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Aims: To determine the prevalence and the impact on prognosis of metabolic alkalosis (MA) in patients admitted for acute heart failure (AHF). Methods and results: The ALCALOTIC is a multicenter, observational cohort study that prospectively included patients admitted for AHF. Patients were classified into four groups according to their acid–base status on admission: acidosis, MA, respiratory alkalosis, and normal pH (reference group for comparison). Primary endpoint was all-cause in-hospital mortality, and secondary endpoints included 30/90-day all-cause mortality, all-cause readmission, and readmission for HF. Associations between endpoints and acid–base alterations were estimated in a multivariate Cox regression model including sex, age, comorbidities, and Barthel index and expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Six hundred sixty-five patients were included (84 years and 57% women), and 40% had acid–base alterations on admission: 188 (28%) acidosis and 78 (12%) alkalosis. The prevalence (95% CI) of MA was 9% (6.8–11.2%). Patients with MA were more women; had fewer comorbidities, better renal function, and higher left ventricle ejection fraction values; and received more treatment with oral acetazolamide during hospitalization and at discharge. MA was not associated with a higher risk of in-hospital mortality and 30/90-day all-cause mortality or readmissions but was associated with a significant increase in readmissions for HF at 30 and 90 days (adjusted HR [95% CI] 3.294 [1.397–7.767], p = 0.006 and 2.314 [1.075–4.978], p = 0.032). Conclusion: The prevalence of MA in patients admitted for AHF was 9%, and its presence was associated with more readmissions for HF but not with all-cause mortality. [ABSTRACT FROM AUTHOR]

The proposed Electron-Ion Collider (EIC) will utilize high- luminosity high-energy electron+proton (e + p) and electron+nucleus (e + A) collisions to solve several fundamental questions including searching for gluon saturation and studying the proton/nuclear structure. Complementary to the ongoing EIC project detector technical prototype carried out by the ePIC collaboration, a Depleted Monolithic Active Pixel Sensor (i.e., MALTA2) based fast timing silicon tracking detector (FMT) has been proposed to provide additional hits for track reconstruction in the forward region at the EIC to improve the overall track reconstruction quality. The fast timing resolution of the MALTA2 technology will help reject background events at the EIC as well. Progress of latest MALTA2 R&D, the development of a new MALTA2 quad-sensor prototype module and impacts of the proposed FMT in EIC physics studies will be discussed.

As large solar energetic particle (SEP) events can add significant radiation dose to astronauts in a short period of time and even induce acute clinical responses during missions, they present a concern for manned space flight operation. To assist the operations team in modeling and monitoring organ doses and any possible acute radiation-induced risks to astronauts during SEP events in real time, ARRT (Acute Radiation Risks Tool) 1.0 has been developed and successfully tested for Artemis I mission. The ARRT 2.0 described in this work integrates an established SEP forecasting model – UMASEP-100, further enabling real-time dose prediction for the upcoming Artemis II and following missions. With the new module linking with UMASEP-100 outputs in real time, the total BFO doses of most significant events can be communicated at the time of onset and hours before the peak. This is based on a flux-dose formula identified from comparing UMASEP-100 results with transport calculation for the events during 1994–2013 and validated with events outside that period. ARRT 2.0 also shows capability to distinguish minor events from significant ones to screen false alarms that will cause disruptions for space activities. This improvement provides additional information for operational teams to make timely decisions in contingent scenarios of severe SEP events to mitigate radiation exposure.

Objetivo. Determinar si el uso de antihipertensivos se asocia a la reducción del riesgo de la fractura de cadera no traumática en pacientes del Hospital Belén de Trujillo, 2017-2022. Métodos. Se llevó a cabo un estudio retrospectivo, analítico y transversal. De acuerdo con los criterios de selección, se incluyeron a 160 pacientes adultos, los cuales se dividieron en 2 grupos: con o sin fractura de cadera no traumática; a continuación, se aplicó la razón de prevalencias y la prueba estadística chi-cuadrado. Resultados. El promedio de edad y la frecuencia de osteoporosis fueron significativamente mayores en el grupo de pacientes con fractura de cadera (p0,05). Conclusiones. El uso de antihipertensivos se asocia a disminución del riesgo de la fractura de cadera no traumática en pacientes del Hospital Belén de Trujillo, 2017-2022 (nivel de evidencia III-B).

