The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

OBJECTIVE The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan. METHODS NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay. RESULTS Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding. CONCLUSION Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.

The impact of the position effect on the factorial structure of the Culture Fair Test (CFT)

The Culture Fair Test (CFT) is a psychometric test of fluid intelligence consisting of four subtests; Series, Classification, Matrices, and Topographies. The four subtests are only moderately intercorrelated, doubting the notion that they assess the same construct (i.e., fluid intelligence). As an explanation of these low correlations, we investigated the position effect. This effect is assumed to reflect implicit learning during testing. By applying fixed-links modeling to analyze the CFT data of 206 participants, we identified position effects as latent variables in the subtests; Classification, Matrices, and Topographies. These position effects were disentangled from a second set of latent variables representing fluid intelligence inherent in the four subtests. After this separation of position effect and basic fluid intelligence, the latent variables representing basic fluid intelligence in the subtests Series, Matrices, and Topographies could be combined to one common latent variable which was highly correlated with fluid intelligence derived from the subtest Classification (r=.72). Correlations between the three latent variables representing the position effects in the Classification, Matrices, and Topographies subtests ranged from r=.38 to r=.59. The results indicate that all four CFT subtests measure the same construct (i.e., fluid intelligence) but that the position effect confounds the factorial structure

Characterization of recombinant class I MHC alloantigen action upon the survival of disparate heart allografts

Previous studies have led to the development of allochimeric class I MHC proteins as agents that effectively induce donor-specific transplantation tolerance in a rat system with or without additional immunosuppression. Within the α1-helical region of RT1.Au, an epitope that conferred immunologic tolerance was discovered. Studies presented herein were designed to test our central hypothesis that allochimeric proteins onfer tolerance in a mouse model. To test this hypothesis, portal vein (PV) injection of wild-type H2Kd and H2Dd proteins were produced in a bacterial expression system and found to specifically prolong the survival of BALB/c (H2d) heart allografts in C57BL/10 (H2b) recipients. Although a single PV injection of 50 μg α1–α 3 H2Kd alone was ineffective, 50 μg α1 –α3 alone slightly prolonged BALB/c heart allograft survivals. In contrast, the combination of 25 μg α1–α 3 H2Kd and 25 μg α1–α 3 H2Dd proteins prolonged BALB/c graft survivals to 20.2 ± 6.4 days (p < 0.004). The effect was donor-specific, since a combination of 25 μg α1–α3 H2Kd and 25 μg α1–α3 H2Dd proteins failed to affect survivals of third-party C3H (H2k k) heart allografts, namely 9.0 ± 0.0 days in treated versus 7.8 ± 0.5 days in untreated hosts. Thus, the combination of two H2K d and H2Dd proteins is more effective in prolonging allograft survival than a single protein produced in a bacterial expression system. A single PV injection (day 0) of 25 μg α1–α 2 H2Kd and 25 μg α1–α 2 H2Dd proteins to C57BL/10 mice prolonged the survival of BALB/c heart allografts to 22.4 ± 4.5 days. Within a WF to ACI rat heart allograft system, a single PV injection of 20 μg 70–77 u-RT1.Aa induced specific tolerance of allografts. This therapy could be combined with CsA to induce transplantation tolerance. However, combination of 70–77u-RT1.Aa with CTLA4Ig, rapamycin, or AG-490 effectively blocked the induction of transplantation tolerance. Tolerance generated by allochimeric protein could be adoptively transferred to naive recipients. Intragraft cytokine mRNA levels showed a bias towards a Th2-type phenotype. Additionally, studies of cytokine signaling and activation of transcription factors revealed a requirement that these pathways remain available for signaling in order for transplantation tolerance to occur. These studies suggest that the generation of regulatory cells are required for the induction of transplantation tolerance through the use of allochimeric proteins. ^

Are Shirking and Leisure Substitutable? An Empirical Test of Efficiency Wages Based on Urban Economic Theory

Recent theoretical work has examined the spatial distribution of unemployment using the efficiency wage model as the mechanism by which unemployment arises in the urban economy. This paper extends the standard efficiency wage model in order to allow for behavioral substitution between leisure time at home and effort at work. In equilibrium, residing at a location with a long commute affects the time available for leisure at home and therefore affects the trade-off between effort at work and risk of unemployment. This model implies an empirical relationship between expected commutes and labor market outcomes, which is tested using the Public Use Microdata sample of the 2000 U.S. Decennial Census. The empirical results suggest that efficiency wages operate primarily for blue collar workers, i.e. workers who tend to be in occupations that face higher levels of supervision. For this subset of workers, longer commutes imply higher levels of unemployment and higher wages, which are both consistent with shirking and leisure being substitutable.

Optimal Test for Parameter Instability When the Unstable Process and the Error Distribution are Unknown

This paper proposes asymptotically optimal tests for unstable parameter process under the feasible circumstance that the researcher has little information about the unstable parameter process and the error distribution, and suggests conditions under which the knowledge of those processes does not provide asymptotic power gains. I first derive a test under known error distribution, which is asymptotically equivalent to LR tests for correctly identified unstable parameter processes under suitable conditions. The conditions are weak enough to cover a wide range of unstable processes such as various types of structural breaks and time varying parameter processes. The test is then extended to semiparametric models in which the underlying distribution in unknown but treated as unknown infinite dimensional nuisance parameter. The semiparametric test is adaptive in the sense that its asymptotic power function is equivalent to the power envelope under known error distribution.

A simulation study using the hybrid statistic and the meta-analysis t-test for data with matched and unmatched subjects in the interim analysis of clinical trials

An interim analysis is usually applied in later phase II or phase III trials to find convincing evidence of a significant treatment difference that may lead to trial termination at an earlier point than planned at the beginning. This can result in the saving of patient resources and shortening of drug development and approval time. In addition, ethics and economics are also the reasons to stop a trial earlier. In clinical trials of eyes, ears, knees, arms, kidneys, lungs, and other clustered treatments, data may include distribution-free random variables with matched and unmatched subjects in one study. It is important to properly include both subjects in the interim and the final analyses so that the maximum efficiency of statistical and clinical inferences can be obtained at different stages of the trials. So far, no publication has applied a statistical method for distribution-free data with matched and unmatched subjects in the interim analysis of clinical trials. In this simulation study, the hybrid statistic was used to estimate the empirical powers and the empirical type I errors among the simulated datasets with different sample sizes, different effect sizes, different correlation coefficients for matched pairs, and different data distributions, respectively, in the interim and final analysis with 4 different group sequential methods. Empirical powers and empirical type I errors were also compared to those estimated by using the meta-analysis t-test among the same simulated datasets. Results from this simulation study show that, compared to the meta-analysis t-test commonly used for data with normally distributed observations, the hybrid statistic has a greater power for data observed from normally, log-normally, and multinomially distributed random variables with matched and unmatched subjects and with outliers. Powers rose with the increase in sample size, effect size, and correlation coefficient for the matched pairs. In addition, lower type I errors were observed estimated by using the hybrid statistic, which indicates that this test is also conservative for data with outliers in the interim analysis of clinical trials.^

Aplicación de la clasificación ATC al análisis de las prescripciones en DAMSU : I : los grupos de medicamentos que encabezan el ranking

