Efficacy of Leukemia Inhibitory Factor as a Therapeutic for Permanent Large Vessel Stroke Differs among Aged Male and Female Rats

Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. Although LIF increased neuronal LIFR expression in vitro, it did not increase LIFR in the aged brain. Levels of LIFR protein in brain tissue were significantly downregulated between young males and aged males/females at 72 h after stroke. These results demonstrated that low LIFR expression reduces the neuroprotective efficacy of LIF in aged rodents of both sexes. Furthermore, the ability of LIF to promote motor improvement is dependent upon sex in aged rodents

Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat

<p>Abstract</p> <p>Background</p> <p>Hypoxia-ischemia (H-I) can produce widespread neurodegeneration and deep cerebral white matter injury in the neonate. Resident microglia and invading leukocytes promote lesion progression by releasing reactive oxygen species, proteases and other pro-inflammatory mediators. After injury, expression of the gelatin-degrading matrix metalloproteinases (MMPs), MMP-2 and MMP-9, are thought to result in the proteolysis of extracellular matrix (ECM), activation of cytokines/chemokines, and the loss of vascular integrity. Thus, therapies targeting ECM degradation and progressive neuroinflammation may be beneficial in reducing H-I – induced neuropathy. Minocycline has MMP-inhibitory properties and is both anti-inflammatory and neuroprotective. AG3340 (prinomastat) is an MMP inhibitor with high selectivity for the gelatinases. The purpose of this study was to determine whether these compounds could limit H-I – induced injury when administered at a delayed time point.</p> <p>Methods</p> <p>Sprague-Dawley rats were exposed to H-I at postnatal day 7 (P7), consisting of unilateral carotid artery ligation followed by 90 min exposure to 8% O₂. Minocycline, AG3340, or vehicle were administered once daily for 6 days, beginning 24 hours after insult. Animals were sacrificed at P14 for neurohistological assessments. Immunohistochemistry was performed to determine the degree of reactive astrogliosis and immune cell activation/recruitment. Neural injury was detected using the Fluoro-Jade stain, a marker that identifies degenerating cells.</p> <p>Results</p> <p>CD11b and glial fibrillary acidic protein (GFAP) immunopositive cells increased in ipsilateral cortex after treatment with vehicle alone, demonstrating microglia/macrophage recruitment and reactive astrogliosis, respectively. Fluoro-Jade staining was markedly increased throughout the fronto-parietal cortex, striatum and hippocampus. Treatment with minocycline or AG3340 inhibited microglia/macrophage recruitment, attenuated astrogliosis and reduced Fluoro-Jade staining when compared to vehicle alone.</p> <p>Conclusion</p> <p>The selective gelatinase inhibitor AG3340 showed equal efficacy in reducing neural injury and dampening neuroinflammation when compared to the anti-inflammatory compound minocycline. Thus, MMP-2 and MMP-9 may be viable therapeutic targets to treat neonatal brain injury.</p

K Corrections For Type Ia Supernovae and a Test for Spatial Variation of the Hubble Constant

Cross-filter K corrections for a sample of "normal" Type Ia supernovae (SNe) have been calculated for a range of epochs. With appropriate filter choices, the combined statistical and systematic K correction dispersion of the full sample lies within 0.05 mag for redshifts z<0.7. This narrow dispersion of the calculated K correction allows the Type Ia to be used as a cosmological probe. We use the K corrections with observations of seven SNe at redshifts 0.3 < z <0.5 to bound the possible difference between the locally measured Hubble constant (H_L) and the true cosmological Hubble constant (H_0).Comment: 6 pages, 3 Postscript figures, uuencoded uses crckapb.sty and psfig.sty. To appear in Thermonuclear Supernovae (NATO ASI), eds. R. Canal, P. Ruiz-LaPuente, and J. Isern. Postscript version is also available at http://www-supernova.lbl.gov

Commentary: Use of BACTRAC Proteomic Database-Uromodulin Protein Expression during Ischemic Stroke

Introduction: Uromodulin (UMOD) is a glycoprotein expressed by the epithelial cells of the thick ascending limb of Henle\u27s loop in the kidney. Research has shown that increased uromodulin expression may be associated with lower risk of cardiovascular disease in adults. Utilizing the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683), a continuously enrolling tissue bank, we aimed to examine the associations between serum uromodulin, age, and high BMI (BMI\u3e 25) and its relationship to stroke in patients. Methods: Arterial blood distal and proximal to the thrombus was collected during a thrombectomy procedure using the BACTRAC protocol and sent to Olink (Boston, MA) to determine proteomic expression via proximity extension assay. Uromodulin expression was recorded and analyzed using two tailed T-tests and linear regressions. Results: The relationship between systemic and intracranial uromodulin, age, high BMI and hypertension were assessed. Systemic and intracranial uromodulin decreased with age (p\u3c 0.0001 and r²= 0.343, p= 0.0416 and r²= 0.102) respectively. Systemic uromodulin expression increased with BMI\u3e 25 (p= 0.014). Presence of hypertension decreased uromodulin’s expression systemically (p= 0.018) and intracranially (p= 0.007). Conclusions: Uromodulin was increased significantly in overweight patients, decreased significantly in older patients, and decreased in patients with hypertension. The increase in uromodulin in people with high BMI could be a protective reaction of the kidney to worsening conditions that make ischemic stroke more likely, with a goal of delaying dangerous outcomes. The decreased expression of uromodulin in older adults could be associated with the decline of general kidney function that accompanies aging. Hypertension can contribute to an AKI by decreasing perfusion to the kidney, therefore decreasing kidney function and uromodulin production. Further analyses are needed to understand the role of uromodulin following ischemic stroke