Studies the plaster-works of a miḥrāb of nasrid chronology which were uncovered in a house of the city of Vélez-Málaga, in the Costa del Sol, and offers the transcription, translation and analysis of the graphic and textual features of the inscriptions as part, in addition to other ornamental elements, of the whole decorative composition displayed around the arch. [ABSTRACT FROM AUTHOR]

Due to the lack of studies in the area of the emotional intelligence development in the family, our objective is to increase scientific knowledge. The present study focuses on determining the differences that exist between the Self-Reported Emotional Intelligence (SEI) of only children and first-born children and, on the other hand, the degree of perceptual adjustment of parents regarding their children. The sample was composed of 405 participants in total: 67 only children, 68 first-born children, 135 fathers and 135 mothers. The instruments used to measure emotional intelligence were the TMMS-24 (self-report emotional intelligence scale) and the PTMMS-24 (perceived emotional intelligence scale). Results show a clear disadvantage in terms of SEI for only children compared with first-born children. Parents of only children have a better capacity to perceive their own child's emotions as compared with parents of first-born children. [ABSTRACT FROM AUTHOR]

The present article approaches engages in a bibliographical investigation on both the processes and cognitive structures related to the reading of Western music notation. In t The conclusions it is suggested that suggests that the musical reading music involves is a special type of cognitive process in which where the mental musical representations have a very important role. The findings had discovered in the research es reported here can enrich new theoretical and practical approaches of to the reading of Western music notation. [ABSTRACT FROM AUTHOR]

The goal of our study was to implement a new methodological focus in two subjects studied during the last year of an Education degree: Applied Musical Technology and Development of musical Expression and its Teaching. This new approach was based on the elaboration of a creative musical project. With this attempt, the students could achieve musical knowledge and technological proficiency required for mastering their courses. The results demonstrate that this type of work foments cooperative attitudes and creativity as well as achieving the educational goals related to the subject content. [ABSTRACT FROM AUTHOR]

Copyright of Electronic Journal of Research in Educational Psychology is the property of Editorial of the University of Almeria (Spain) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Refeeding syndrome can be defined as the metabolic alterations developed by rapid nutrition repletion (oral, enteral as well as parenteral feeding) of severely malnourished patients. Refeeding syndrome is a potentially fatal clinical condition and it is often underdiagnosed in non-specialized nutrition units. The most important key for its prevention is to identify patients at high risk for developing refeeding syndrome, before nutrition repletion. The present case describes the steps to prevent refeeding syndrome as well as the clinical recommendations to restart nutrition support. [ABSTRACT FROM AUTHOR]

This work is an adaptation of a previous one. It analyses the effects of music notation software on the ability of students to identify and sing intervals. The study compares the achievement of twenty-four students who were eight to eleven years old and from the first four levels of music class. The sample was randomly assigned to either the two experimental groups, using the computer program during ten sessions which were twenty minutes long, or to the control group which made theoretical exercises. The results showed no significant difference between groups, although there were observed motivation attitudes in pupils during sessions. [ABSTRACT FROM AUTHOR]

The European Entrepreneurship Competence Framework (EntreComp) offers a comprehensive description of the knowledge, skills, and attitudes that people need to develop for an entrepreneurial mindset. The use of the framework as a self-assessment tool has garnered attention, but there is scarce presence of instruments that address the whole set of competencies proposed by Entrecomp. In view of the lack of specific tools, the objective of this research was to assess the evidence of validity and reliability of a new questionnaire. The sample was composed of 742 college students from several Spanish universities between 17- and 64-years-old, with 34.6% being men and 65.4% being women. To evaluate the validity based on relationships with other measures, the Entrepreneurial Intention and Entrepreneurial Self-Capital scales were also administered. Confirmatory factor analysis showed an internal structure made up of four dimensions: Ideas and Opportunities, Personal Resources, Specific Knowledge, and Into Action. The results showed satisfactory evidence of validity based on relationships with Entrepreneurial Intention and Entrepreneurial Self-Capital and good reliability. The questionnaire has good psychometric properties and can be an easy and useful tool for the self-assessment of entrepreneurial competencies within the EntreComp framework. [ABSTRACT FROM AUTHOR]