Este es un estudio sobre utilización de medicamentos donde se analiza la evolución de la prescripción, en DAMSU de UNCuyo, de los 14 grupos terapéuticos (GT) de la clasificación ATC, durante 4 años consecutivos. Su objetivo fue determinar la prevalencia de las prescripciones en los 3 primeros niveles de la clasificación. Los datos fueron recolectados en los meses de abril, junio, setiembre y diciembre utilizando la metodología del DURG y procesados con un programa EPI INFO. Las comparaciones estadísticas fueron realizadas mediante la Prueba no paramétrica de los Signos. El ranking de GT fue constante pero el total de prescripciones disminuyó significativamente entre 2004 y 2007. Los GT del 1º nivel: S. Nervioso (N), S. cardiovascular (C), Digestivo y Metabolismo (A) y Músculo-esquelético (M), ocuparon, en orden decreciente, los cuatro primeros puestos del ranking durante los 4 años. De estos GT fueron analizados los subgrupos del 2º y 3º nivel. La prescripción de Psicolépticos + Psicoanalépticos superó a la de Analgésicos en el grupo N. En el grupo C los Agentes Antihipertensivos, y entre ellos los IECAs, encabezaron el ranking. Las vitaminas fueron las primeras en el GT A y el subgrupo de Antiinflamatorios y Antirreumáticos en el GT M. Se discuten estos resultados en función de la racionalidad de las prescripciones.

Stable oxygen and carbon isotope ratios of foraminifera and test results after different sample cleaning procedures from ODP Leg 207 sediments

We report oxygen and carbon stable isotope analyses of foraminifers, primarily planktonic, sampled at low resolution in the Cretaceous and Paleogene sections from Sites 1257, 1258, and 1260. Data from two samples from Site 1259 are also reported. The very low resolution of the data only allows us to detect climate-driven isotopic events on the timescale of more than 500 k.y. A several million-year-long interval of overall increase in planktonic 18O is seen in the Cenomanian at Site 1260. Before and after this interval, foraminifers from Cenomanian and Turonian black shales have d18O values in the range -4.2 per mil to -5.0 per mil, suggestive of upper ocean temperatures higher than modern tropical values. The d18O values of upper ocean dwelling Paleogene planktonics exhibit a long-term increase from the early Eocene to the middle Eocene. During shipboard and postcruise processing, it proved difficult to extract well-preserved foraminifer tests from black shales by conventional techniques. Here, we report results of a test of procedures for cleaning foraminifers in Cretaceous organic-rich mudstone sediments using various combinations of soaking in bleach, Calgon/hydrogen peroxide, or Cascade, accompanied by drying, repeat soaking, or sonication. A procedure that used 100% bleach, no detergent, and no sonication yielded the largest number of clean, whole individual foraminifers with the shortest preparation time. We found no significant difference in d18O or d13C values among sets of multiple samples of the planktonic foraminifer Whiteinella baltica extracted following each cleaning procedure.

Contribution to the Analysis, Design and Assessment of Compact Antenna Test Ranges At Millimeter Wavelengths - Contribución al Análisis, Diseño y Caracterización de Sistemas de Medida de Antenas en Rango Compacto para Frecuencias Milimétricas

This Doctoral Thesis entitled Contribution to the analysis, design and assessment of compact antenna test ranges at millimeter wavelengths aims to deepen the knowledge of a particular antenna measurement system: the compact range, operating in the frequency bands of millimeter wavelengths. The thesis has been developed at Radiation Group (GR), an antenna laboratory which belongs to the Signals, Systems and Radiocommunications department (SSR), from Technical University of Madrid (UPM). The Radiation Group owns an extensive experience on antenna measurements, running at present four facilities which operate in different configurations: Gregorian compact antenna test range, spherical near field, planar near field and semianechoic arch system. The research work performed in line with this thesis contributes the knowledge of the first measurement configuration at higher frequencies, beyond the microwaves region where Radiation Group features customer-level performance. To reach this high level purpose, a set of scientific tasks were sequentially carried out. Those are succinctly described in the subsequent paragraphs. A first step dealed with the State of Art review. The study of scientific literature dealed with the analysis of measurement practices in compact antenna test ranges in addition with the particularities of millimeter wavelength technologies. Joint study of both fields of knowledge converged, when this measurement facilities are of interest, in a series of technological challenges which become serious bottlenecks at different stages: analysis, design and assessment. Thirdly after the overview study, focus was set on Electromagnetic analysis algorithms. These formulations allow to approach certain electromagnetic features of interest, such as field distribution phase or stray signal analysis of particular structures when they interact with electromagnetic waves sources. Properly operated, a CATR facility features electromagnetic waves collimation optics which are large, in terms of wavelengths. Accordingly, the electromagnetic analysis tasks introduce an extense number of mathematic unknowns which grow with frequency, following different polynomic order laws depending on the used algorithmia. In particular, the optics configuration which was of our interest consisted on the reflection type serrated edge collimator. The analysis of these devices requires a flexible handling of almost arbitrary scattering geometries, becoming this flexibility the nucleus of the algorithmia’s ability to perform the subsequent design tasks. This thesis’ contribution to this field of knowledge consisted on reaching a formulation which was powerful at the same time when dealing with various analysis geometries and computationally speaking. Two algorithmia were developed. While based on the same principle of hybridization, they reached different order Physics performance at the cost of the computational efficiency. Inter-comparison of their CATR design capabilities was performed, reaching both qualitative as well as quantitative conclusions on their scope. In third place, interest was shifted from analysis - design tasks towards range assessment. Millimetre wavelengths imply strict mechanical tolerances and fine setup adjustment. In addition, the large number of unknowns issue already faced in the analysis stage appears as well in the on chamber field probing stage. Natural decrease of dynamic range available by semiconductor millimeter waves sources requires in addition larger integration times at each probing point. These peculiarities increase exponentially the difficulty of performing assessment processes in CATR facilities beyond microwaves. The bottleneck becomes so tight that it compromises the range characterization beyond a certain limit frequency which typically lies on the lowest segment of millimeter wavelength frequencies. However the value of range assessment moves, on the contrary, towards the highest segment. This thesis contributes this technological scenario developing quiet zone probing techniques which achieves substantial data reduction ratii. Collaterally, it increases the robustness of the results to noise, which is a virtual rise of the setup’s available dynamic range. In fourth place, the environmental sensitivity of millimeter wavelengths issue was approached. It is well known the drifts of electromagnetic experiments due to the dependance of the re sults with respect to the surrounding environment. This feature relegates many industrial practices of microwave frequencies to the experimental stage, at millimeter wavelengths. In particular, evolution of the atmosphere within acceptable conditioning bounds redounds in drift phenomena which completely mask the experimental results. The contribution of this thesis on this aspect consists on modeling electrically the indoor atmosphere existing in a CATR, as a function of environmental variables which affect the range’s performance. A simple model was developed, being able to handle high level phenomena, such as feed - probe phase drift as a function of low level magnitudes easy to be sampled: relative humidity and temperature. With this model, environmental compensation can be performed and chamber conditioning is automatically extended towards higher frequencies. Therefore, the purpose of this thesis is to go further into the knowledge of millimetre wavelengths involving compact antenna test ranges. This knowledge is dosified through the sequential stages of a CATR conception, form early low level electromagnetic analysis towards the assessment of an operative facility, stages for each one of which nowadays bottleneck phenomena exist and seriously compromise the antenna measurement practices at millimeter wavelengths.

Characterization and Test of a Data Acquisition System for PET

A small Positron Emission Tomography demonstrator based on LYSO slabs and Silicon Photomultiplier matrices is under construction at the University and INFN of Pisa. In this paper we present the characterization results of the read-out electronics and of the detection system. Two SiPM matrices, composed by 8 × 8 SiPM pixels, 1.5 mm pitch, have been coupled one to one to a LYSO crystals array. Custom Front-End ASICs were used to read the 64 channels of each matrix. Data from each Front-End were multiplexed and sent to a DAQ board for the digital conversion; a motherboard collects the data and communicates with a host computer through a USB port. Specific tests were carried out on the system in order to assess its performance. Futhermore we have measured some of the most important parameters of the system for PET application.

