Fibre laser hydrophones for cosmic ray particle detection

The detection of ultra high energetic cosmic neutrinos provides a unique means to search for extragalactic sources that accelerate particles to extreme energies. It allows to study the neutrino component of the GZK cut-off in the cosmic ray energy spectrum and the search for neutrinos beyond this limit. Due to low expected flux and small interaction cross-section of neutrinos with matter large experimental set-ups are needed to conduct this type of research. Acoustic detection of cosmic rays may provide a means for the detection of ultra-high energetic neutrinos. Using relative low absorption of sound in water, large experimental set-ups in the deep sea are possible that are able to detect these most rare events, but it requires highly sensitive hydrophones as the thermo-acoustic pulse originating from a particle shower in water has a typical amplitude as low as a mPa. It has been shown in characterisation measurements that the fibre optic hydrophone technology as designed and realised at TNO provides the required sensitivity. Noise measurements and pulse reconstruction have been conducted that show that the hydrophone is suited as a particle detector.Comment: Submitted to the proceedings of "13th Topical Seminar on Innovative Particle and Radiation Detectors (IPRD13)

Establishing reference in language comprehension: An electrophysiological perspective

The electrophysiology of language comprehension has long been dominated by research on syntactic and semantic integration. However, to understand expressions like "he did it" or "the little girl", combining word meanings in accordance with semantic and syntactic constraints is not enough--readers and listeners also need to work out what or who is being referred to. We review our event-related brain potential research on the processes involved in establishing reference, and present a new experiment in which we examine when and how the implicit causality associated with specific interpersonal verbs affects the interpretation of a referentially ambiguous pronoun. The evidence suggests that upon encountering a singular noun or pronoun, readers and listeners immediately inspect their situation model for a suitable discourse entity, such that they can discriminate between having too many, too few, or exactly the right number of referents within at most half a second. Furthermore, our implicit causality findings indicate that a fragment like "David praised Linda because..." can immediately foreground a particular referent, to the extent that a subsequent "he" is at least initially construed as a syntactic error. In all, our brain potential findings suggest that referential processing is highly incremental, and not necessarily contingent upon the syntax. In addition, they demonstrate that we can use ERPs to relatively selectively keep track of how readers and listeners establish reference

Initial antibiotic therapy for postoperative moderate or severe diabetic foot infections: Broad versus narrow spectrum, empirical versus targeted

AIM To retrospectively evaluate clinical and microbiological outcomes after combined surgical and medical therapy for diabetic foot infections (DFIs), stratifying between the empirical versus the targeted nature, and between an empirical broad versus a narrow-spectrum, antibiotic therapy. METHODS We retrospectively assessed the rate of ultimate therapeutic failures for each of three types of initial postoperative antibiotic therapy: adequate empirical therapy; culture-guided therapy; and empirical inadequate therapy with a switch to targeted treatment based on available microbiological results. RESULTS We included data from 332 patients who underwent 716 DFI episodes of surgical debridement, including partial amputations. Clinical failure occurred in 40 of 194 (20.6%) episodes where adequate empirical therapy was given, in 77 of 291 (26.5%) episodes using culture-guided (and correct) therapy from the start, and in 73 of 231 (31.6%) episodes with switching from empirical inadequate therapy to culture-targeted therapy. Equally, a broad-spectrum antibiotic choice could not alter this failure risk. Group comparisons, Kaplan-Meier curves and Cox regression analyses failed to show either statistical superiority or inferiority of any of the initial antibiotic strategies. CONCLUSIONS In this study, the microbiological adequacy of the initial antibiotic regimen after (surgical) debridement for DFI did not alter therapeutic outcomes. We recommend that clinicians follow the stewardship approach of avoiding antibiotic de-escalation and start with a narrow-spectrum regimen based on the local epidemiology

Climacteric Lowers Plasma Levels of Platelet-Derived Microparticles: A Pilot Study in Pre-versus Postmenopausal Women