This article describes a bibliometrical analysis of articles on research in Music Education published from 1995 to 2007 and included in ERIC database. These articles represent 54% of all music education articles included in this database. The results show a list with 10 journals which has more than 20 of these articles. The sum of the articles contained in the first four journals is equivalent to 60% of music education articles published from 1995 to 2007. None of these journals are at JCR Social Sciences. Almost all authors of the revised articles usually work alone and occasionally. It seems that there are not research groups or strong consolidated research directions. The most common subjects are: students (attitudes, motivation and effectiveness); teachers; musical composition (activities and music techniques). [ABSTRACT FROM AUTHOR]

Numerical results obtained using a full-wave hybrid technique (comprising a new formulation of the coupled-mode method and the mode-matching method) for treating 3-D isotropic-chiral-material discontinuities in rectangular waveguides with perfect electrically conducting walls were compared with experimental data. For that purpose, samples of an isotropic chiral material were manufactured as composite materials. These samples were then fully characterized in the X-band. The measured constitutive parameters were used in the full-wave hybrid technique to predict the scattering parameters of three different structures-each a waveguide filled partially with the isotropic chiral material. The scattering parameters were also measured. The predicted and measured scattering parameters were in reasonably good agreement. [ABSTRACT FROM AUTHOR]

Copyright of Electronic Journal of Research in Educational Psychology is the property of Editorial of the University of Almeria (Spain) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This study shows a quantitative assessment of the use of Extreme Ultraviolet (EUV) observations in the prediction of Solar Energetic Proton (SEP) events. The UMASEP scheme (Space Weather, 9, S07003, 2011; 13, 2015, 807–819) forecasts the occurrence and the intensity of the first hours of SEP events. In order to predict well-connected events, this scheme correlates Solar Soft X-rays (SXR) with differential proton fluxes of the GOES satellites. In this study, we explore the use of the EUV time history from GOES-EUVS and SDO-AIA instruments in the UMASEP scheme. This study presents the results of the prediction of the occurrence of well-connected >10 MeV SEP events, for the period from May 2010 to December 2017, in terms of Probability of Detection (POD), False Alarm Ratio (FAR), Critical Success Index (CSI), and the average and median of the warning times. The UMASEP/EUV-based models were calibrated using GOES and SDO data from May 2010 to October 2014, and validated using out-of-sample SDO data from November 2014 to December 2017. The best results were obtained by those models that used EUV data in the range 50–340 Å. We conclude that the UMASEP/EUV-based models yield similar or better POD results, and similar or worse FAR results, than those of the current real-time UMASEP/SXR-based model. The reason for the higher POD of the UMASEP/EUV-based models in the range 50–340 Å, was due to the high percentage of successful predictions of well-connected SEP events associated with 10 MeV SEP events, improves the overall performance, obtaining a POD of 92.9% (39/42) compared with 81% (34/42) of the current tool, and a slightly worse FAR of 31.6% (18/57) compared with 29.2% (14/58) of the current tool.

The present article outlines the analysis of the relationships between the Arabic literature and the European literature, in two fundamental aspects and its causes: on the one hand, the imbalance in the mutual knowledge, and on the other hand, the existence of deep and meaningful affinities between both; that they have been customarily analyzed in direct influence terms of given European authors on concrete Arabic writers. [ABSTRACT FROM AUTHOR]