Full scale test for explosion water barriers in small cross-section galleries

Underground coal mines explosions generally arise from the inflammation of a methane/air mixture. This explosion can also generate a subsequent coal dust explosion. Traditionally such explosions have being fought eliminating one or several of the factors needed by the explosion to take place. Although several preventive measures are taken to prevent explosions, other measures should be considered to reduce the effects or even to extinguish the flame front. Unlike other protection methods that remove one or two of the explosion triangle elements, namely; the ignition source, the oxidizing agent and the fuel, explosion barriers removes all of them: reduces the quantity of coal in suspension, cools the flame front and the steam generated by vaporization removes the oxygen present in the flame. Passive water barriers are autonomous protection systems against explosions that reduce to a satisfactory safety level the effects of methane and/or flammable dust explosions. The barriers are activated by the pressure wave provoked in the explosion destroying the barrier troughs and producing a uniform dispersion of the extinguishing agent throughout the gallery section in quantity enough to extinguish the explosion flame. Full scale tests have been carried out in Polish Barbara experimental mine at GIG Central Mining Institute in order to determine the requirements and the optimal installation conditions of these devices for small sections galleries which are very frequent in the Spanish coal mines. Full scale tests results have been analyzed to understand the explosion timing and development, in order to assess on the use of water barriers in the typical small crosssection Spanish galleries. Several arrangements of water barriers have been designed and tested to verify the effectiveness of the explosion suppression in each case. The results obtained demonstrate the efficiency of the water barriers in stopping the flame front even with smaller amounts of water than those established by the European standard. According to the tests realized, water barriers activation times are between 0.52 s and 0.78 s and the flame propagation speed are between 75 m/s and 80 m/s. The maximum pressures (Pmax) obtained in the full scale tests have varied between 0.2 bar and 1.8 bar. Passive barriers protect effectively against the spread of the flame but cannot be used as a safeguard of the gallery between the ignition source and the first row of water troughs or bags, or even after them, as the pressure could remain high after them even if the flame front has been extinguished.

Real-time reliability test for a CPV module based on a power degradation model

Models based on degradation are powerful and useful tools to evaluate the reliability of those devices in which failure happens because of degradation in the performance parameters. This paper presents a procedure for assessing the reliability of concentrator photovoltaic (CPV) modules operating outdoors in real-time conditions. With this model, the main reliability functions are predicted. This model has been applied to a real case with a module composed of GaAs single-junction solar cells and total internal reflection (TIR) optics

Preliminary test to characterize the soundscape of the Plaza Mayor in Madrid

This paper is a first step of a research about the analysis of the richness of the existing sounds in the Plaza Mayor, due to the old and traditional shops and bars under its porticoes together with the huge daily affluence of people. In this paper we study the sound preferences of the salesmen and bar tenders at those traditional shops. These sound preferences include particular sounds, time of occurrence and date of specific annoying and pleasant sounds perceived at the square and the shops surrounding it. To carry out this study, several noise level measurements and socio-acoustic surveys were held. We will also try to correlate sound preferences and annoyance with noise levels of specific events existing at this particular square.

Design and Test of a High QoS Radio Network for CBTC Systems in Subway Tunnels

Communications Based Train Control Systems require high quality radio data communications for train signaling and control. Actually most of these systems use 2.4GHz band with proprietary radio transceivers and leaky feeder as distribution system. All them demand a high QoS radio network to improve the efficiency of railway networks. We present narrow band, broad band and data correlated measurements taken in Madrid underground with a transmission system at 2.4 GHz in a test network of 2 km length in subway tunnels. The architecture proposed has a strong overlap in between cells to improve reliability and QoS. The radio planning of the network is carefully described and modeled with narrow band and broadband measurements and statistics. The result is a network with 99.7% of packets transmitted correctly and average propagation delay of 20ms. These results fulfill the specifications QoS of CBTC systems.