Analysis of 3 years of data from the gravitational wave detectors EXPLORER and NAUTILUS

We performed a search for short gravitational wave bursts using about 3 years of data of the resonant bar detectors Nautilus and Explorer. Two types of analysis were performed: a search for coincidences with a low background of accidentals (0.1 over the entire period), and the calculation of upper limits on the rate of gravitational wave bursts. Here we give a detailed account of the methodology and we report the results: a null search for coincident events and an upper limit that improves over all previous limits from resonant antennas, and is competitive, in the range h_rss ~1E-19, with limits from interferometric detectors. Some new methodological features are introduced that have proven successful in the upper limits evaluation.Comment: 12 pages, 12 figure

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk

Hydrogen Bond Dynamics Near A Micellar Surface: Origin of the Universal Slow Relaxation at Complex Aqueous Interfaces

The dynamics of hydrogen bonds among water molecules themselves and with the polar head groups (PHG) at a micellar surface have been investigated by long molecular dynamics simulations. The lifetime of the hydrogen bond between a PHG and a water molecule is found to be much longer than that between any two water molecules, and is likely to be a general feature of hydrophilic surfaces of organized assemblies. Analyses of individual water trajectories suggest that water molecules can remain bound to the micellar surface for more than a hundred picosecond. The activation energy for such a transition from the bound to a free state for the water molecules is estimated to be about 3.5kcal/mole.Comment: 12 pages. Phys. Rev. Lett. (Accepted) (2002

Redox-induced activation of the proton pump in the respiratory complex I

Significance Complex I is a redox-driven proton pump, central for aerobic energy transduction. We show here by large-scale quantum and classical molecular simulations how reduction of quinone (Q) in the hydrophilic domain of complex I activates the proton pump in the membrane domain. Our simulations indicate that reduction of Q leads to local charge redistributions that trigger conformational changes via an array of alternating charged residues in the membrane domain, nearly 40 Å away. These mechanistic observations are supported by site-directed mutagenesis of a key residue triggering the activation process. The combined data provide molecular insight into how the long-range energy transduction is accomplished by complex I.</jats:p

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types

Significant narrowing of the circumflex artery leads to worse outcomes than right coronary artery narrowing in patients with anterior myocardial infarction treated invasively

BACKGROUND: Occlusion of the circumflex artery (Cx) often does not present signs in the ECG. It can lead to delayed angiography during ST-elevation myocardial infarction (STEMI). The aim of this analysis was to determine if Cx narrowing is related to diverse outcomes in comparison with right coronary artery (RCA) stenosis in patients with STEMI, treated with percutaneous coronary intervention (PCI) of the left descending artery (LAD). METHODS AND RESULTS: Inclusion criteria were as follows: first STEMI treated with PCI of the LAD and additional significant (≥ 70 %) Cx or RCA narrowing—two-vessel disease. A total of 234 consecutive patients with STEMI were included. Total mortality was estimated during long-term follow-up, at mean 639 (± 224) days after STEMI. Patients with Cx narrowing constituted 46 % (N = 108) of the study population, and patients with RCA narrowing amounted to 54 % (N = 126). Patients with narrowing of the Cx had worse long-term outcomes in terms of mortality than patients with RCA narrowing (22 vs. 11 %, p < 0.05, respectively). Multiple regression analysis showed independent risk factors for death during long-term follow-up such as: age, ejection fraction and Cx narrowing. CONCLUSION: Significant Cx narrowing leads to worse outcomes than RCA narrowing in patients with STEMI treated with PCI of the LAD

Protocol for a multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE)

Introduction Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord which causes motor and sensory disturbance and limited recovery in 50% of patients. Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). Intravenous immunoglobulin (IVIG) has also been used as an adjunct to steroids, but evidence is lacking. We propose the first randomised control trial in adults and children, to determine the benefit of additional treatment with IVIG. Methods and analysis 170 adults and children aged over 1 year with acute first episode TM or neuromyelitis optica (with myelitis) will be recruited over a 2.5-year period and followed up for 12 months. Participants randomised to the control arm will receive standard therapy of intravenous methylprednisolone (IVMP). The intervention arm will receive the above standard therapy, plus additional IVIG. Primary outcome will be a 2-point improvement on the American Spinal Injury Association (ASIA) Impairment scale at 6 months postrandomisation by blinded assessors. Additional secondary and tertiary outcome measures will be collected: ASIA motor and sensory scales, Kurtzke expanded disability status scale, International Spinal Cord Injury (SCI) Bladder/Bowel Data Set, Client Services Receipt Index, Pediatric Quality of Life Inventory, EQ-5D, SCI Pain and SCI Quality of Life Data Sets. Biological samples will be biobanked for future studies. After 6-months' follow-up of the first 52 recruited patients futility analysis will be carried out. Health economics analysis will be performed to calculate cost-effectiveness. After 6 months’ recruitment futility analysis will be performed

Optogenetic targeting of cardiac myocytes and non-myocytes: tools, challenges and utility

In optogenetics, light-activated proteins are used to monitor and modulate cellular behaviour with light. Combining genetic targeting of distinct cellular populations with defined patterns of optical stimulation enables one to study specific cell classes in complex biological tissues. In the current study we attempted to investigate the functional relevance of heterocellular electrotonic coupling in cardiac tissue in situ. In order to do that, we used a Cre-Lox approach to express the light-gated cation channel Channelrhodopsin-2 (ChR2) specifically in either cardiac myocytes or non-myocytes. Despite high specificity when using the same Cre driver lines in a previous study in combination with a different optogenetic probe, we found patchy off-target ChR2 expression in cryo-sections and extended z-stack imaging through the ventricular wall of hearts cleared using CLARITY. Based on immunohistochemical analysis, single-cell electrophysiological recordings and whole-genome sequencing, we reason that non-specificity is caused on the Cre recombination level. Our study highlights the importance of careful design and validation of the Cre recombination targets for reliable cell class specific expression of optogenetic tools

Analysis of the peripapillary and macular regions using OCT angiography in patients with schizophrenia and bipolar disorder

Purpose: To measure RNFL and vasculature around the optic disc and in the macula in patients with schizophrenia (SZ) and bipolar disorder (BD) using optical coherence tomography angiography (OCTA). Methods: 24 eyes of patients with SZ and 16 eyes of patients with BD as well as 30 eyes of healthy subjects were examined with OCTA. The radiant peripapillary capillary (RPC) density and RNFL thickness were measured in the peripapillary area. Moreover, macular thickness and vessel density were measured in both superficial and deep layers. Results: Significantly decreased values of vessel density in the macular deep vascular complex were found in the eyes of patients with SZ, compared to BD and the control group. The macular thickness in the whole vascular complex and in the fovea was significantly lower in SZ and BD group than in the control group. The radiant peripapillary vascular density and RNFL thickness were similar across groups. Conclusions: The retinal microvascular dysfunction occurs in the macula in patients with SZ and BD, but not around optic disc. OCTA can become an essential additional diagnostic tool in detection of psychiatric disorders

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing