Limited Ability to Activate Protein C Confers Left Atrial Endocardium A Thrombogenic Phenotype: A Role in Cardioembolic Stroke?

Background and Purpose—Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. Methods—We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. Results—We found the ability to activate protein C decreased by half (P 0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5 19.9 and 72.1 18.8 arbitrary intensity units, mean standard deviation; P 0.028). No differences were detected in endothelial protein C receptor expression. Conclusions—Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke

Association of increased fibrinogen concentration with impaired activation of anticoagulant protein C

BACKGROUND: Low levels of activated protein C (APC) are a risk factor for venous thrombosis. The mechanisms leading to interindividual differences in APC are not totally elucidated. Protein C is activated by the thrombin-thrombomodulin complex. As thrombin binds to fibrinogen and thrombomodulin through a common region, it is conceivable that fibrinogen influences the activation of protein C. This would help to explain the association between high levels of fibrinogen and an increased thrombotic risk. METHODS: We analyzed the association between circulating APC levels and fibrinogen concentration in 382 healthy subjects. Subsequently, we studied the effect of increasing fibrinogen concentrations on the APC generation on cultured endothelial cells. RESULTS: An independent inverse association between circulating APC levels and fibrinogen was found [betacoefficient, -0.16; 95% confidence interval (95% CI) -0.26, -0.06; P = 0.001]. For each 100 mg dL(-1) increase in fibrinogen, the independent risk of having low APC levels (<0.7 ng mL(-1)) was almost three times higher (OR 2.8; 95% CI 1.1, 7.2; P = 0.04). Accordingly, a notable association between increasing fibrinogen concentrations and the reduction in the thrombin-thrombomodulin dependent activation of protein C on endothelial cells was found (r = -0.57; P = 0.002). CONCLUSIONS: We present evidence of an inverse association between circulating APC and fibrinogen levels. According to this finding together with the results of our in vitro experiments, we propose that the impairment in the generation of APC on endothelial cells constitutes a new prothrombotic mechanism of fibrinogen

In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: Their action on acute and chronic phases of chagas disease

The in vitro and in vivo anti-Trypanosoma cruzi activity of the pyrazole-containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3.The authors thank the MCINN Projects: Consolider Ingenio CSD2010-00065 and CTQ2009-14288-C04-01, the FEDER funds and Generalitat Valenciana PROMETEO 2011/008, the Santander-Universidad Complutense Research Program GR58/08-921371-891, and the Spanish MEC Project CGL2008-03687-E/BOS for financial support. J.P. thanks MCINN for a predoctoral fellowship

Transcripción humana o asistencia a la transcripción automática interactiva: reconocimiento automático del texto, anotación y edición erudita en el siglo XXI

