Elucidating and Pharmacologically Targeting Secondary Injury Cascades following Neural Injury

3.4 million concussions occur each year in the United States. Recent evidence suggests that some of these individuals are susceptible to neurodegenerative disease development following traumatic brain injury. The unknown factor is how acute injury contributes to this degenerative process. A prominent neurotrauma related neurodegenerative disease is chronic traumatic encephalopathy (CTE). CTE is defined by neurofibrillary tau tangles with a perivascular distribution and mood disturbances. In order to elucidate the pathologic changes associated with CTE, it is imperative to utilize adequate preclinical models. We have strategically developed and tested a clinically relevant rodent blast model. The model reliably produces a CTE phenotype including tauopathy, cell death, impulsivity, and cognitive decline. Using this validated model, we investigated several important secondary injury cascades that link acute brain injury to chronic neurodegenerative changes. More importantly, we pharmacologically targeted these pathways and found improved pathologic and behavioral outcomes. In chapter 1, we discuss the potential mechanisms linking acute injury to CTE in athletes and soldiers. In chapter 2, we highlight the physics behind the compression wave produced by our model and how this wave produces injury. In chapter 3, data is presented regarding the CTE phenotype generated by our model following repetitive blast exposure in rodents. Chapter 4 focuses on the role of blood brain barrier disruption and how targeting protein kinase C activity with bryostatin reduces this disruption. In chapter 5, we look at the role endoplasmic reticulum stress plays in human pathologic specimens from patients diagnosed with CTE and in rodents following repeat blast. We found that docosahexaenoic acid successfully targeted endoplasmic reticulum stress, reduced tauopathy, and improved cognitive performance. In chapter 6, we looked at lipoic acid and its role in reducing NADPH oxidative stress following repetitive neurotrauma. We found that lipoic acid reduces impulsive-like behavior and decreased cell death. Finally, in chapter 7 we discuss important strategies for improving preclinical models going forward and what needs to be investigated to improve our understanding of CTE. In this dissertation, we highlight important secondary injury cascades including blood brain barrier disruption, protein kinase C activity, endoplasmic reticulum stress, and oxidative stress that warrant further investigation for the development of novel treatment approaches for CTE

New Constraints on the Energetics, Progenitor Mass, and Age of the Supernova Remnant G292.0+1.8 Containing PSR J1124-5916

We present spatially resolved spectroscopy of the supernova remnant (SNR) G292.0+1.8 with the Chandra X-ray observatory. This SNR contains the 135 ms pulsar, J1124-5916. We apply non-equilibrium ionization (NEI) models to the data. By comparing the derived abundances with those predicted from nucleosynthesis models, we estimate a progenitor mass of 30-40 solar masses. We also derive the intrinsic parameters of the supernova explosion such as its energy, the age of the SNR, the blast wave velocity, and the swept-up mass. In the Sedov interpretation, our estimated SNR age of 2,600 years is close to the pulsar's characteristic age of 2,900 years. This confirms the pulsar/SNR association and relaxes the need for the pulsar to have a non-canonical value for the braking index, a large period at birth or a large transverse velocity. We discuss the properties of the pulsar wind nebula (PWN) in the light of the Kennel and Coroniti model and estimate the pulsar wind magnetization parameter. We also report the first evidence for steepening of the power law spectral index with increasing radius from the pulsar.Comment: 5 pages, 3 figures. To appear in ApJL, Feb 1 2003 (submitted Oct 9 2002, accepted Dec 19 2002

Chandra Detection of the X-ray counterpart of the High-magnetic field Radio Pulsar J1119-6127 in the Supernova Remnant G292.2-0.5

We report the Chandra Advanced CCD Imaging Spectrometer detection of the X-ray counterpart of the high magnetic field, ~1600 year-old, 407 ms radio pulsar J1119-6127 associated with the supernova remnant G292.2-0.5. The powerful imaging capability of Chandra also unveiled, for the first time, a faint 3"x6" pulsar wind nebula (PWN) at energies above ~1.2 keV. The X-ray emission from the pulsar and its associated nebula is well described by an absorbed power law model with a photon index of 2.2 (1.9-2.8). The corresponding 0.5-10 keV unabsorbed X-ray luminosity is 5.5(2.2-15.5)x10^32 ergs/s (at 6 kpc). When compared to two other pulsars with similar spin and magnetic properties, J1119-6127 stands out as being the least efficient at turning rotational kinetic energy into X-ray emission. This study shows that high magnetic field radio pulsars can be significant X-ray emitters and Chandra is needed to study the emission properties of the pulsars and associated faint PWNe.Comment: 6 pages, 5 figures. To appear in ApJL July 10 2003 (submitted April 10 2003, accepted May 22 2003

Antennae on transmitters on free-living marine animals: Balancing budgets on the high wire