Background: Climacteric increases the risk of thrombotic events by alteration of plasmatic coagulation. Up to now, less is known about changes in platelet-(PMP) and endothelial cell-derived microparticles (EMP). Methods: In this prospective study, plasma levels of microparticles (MP) were compared in 21 premenopausal and 19 postmenopausal women. Results: No altered numbers of total MP or EMP were measured within the study groups. However, the plasma values of CD61-exposing MP from platelets/megakaryocytes were higher in premenopausal women (5,364 x 10(6)/l, range 4,384-17,167) as compared to postmenopausal women (3,808 x 10(6)/l, range 2,009-8,850; p = 0.020). This differentiation was also significant for the subgroup of premenopausal women without hormonal contraceptives (5,364 x 10(6)/l, range 4,223-15,916; p = 0.047; n = 15). Furthermore, in premenopausal women, higher plasma levels of PMP exposing CD62P were also present as compared to postmenopausal women (288 x 10(6)/l, range 139-462, vs. 121 x 10(6)/l, range 74-284; p = 0.024). This difference was also true for CD63+ PMP levels (281 x 10(6)/l, range 182-551, vs. 137 x 10(6)/l, range 64-432; p = 0.015). Conclusion: Climacteric lowers the level of PMP but has no impact on the number of EMP in women. These data suggest that PMP and EMP do not play a significant role in enhancing the risk of thrombotic events in healthy, postmenopausal women. Copyright (C) 2012 S. Karger AG, Base

Active caspase-3 is removed from cells by release of caspase-3-enriched vesicles

AbstractCleavage of Rho associated Coiled Coil kinase I (ROCK I) by caspase-3 contributes to membrane blebbing. Whether caspase-3 and ROCK I also play a role in the release of membrane vesicles is unknown. Therefore, we transfected a human breast cancer cell line (MCF-7) that is caspase-3 deficient, lacks membrane blebbing, and does not release membrane vesicles, with caspase-3. Cells expressing caspase-3 demonstrate both ROCK I-mediated membrane blebbing, and release of small (400–600nm) membrane vesicles in a ROCK I-independent manner. These membrane vesicles contain caspase-3, and are enriched in caspase-3 activity compared to the releasing cells. Caspase-3-containing vesicles are taken up by untransfected cells but the cells do not show any sign of apoptosis. In conclusion, we show that the release of caspase-3-enriched membrane vesicles and membrane blebbing are two differentially regulated processes. Furthermore, we hypothesize that packaging of caspase-3 into membrane vesicles contributes to cellular homeostasis by the removal of caspase-3, and concurrently, protects the cells' environment from direct exposure to caspase-3 activity

Nanopods: A New Bacterial Structure and Mechanism for Deployment of Outer Membrane Vesicles

Background: Bacterial outer membrane vesicles (OMV) are packets of periplasmic material that, via the proteins and other molecules they contain, project metabolic function into the environment. While OMV production is widespread in proteobacteria, they have been extensively studied only in pathogens, which inhabit fully hydrated environments. However, many (arguably most) bacterial habitats, such as soil, are only partially hydrated. In the latter, water is characteristically distributed as films on soil particles that are, on average thinner, than are typical OMV (ca. ≤10 nm water film vs. 20 to >200 nm OMV;). Methodology/Principal Findings: We have identified a new bacterial surface structure, termed a "nanopod", that is a conduit for projecting OMV significant distances (e.g., ≥6 µm) from the cell. Electron cryotomography was used to determine nanopod three-dimensional structure, which revealed chains of vesicles within an undulating, tubular element. By using immunoelectron microscopy, proteomics, heterologous expression and mutagenesis, the tubes were determined to be an assembly of a surface layer protein (NpdA), and the interior structures identified as OMV. Specific metabolic function(s) for nanopods produced by Delftia sp. Cs1-4 are not yet known. However, a connection with phenanthrene degradation is a possibility since nanopod formation was induced by growth on phenanthrene. Orthologs of NpdA were identified in three other genera of the Comamonadaceae family, and all were experimentally verified to form nanopods. Conclusions/Significance: Nanopods are new bacterial organelles, and establish a new paradigm in the mechanisms by which bacteria effect long-distance interactions with their environment. Specifically, they create a pathway through which cells can effectively deploy OMV, and the biological activity these transmit, in a diffusion-independent manner. Nanopods would thus allow environmental bacteria to expand their metabolic sphere of influence in a manner previously unknown for these organisms

Natriuresis guided therapy in acute heart failure:rationale and design of the Pragmatic Urinary Sodium-based Treatment algoritHm in Acute Heart Failure (PUSH-AHF) trial

