Abeta assemblies, these antibodies provide tools by which pathological Abeta assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.
- Published
- 2007
38. Endotoxaemic myocardial dysfunction: the role of coronary driving pressure in subendocardial perfusion
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Clara B, Lorigados, Suely K, Ariga, Tiago R, Batista, Irineu T, Velasco, and Francisco G, Soriano
- Subjects
Male ,Microcirculation ,Hemodynamics ,Heart ,Coronary Vessels ,Shock, Septic ,Endotoxemia ,Ventricular Function, Left ,Rats ,Norepinephrine ,Coronary Circulation ,Animals ,Metaraminol ,Rats, Wistar - Abstract
To investigate the role of coronary driving pressure (CDP) in myocardial microcirculatory blood flow during sepsis. We hypothesised that in septic shock there is an impaired autoregulation of microcirculation, and blood flow is totally dependent on CDP. We analysed the effect of lipopolysaccharide (LPS)-induced shock on myocardial microcirculation, separating subendocardial and epicardial areas. We then studied the effect of CDP increases using noradrenaline (NOR) or metaraminol (Aramine [ARA]) on myocardial microcirculation and function, and we analysed the effect of volume infusion on CDP and myocardial function.Endotoxaemia was induced in male Wistar rats by an intraperitoneal injection of LPS 10 mg/kg. Animals were divided into a control (CT) group, an LPS-injected group, and an LPS-injected group treated with saline fluid, NOR or ARA.Ninety minutes later, a haemodynamic evaluation was performed. NOR or ARA were used to manage the mean arterial pressure (MAP) and CDP, and we inserted a catheter into the left ventricle to measure cardiac parameters. To measure blood flow in the myocardium and other organs, microspheres were introduced into the left ventricle using an infusion pump.After LPS treatment, left ventricular (LV) systolic function (dP/dt max) and diastolic function (dP/dt min) decreased by 34% and 15%, respectively, and load-independent indices (LV contractility in ejection phase and dP/dt max÷end-diastolic volume) were reduced. The CDP was also reduced (by 58%) in the endotoxaemic rats. Myocardial blood flow was reduced (by 80%) in animals with an MAP≤65 mmHg. NOR increased the CDP (LPS, 38 mmHg [SEM, 2 mmHg]; LPS+NOR, 59 mmHg [SEM, 3 mmHg]) and microcirculatory perfusion (LPS, 2 mL/min/g tissue [SEM, 0.6 mL/min/g]; LPS+NOR, 6.2 mL/min/g [SEM, 0.8 mL/min/g]). ARA was also effective in improve microcirculation but saline volume infusion was ineffective in improving CDP or myocardial function. CDP showed a significant correlation with subendocardial blood flow.Myocardial blood flow in the LV subendocardium and the right ventricle decreases in endotoxaemic rats. Increasing CDP improves myocardial blood flow and function. Thus, in endotoxaemia, microcirculatory blood flow is pressure dependent, suggesting that it may be beneficial to treat patients with sepsis using a higher CDP.
- Published
- 2015
39. Determination of IBIS mask transmission matrix
- Author
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J. Rodrigo, María José Rodríguez-Álvarez, J. L. Gasent, Filomeno Sanchez, R. Chato, T. Velasco, and Victor Reglero
- Subjects
Physics ,Ibis ,Nuclear and High Energy Physics ,Photon ,biology ,business.industry ,Astrophysics::High Energy Astrophysical Phenomena ,Monte Carlo method ,Astrophysics::Instrumentation and Methods for Astrophysics ,biology.organism_classification ,Integrated circuit layout ,Optics ,Transmission (telecommunications) ,Satellite ,Coded aperture ,business ,Instrumentation ,Energy (signal processing) - Abstract
The high-angular resolution imager IBIS is one of the two main instruments aboard the ESA INTEGRAL satellite launched in October 2002. IBIS uses coded aperture mask technique in order to provide the required imaging capabilities for energies between 15 and 10 MeV.The precise knowledge of the coded mask response function critically determine the IBIS imaging performances. In this paper, we present a general description of the IBIS coded mask design together with its main features. Transparency and homogeneity values of the IBIS mask flight model from our laboratory measurements are presented with indication of the instrumental set-up used and accuracy achieved. Mask transmission as a function of the energy and incident angle is presented and compared with Monte Carlo simulations. Finally, the mask transmission matrix for on-axis photons corrected for sources at infinity is also discussed.
