Substance P Causes Seizures in Neurocysticercosis

Neurocysticercosis (NCC), a helminth infection of the brain, is a major cause of seizures. The mediators responsible for seizures in NCC are unknown, and their management remains controversial. Substance P (SP) is a neuropeptide produced by neurons, endothelial cells and immunocytes. The current studies examined the hypothesis that SP mediates seizures in NCC. We demonstrated by immunostaining that 5 of 5 brain biopsies from NCC patients contained substance P (SP)-positive (+) cells adjacent to but not distant from degenerating worms; no SP+ cells were detected in uninfected brains. In a rodent model of NCC, seizures were induced after intrahippocampal injection of SP alone or after injection of extracts of cysticercosis granuloma obtained from infected wild type (WT), but not from infected SP precursor-deficient mice. Seizure activity correlated with SP levels within WT granuloma extracts and was prevented by intrahippocampal pre-injection of SP receptor antagonist. Furthermore, extracts of granulomas from WT mice caused seizures when injected into the hippocampus of WT mice, but not when injected into SP receptor (NK1R) deficient mice. These findings indicate that SP causes seizures in NCC, and, suggests that seizures in NCC in humans may be prevented and/or treated with SP-receptor antagonists

Lessons Learned in Applying the U.S. EPA Proposed Cancer Guidelines to Specific Compounds

An expert panel was convened to evaluate the U.S. Environmental Protection Agency’s “Proposed Guidelines for Carcinogen Risk Assessment” through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel’s activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical’s mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted

Common Data Elements for Traumatic Brain Injury: Recommendations From the Biospecimens and Biomarkers Working Group

Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers Working Group was to provide recommendations for core data elements for TBI research and develop best practice guidelines to standardize the quality and accessibility of these specimens. Consensus recommendations were developed through interactions with focus groups and input from stakeholders participating in the interagency workshop on Standardization of Data Collection in TBI and Psychological Health held in Washington, DC, in March 2009. With the adoption of these standards and best practices, future investigators will be able to obtain data across multiple studies with reduced costs and effort and accelerate the progress of genomic, proteomic, and metabolomic research in TBI

Are SMBHs shrouded by "super-Oort" clouds of comets and asteroids?

The last decade has seen a dramatic confirmation that an in situ star formation is possible inside the inner parsec of the Milky Way. Here we suggest that giant planets, solid terrestrial-like planets, comets and asteroids may also form in these environments, and that this may have observational implications for Active Galactic Nuclei (AGN). Like in debris discs around main sequence stars, collisions of large solid objects should initiate strong fragmentation cascades. The smallest particles in such a cascade - the microscopic dust - may provide a significant opacity. We put a number of observational and physical constraints on AGN obscuring torii resulting from such fragmentation cascades. We find that torii fed by fragmenting asteroids disappear at both low and high AGN luminosities. At high luminosities, $L \sim L_{\rm Edd}$, where $L_{\rm Edd}$ is the Eddington limit, the AGN radiation pressure blows out the microscopic dust too rapidly. At low luminosities, on the other hand, the AGN discs may avoid gravitational fragmentation into stars and solids. We also note that these fragmentation cascades may be responsible for astrophysically "large" dust particles of approximately micrometer sizes that were postulated by some authors to explain unusual absorption properties of the AGN torii.Comment: a typo in the title correcte

Fragment Production and Survival in Irradiated Disks: A Comprehensive Cooling Criterion

Accretion disks that become gravitationally unstable can fragment into stellar or sub-stellar companions. The formation and survival of these fragments depends on the precarious balance between self-gravity, internal pressure, tidal shearing, and rotation. Disk fragmentation depends on two key factors (1) whether the disk can get to the fragmentation boundary of Q=1, and (2) whether fragments can survive for many orbital periods. Previous work suggests that to reach Q=1, and have fragments survive, a disk must cool on an orbital timescale. Here we show that disks heated primarily by external irradiation always satisfy the standard cooling time criterion. Thus even though irradiation heats disks, and makes them more stable in general, once they reach the fragmentation boundary, they fragment more easily. We derive a new cooling criterion that determines fragment survival, and calculate a pressure modified Hill radius, which sets the maximum size of pressure-supported objects in a Keplerian disk. We conclude that fragmentation in protostellar disks might occur at slightly smaller radii than previously thought, and recommend tests for future simulations that will better predict the outcome of fragmentation in real disks.Comment: 14 pages, 4 figures, accepted to Ap