AIMS: Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have shown that measuring natriuresis early after hospital admission could reliably identify patients with a poor diuretic response during hospitalization who might require enhanced diuretic treatment. This study will test the hypothesis that natriuresis guided therapy in patients with acute HF improves natriuresis and clinical outcomes. METHODS: The Pragmatic Urinary Sodium-based Treatment algoritHm in Acute Heart Failure (PUSH-AHF) is a pragmatic, single-centre, randomized, controlled, open-label study, aiming to recruit 310 acute HF patients requiring treatment with intravenous loop diuretics. Patients will be randomized to natriuresis guided therapy or standard of care. Natriuresis will be determined at set time points after initiation of intravenous loop diuretics, and treatment will be adjusted based on the urinary sodium levels in the natriuresis guided group using a pre-specified stepwise approach of increasing doses of loop diuretics and the initiation of combination diuretic therapy. The co-primary endpoint is 24-hour urinary sodium excretion after start of loop diuretic therapy and a combined endpoint of all-cause mortality or first HF rehospitalization at 6 months. Secondary endpoints include 48- and 72-hour sodium excretion, length of hospital stay, and percentage change in N-terminal pro Brain Natriuretic Peptide at 48 and 72 hours. CONCLUSION: The PUSH-AHF study will investigate whether natriuresis guided therapy, using a pre-specified stepwise diuretic treatment approach, improves natriuresis and clinical outcomes in patients with acute HF. This article is protected by copyright. All rights reserved

Cellular origin and microRNA profiles of circulating extracellular vesicles in different stages of diabetic nephropathy

Background: Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter disease progression by microRNA (miRNA) transfer. Methods: In this study, we aimed to characterize the cellular origin and miRNA content of EVs in plasma samples of type 2 diabetes patients at various stages of DN. Type 2 diabetes patients were classified in three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. The concentration and cellular origin of plasma EVs were measured by flow cytometry. A total of 752 EV miRNAs were profiled in 18 subjects and differentially expressed miRNAs were validated. Results: Diabetic patients with microalbuminuria and/or macroalbuminuria showed elevated concentrations of total EVs and EVs from endothelial cells, platelets, leucocytes and erythrocytes compared with diabetic controls. miR-99a-5p was upregulated in macroalbuminuric patients compared with normoalbuminuric and microalbuminuric patients. Transfection of miR-99a-5p in cultured human podocytes downregulated mammalian target of rapamycin (mTOR) protein expression and downregulated the podocyte injury marker vimentin. Conclusions: Type 2 diabetes patients with microalbuminuria and macroalbuminuria display differential EV profiles. miR-99a-5p expression is elevated in EVs from macroalbuminuria and mTOR is its validated mRNA target

The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation

Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders

Clinical importance of urinary sodium excretion in acute heart failure

Aims: Urinary sodium assessment has recently been proposed as a target for loop diuretic therapy in acute heart failure (AHF). We aimed to investigate the time course, clinical correlates and prognostic importance of urinary sodium excretion in AHF. Methods and results: In a prospective cohort of 175 consecutive patients with an admission for AHF we evaluated urinary sodium excretion 6 h after initiation of loop diuretic therapy. Clinical outcome was all-cause mortality or heart failure rehospitalization. Mean age was 71 ± 14 years, and 44% were female. Median urinary sodium excretion was 130 (67–229) mmol at 6 h, 347 (211–526) mmol at 24 h, and decreased from day 2 to day 4. Lower urinary sodium excretion was independently associated with male gender, younger age, renal dysfunction and pre-admission loop diuretic use. There was a strong association between urinary sodium excretion at 6 h and 24 h urine volume (beta = 0.702, P < 0.001). Urinary sodium excretion after 6 h was a strong predictor of all-cause mortality after a median follow-up of 257 days (hazard ratio 3.81, 95% confidence interval 1.92–7.57; P < 0.001 for the lowest vs. the highest tertile of urinary sodium excretion) independent of established risk factors and urinary volume. Urinary sodium excretion was not associated with heart failure rehospitalization. Conclusion: In a modern, unselected, contemporary AHF population, low urinary sodium excretion during the first 6 h after initiation of loop diuretic therapy is associated with lower urine output in the first day and independently associated with all-cause mortality