This paper studies the use of electron data from the Electron Proton Alpha Monitor (EPAM) on board the Advanced Composition Explorer (ACE) in the UMASEP (University of Málaga Solar particle Event Predictor) scheme [Núñez, Space Weather 9 (2011) S07003; Núñez, Space Weather 13 (2015)] for predicting well-connected >10 MeV Solar Energetic Proton (SEP) events. In this study, the identification of magnetic connection to a solar particle source is done by correlating Geostationary Operational Environmental Satellites (GOES) Soft X-Ray (SXR) fluxes with ACE EPAM electrons fluxes with energies of 0.175–0.375 MeV. The forecasting performance of this model, called Well-Connected Prediction with electrons (WCP-electrons), was evaluated for a 16-year period from November 2001 to October 2017. This performance is compared with that of the component of current real-time tool UMASEP-10, called here WCP-protons model, which predicts the same type of events by correlating GOES SXR with differential proton fluxes with energies of 9–500 MeV. For the aforementioned period, the WCP-electrons model obtained a Probability of Detection (POD) of 50.0%, a False Alarm Ratio (FAR) of 39% and an Average Warning Time (AWT) of 1 h 44 min. The WCP-protons model obtained a POD of 78.0%, a FAR of 22% and an AWT of 1 h 3 min. These results show that the use of ACE EPAM electron data in the UMASEP scheme obtained a better anticipation time (additional 41 min on average) but a lower performance in terms of POD and FAR. We also analyzed the use of a combined model, composed of WCP-electrons and WCP-protons, working in parallel (i.e. the combined model issues a forecast when any of the individual models emits a forecast). The combined model obtained the best POD (84%), and a FAR and AWT (34.4% and 1 h 34 min, respectively) which is in between those of the individual models.

Solar energetic particles (SEPs), especially protons and heavy ions, may be a space-weather hazard when they impact spacecraft and the terrestrial atmosphere. Forecasting schemes have been developed, which use earlier signatures of particle acceleration to predict the arrival of solar protons and ions in the space environment of the Earth. The UMASEP (University of MAlaga Solar particle Event Predictor) scheme forecasts the occurrence and the importance of an SEP event based on combined observations of soft X-rays, their time derivative and protons above 10 MeV at geosynchronous orbit. We explore the possibility to replace the derivative of the soft X-ray time history with the microwave time history in the UMASEP scheme. To this end we construct a continuous time series of observations for a 13-month period from December 2011 to December 2012 at two microwave frequencies, 4.995 and 8.8 GHz, using data from the four Radio Solar Telescope Network (RSTN) patrol stations of the US Air Force, and feed this time series to the UMASEP prediction scheme. During the selected period the Geostationary Operational Environmental Satellites (GOES) detected nine SEP events related to activity in the western solar hemisphere. We show that the SEP forecasting using microwaves has the same probability of detection as the method using soft X-rays, but no false alarm in the considered period, and a slightly increased warning time. A detailed analysis of the missed events is presented. We conclude that microwave patrol observations improve SEP forecasting schemes that employ soft X-rays. High-quality microwave data available in real time appear as a significant addition to our ability to predict SEP occurrence.

Varios años de investigaciones sistemáticas en torno al pasado cultural de la región del Tiris, han permitido identificar y documentar un extenso legado material. Las líneas que siguen pretenden socializar parte de los resultados alcanzados en el estudio de uno de esos elementos patrimoniales, la cerámica. A estos efectos, se presentará la seriación cronológica proporcionada por el estudio cronométrico desarrollado mediante la técnica TL, así como el estudio tecnotipológico de los fragmentos analizados. Ambas consideraciones serán interpretadas de forma conjunta en un apartado final en el que se establecerán una serie de propuestas que necesariamente deberán ser cotejadas en el futuro.