Implications For The Hubble Constant from the First Seven Supernovae at z >= 0.35

The Supernova Cosmology Project has discovered over twenty-eight supernovae (SNe) at 0.35 <z < 0.65 in an ongoing program that uses Type Ia SNe as high-redshift distance indicators. Here we present measurements of the ratio between the locally observed and global Hubble constants, H_0^L/H_0^G, based on the first 7 SNe of this high-redshift data set compared with 18 SNe at z <= 0.1 from the Calan/Tololo survey. If Omega_M <= 1, then light-curve-width corrected SN magnitudes yield H_0^L/H_0^G < 1.10 (95% confidence level) in both a Lambda=0 and a flat universe. The analysis using the SNe Ia as standard candles without a light-curve-width correction yields similar results. These results rule out the hypothesis that the discrepant ages of the Universe derived from globular clusters and recent measurements of the Hubble constant are attributable to a locally underdense bubble. Using the Cepheid-distance-calibrated absolute magnitudes for SNe Ia of Sandage (1996}, we can also measure the global Hubble constant, H_0^G. If Omega_M >= 0.2, we find that H_0^G < 70 km/s/Mpc in a Lambda=0 universe and H_0^G < 78 km/s/Mpc in a flat universe, correcting the distant and local SN apparent magnitudes for light curve width. Lower results for H_0^G are obtained if the magnitudes are not width corrected.Comment: 13 pages, 2 Postscript figures. Preprint also available at http://www-supernova.lbl.gov . To appear in ApJ Letter

The distant Type Ia supernova rate

We present a measurement of the rate of distant Type Ia supernovae derived using 4 large subsets of data from the Supernova Cosmology Project. Within this fiducial sample, which surveyed about 12 square degrees, thirty-eight supernovae were detected at redshifts 0.25--0.85. In a spatially-flat cosmological model consistent with the results obtained by the Supernova Cosmology Project, we derive a rest-frame Type Ia supernova rate at a mean redshift $z\simeq0.55$ of $1.53 {^{+0.28}_{-0.25}} {^{+0.32}_{-0.31}} 10^{-4} h^3 {\rm Mpc}^{-3} {\rm yr}^{-1}$ or $0.58 {^{+0.10}_{-0.09}} {^{+0.10}_{-0.09}} h^2 {\rm SNu}$ (1 SNu = 1 supernova per century per $10^{10}$\Lbsun), where the first uncertainty is statistical and the second includes systematic effects. The dependence of the rate on the assumed cosmological parameters is studied and the redshift dependence of the rate per unit comoving volume is contrasted with local estimates in the context of possible cosmic star formation histories and progenitor models.Comment: 40 pages and 7 figures. Accepted for publication in the Astrophysical Journal. Preprint also available at http://supernova.lbl.go

The sky brightness and transparency in i-band at Dome A, Antarctica

The i-band observing conditions at Dome A on the Antarctic plateau have been investigated using data acquired during 2008 with the Chinese Small Telescope ARray. The sky brightness, variations in atmospheric transparency, cloud cover, and the presence of aurorae are obtained from these images. The median sky brightness of moonless clear nights is 20.5 mag arcsec^{-2} in the SDSS $i$ band at the South Celestial Pole (which includes a contribution of about 0.06 mag from diffuse Galactic light). The median over all Moon phases in the Antarctic winter is about 19.8 mag arcsec^{-2}. There were no thick clouds in 2008. We model contributions of the Sun and the Moon to the sky background to obtain the relationship between the sky brightness and transparency. Aurorae are identified by comparing the observed sky brightness to the sky brightness expected from this model. About 2% of the images are affected by relatively strong aurorae.Comment: There are 1 Latex file and 14 figures accepted by A

The PLATO Dome A Site-Testing Observatory : instrumentation and first results

The PLATeau Observatory (PLATO) is an automated self-powered astrophysical observatory that was deployed to Dome A, the highest point on the Antarctic plateau, in 2008 January. PLATO consists of a suite of site-testing instruments designed to quantify the benefits of the Dome A site for astronomy, and science instruments designed to take advantage of the unique observing conditions. Instruments include CSTAR, an array of optical telescopes for transient astronomy; Gattini, an instrument to measure the optical sky brightness and cloud cover statistics; DASLE, an experiment to measure the statistics of the meteorological conditions within the near-surface layer; Pre-HEAT, a submillimeter tipping radiometer measuring the atmospheric transmission and water vapor content and performing spectral line imaging of the Galactic plane; and Snodar, an acoustic radar designed to measure turbulence within the near-surface layer. PLATO has run completely unattended and collected data throughout the winter 2008 season. Here we present a detailed description of the PLATO instrument suite and preliminary results obtained from the first season of operation