Heterogeneity of glomerular perfusion and filtration induced by epinephrine and norepinephrine

The role of catecholamines in the distribution of intrarenal blood flow and in single-nephron glomerular filtration rate (SNGFR) was evaluated in anesthetized Wistar rats by the Hanssen technique. Epinephrine (EPI) and norepinephrine (NOR) were infused to produce elevations of 20-30 mmHg in mean arterial pressure. Superficial and juxtamedullary nephron perfusion and filtration were determined by the presence of Prussian blue dye. In the control group, 100% of the nephrons presented a homogeneous pattern of perfusion and filtration. In contrast, a heterogeneous distribution of the dye was found even in the larger arteries (arciform and radial), indicating variable perfusion and filtration in both superficial and juxtamedullary nephrons. The effects of EPI and NOR were also evaluated in the superficial cortex by the micropuncture technique in two additional groups of Munich-Wistar rats. Mean SNGFR was 27% and 54% lower in the EPI- and NOR-treated groups, respectively. No change in mean intraglomerular hydraulic pressure was observed after EPI or NOR infusion in spite of a highly scattered pattern, indicating an important variability in perfusion along the superficial cortex, and/or different sensitivity of the pre- and post-glomerular arterioles. The present data suggest that EPI and NOR may affect intrarenal hemodynamics by modifying perfusion and filtration in both superficial and juxtamedullary glomeruli and not by shifting blood flow from superficial to juxtamedullary nephrons. The heterogeneous pattern of perfusion was a consequence of differential vasoconstriction along the intrarenal arteries, probably due to different density and/or sensitivity of the adrenergic receptor subtypes present in the intrarenal vascular tree.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

On the bolometric quiescent luminosity and luminosity swing of black hole candidate and neutron star low mass X-ray transients

Low mass X-ray transients (LMXRTs) hosting black hole candidates (BHCs) display on average a factor of ~100 larger swing in the minimum (quiescent) to maximum (outburst) X-ray luminosity than neutron stars (NSs), despite the fact that the swing in the mass inflow rate is likely in the same range. Advection dominated accretion flows (ADAFs) were proposed to interpret such a difference. The residual optical/UV emission of quiescent LMXRTs, after subtraction of the companion star spectrum, is produced by synchrotron radiation in the (latest version) of ADAF and therefore is part of the ADAF's luminosity budget. We demonstrate that, once the residual optical/UV emission is taken into account, the bolometric luminosity swing of BHCs is consistent with that of NSs. We explore here an alternative scenario to ADAFs in which very little mass accretion onto the collapsed star takes place in the quiescence intervals. The residual optical/UV emission of BHCs are expected to derive from the energy released by the matter transferred from the companion star at radii comparable to the circularisation radius. The quiescent X-ray luminosity originates either from accretion onto the BH at very low rates and/or from coronal activity in the companion star or in the outer disk. For comparably small mass inflow rates, the NSs in these systems are likely in the radio pulsar regime. In the interaction of the radio pulsar relativistic wind with matter transferred from the companion star, a shock forms, the power law-like emission of which powers both the harder X-ray emission and most of the residual optical/UV. The soft, thermal-like X-ray component may arise from the cooling of the NS surface. This scenario matches well both the X-ray and bolometric luminosity swing of LMXRTs. (ABRIDGED).Comment: 13 pages (including 2 postscript figures - use emulateapj macro). Accepted for publication in Ap

Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion

Endocardial Approach for Substrate Ablation in Brugada Syndrome

Radiofrequency ablation (RFA) in Brugada syndrome (BrS) has been performed by both endocardial and epicardial. The substrate in BrS is not completely understood. We investigate the functional endocardial substrate and its correlation with clinical, electrophysiological and ECG findings in order to guide an endocardial ablation. Two patients agreed to undergo an endocardial biopsy and the samples were examined with transmission electron microscopy (TEM) to investigate the correlation between functional and ultrastructural alterations. About 13 patients (38.7 ± 12.3 years old) with spontaneous type 1 ECG BrS pattern, inducible VF with programmed ventricular stimulation (PVS) and syncope without prodromes were enrolled. Before endocardial mapping, the patients underwent flecainide testing with the purpose of measuring the greatest ST-segment elevation for to be correlated with the size and location of substrate in the electro-anatomic map. Patients underwent endocardial bipolar and electro-anatomic mapping with the purpose of identify areas of abnormal electrograms (EGMs) as target for RFA and determine the location and size of the substrate. When the greatest ST-segment elevation was in the third intercostal space (ICS), the substrate was located upper in the longitudinal plane of the right ventricular outflow tract (RVOT) and a greatest ST-segment elevation in fourth ICS correspond with a location of substrate in lower region of longitudinal plane of RVOT. A QRS complex widening on its initial and final part, with prolonged transmural and regional depolarization time of RVOT corresponded to the substrate located in the anterior-lateral region of RVOT. A QRS complex widening rightwards and only prolonged transmural depolarization time corresponded with a substrate located in the anterior, anterior-septal or septal region of RVOT. RFA of endocardial substrate suppressed the inducibility and ECG BrS pattern during 34.7 ± 15.5 months. After RFA, flecainide testing confirmed elimination of the ECG BrS pattern. Endocardial biopsy showed a correlation between functional and ultrastructural alterations. Endocardial RFA can eliminate the BrS phenotype and inducibility during programmed ventricular stimulation (PVS)

Endocardial Approach for Substrate Ablation in Brugada Syndrome: Epicardial, Endocardial or Transmural Substrate?

Background: Radiofrequency ablation (RFA) in Brugada syndrome (BrS) has been performed both endocardially and epicardially. The substrate in BrS is thus unclear.Objectives: To investigate the functional endocardial substrate and its correlation with clinical, electrophysiological and ECG findings in order to guide an endocardial ablation.Methods: Thirteen patients (38.7±12.3 years old) with spontaneous type 1 ECG BrS pattern, inducible VF with programmed ventricular stimulation (PVS) and syncope without prodromes were enrolled. Before to endocardial mapping the patients underwent flecainide testing with the purpose of measuring the greatest ST-segment elevation for to be correlated with the size and location of substrate in the electro-anatomic map. Patients underwent endocardial bipolar and electro-anatomic mapping with the purpose of identify areas of abnormal electrograms (EGMs) as target for RFA and determine the location and size of the substrate.Results: When the greatest ST-segment elevation was in the 3rd intercostal space (ICS), the substrate was located upper in the longitudinal plane of the right ventricular outflow tract (RVOT) and a greatest ST-segment elevation in 4th ICS correspond with a location of substrate in lower region of longitudinal plane of RVOT. A QRS complex widening on its initial and final part, with prolonged transmural and regional depolarization time of RVOT corresponded to the substrate locateded in the anterior-lateral region of RVOT. A QRS complex widening rightwards and only prolonged transmural depolarization time corresponded with a substrate located in the anterior, anterior-septal or septal region of RVOT. RFA of endocardial substrate suppressed the inducibility and ECG BrS pattern during 34.7±15.5 months. After RFA, flecainide testing confirmed elimination of the ECG BrS pattern. Endocardial biopsy showed a correlation between functional and ultrastructural alterations in two patients.Keywords: Brugada syndrome; Radiofrequency catheter ablation; Electrocardiography; Mapping; Biopsy.Conclusion: Endocardial RFA can eliminate the BrS phenotype and inducibility during PVS.Fil: Tauber, Pablo E.. Centro Modelo del Corazón; Argentina. Gobierno de Tucumán. Ministerio de Salud. Hospital Centro de Salud "Zenón J. Santillán"; ArgentinaFil: Mansilla, Virginia. Centro Modelo del Corazón; ArgentinaFil: Brugada, Pedro. Free University of Brussels. Cardiovascular Division. Cardiovascular Institute; BélgicaFil: Sanchez, Sara Serafina del V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; ArgentinaFil: Honore, Stella Maris. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Elizari, Marcelo. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Chain Molina, Sergio. Centro Modelo del Corazón; ArgentinaFil: Albano, Félix A.. Gobierno de Tucumán. Ministerio de Salud. Hospital Centro de Salud "Zenón J. Santillán"; ArgentinaFil: Corbalán, Ricardo R.. Centro Modelo del Corazón; ArgentinaFil: Figueroa Castellanos, Federico. Clínica Mayo; ArgentinaFil: Alzugaray, Damián. Abbott; Argentin