A case is reported of a patient who developed Acinetobacter meningitis after an external ventricular drainage system had been fitted for control of intracranial pressure. During the process, nine strains of Acinetobacter isolated from her cerebrospinal fluid were indistinguishable by analysis of total genomic DNA by pulse-field gel electrophoresis. The first eight strains were sensitive to meropenem and imipenem (MICs <1 g/l). The MIC of the last one, which had been recovered after 32 days during two courses of treatment with meropenem, increased to >32 g/l for meropenem, while with imipenem the increase was minimal (MIC=1.5 g/l). The microorganism persisted in the central nervous system despite the administration of different antimicrobials, including intraventricular aminoglycosides and six changes in the external ventricular system. The patient died 68 days after admission to the intensive care unit from bilateral cerebral ischemic lesions, intraventricular hemorrhage and cerebral edema with endocraneal hypertension, the Acinetobacter ventriculitis also contributing to this state. [ABSTRACT FROM AUTHOR]

A web-based prototype system for predicting solar energetic particle (SEP) events and solar flares for use by space launch operators is presented. The system has been developed as a result of the European Space Agency (ESA) project SEPsFLAREs (Solar Events Prediction system For space LAunch Risk Estimation). The system consists of several modules covering the prediction of solar flares and early SEP Warnings (labeled Warning tool), the prediction of SEP event occurrence and onset, and the prediction of SEP event peak and duration. In addition, the system acquires data for solar flare nowcasting from Global Navigation Satellite Systems (GNSS)-based techniques (GNSS Solar Flare Detector, GSFLAD and the Sunlit Ionosphere Sudden Total Electron Content Enhancement Detector, SISTED) as additional independent products that may also prove useful for space launch operators.

Fundamento: Conocer la opinión de los médicos de atención primaria de Ourense (España) con respecto a algunos aspectos de su prescripción como el conocimiento del precio de los fármacos, la prescripción inducida percibida, la relación con la industria farmacéutica y la opinión del médico sobre posibles medidas reductoras del gasto farmacéutico. Métodos: En este estudio transversal descriptivo, se entrevistó mediante un cuestionario postal, previamente probado, a todos los médicos de atención primaria (MAP) de la provincia de Ourense (243). En él se recogían características demográficas de los facultativos, influencia del coste en la prescripción, estimación del precio de 15 fármacos de uso habitual y la opinión sobre diversos aspectos relacionados con la prescripción inducida, la industria farmacéutica y diversas estrategias para contener el gasto en farmacia. Para el análisis de los resultados se utilizaron pruebas de ji², t de Student y análisis de la varianza, así como el coeficiente de correlación de Spearman según cumpliera con un error alfa de 0,05. Resultados. El nivel de participación de los encuestados fue del 42,8 % (104). La duración media diaria de la visita de los delegados farmacéuticos fue de 13,6 minutos, siendo las novedades el punto de mayor interés. Casi un 27 % admitía participar en ensayos clínicos patrocinados por la industria. El 23 % consideraba el precio una prioridad al prescribir. La prescripción inducida suponía el 39,7 % del total. Los facultativos eligieron mayoritariamente el copago para reducir el gasto farmacéutico. En la estimación del precio el porcentaje de error global fue del 45,7 %, subestimando los más caros y sobrestimando los más baratos. Conclusiones. Existe un desconocimiento importante del precio de los fármacos entre los MAP. La mayor parte de los médicos no consideran que el precio del fármaco deba ser una prioridad al prescribir. Hay un porcentaje elevado de prescripción inducida percibida. Respecto al gasto farmacéutico, la mayor parte de los MAP considera las medidas económicas, en concreto el copago, como las más efectivas para su contención.

This paper aims at providing an overview of latest advances in space weather modeling in an operational environment in Europe, including both the introduction of new models and improvements to existing codes and algorithms that address the broad range of space weather’s prediction requirements from the Sun to the Earth. For each case, we consider the model’s input data, the output parameters, products or services, its operational status, and whether it is supported by validation results, in order to build a solid basis for future developments. This work is the output of the Sub Group 1.3 “Improvement of operational models” of the European Cooperation in Science and Technology (COST) Action ES0803 “Developing Space Weather Products and services in Europe” and therefore this review focuses on the progress achieved by European research teams involved in the action.