[EN] Computer assisted transcription tools can speed up the initial process of reading and transcribing texts. At the same time, new annotation tools open new ways of accessing the text in its graphical form. The balance and value of each method still needs to be explored. STATE, a complete assisted transcription system for ancient documents, was presented to the audience of the 2013 International Medieval Congress at Leeds. The system offers a multimodal interaction environment to assist humans in transcribing ancient documents: the user can type, write on the screen with a stylus, or utter a word. When one of these actions is used to correct an erroneous word, the system uses this new information to look for other mistakes in the rest of the line. The system is modular, composed of different parts: one part creates projects from a set of images of documents, another part controls an automatic transcription system, and the third part allows the user to interact with the transcriptions and easily correct them as needed. This division of labour allows great flexibility for organising the work in a team of transcribers.[ES] Las herramientas de ayuda a la transcripción automática pueden acelerar el proceso inicial de la lectura y transcripción de textos. Al mismo tiempo, las nuevas herramientas de anotación aportan nuevas formas de acceder al texto en su forma original gráfica. Sin embargo, todavía es necesario evaluar las bondades y capacidades de los distintos métodos. STATE, un completo sistema de asistencia a la transcripción de documentos antiguos, se presentó a la audiencia del International Medieval Congress de 2013 celebrado en Leeds. El sistema ofrece un entorno de interacción multimodal para ayudar a las personas en la transcripción de documentos antiguos: el usuario puede teclear, escribir en la pantalla con un lápiz óptico o corregir usando la voz. Cada vez que el usuario cambia de esta forma una palabra, el sistema utiliza la corrección para buscar errores en el resto de la línea. El sistema está dividido en diferentes módulos: uno crea proyectos a partir de un conjunto de imágenes de documentos, otro módulo controla el sistema de transcripción automática, y un tercer módulo permite al usuario interactuar con las transcripciones y corregirlas fácilmente cuando sea necesario. Esta división de las tareas permite una gran flexibilidad para organizar el trabajo de los transcriptores en equipo.Work supported by the Spanish Government (TIN2010-18958) and the Generalitat Valenciana (Prometeo/2010/028)Castro-Bleda, MJ.; Vilar Torres, JM.; España Boquera, S.; Llorens, D.; Marzal Varó, A.; Prat, F.; Zamora Martínez, FJ. (2014). Human or computer assisted interactive transcription: automated text recognition, text annotation, and scholarly edition in the twenty-first century. Mirabilia Journal. 18(1):247-253. http://hdl.handle.net/10251/61398S24725318

Measuring socio-demographic differences in volunteers with a value-based index: illustration in a mega event

The phenomenon of volunteering can be analysed as a consumer experience through the concept of value as a trade-off between benefits and costs. In event volunteering, both the expected value (pre-experienced) and the perceived value (post-experienced) of volunteering can be assessed. With this purpose, an online quantitative survey is conducted with a sample of 711 volunteers in a religious mega event, with questions related to five dimensions of their experience: efficiency, social value, play, spirituality and time spent. These five scales, properly tested are used for building a multidimensional index of both the expected and perceived value of the volunteer experience. ANOVAs test show significant differences on the index in both moments upon the socio-demographic profiles: negative expectations/experience balance by age, contrasted results by sex, and more experienced volunteers being more critical with the value experienced. Implications for event managers are proposed, in line with the motivation of volunteers

Comparative efficacy of two primary care interventions to assist withdrawal from long term benzodiazepine use: A protocol for a clustered, randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Although benzodiazepines are effective, long-term use is not recommended because of potential adverse effects; the risks of tolerance and dependence; and an increased risk of hip fractures, motor vehicle accidents, and memory impairment. The estimated prevalence of long-term benzodiazepine use in the general population is about 2,2 to 2,6%, is higher in women and increases steadily with age. Interventions performed by General Practitioners may help patients to discontinue long-term benzodiazepine use. We have designed a trial to evaluate the effectiveness and safety of two brief general practitioner-provided interventions, based on gradual dose reduction, and will compare the effectiveness of these interventions with that of routine clinical practice.</p> <p>Methods/Design</p> <p>In a three-arm cluster randomized controlled trial, general practitioners will be randomly allocated to: a) a group in which the first patient visit will feature a structured interview, followed by visits every 2-3 weeks to the end of dose reduction; b) a group in which the first patient visit will feature a structured interview plus delivery of written instructions to self-reduce benzodiazepine dose, or c) routine care. Using a computerized pharmaceutical prescription database, 495 patients, aged 18-80 years, taking benzodiazepine for at least 6 months, will be recruited in primary care health districts of three regions of Spain (the Balearic Islands, Catalonia, and Valencia). The primary outcome will be benzodiazepine use at 12 months. The secondary outcomes will include measurements of anxiety and depression symptoms, benzodiazepine dependence, quality of sleep, and alcohol consumption.</p> <p>Discussion</p> <p>Although some interventions have been shown to be effective in reducing benzodiazepine consumption by long-term users, the clinical relevance of such interventions is limited by their complexity. This randomized trial will compare the effectiveness and safety of two complex stepped care interventions with that of routine care in a study with sufficient statistical power to detect clinically relevant differences.</p> <p>Trial Registration</p> <p>Current Controlled Trials: <a href="http://www.controlled-trials.com/ISRCTN13024375">ISRCTN13024375</a></p