The effect of externally mounted antennae on the energetics of penguins was studied by mounting various antennae on a transducer fixed to a model Magellanic penguin Spheniscus magellanicus to determine drag, run at speeds of up to 2 m s–1 in a swim canal. For rigid antennae set perpendicular to the water flow, measured drag increased with increasing swim speed. Increasing antenna length (for lengths between 100 and 200 mm) or diameter (for diameters between 1 and 4 mm) resulted in accelerating increased drag as a function of both antenna length and diameter. Where antennae were positioned at acute angles to the water flow, drag was markedly reduced, as was drag at higher speeds in flexible antennae. These results were incorporated in a model on the foraging energetics of free-living Magellanic penguins using data (on swim speeds, intervals between prey encounters, amount ingested per patch and dive durations) derived from previously published work and from a field study conducted on birds from a colony at Punta Norte, Argentina, using data loggers. The field work indicated that free-living birds have a foraging efficiency (net energy gain/net energy loss) of about 2.5. The model predicted that birds equipped with the largest rigid external antennae tested (200 mm × 3 mm diameter), set perpendicular to water flow, increased energy expenditure at normal swim speeds of 1.77 m s–1 by 79% and at prey capture speeds of 2.25 m s–1 by 147%, and ultimately led to a foraging efficiency that was about 5 times less than that of unequipped birds. Highly flexible antennae were shown to reduce this effect considerably. Deleterious antenna-induced effects are predicted to be particularly critical in penguins that have to travel fast to capture prey. Possible measures taken by the birds to increase foraging efficiency could include reduced travelling speed and selection of smaller prey types. Suggestions are made as to how antenna-induced drag might be minimized for future studies on marine diving animal

X-ray Observation and Analysis of The Composite Supernova Remnant G327.1-1.1

Based on the data from the observation of the SNR G327.1-1.1 by ASCA and ROSAT, we find that G327.1-1.1 is a composite remnant with both a nonthermal emission component and a diffuse thermal emission component. The nonthermal component is well fitted by a power-law model with photon index about 2.2. This component is attributed to the emission from the synchrotron nebula powered by an undiscovered central pulsar. The thermal component has a temperature of about 0.4 keV. We attribute it to the emission from the shock-heat swept-up ISM. Its age, explosion energy and density of ambient medium are derived from the observed thermal component. Some charactistics about the synchrotron nebula are also derived. We search for the pulsed signal, but has not found it. The soft X-ray(0.4 - 2 keV) and hard X-ray(2 - 10 keV) images are different, but they both elongate in the SE-NW direction. And this X-ray SE-NW elongation is in positional coincidence with the radio ridge in MOST 843MHz radio map. We present a possibility that the X-ray nonthermal emission mainly come from the trail produced by a quickly moving undiscoverd pulsar, and the long radio ridge is formed when the pulsar is moving out of the boundary of the plerionic structure.Comment: 20 pages, 4 Postscript figures, aasms4.sty and psfig.sty, to be published in Astrophysical Journal, January 20, 1999, Vol. 51

Parallax and Kinematics of PSR B0919+06 from VLBA Astrometry and Interstellar Scintillometry

Results are presented from a long-term astrometry program on PSR B0919+06 using the NRAO Very Long Baseline Array. With ten observations (seven epochs) between 1994--2000, we measure a proper motion of 18.35 +/- 0.06 mas/yr in RA, 86.56 +/- 0.12 mas/yr in Dec, and a parallax of 0.83 +/- 0.13 mas (68% confidence intervals). This yields a pulsar distance of 1.21 +/- 0.19 kpc, making PSR B0919+06 the farthest pulsar for which a trigonometric parallax has been obtained, and the implied pulsar transverse speed is 505 +/- 80 km/s. Combining the distance estimate with interstellar scintillation data spanning 20 years, we infer the existence of a patchy or clumpy scattering screen along the line of sight in addition to the distributed electron density predicted by models for the Galaxy, and constrain the location of this scattering region to within about 250 parsecs of the Sun. Comparison with the lines of sight towards other pulsars in the same quadrant of the Galaxy permits refinement of our knowledge of the local interstellar matter in this direction.Comment: 12 pages, includes 4 figures and 3 tables, uses AASTeX 5 (included); ApJ submitte

Lung Cancer Metastasis Presenting as a Solitary Skull Mass

Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care

Ultraviolet and Optical Observations of OB Associations and Field Stars in the Southwest Region of the Large Magellanic Cloud

Using photometry from the Ultraviolet Imaging Telescope (UIT) and photometry and spectroscopy from three ground-based optical datasets we have analyzed the stellar content of OB associations and field areas in and around the regions N 79, N 81, N 83, and N 94 in the LMC. We compare data for the OB association Lucke-Hodge 2 (LH 2) to determine how strongly the initial mass function (IMF) may depend on different photometric reductions and calibrations. We also correct for the background contribution of field stars, showing the importance of correcting for field star contamination in determinations of the IMF of star formation regions. It is possible that even in the case of an universal IMF, the variability of the density of background stars could be the dominant factor creating the differences between calculated IMFs for OB associations. We have also combined the UIT data with the Magellanic Cloud Photometric Survey to study the distribution of the candidate O-type stars in the field. We find a significant fraction, roughly half, of the candidate O-type stars are found in field regions, far from any obvious OB associations. These stars are greater than 2 arcmin (30 pc) from the boundaries of existing OB associations in the region, which is a distance greater than most O-type stars with typical dispersion velocities will travel in their lifetimes. The origin of these massive field stars (either as runaways, members of low-density star-forming regions, or examples of isolated massive star formation) will have to be determined by further observations and analysis.Comment: 16 pages, 10 figures (19 PostScript files), tabular data + header file for Table 1 (2 ASCII files). File format is LaTeX/AASTeX v.502 using the emulateapj5 preprint style (included). Also available at http://www.boulder.swri.edu/~joel/papers.html . To appear in the February 2001 issue of the Astronomical Journa