- Published
- 2005
40. Self-Assembly of Aβ1-42 into Globular Neurotoxins
- Author
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Grant A. Krafft, William L. Klein, Lei Chang, Bryan W. Jones, Pascale N. Lacor, Sara J. Fernandez, Kirsten L. Viola, Brett A. Chromy, Peleg M. Horowitz, Mary P. Lambert, Caleb E. Finch, Richard Nowak, and Pauline T. Velasco
- Subjects
Amyloid β ,Cell Survival ,Protein Conformation ,Neurotoxins ,Peptide ,Ligands ,Fibril ,PC12 Cells ,Biochemistry ,Body Temperature ,Diffusion ,Epitopes ,Protein structure ,Animals ,Humans ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Plant Extracts ,Nitroblue Tetrazolium ,Ginkgo biloba ,Peptide Fragments ,Rats ,Crystallography ,Neuroprotective Agents ,chemistry ,Biophysics ,Self-assembly - Abstract
Amyloid beta 1-42 (Abeta(1-42)) is a self-associating peptide that becomes neurotoxic upon aggregation. Toxicity originally was attributed to the presence of large, readily formed Abeta fibrils, but a variety of other toxic species are now known. The current study shows that Abeta(1-42) can self-assemble into small, stable globular assemblies free of fibrils and protofibrils. Absence of large molecules was verified by atomic force microscopy (AFM) and nondenaturing gel electrophoresis. Denaturing electrophoresis revealed that the globular assemblies comprised oligomers ranging from trimers to 24mers. Oligomers prepared at 4 degrees C stayed fibril-free for days and remained so when shifted to 37 degrees C, although the spectrum of sizes shifted toward larger oligomers at the higher temperature. The soluble, globular Abeta(1-42) oligomers were toxic to PC12 cells, impairing reduction of MTT and interfering with ERK and Rac signal transduction. Occasionally, oligomers were neither toxic nor recognized by toxicity-neutralizing antibodies, suggesting that oligomers could assume alternative conformations. Tests for oligomerization-blocking activity were carried out by dot-blot immunoassays and showed that neuroprotective extracts of Ginkgo biloba could inhibit oligomer formation at very low doses. The observed neurotoxicity, structure, and stability of synthetic Abeta(1-42) globular assemblies support the hypothesis that Abeta(1-42) oligomers play a role in triggering nerve cell dysfunction and death in Alzheimer's disease.
- Published
- 2003
41. A coded mask for γ-ray astronomy. Design and calibration
- Author
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Filomeno Sanchez, T. Velasco, R. Chato, J. M. Rodrigo, and J. L. Gasent
- Subjects
Physics ,Nuclear and High Energy Physics ,Spectrometer ,business.industry ,Astrophysics::High Energy Astrophysical Phenomena ,Astrophysics::Instrumentation and Methods for Astrophysics ,Integrated circuit layout ,On board ,Optics ,Quality (physics) ,Calibration ,Satellite ,Coded aperture ,business ,Instrumentation ,Remote sensing - Abstract
The high-resolution γ-ray spectrometer (SPI) is one of the two main instruments on board the ESA INTEGRAL satellite successfully launched in October 2002. SPI uses coded aperture mask technique in order to have imaging capabilities at the energy band (20 keV–8 MeV) it will study celestial sources. The SPI imaging performance depends critically on the quality of the coded mask response and also on the precise knowledge of such response function. In this paper we present a general description of the SPI Coded Mask design together with its main features. Scientific impact of INTEGRAL SPI Coded Mask design on the instrument capabilities is also discussed. Results obtained for Mask calibration at different energies and incident angles are presented.