Optical and X-ray Transients from Planet-Star Mergers

We evaluate the prompt observational signatures of the merger between a massive close-in planet (a `hot Jupiter') and its host star, events with an estimated Galactic rate of ~0.1-1/yr. Depending on the ratio of the mean density of the planet rho_p to that of the star rho_star, a merger results in three possible outcomes. If rho_p/rho_star > 5, then the planet directly plunges below the stellar atmosphere before being disrupted by tidal forces. Dissipation of orbital energy creates a hot wake behind the planet, producing a EUV/soft X-ray transient as the planet sinks below the stellar surface. The peak luminosity L_X ~ 1e36 erg/s is achieved weeks-months prior to merger, after which the stellar surface is enshrouded by an outflow. The final inspiral is accompanied by an optical transient powered by the recombination of hydrogen in the outflow, which peaks at L~1e37-38 erg/s on a timescale ~days. If instead rho_planet/rho_star < 5, then Roche Lobe overflow occurs above the stellar surface. For rho_p/rho_star < 1, mass transfer is stable, resulting the planet being accreted on a relatively slow timescale. However, for 1 < rho_p/rho_star < 5, mass transfer may instead be unstable, resulting in the planet being dynamically disrupted into an accretion disk around the star. Super-Eddington outflows from the disk power an optical transient with L~1e37-38 erg/s and characteristic duration ~week-months. The disk itself becomes visible once the accretion rate become sub-Eddington, resulting in a bolometric brightening and spectral shift to the UV. Optical transients from planet merger events may resemble classical novae, but are distinguished by lower ejecta mass and velocity ~100s km/s, and by hard pre- and post-cursor emission, respectively. Promising search strategies include combined optical, UV, and X-ray surveys of nearby massive galaxies with cadences from days to months.Comment: 20 pages, 11 figures, 2 tables, submitted to MNRA

Cosmic Rays from the Knee to the Highest Energies

This review summarizes recent developments in the understanding of high-energy cosmic rays. It focuses on galactic and presumably extragalactic particles in the energy range from the knee (10^15 eV) up to the highest energies observed (>10^20 eV). Emphasis is put on observational results, their interpretation, and the global picture of cosmic rays that has emerged during the last decade.Comment: Invited review, submitted to Progress in Particle and Nuclear Physic

Star Formation and Dynamics in the Galactic Centre

The centre of our Galaxy is one of the most studied and yet enigmatic places in the Universe. At a distance of about 8 kpc from our Sun, the Galactic centre (GC) is the ideal environment to study the extreme processes that take place in the vicinity of a supermassive black hole (SMBH). Despite the hostile environment, several tens of early-type stars populate the central parsec of our Galaxy. A fraction of them lie in a thin ring with mild eccentricity and inner radius ~0.04 pc, while the S-stars, i.e. the ~30 stars closest to the SMBH (<0.04 pc), have randomly oriented and highly eccentric orbits. The formation of such early-type stars has been a puzzle for a long time: molecular clouds should be tidally disrupted by the SMBH before they can fragment into stars. We review the main scenarios proposed to explain the formation and the dynamical evolution of the early-type stars in the GC. In particular, we discuss the most popular in situ scenarios (accretion disc fragmentation and molecular cloud disruption) and migration scenarios (star cluster inspiral and Hills mechanism). We focus on the most pressing challenges that must be faced to shed light on the process of star formation in the vicinity of a SMBH.Comment: 68 pages, 35 figures; invited review chapter, to be published in expanded form in Haardt, F., Gorini, V., Moschella, U. and Treves, A., 'Astrophysical Black Holes'. Lecture Notes in Physics. Springer 201