Abstract Background To examine the influence of ethnicity on liver transaminases among adolescents with type 2 diabetes mellitus (T2DM). Methods A retrospective medical chart review of 57 (30 males and 27 females) newly diagnosed patients with T2DM. Ethnicity was determined by self-report and height, weight, body mass index (BMI) and glycosylated hemoglobin (HbA1c) were obtained using standard clinical procedures. Fasting levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) were collected prior to the initiation of any therapy. Results Age, gender, height, weight, BMI, and HbA1c did not differ between ethnic groups. Compared to African-Americans, Hispanics had significantly higher ALT (23.9 ± 3.4 vs. 107.8 ± 20.3, p=0.002) and AST (17.7 ± 2.5 vs. 71.1 ± 15.7, p Conclusions These preliminary findings suggest that Hispanic children with T2DM may be at higher risk for developing non-alcoholic fatty liver disease and indicate that a comprehensive hepatic evaluation is warranted in this population. Future studies that incorporate more precise and proximal measures of liver health are warranted in this population.

Abstract Background Single-domain antibodies (sdAbs), also known as nanobodies or VHHs, are characterized by high stability and solubility, thus maintaining the affinity and therapeutic value provided by conventional antibodies. Given these properties, VHHs offer a novel alternative to classical antibody approaches. To date, VHHs have been produced mainly in E. coli, yeast, plants and mammalian cells. To apply the single-domain antibodies as a preventive or therapeutic strategy to control rotavirus infections in developing countries (444,000 deaths in children under 5 years of age) has to be minimized their production costs. Results Here we describe the highly efficient expression of functional VHHs by the Improved Baculovirus Expression System (IBES® technology), which uses a baculovirus expression vector in combination with Trichoplusia ni larvae as living biofactories. Two VHHs, named 3B2 and 2KD1, specific for the inner capsid protein VP6 of Group A rotavirus, were expressed in insect larvae. The IBES® technology achieved very high expression of 3B2 and 2KD1, reaching 2.62% and 3.63% of the total soluble protein obtained from larvae, respectively. These expression levels represent up to 257 mg/L of protein extract after insect processing (1 L extract represents about 125 g of insect biomass or about 375 insect larvae). Larva-derived antibodies were fully functional when tested in vitro and in vivo, neutralizing Group A rotaviruses and protecting offspring mice against rotavirus-induced diarrhea. Conclusions Our results open up the possibility of using insects as living biofactories (IBES® technology) for the cost-efficient production of these and other fully functional VHHs to be used for diagnostic or therapeutic purposes, thereby eliminating concerns regarding the use of bacterial or mammalian cells. To the best of our knowledge, this is the first time that insects have been used as living biofactories to produce a VHH molecule.

Abstract Background Patients with end-stage renal disease (ESRD) and Mycobacterium tuberculosis infection pose a high risk of developing active TB disease. It is therefore important to detect latent TB infection (LTBI) to be able to offer treatment and prevent progression to TB disease. We assessed the value of the tuberculin skin test (TST) and of an interferon-gamma release assay (Quantiferon®-TB Gold in-Tube, QFT) for diagnosing LTBI in ESRD patients, after prolonged exposure to a highly contagious TB case in a haemodialysis unit. As a high number of patients presented erythema without induration in the TST response, this type of reaction was also analysed. Method The TST and QFT were simultaneously performed twelve weeks after the last possible exposure to a bacilliferous TB patient. If the first TST (TST-1) was negative, a second TST (TST-2) was performed 15 days later to detect a booster response. A comparison was made between the TST responses (including those cases with erythema without induration) and those for the QFT. The correlation with risk of infection and the concordance between tests were both analysed. Results A total of 52 patients fulfilled the inclusion criteria. Overall, 11 patients (21.2%) had a positive TST response: 3 for TST-1 and 8 for TST-2, and 18 patients (34.6%) showed a positive QFT response (p = 0.065). Erythema without induration was found in 3 patients at TST-1 and in a further 9 patients at TST-2. The three patients with erythema without induration in TST-1 had a positive TST-2 response. Concordance between TST and QFT was weak for TST-1 (κ = 0.21); it was moderate for overall TST (κ = 0.49); and it was strong if both induration and erythema (κ = 0.67) were considered. Conclusions In patients with ESRD, erythema without induration in the TST response could potentially be an indicator of M. tuberculosis infection. The QFT shows better accuracy for LTBI diagnosis than the TST.