- Published
- 2003
42. Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated Aβ Oligomers
- Author
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Aditi Das, Michael T. Marty, Matthew R. Marunde, William L. Klein, Haoming Jiang, Chi Hao Luan, Benjamin D. Kuhns, Pauline T. Velasco, Kyle C. Wilcox, and Stephen G. Sligar
- Subjects
High-throughput screening ,Synaptic Membranes ,lcsh:Medicine ,Plasma protein binding ,Biology ,In Vitro Techniques ,Alzheimer Disease ,Animals ,Binding site ,lcsh:Science ,Lipid bilayer ,Nanodisc ,Multidisciplinary ,Amyloid beta-Peptides ,Binding Sites ,Drug discovery ,lcsh:R ,Small molecule ,Rats ,Biochemistry ,Membrane protein ,Biophysics ,lcsh:Q ,Protein Binding ,Synaptosomes ,Research Article - Abstract
Despite their value as sources of therapeutic drug targets, membrane proteomes are largely inaccessible to high-throughput screening (HTS) tools designed for soluble proteins. An important example comprises the membrane proteins that bind amyloid β oligomers (AβOs). AβOs are neurotoxic ligands thought to instigate the synapse damage that leads to Alzheimer's dementia. At present, the identities of initial AβO binding sites are highly uncertain, largely because of extensive protein-protein interactions that occur following attachment of AβOs to surface membranes. Here, we show that AβO binding sites can be obtained in a state suitable for unbiased HTS by encapsulating the solubilized synaptic membrane proteome into nanoscale lipid bilayers (Nanodiscs). This method gives a soluble membrane protein library (SMPL)--a collection of individualized synaptic proteins in a soluble state. Proteins within SMPL Nanodiscs showed enzymatic and ligand binding activity consistent with conformational integrity. AβOs were found to bind SMPL Nanodiscs with high affinity and specificity, with binding dependent on intact synaptic membrane proteins, and selective for the higher molecular weight oligomers known to accumulate at synapses. Combining SMPL Nanodiscs with a mix-incubate-read chemiluminescence assay provided a solution-based HTS platform to discover antagonists of AβO binding. Screening a library of 2700 drug-like compounds and natural products yielded one compound that potently reduced AβO binding to SMPL Nanodiscs, synaptosomes, and synapses in nerve cell cultures. Although not a therapeutic candidate, this small molecule inhibitor of synaptic AβO binding will provide a useful experimental antagonist for future mechanistic studies of AβOs in Alzheimer's model systems. Overall, results provide proof of concept for using SMPLs in high throughput screening for AβO binding antagonists, and illustrate in general how a SMPL Nanodisc system can facilitate drug discovery for membrane protein targets.
- Published
- 2014
43. Erratum to: A glycine zipper motif mediates the formation of toxic beta-amyloid oligomers in vitro and in vivo
- Author
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Pauline T. Velasco, Natalie Dingwell, Virginia Fonte, Christine M. Roberts, Gretchen H. Stein, Christopher D. Link, Patrick K. Gonzales, Michael A. Silverman, Pascale N. Lacor, Vishantie Dostal, Emily Y Fan, and Jordi Magrané
- Subjects
0303 health sciences ,Zipper ,business.industry ,education ,Clinical Neurology ,Correction ,Bioinformatics ,humanities ,In vitro ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Biochemistry ,In vivo ,Medicine ,Neurology (clinical) ,business ,Molecular Biology ,health care economics and organizations ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
After publication of this work, we noted that we inadvertently failed to include the complete list of all co-authors. The full list of authors has now been added and the Authors' contributions section has been modified accordingly.
