355 research outputs found

    Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury

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    Exposure to hypoxic-ischemic insults during the neonatal or perinatal developmental periods produces various forms of pathology. Injuries that occur in response to these events often manifest as severe cognitive and/or motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of hypoxic-ischemic injury, there is a growing need for effective therapies that can be delivered at delayed time points. Much of the research into mechanisms of neural injury has focused on molecular targets associated with excitotoxicity and free oxygen radicals. Despite repeated success in animal models, these compounds have failed to show efficacy in clinical trials. Increasing evidence indicates that hypoxic-ischemic injury in the neonate is progressive, and the resulting neuropathies are linked to the activation of neuroinflammatory processes that occur in response to the initial wave of cell death. Understanding this latter response, therefore, will be critical in the development of novel therapies to block the progression of the injury. In this review, we summarize emerging concepts from rodent models concerning the regulation of various cytokines, chemokines, and matrix metalloproteinases in response to ischemia, and the various ways in which the delayed neuroinflammatory response may contribute to the progressive nature of neonatal hypoxic-ischemic injury in rat. Finally, we discuss data that supports the potential to target these neuroinflammatory signals at clinically relevant time points

    Infrared to Ultraviolet Wavelength-Dependent Variations Within the Pulse Profile Peaks of the Crab Nebula Pulsar

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    We present evidence of wavelength-dependent variations within the infrared, optical, and ultraviolet pulse profile peaks of the Crab Nebula pulsar. The leading and trailing edge half-width half-maxima of the peaks display clear differences in their wavelength dependences. In addition, phase-resolved infrared-to-ultraviolet color spectra show significant variations from the leading to trailing edges of the peaks. The color variations between the leading and trailing edges remain significant over phase differences smaller than 0.0054, corresponding to timescales of <180Ό<180 \mus. These results are not predicted by any current models of the pulsar emission mechanism and offer new challenges for the development of such models.Comment: 12 pages, 4 figure

    Neuroprotective Activity of Leukemia Inhibitory Factor Is Relayed through Myeloid Zinc Finger-1 in a Rat Model of Stroke

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    The aim of this study was to determine whether leukemia inhibitory factor (LIF) exerts its neuroprotective effects through signal transduction of the transcription factor myeloid zinc finger-1 (MZF-1). According to the hypothesis of this study, MZF-1 mediates LIF-induced neuroprotective signaling during ELVO through increased expression and transcriptional activity. To determine the in vivo role of MZF-1 in LIF-induced neuroprotection, we used Genomatix software was used to MZF-1 sites in the promoter region of the rat superoxide dismutase 3 (SOD3) gene. Stroke was induced via middle cerebral artery occlusion, and animals were administered PBS or 125 ÎŒg/kg LIF at 6, 24, and 48 h after the injury. MZF-1 binding activity was measured using electrophoretic mobility shift assay (EMSA) and its expression/localization were determined using western blot and immunohistochemical analysis. To determine whether MZF-1 relays LIF-induced neuroprotection in vitro, primary cultured neurons were subjected to oxygen-glucose deprivation (OGD) after treatment with PBS or LIF. MZF-1 expression was measured in vitro using real time PCR and immunohistochemical staining. Transfection with siRNA was used to determine whether LIF protected cultured neurons against OGD after silencing MZF-1 expression. Four MZF-1 binding sites were identified by Genomatix, and EMSA confirmed in vivo binding activity in brain after MCAO. LIF significantly increased MZF-1 protein levels compared to PBS treatment at 72 h post-MCAO. In vivo nuclear localization of MZF-1 as well as co-localization of SOD3 and MZF-1 was observed in the cortical neurons of LIF-treated rats. Primary cultured neurons treated with LIF had significantly higher levels of MZF-1 mRNA and protein after LIF treatment compared to neurons treated with PBS. Finally, knockdown MZF-1 using siRNA counteracted the neuroprotective effects of LIF in vitro. These data demonstrate that LIF-mediated neuroprotection is dependent upon MZF-1 activity. Furthermore, these findings identify a novel neuroprotective pathway that employs MZF-1, a transcription factor associated with hematopoietic gene expression

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

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    <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% O<sub>2</sub>. 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

    Cosmology from Type Ia Supernovae

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    This presentation reports on first evidence for a low-mass-density/positive-cosmological-constant universe that will expand forever, based on observations of a set of 40 high-redshift supernovae. The experimental strategy, data sets, and analysis techniques are described. More extensive analyses of these results with some additional methods and data are presented in the more recent LBNL report #41801 (Perlmutter et al., 1998; accepted for publication in Ap.J.), astro-ph/9812133 . This Lawrence Berkeley National Laboratory reprint is a reduction of a poster presentation from the Cosmology Display Session #85 on 9 January 1998 at the American Astronomical Society meeting in Washington D.C. It is also available on the World Wide Web at http://supernova.LBL.gov/ This work has also been referenced in the literature by the pre-meeting abstract citation: Perlmutter et al., B.A.A.S., volume 29, page 1351 (1997).Comment: 9 pages, 8 color figs. Presented at Jan '98 AAS Meeting, also cited as BAAS,29,1351(1997). Archived here in response to requests; see more extensive analyses in ApJ paper (astro-ph/9812133

    The distant Type Ia supernova rate

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    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≃0.55z\simeq0.55 of 1.53−0.25+0.28−0.31+0.3210−4h3Mpc−3yr−11.53 {^{+0.28}_{-0.25}} {^{+0.32}_{-0.31}} 10^{-4} h^3 {\rm Mpc}^{-3} {\rm yr}^{-1} or 0.58−0.09+0.10−0.09+0.10h2SNu0.58 {^{+0.10}_{-0.09}} {^{+0.10}_{-0.09}} h^2 {\rm SNu} (1 SNu = 1 supernova per century per 101010^{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

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

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    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

    Translational Evaluation of Acid/Base and Electrolyte Alterations in Rodent Model of Focal Ischemia

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    BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion. METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient middle cerebral artery occlusion models. RESULTS: Analysis indicated significant differences in the blood gas and electrolytes between pre- to post-middle cerebral artery occlusion. A decrease in pH and sodium with increases in carbon dioxide, potassium, ionized calcium, and glucose changes were found in both middle cerebral artery occlusion models; while hematocrit and hemoglobin were significant in the transient model. pH and ionized calcium were predictors of infarct volume in the permanent model, as changes in pH and ionized calcium decreased, infarct volume increased. CONCLUSIONS: There are acute changes in acid/base balance and electrolytes during stroke in transient and permanent rodent models. Additionally, we found pH and ionized calcium changes predicted stroke volume in the permanent middle cerebral artery occlusion model. These preliminary findings are novel, and warrant further exploration in human conditions

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

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    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
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