Abstract Background Post-herpetic neuralgia (PHN) is a common type of neuropathic pain that can severely affect quality of life. NGX-4010, a capsaicin 8% dermal patch, is a localized treatment that can provide patients with significant pain relief for up to 3 months following a single 60-minute application. The NGX-4010 application can be associated with application-site pain and in previous clinical trials pretreatment with a topical 4% lidocaine anesthetic was used to enhance tolerability. The aim of the current investigation was to evaluate tolerability of NGX-4010 after pretreatment with lidocaine 2.5%/prilocaine 2.5% anesthetic cream. Methods Twenty-four patients with PHN were pretreated with lidocaine 2.5%/prilocaine 2.5% cream for 60 minutes before receiving a single 60-minute application of NGX-4010. Tolerability was assessed by measuring patch application duration, the proportion of patients completing over 90% of the intended treatment duration, application site-related pain using the Numeric Pain Rating Scale (NPRS), and analgesic medication use to relieve such pain. Safety was assessed by monitoring adverse events (AEs) and dermal irritation using dermal assessment scores. Results The mean treatment duration of NGX-4010 was 60.2 minutes and all patients completed over 90% of the intended patch application duration. Pain during application was transient. A maximum mean change in NPRS score of +3.0 was observed at 55 minutes post-patch application; pain scores gradually declined to near pre-anesthetic levels (+0.71) within 85 minutes of patch removal. Half of the patients received analgesic medication on the day of treatment; by Day 7, no patients required medication. The most common AEs were application site-related pain, erythema, edema, and pruritus. All patients experienced mild dermal irritation 5 minutes after patch removal, which subsequently decreased; at Day 7, no irritation was evident. The maximum recorded dermal assessment score was 2. Conclusion NGX-4010 was well tolerated following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with PHN. The tolerability of the patch application appeared comparable with that seen in other studies that used 4% lidocaine cream as the pretreatment anesthetic. This study is registered at http://www.clinicaltrials.gov as number NCT00916942.

Abstract Background There are currently no purification methods capable of producing the large amounts of fish rhabdoviral glycoprotein G (gpG) required for diagnosis and immunisation purposes or for studying structure and molecular mechanisms of action of this molecule (ie. pH-dependent membrane fusion). As a result of the unavailability of large amounts of the gpG from viral haemorrhagic septicaemia rhabdovirus (VHSV), one of the most dangerous viruses affecting cultured salmonid species, research interests in this field are severely hampered. Previous purification methods to obtain recombinant gpG from VHSV in E. coli, yeast and baculovirus grown in insect cells have not produced soluble conformations or acceptable yields. The development of large-scale purification methods for gpGs will also further research into other fish rhabdoviruses, such as infectious haematopoietic necrosis virus (IHNV), spring carp viremia virus (SVCV), hirame rhabdovirus (HIRRV) and snakehead rhabdovirus (SHRV). Findings Here we designed a method to produce milligram amounts of soluble VHSV gpG. Only the transmembrane and carboxy terminal-deleted (amino acid 21 to 465) gpG was efficiently expressed in insect larvae. Recognition of G21-465 by ß-mercaptoethanol-dependent neutralizing monoclonal antibodies (N-MAbs) and pH-dependent recognition by sera from VHSV-hyperimmunized or VHSV-infected rainbow trout (Oncorhynchus mykiss) was demonstrated. Conclusions Given that the purified G21-465 conserved some of its most important properties, this method might be suitable for the large-scale production of fish rhabdoviral gpGs for use in diagnosis, fusion and antigenicity studies.

