Hamiltonian Noether theorem for gauge systems and two time physics

The Noether theorem for Hamiltonian constrained systems is revisited. In particular, our review presents a novel method to show that the gauge transformations are generated by the conserved quantities associated with the first class constraints. We apply our results to the relativistic point particle, to the Friedberg et al. model and, with special emphasis, to two time physics.Comment: 20 pages, Latex, references added, the "massless" sense of (87) is clarifie

Reversion of Severe Mitral Insufficiency in Peripartum Cardiomyopathy Using Levosimendan

Idiopathic peripartum cardiomyopathy presenting with heart failure is a true diagnostic and treatment challenge. Goal oriented clinical management aims at the relapse of left ventricular systolic dysfunction. A 35-year-old patient on her 12th day post-delivery presents progressive signs of heart failure. Transthoracic echocardiography showed severe mitral insufficiency, mild left ventricular dysfunction, mild tricuspid insufficiency, severe pulmonary hypertension, and right atrial enlargement. With wet and cold heart failure signs, the patient was a candidate for inodilator cardiovascular support and volume depletion therapy. As the patient presented a persistent tachycardia at rest, levosimendan was chosen over dobutamine. Levosimendan was administered at a dose of 0.2 g/kg/min during a period of 24 hours. After inodilator therapy, the patient's signs and symptoms of heart failure began to decrease, showing improvement of dyspnea, mitral murmur grade went from IV/IV to II/IV, filling pressures and systemic and pulmonary resistance indexes decreased, arterial blood gases improved, and an echocardiography performed 72 h later showed non-dilated cardiomyopathy, mild cardiac contractile dysfunction, mild mitral insufficiency, type I diastolic dysfunction and improvement of pulmonary hypertension. Cardiovascular function in peripartum cardiomyopathy tends to go back to normality in 23-41% of the cases, but in a large group of patients, severe ventricle dysfunction remains months after initial symptoms. This article describes the diagnostic process of a patient with peripartum cardiomyopathy and a successful reversion of a severe case of mitral insufficiency using levosimendan as a new therapeutic strategy in this clinical context

RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.

We thank Dr. Shiva Malek and her colleagues (Genentech Inc.) for sharing their results with us before publication. We also thank M. San Roman, R. Villar, M.C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, O. Dominguez, and S. Ortega for excellent technical support. This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN); the Spanish Ministry of Science, Innovation, and Universities (RTC-2017-6576-1 and RTI2018094664-B-I00) and the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM) to M.B., as well as by a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00) to M.B. and M.M. M.B. is a recipient of an Endowed Chair from the AXA Research Fund. M.S., P.N., and F.F.-G. were supported by FPU fellowships from the Spanish Ministry of Education. L.E.-B. was a recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. S.G.-A. is a recipient of a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC).S

Analysis of results of effective dose estimation obtained from RADAR 2017 dose assessment model for nuclear medicine procedures

EP-296 Aim/Introduction: To analyze the results of effective dose (E) estimation of the most frequent procedures using photon emitters in Nuclear Medicine, obtained from RADAR 2017 dose assessment model. To compare these results with those obtained from ICRP 128 (2015) recommendations, and to assess how using each dose assessment model can change E results. Materials and Methods: E estimation data was collected from photon emitter procedures performed during the last year in our department, obtained from RADAR 2017 dose estimation model for age groups: = 1 year old; >1-5 years old ; >5- 10 years old, >10- 15 years old and adults. Injected activity was the one recommended by international guidelines and EANM Pediatric and Dosimetry Committees. Hybrid exams (SPECT / CT) and procedures for which there is no RADAR 2017 dosimetry estimation were excluded. Results for (E) were compared with those obtained by using ICRP 128 (2015) recommendations. Results: With RADAR 2017 dose evaluation model we obtained a lower mean value of E on most of the procedures that were analyzed, being significantly lower for Renogram, Renal scintigraphy on >10-15 years old, Thyroid scintigraphy, Meckel’s scan and Bone Scan (0.12 to 1.16 mSv, 25% to 67%). Brain perfusion and Renal scintigraphy on ages under 10 obtained a significantly greater difference for E (0.33 to 2.85 mSv, 26% to 29%). Conclusion: These results are an updated collection of estimated E values for photon-emitting radiopharmaceuticals commonly used in Nuclear Medicine, considering RADAR 2017 dose assessment model compared to ICRP 128) recommendations. Methodological changes on estimation lead to lower E for most of diagnostic procedures using photon emitters, this is of special interest for patients undergoing repeated ionizing radiation (dosimetry history)

Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing

WBP2 encodes the WW domain-binding protein 2 that acts as a transcriptional coactivator for estrogen receptor a (ESR1) and progesterone receptor (PGR). We reported that the loss of Wbp2 expression leads to progressive high-frequency hearing loss in mouse, as well as in two deaf children, each carrying two different variants in the WBP2 gene. The earliest abnormality we detect in Wbp2-deficient mice is a primary defect at inner hair cell afferent synapses. This study defines a new gene involved in the molecular pathway linking hearing impairment to hormonal signalling and provides new therapeutic targets

Observation of Pulsed Gamma-rays Above 25 GeV from the Crab Pulsar with MAGIC

One fundamental question about pulsars concerns the mechanism of their pulsed electromagnetic emission. Measuring the high-end region of a pulsar's spectrum would shed light on this question. By developing a new electronic trigger, we lowered the threshold of the Major Atmospheric gamma-ray Imaging Cherenkov (MAGIC) telescope to 25 GeV. In this configuration, we detected pulsed gamma-rays from the Crab pulsar that were greater than 25 GeV, revealing a relatively high cutoff energy in the phase-averaged spectrum. This indicates that the emission occurs far out in the magnetosphere, hence excluding the polar-cap scenario as a possible explanation of our measurement. The high cutoff energy also challenges the slot-gap scenario.Comment: Slight modification of the analysis: Fitting a more general function to the combined data set of COMPTEL, EGRET and MAGIC. Final result and conclusion is unchange

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.We thank S. Ortega for the generation of the Cdk4FxKD mouse model; and M. San Roman, R. Villar, M. C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, J. Klett, A. Cebria, A. Otero, O. Dominguez, G. Luengo, G. Garaulet, F. Mulero, and D. Megias for excellent technical support. This work was supported by European Research Council Grant ERC-2015-AdG/695566, THERACAN, Spanish Ministry of Science, Innovation, and Universities Grant RTC-2017-6576-1, and the Autonomous Community of Madrid Grant B2017/BMD-3884 iLUNG-CM (to M.B.); Spanish Ministry of Science, Innovation, and Universities Grant RTI2018-094664B-I00 (to M.B. and M.M.); and National Natural Science Foundation of China Grant 31771469 (to H.W.). M.B. is a recipient of an Endowed Chair from the AXA Research Fund. L.E.-B. is the recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. F.F.-G., M.S., and P.N. were supported by an FPU fellowships from the Spanish Ministry of Education.S

INPUT DEVICE RESEARCH FOR DIGITAL PATHOLOGY. AN ERGONOMIC OUTLOOK

Introduction/ Background Digital Pathology represents a technological innovation that introduces changes in the traditional work of pathologists. In this regard, an important issue that has not been enough emphasized is the image handling from an ergonomic point of view to avoid work-related musculoskeletal disorders (MSD). Aims The aim of this study was to investigate a proper input device for digital pathology. Methods Research was conducted in two phases: 1. Comparative study to find an optimal external controller. Eight medical students analyzed 11 input devices: keyboard (HP), conventional mouse (HP), vertical mouse (CLS), touchpad (Logitech), 3 trackballs (Logitech, Kensington Expert and Ulove), Rollermouse (Contour), Ergopointer (Märzhäuser Sensotech), gamepad (Logitech) and a touchless device (Leap-Motion), using them with the Image Viewer software (Ventana). The web-based Fitts´ law test (UC Berkeley) was used to objectify the accuracy of each device, randomly. 12 items were included in the questionnaire: comfort, technical aspects (cursor movement and objective achievement), prospects, overall satisfaction, prior experience, and others. 2. Evaluation by two experienced pathologists (MPR and ANO, 55 and 50 year-old, respectively) the best rated input device and comparison with a voice recognition system (Invox Medical Dictation) using a headset microphone (Plantronics), rating perceived workload using NASA Task Load Index with 28 whole slide images. Digital Image Hub (Leica) with a 4 MegaPixel display (Barco) was used. Data were processed with SPSS 21.0. Results Correlation between technical aspects of the evaluated devices and accuracy (Fitts´ law test), and comfort with overall satisfaction existed (p<0.05). The assessment concluded that vertical mouse was the best rated input device. However, it has a slightly higher perceived workload in comparison with the voice recognition system, which was the proper controller for digital pathology in this study. Conclusion: We describe a methodology that can study and compare input devices for future workstations in digital pathology. Pathologists should be involved in this process trying to find ergonomic devices that prevent MSD. Voice recognition can function as a good handsfree device for digital pathology and could be considered in physical disability situations. Further studies using electromyography, accelerometry and 3D reconstruction analysis could provide additional ergonomic information