Integral strategy to supportive care in breast cancer survivors through occupational therapy and a m-health system: design of a randomized clinical trial

Background: Technological support using e-health mobile applications (m-health) is a promising strategy to improve the adherence to healthy lifestyles in breast cancer survivors (excess in energy intake or low physical activity are determinants of the risk of recurrence, second cancers and cancer mortality). Moreover, cancer rehabilitation programs supervised by health professionals are needed due to the inherent characteristics of these breast cancer patients. Our main objective is to compare the clinical efficacy of a m-health lifestyle intervention system alone versus an integral strategy to improve Quality of Life in breast cancer survivors. Methods: This therapeutic superiority study will use a two-arm, assessor blinded parallel RCT design. Women will be eligible if: they are diagnosed of stage I, II or III-A breast cancer; are between 25 and 75 years old; have a Body Mass Index > 25 kg/m2; they have basic ability to use mobile apps; they had completed adjuvant therapy except for hormone therapy; and they have some functional shoulder limitations. Participants will be randomized to one of the following groups: integral group will use a mobile application (BENECA APP) and will receive a face-to-face rehabilitation (8-weeks); m-health group will use the BENECA app for 2-months and will received usual care information. Study endpoints will be assessed after 8 weeks and 6 months. The primary outcome will be Quality of Life measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core and breast module. The secondary outcomes: body composition; upper-body functionality (handgrip, Disability of the Arm, Shoulder and Hand questionnaire, goniometry); cognitive function (Wechsler Adult Intelligence Scale, Trail Making Test); anxiety and depression (Hospital Anxiety and Depression Scale); physical fitness (Short version of the Minnesota Leisure Time Physical Activity Questionnaire, Self-Efficacy Scale for Physical Activity); accelerometry and lymphedema. Discussion: This study has been designed to seek to address the new needs for support and treatment of breast cancer survivors, reflecting the emerging need to merge new low cost treatment options with much-needed involvement of health professionals in this type of patients. Trial registration: ClinicalTrials.gov Identifier: NCT02817724 (date of registration: 22/06/2016).The study was funded by the Spanish Ministry of Economy and Competitiveness (Plan Estatal de I + D + I 2013-2016), Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI14/01627), Fondos Estructurales de la Unión Europea (FEDER) and by the Spanish Ministry of Education (FPU14/01069). This is part of a Ph.D. Thesis conducted in the Clinical Medicine and Public Health Doctoral Studies of the University of Granada, Spain

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Seawater disinfection by chlorine dioxide and sodium hypochlorite. A comparison of biofilm formation

11 pages, 6 figures, 3 tablesContinuous seawater disinfection by chlorine dioxide (ClO2) was studied at residual concentrations of 0.2 and 0.4 mg ClO2 L -1 and compared with sodium hypochlorite (NaClO) disinfection at 1 mg L-1 of free chlorine. The results revealed that both disinfectants decrease the biological activity and cell counts in seawater. When NaClO was used, both the cell counts and the adenosine triphosphate (ATP) level were diminished (1.8 log and 76 %, respectively); however, when ClO2 was used, the ATP level decreased to the same level as with NaClO (78-84 %), but the cell counts were reduced only weakly (∼0.1 log). The biofilm concentration in seawater without disinfectants reached 700 pg ATP cm-2 after 40 days, whereas in the treated lines, the biofilms remained below 1 pg ATP cm -2 irrespective of the disinfectant and dose used. ClO2 generated much less trihalomethanes than NaClO (<1 vs. 154 μg L -1). Bromoform (77-96 %) was the predominant chemical species found in disinfected seawater. © Springer International Publishing Switzerland 2014The authors are grateful to Ercros for their financial support through the Fundació Bosch i GimperaPeer Reviewe