Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Alemtuzumab; Disease-modifying therapy; Multiple sclerosisAlemtuzumab; Teràpia modificadora de la malaltia; Esclerosi múltipleAlemtuzumab; Terapia modificadora de la enfermedad; Esclerosis múltipleBackground and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course.The TOPAZ study as well as writing and editorial support for this article were funded by Sanofi

Caspase activation in etoposide‐treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion

Activation of the extracellular signal‐regulated kinases (ERKs) 1 and 2 is correlated to cell survival, but in some cases ERKs can act in signal transduction pathways leading to apoptosis. Treatment of mouse fibroblasts with 20 μM etoposide elicited a sustained phosphorylation of ERK 1/2, that increased until 24 h from the treatment in parallel with caspase activity. The inhibitor of ERK activation PD98059 abolished caspase activation, but caspase inhibition did not reduce ERK 1/2 phosphorylation, suggesting that ERK activation is placed upstream of caspases. Both ERK and caspase activation were blocked in cells depleted of polyamines by the ornithine decarboxylase inhibitor α‐difluoromethylornithine (DFMO). In etoposide‐treated cells, DFMO also abolished phosphorylation of c‐Jun NH2‐terminal kinases triggered by the drug. Polyamine replenishment with exogenous putrescine restored the ability of the cells to undergo caspase activation and ERK 1/2 phosphorylation in response to etoposide. Ornithine decarboxylase activity decreased after etoposide, indicating that DFMO exerts its effect by depleting cellular polyamines before induction of apoptosis. These results reveal a role for polyamines in the transduction of the death signal triggered by etoposide

Statistical downscaling in the tropics can be sensitive to reanalysis choice: A case study for precipitation in the Philippines

This work shows that local-scale climate projections obtained by means of statistical downscaling are sensitive to the choice of reanalysis used for calibration. To this aim, a generalized linear model (GLM) approach is applied to downscale daily precipitation in the Philippines. First, the GLMs are trained and tested separately with two distinct reanalyses (ERA-Interim and JRA-25) using a cross-validation scheme over the period 1981–2000. When the observed and downscaled time series are compared, the attained performance is found to be sensitive to the reanalysis considered if climate change signal–bearing variables (temperature and/or specific humidity) are included in the predictor field. Moreover, performance differences are shown to be in correspondence with the disagreement found between the raw predictors from the two reanalyses. Second, the regression coefficients calibrated either with ERA-Interim or JRA-25 are subsequently applied to the output of a global climate model (MPI-ECHAM5) in order to assess the sensitivity of local-scale climate change projections (up to 2100) to reanalysis choice. In this case, the differences detected in present climate conditions are considerably amplified, leading to “delta-change” estimates differing by up to 35% (on average for the entire country) depending on the reanalysis used for calibration. Therefore, reanalysis choice is an important contributor to the uncertainty of local-scale climate change projections and, consequently, should be treated with as much care as other better-known sources of uncertainty (e.g., the choice of the GCM and/or downscaling method). Implications of the results for the entire tropics, as well as for the model output statistics downscaling approach are also briefly discussed.The authors are grateful to the free distribution of the ECMWF ERA-Interim (http://www.ecmwf.int/en/research/climate-reanalysis/era-interim), JMA JRA-25 (http://jra.kishou.go.jp/JRA-25/index_en.html), and MPI-ECHAM5 data (http://cera-www.dkrz.de/WDCC/ui/Compact.jsp?acronym=ENSEMBLES_MPEH5_SRA1B_3_D) and acknowledge PAGASA for the observational data provided. This study was supported by the EU projects QWeCI and SPECS, funded by the European Commission through the Seventh Framework Programme for Research under Grant Agreements 243964 and 308378, respectively. RM also acknowledges the EU project EUPORIAS, funded by the European Commission through the Seventh Framework Programme for Research under Grant Agreement 308291. SB is grateful to the CSIC-JAE-Predoc Program for financial support

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

CMB observations from the CBI and VSA: A comparison of coincident maps and parameter estimation methods