- Published
- 2014
44. Enabling cross-platform clinical decision support through Web-based decision support in commercial electronic health record systems: proposal and evaluation of initial prototype implementations
- Author
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Mingyuan, Zhang, Ferdinand T, Velasco, R Clayton, Musser, and Kensaku, Kawamoto
- Subjects
Systems Integration ,Internet ,Medical Records Systems, Computerized ,Commerce ,ComputingMilieux_COMPUTERSANDSOCIETY ,Feasibility Studies ,Humans ,Articles ,Decision Support Systems, Clinical ,Risk Assessment ,Software - Abstract
Enabling clinical decision support (CDS) across multiple electronic health record (EHR) systems has been a desired but largely unattained aim of clinical informatics, especially in commercial EHR systems. A potential opportunity for enabling such scalable CDS is to leverage vendor-supported, Web-based CDS development platforms along with vendor-supported application programming interfaces (APIs). Here, we propose a potential staged approach for enabling such scalable CDS, starting with the use of custom EHR APIs and moving towards standardized EHR APIs to facilitate interoperability. We analyzed three commercial EHR systems for their capabilities to support the proposed approach, and we implemented prototypes in all three systems. Based on these analyses and prototype implementations, we conclude that the approach proposed is feasible, already supported by several major commercial EHR vendors, and potentially capable of enabling cross-platform CDS at scale.
- Published
- 2014
45. Elucidating molecular mass and shape of a neurotoxic Aβ oligomer
- Author
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Erika N. Cline, Kevin Luo, Kirsten L. Viola, William L. Klein, Adriano Sebollela, Pauline T. Velasco, Vinayak P. Dravid, Gina Mirela Mustata, Gajendra S. Shekhawat, and Kyle C. Wilcox
- Subjects
Physiology ,Microscopy, Atomic Force ,Hippocampus ,Biochemistry ,Oligomer ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Immunotoxin ,neurotoxicity ,Cells, Cultured ,Neurons ,0303 health sciences ,Chemistry ,Immunotoxins ,SISTEMA NERVOSO CENTRAL ,Brain ,General Medicine ,Human brain ,3. Good health ,medicine.anatomical_structure ,Chromatography, Gel ,Female ,AFM ,Alzheimer's disease ,Alzheimer’s disease ,Research Article ,NU4 antibody ,medicine.drug_class ,Aβ oligomer ,Cognitive Neuroscience ,Monoclonal antibody ,Antibodies ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Animals ,Humans ,030304 developmental biology ,Amyloid beta-Peptides ,Molecular mass ,Neurotoxicity ,Cell Biology ,Embryo, Mammalian ,medicine.disease ,In vitro ,Rats ,030217 neurology & neurosurgery - Abstract
Alzheimer's disease (AD), the most prevalent type of dementia, has been associated with the accumulation of amyloid β oligomers (AβOs) in the central nervous system. AβOs vary widely in size, ranging from dimers to larger than 100 kDa. Evidence indicates that not all oligomers are toxic, and there is yet no consensus on the size of the actual toxic oligomer. Here we used NU4, a conformation-dependent anti-AβO monoclonal antibody, to investigate size and shape of a toxic AβO assembly. By using size-exclusion chromatography and immuno-based detection, we isolated an AβO-NU4 complex amenable for biochemical and morphological studies. The apparent molecular mass of the NU4-targeted oligomer was 80 kDa. Atomic force microscopy imaging of the AβO-NU4 complex showed a size distribution centered at 5.37 nm, an increment of 1.5 nm compared to the size of AβOs (3.85 nm). This increment was compatible with the size of NU4 (1.3 nm), suggesting a 1:1 oligomer to NU4 ratio. NU4-reactive oligomers extracted from AD human brain concentrated in a molecular mass range similar to that found for in vitro prepared oligomers, supporting the relevance of the species herein studied. These results represent an important step toward understanding the connection between AβO size and toxicity.