XIPE: the X-ray Imaging Polarimetry Explorer

X-ray polarimetry, sometimes alone, and sometimes coupled to spectral and temporal variability measurements and to imaging, allows a wealth of physical phenomena in astrophysics to be studied. X-ray polarimetry investigates the acceleration process, for example, including those typical of magnetic reconnection in solar flares, but also emission in the strong magnetic fields of neutron stars and white dwarfs. It detects scattering in asymmetric structures such as accretion disks and columns, and in the so-called molecular torus and ionization cones. In addition, it allows fundamental physics in regimes of gravity and of magnetic field intensity not accessible to experiments on the Earth to be probed. Finally, models that describe fundamental interactions (e.g. quantum gravity and the extension of the Standard Model) can be tested. We describe in this paper the X-ray Imaging Polarimetry Explorer (XIPE), proposed in June 2012 to the first ESA call for a small mission with a launch in 2017 but not selected. XIPE is composed of two out of the three existing JET-X telescopes with two Gas Pixel Detectors (GPD) filled with a He-DME mixture at their focus and two additional GPDs filled with pressurized Ar-DME facing the sun. The Minimum Detectable Polarization is 14 % at 1 mCrab in 10E5 s (2-10 keV) and 0.6 % for an X10 class flare. The Half Energy Width, measured at PANTER X-ray test facility (MPE, Germany) with JET-X optics is 24 arcsec. XIPE takes advantage of a low-earth equatorial orbit with Malindi as down-link station and of a Mission Operation Center (MOC) at INPE (Brazil).Comment: 49 pages, 14 figures, 6 tables. Paper published in Experimental Astronomy http://link.springer.com/journal/1068

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Subclinical thyroid dysfunction and incident diabetes:a systematic review and an individual participant data analysis of prospective cohort studies

Objective: Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes.Methods: We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up.Results: Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses.Conclusions: This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes.Significance statement: Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.</p

Swift XRT and VLT Observations of the Afterglow of GRB 041223

The Swift Gamma-Ray Burst Explorer, launched on 2004 November 20, is a multiwavelength, autonomous, rapid-slewing observatory for gamma-ray burst (GRB) astronomy. On 2004 December 23, during the activation phase of the mission, the Swift X-Ray Telescope (XRT) was pointed at a burst discovered earlier that day by the Swift Burst Alert Telescope. A fading, uncataloged X-ray source was discovered by the XRT and was observed over a period of about 3 hours, beginning 4.6 hours after the burst. The X-ray detection triggered a VLT observation of the optical/NIR counterpart, located about 1.1 arcseconds from the XRT position. The X-ray counterpart faded rapidly, with a power law index of -1.72 +/- 0.20. The average unabsorbed X-ray flux 4.6-7.9 hours after the burst was 6.5 x 10^{-12} erg cm^{-2} s^{-1} in the 0.5-10 keV band, for a power-law spectrum of photon index 2.02 +/- 0.13 with Galactic absorption. The NIR counterpart was observed at three epochs between 16 and 87 hours after the burst, and faded with a power-law index of -1.14 +/- 0.08 with a reddening-corrected SED power-law slope of -0.40 +/- 0.03. We find that the X-ray and NIR data are consistent with a two-component jet in a wind medium, with an early jet break in the narrow component and an underlying electron index of 1.8-2.0.Comment: 16 pages, including 4 figures. Accepted by Astrophysical Journal (Letters) on 15 February 200

an individual participant data meta-analysis

Background The impact of neuraminidase inhibitors (NAIs) on influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. Methods A worldwide meta- analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) ‘pandemic influenza’. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. Results Of 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64–1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44–1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71–1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55–0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54–0·85; P = 0·001)]. Conclusions Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support