We present coincident observations of the Cosmic Microwave Background (CMB) from the Very Small Array (VSA) and Cosmic Background Imager (CBI) telescopes. The consistency of the full datasets is tested in the map plane and the Fourier plane, prior to the usual compression of CMB data into flat bandpowers. Of the three mosaics observed by each group, two are found to be in excellent agreement. In the third mosaic, there is a 2 sigma discrepancy between the correlation of the data and the level expected from Monte Carlo simulations. This is shown to be consistent with increased phase calibration errors on VSA data during summer observations. We also consider the parameter estimation method of each group. The key difference is the use of the variance window function in place of the bandpower window function, an approximation used by the VSA group. A re-evaluation of the VSA parameter estimates, using bandpower windows, shows that the two methods yield consistent results.Comment: 10 pages, 6 figures. Final version. Accepted for publication in MNRA

Modeling and characterization of the SPIDER half-wave plate

Spider is a balloon-borne array of six telescopes that will observe the Cosmic Microwave Background. The 2624 antenna-coupled bolometers in the instrument will make a polarization map of the CMB with approximately one-half degree resolution at 145 GHz. Polarization modulation is achieved via a cryogenic sapphire half-wave plate (HWP) skyward of the primary optic. We have measured millimeter-wave transmission spectra of the sapphire at room and cryogenic temperatures. The spectra are consistent with our physical optics model, and the data gives excellent measurements of the indices of A-cut sapphire. We have also taken preliminary spectra of the integrated HWP, optical system, and detectors in the prototype Spider receiver. We calculate the variation in response of the HWP between observing the CMB and foreground spectra, and estimate that it should not limit the Spider constraints on inflation

Pointing control for the SPIDER balloon-borne telescope

We present the technology and control methods developed for the pointing system of the SPIDER experiment. SPIDER is a balloon-borne polarimeter designed to detect the imprint of primordial gravitational waves in the polarization of the Cosmic Microwave Background radiation. We describe the two main components of the telescope's azimuth drive: the reaction wheel and the motorized pivot. A 13 kHz PI control loop runs on a digital signal processor, with feedback from fibre optic rate gyroscopes. This system can control azimuthal speed with < 0.02 deg/s RMS error. To control elevation, SPIDER uses stepper-motor-driven linear actuators to rotate the cryostat, which houses the optical instruments, relative to the outer frame. With the velocity in each axis controlled in this way, higher-level control loops on the onboard flight computers can implement the pointing and scanning observation modes required for the experiment. We have accomplished the non-trivial task of scanning a 5000 lb payload sinusoidally in azimuth at a peak acceleration of 0.8 deg/s$^2$, and a peak speed of 6 deg/s. We can do so while reliably achieving sub-arcminute pointing control accuracy.Comment: 20 pages, 12 figures, Presented at SPIE Ground-based and Airborne Telescopes V, June 23, 2014. To be published in Proceedings of SPIE Volume 914

Search for Event Rate Modulation in XENON100 Electronic Recoil Data

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an un-binned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1 sigma for all periods suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8 sigma, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of WIMPs to electrons is excluded at 4.8 sigma.Comment: 6 pages, 4 figure

In-cell NMR characterization of the secondary structure populations of a disordered conformation of α-Synuclein within E. coli cells

α-Synuclein is a small protein strongly implicated in the pathogenesis of Parkinson’s disease and related neurodegenerative disorders. We report here the use of in-cell NMR spectroscopy to observe directly the structure and dynamics of this protein within E. coli cells. To improve the accuracy in the measurement of backbone chemical shifts within crowded in-cell NMR spectra, we have developed a deconvolution method to reduce inhomogeneous line broadening within cellular samples. The resulting chemical shift values were then used to evaluate the distribution of secondary structure populations which, in the absence of stable tertiary contacts, are a most effective way to describe the conformational fluctuations of disordered proteins. The results indicate that, at least within the bacterial cytosol, α-synuclein populates a highly dynamic state that, despite the highly crowded environment, has the same characteristics as the disordered monomeric form observed in aqueous solution