- Published
- 2014
46. Properties of Purified Lens Transglutaminase and Regulation of its Transamidase/Crosslinking Activity by GTP
- Author
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S. N. Prasanna Murthy, Pauline T. Velasco, and Laszlo Lorand
- Subjects
Erythrocytes ,GTP' ,Tissue transglutaminase ,G protein ,Guinea Pigs ,Catalysis ,Cataract ,Cellular and Molecular Neuroscience ,Crystallin ,Lens, Crystalline ,medicine ,Animals ,Humans ,Polyacrylamide gel electrophoresis ,chemistry.chemical_classification ,Transglutaminases ,biology ,Chromatography, Ion Exchange ,Ligand (biochemistry) ,Crystallins ,Sensory Systems ,Ophthalmology ,Cross-Linking Reagents ,medicine.anatomical_structure ,Enzyme ,Liver ,Biochemistry ,chemistry ,Lens (anatomy) ,biology.protein ,Calcium ,Electrophoresis, Polyacrylamide Gel ,Guanosine Triphosphate ,Rabbits - Abstract
On account of its protein crosslinking activity, the Ca2+-dependent transglutaminase of the lens is likely to be involved in the formation of cataracts. We have now purified the rabbit lens enzyme to near homogeneity as judged by SDS-PAGE (Mr approximately 78 kDa), and a key feature of the procedure was the use of a highly selective affinity chromatographic step with a fibronectin fragment as ligand. The catalytic activity of the lens transglutaminase, measured by the incorporation of dansylcadaverine into dimethylcasein, was compared with those of two similar enzymes isolated from human red cells and from guinea pig liver, respectively. All three enzymes were inhibited by GTP, but the lens enzyme was most sensitive to inhibition by the nucleotide. Moreover, GTP was also shown to inhibit the formation of the approximately 55 kDa betacrystallin dimers in the Ca2+-treated rabbit lens homogenate, proving that the nucleotide is a negative regulator for the crosslinking activity of transglutaminase in this tissue.
- Published
- 1998
47. Novel Inhibitors Against the Transglutaminase-catalysed Crosslinking of Lens Proteins
- Author
-
Laszlo Lorand, Andrew M. Stern, and Pauline T. Velasco
- Subjects
Tissue transglutaminase ,Lysine ,Lens protein ,Cellular and Molecular Neuroscience ,Crystallin ,Lens, Crystalline ,medicine ,Animals ,Enzyme Inhibitors ,chemistry.chemical_classification ,Transglutaminases ,biology ,Calpain ,Imidazoles ,Crystallins ,Sensory Systems ,Ophthalmology ,Cross-Linking Reagents ,Enzyme ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Enzyme inhibitor ,Lens (anatomy) ,biology.protein ,Rabbits - Abstract
Post-translational modifications by transglutaminase may contribute to the remodeling of cellular architecture in the development of lens fiber cells, and there is evidence that the enzyme may also play a role in cataract formation. It catalyses hydrolytic deamidations as well as amide exchanges on select glutamine side chains at endo positions in a small subset of proteins of the lens. N epsilon(gamma-glutamyl)lysine crosslinks, the characteristic hallmarks of transglutaminase activity, were identified in polymers isolated from human cataract. Following up on our earlier studies relating to the inhibition of protein crosslinking by the Ca(2+)-activated transglutaminase in the lens, we have now examined the effects of 2-[(2-oxopropyl)thio]-imidazolium derivatives, recently described as active site-directed inhibitors for this family of enzymes. First, we have shown that the compounds at concentrations of 1-2 microM were effective in blocking the transamidating activities of partially purified lens transglutaminase. Then we focused on their efficacy in preventing the formation of the ca. 55 kDa beta crystallin dimers in the whole lens tissue. The production of these dimers, crosslinked by N epsilon(gamma-glutamyl)lysine isopeptide bridges, is an early sign of transglutaminase action in rabbit lens, and it can be readily documented by the SDS-PAGE analysis of proteins remaining in the soluble phase after brief exposure of the homogenate to Ca2+. The new compounds proved to be potent inhibitors of transglutaminase also in this preparation, preventing the crosslinking event at ca. 1 microM concentration. Moreover, even when applied at a 1,000-fold greater concentration (2 mM), they did not interfere with the action of calpain which, similarly to the activation of the transglutaminase system, is triggered by the addition of Ca2+. The high selectivity of the new compounds for differentially blocking only the transglutaminase and not the calpain of the lens, is all the more remarkable because these two enzymes share several mechanistic and structural similarities.
- Published
- 1998
48. Comprehensive Multimodality Blood Conservation: 100 Consecutive CABG Operations Without Transfusion
- Author
-
John D. Klemperer, Robert E. Helm, William DeBois, Samuel J. Lang, Maureen E. Gomez, Ferdinand T. Velasco, Todd K. Rosengart, Nasser K. Altorki, Jeffrey P. Gold, O. Wayne Isom, Stephen J. Thomas, and Karl H. Krieger
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Blood transfusion ,Cost effectiveness ,Cost-Benefit Analysis ,medicine.medical_treatment ,Blood Loss, Surgical ,Preoperative care ,Risk Factors ,Preoperative Care ,Humans ,Medicine ,Blood Transfusion ,Prospective Studies ,Derivation ,Coronary Artery Bypass ,Risk factor ,Prospective cohort study ,Postoperative Care ,Intraoperative Care ,business.industry ,Combined Modality Therapy ,Surgery ,medicine.anatomical_structure ,Anesthesia ,Cardiology and Cardiovascular Medicine ,Complication ,business ,Algorithms ,Artery - Abstract
Despite the recent introduction of a number of technical and pharmacologic blood conservation measures, bleeding and allogeneic transfusion remain persistent problems in open heart surgical procedures. We hypothesized that a comprehensive multimodality blood conservation program applied algorithmically on the basis of bleeding and transfusion risk would provide a maximum, cost-effective, and safe reduction in postoperative bleeding and allogeneic blood transfusion.One hundred consecutive patients undergoing coronary artery bypass grafting were prospectively enrolled in a risk factor-based multimodality blood conservation program (MMD group). To evaluate the relative efficacy and safety of this comprehensive approach, comparison was made with a similar group of 90 patients undergoing coronary artery bypass grafting to whom the multimodality blood conservation program was not applied but in whom an identical set of transfusion guidelines was enforced (control group). To evaluate the cost effectiveness of the multimodality program, comparison was also made between patients in the MMD group and a consecutive series of contemporaneous, diagnostic-related group-matched patients.One hundred consecutive patients in the MMD group underwent coronary artery bypass grafting without allogeneic transfusion. This compared favorably with the control population in whom a mean of 2.2 +/- 6.7 units of allogeneic blood was transfused per patient (34 patients [38%] received transfusion). In addition, the volume of postoperative blood loss at 12 hours in the control group was almost double that of the MMD group (660 +/- 270 mL versus 370 +/- 180 mL [p0.001]). Total costs for the MMD group in each of the three major diagnostic-related groups were equivalent to or significantly less than those in the consecutive series of diagnostic-related group-matched patients.Comprehensive risk factor-based application of multiple blood conservation measures in an optimized, integrated, and algorithmic manner can significantly decrease bleeding and need of allogeneic transfusion in coronary artery bypass grafting in a safe and cost-effective manner.