Abstract Background Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. Methods Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. Conclusions A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

Abstract Background DNA-damage assays, quantifying the initial number of DNA double-strand breaks induced by radiation, have been proposed as a predictive test for radiation-induced toxicity. Determination of radiation-induced apoptosis in peripheral blood lymphocytes by flow cytometry analysis has also been proposed as an approach for predicting normal tissue responses following radiotherapy. The aim of the present study was to explore the association between initial DNA damage, estimated by the number of double-strand breaks induced by a given radiation dose, and the radio-induced apoptosis rates observed. Methods Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radio-induced apoptosis at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results Radiation-induced apoptosis increased in order to radiation dose and data fitted to a semi logarithmic mathematical model. A positive correlation was found among radio-induced apoptosis values at different radiation doses: 1, 2 and 8 Gy (p < 0.0001 in all cases). Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). A statistically significant inverse correlation was found between initial damage to DNA and radio-induced apoptosis at 1 Gy (p = 0.034). A trend toward 2 Gy (p = 0.057) and 8 Gy (p = 0.067) was observed after 24 hours of incubation. Conclusions An inverse association was observed for the first time between these variables, both considered as predictive factors to radiation toxicity.

Abstract Background The ability of an intracellular pathogen to establish infection depends on the capacity of the organism to survive and replicate inside the host. Mycobacterium fortuitum is a bacteria that contains genes involved in the detoxification of the oxygen reactive species such as those produced by the host during the infection. In this work, we investigate the effects of hydrogen peroxide on the transcription and expression of these genes by developing a real time quantitative PCR technique (qRT-PCR) using the ribosomal promoter region (rrnA-P1) as reference product for quantification of the mRNA levels. Results M. fortuitum cultures were treated with different hydrogen peroxide concentrations (0.02 to 20 mM) during several periods of time (30 to 120 minutes). The activity of the enzymes KatGII and SodA, and the transcription of corresponding genes were evaluated. The transcriptional regulator furAII gene was also studied. The ribosomal promoter region rrnA-P1 was validated as referential product under the stress conditions checked by qRT-PCR. Minor changes were observed under the conditions tested except when bacteria were incubated in the presence of 20 mM hydrogen peroxide. Under those conditions, the levels of transcription of the three genes under study increased at 30 minutes of treatment. The viability of the bacteria was not influenced under the conditions tested. Conclusion In this work, we have quantified transcriptional responses to stress suggesting that, the opportunistic pathogen M. fortuitum is more resistant and differs in behaviour in the presence of hydrogen peroxide, when compared to the major pathogen Mycobacterium tuberculosis and the saprophyte Mycobacterium smegmatis. Besides, we demonstrate the mycobacterial non-coding region rrnA-P1 to be a suitable reference product in the analysis of qRT-PCR transcriptional data of M. fortuitum.

Abstract Background The putative tumor suppressor WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome area 16q23.3-24.1. This region is a frequent target for loss of heterozygosity and chromosomal rearrangement in ovarian, breast, hepatocellular, prostate carcinomas and other neoplasias. The goal of these studies was to evaluate WWOX protein expression levels in ovarian carcinomas to determine if they correlated with clinico-pathological parameters, thus providing additional support for WWOX functioning as a tumor suppressor. Methods We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by χ2 test with Yates' correction. The basic significance level was fixed at p < 0.05. Results Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03). Conclusion These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.

Abstract Background Iron is necessary for neuronal function but in excess generates neurodegeneration. Although most of the components of the iron homeostasis machinery have been described in neurons, little is known about the particulars of their iron homeostasis. In this work we characterized the response of SH-SY5Y neuroblastoma cells and hippocampal neurons to a model of progressive iron accumulation. Results We found that iron accumulation killed a large proportion of cells, but a sub-population became resistant to iron. The surviving cells evoked an adaptative response consisting of increased synthesis of the iron-storage protein ferritin and the iron export transporter IREG1, and decreased synthesis of the iron import transporter DMT1. Increased expression of IREG1 was further substantiated by immunocytochemistry and iron efflux experiments. IREG1 expression directly correlated with iron content in SH-SY5Y and hippocampal cells. Similarly, a high correlation was found between IREG1 expression and the rate of iron efflux from SH-SY5Y cells. Conclusions Neuronal survival of iron accumulation associates with increased expression of the efflux transporter IREG1. Thus, the capacity of neurons to express IREG1 may be one of the clues to iron accumulation survival.