- Published
- 1998
49. Hydrolysis of γ:ϵ Isopeptides by Cytosolic Transglutaminases and by Coagulation Factor XIIIa
- Author
-
Pauline T. Velasco, Laszlo Lorand, K. N. Parameswaran, Ellen C. Chen, Xiang-Fei Cheng, and James H. Wilson
- Subjects
Stereochemistry ,Guinea Pigs ,Lysine ,Glutamic Acid ,Peptide ,Biochemistry ,Structure-Activity Relationship ,Hydrolysis ,Cytosol ,Thrombin ,medicine ,Animals ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Transglutaminases ,Cell Biology ,Methylamide ,Hydrogen-Ion Concentration ,Isopeptidase activity ,Kinetics ,Spectrometry, Fluorescence ,Enzyme ,chemistry ,Calcium ,Peptides ,Linker ,medicine.drug - Abstract
Nepsilon-(gamma-glutamyl)lysine cross-links, connecting various peptide chain segments, are frequently the major products in transglutaminase-catalyzed reactions. We have now investigated the effectiveness of these enzymes for hydrolyzing the gamma:epsilon linkage. Branched compounds were synthesized, in which the backbone on the gamma-side of the cross-bridge was labeled with a fluorophor (5-(dimethylamino)-1-naphthalenesulfonyl or 2-aminobenzoyl) attached through an epsilon-aminocaproyl linker in the N-terminal position, and the other branch of the bridge was constructed with Lys methylamide or diaminopentane blocked by 2,4-dinitrophenyl at the Nalpha position. Hydrolysis of the cross-link could be followed in these internally quenched substrates by an increase in fluorescence. In addition to the thrombin and Ca2+-activated human coagulation Factor XIIIa, cytosolic transglutaminases from human red cells and from guinea pig liver were tested. All three enzymes were found to display good isopeptidase activities, with Km values of 10(-4) to 10(-5) M. Inhibitors of transamidation were effective in blocking the hydrolysis by the enzymes, indicating that expression of isopeptidase activity did not require unusual protein conformations. We suggest that transglutaminases may play a dynamic role in biology not only by promoting the formation but also the breaking of Nepsilon-(gamma-glutamyl)lysine isopeptides.
- Published
- 1997
50. Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies
- Author
-
Amanda L. Eckermann, Pauline T. Velasco, William L. Klein, Adriano Sebollela, Kevin B. Lee, Marie C. Heffern, Kirsten L. Viola, Izolda A. Popova, Benjamin N. Tiano, Pascale N. Lacor, Xiao-xia Sun, and Thomas J. Meade
- Subjects
Amyloid ,Physiology ,Immunoprecipitation ,Amyloid beta ,Cognitive Neuroscience ,Population ,Blotting, Western ,Peptide ,Biochemistry ,Oligomer ,chemistry.chemical_compound ,Humans ,education ,chemistry.chemical_classification ,education.field_of_study ,Amyloid beta-Peptides ,biology ,Cell Biology ,General Medicine ,Peptide Fragments ,Monomer ,chemistry ,Synapses ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Single-Chain Antibodies - Abstract
Amyloid β42 self-assembly is complex, with multiple pathways leading to large insoluble fibrils or soluble oligomers. Oligomers are now regarded as most germane to Alzheimer's pathogenesis. We have investigated the hypothesis that oligomer formation itself occurs through alternative pathways, with some leading to synapse-binding toxins. Immediately after adding synthetic peptide to buffer, solutions of Aβ42 were separated by a 50 kDa filter and fractions assessed by SDS-PAGE silver stain, Western blot, immunoprecipitation, and capacity for synaptic binding. Aβ42 rapidly assembled into aqueous-stable oligomers, with similar protein abundance in small (50 kDa) and large (50 kDa) oligomer fractions. Initially, both fractions were SDS-labile and resolved into tetramers, trimers, and monomers by SDS-PAGE. Upon continued incubation, the larger oligomers developed a small population of SDS-stable 10-16mers, and the smaller oligomers generated gel-impermeant complexes. The two fractions associated differently with neurons, with prominent synaptic binding limited to larger oligomers. Even within the family of larger oligomers, synaptic binding was associated with only a subset of these species, as a new scFv antibody (NUsc1) immunoprecipitated only a small portion of the oligomers while eliminating synaptic binding. Interestingly, low doses of the peptide KLVFFA blocked assembly of the 10-16mers, and this result was associated with loss of the smaller clusters of oligomers observed at synaptic sites. What distinguishes these smaller clusters from the unaffected larger clusters is not yet known. Results indicate that distinct species of Aβ oligomers are generated by alternative assembly pathways and that synapse-binding subpopulations of Aβ oligomers could be specifically targeted for Alzheimer's therapeutics.
- Published
- 2012
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