The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease

Pion photoproduction off the proton in a gauge-invariant chiral unitary framework

We investigate pion photoproduction off the proton in a manifestly gauge-invariant chiral unitary extension of chiral perturbation theory. In a first step, we consider meson-baryon scattering taking into account all next-to-leading order contact interactions. The resulting low-energy constants are determined by a fit to s-wave pion-nucleon scattering and the low-energy data for the reaction pi- p --> eta n. To assess the theoretical uncertainty, we perform two different fit strategies. Having determined the low-energy constants, we then analyse the data on the s-wave multipole amplitudes E0+ of pion and eta photoproduction. These are parameter-free predictions, as the two new low-energy constants are determined by the neutron and proton magnetic moments.Comment: 23 pages, 17 figure

The 2006 July 17 Java (Indonesia) tsunami from satellite imagery and numerical modelling: A single or complex source?

The Mw 7.8 2006 July 17 earthquake off the southern coast of Java, Indonesia, has been responsible for a very large tsunami causing more than 700 casualties. The tsunami has been observed on at least 200 km of coastline in the region of Pangandaran (Wes

Constraining q_0 with Cluster Gas Mass Fractions: A Feasibility Study

As the largest gravitationally bound objects in the universe, clusters of galaxies may contain a fair sample of the baryonic mass fraction of the universe. Since the gas mass fraction from the hot ICM is believed to be constant in time, the value of the cosmological deceleration parameter $q_0$ can be determined by comparing the calculated gas mass fraction in nearby and distant clusters (Pen 1997). To test the potential of this method, we compare the gas fractions derived for a sample of luminous ($L_X > 10^{45}$erg s$^{-1}$), nearby clusters with those calculated for eight luminous, distant ($0.3 < z < 0.6$) clusters using ASCA and ROSAT observations. For consistency, we evaluate the gas mass fraction at a fixed physical radius of 1 $h_{50}^{-1}$ Mpc (assuming $q_0=0.0$). We find a best fit value of $q_0 = 0.07$ with -0.47 < q_0 < 0.67 at 95% confidence. We also determine the gas fraction using the method of Evrard, Metzler, & Navarro (1997) to find the total mass within $r_{500}$, the radius where the mean overdensity of matter is 500 times the critical density. In simulations, this method reduces the scatter in the determination of gravitational mass without biasing the mean. We find that it also reduces the scatter in actual observations for nearby clusters, but not as much as simulations suggest. Using this method, the best fit value is $q_0 = 0.04$ with -0.50 < q_0 < 0.64. The excellent agreement between these two methods suggests that this may be a useful technique for determining $q_0$. The constraints on $q_0$ should improve as more distant clusters are studied and precise temperature profiles are measured to large radii.Comment: 8 pages, 4 figures, uses emulateapj.sty, onecolfloat.st

U-Pb zircon dating of the Gruf Complex: disclosing the late Variscan granulitic lower crust of Europe stranded in the Central Alps

Permian granulites associated with noritic intrusions and websterites are a common feature of the post-Variscan European crust. Such granulites are common in the Southern Alps (e.g. Ivrea Zone), but occur only in the Gruf Complex in the Central Alps. To understand the geotectonic significance of these granulites, in particular in the context of Alpine migmatisation, zircons from 15 high-grade samples have been U-Pb dated by SHRIMP II analysis. Oscillatory zoned zircons from charnockite sheets, interpreted as melts generated through granulite facies fluid-absent biotite melting at 920-940°C, yield ages of 282-260Ma. Some of these zircons contain inclusions of opx, unequivocally attributable to the granulite facies, thus confirming a Permian age for the charnockites and associated granulites. Two samples from an enclave-rich orthogneiss sheet yield Cambrian and Ordovician zircon cores. Two deformed leucogranites and six ortho- and augengneisses, which compose two-thirds of the Gruf Complex, give zircon ages of 290-260Ma. Most zircons have milky rims with ages of 34-29Ma. These rims date the Alpine amphibolite facies migmatisation, an interpretation confirmed by directly dating a leucosome pocket from upper amphibolite facies metapelites. The Gruf charnockites associated with metre-scale schlieren and boudins of opx-sapphirine-garnet-granulites, websterites and gabbronorites can thus be identified as part of the post-Variscan European lower crust. A geotectonic reconstruction reveals that this piece of lower crust stranded in the (European) North upon rifting of the Neotethys, such contrasting the widespread granulite units in the Southern Alps. Emplacement of the Gruf lower crust into its present-day position occurred during migmatisation and formation of the Bergell Pluton in the aftermath of the breakoff of the European sla

The interactive effect of change in perceived stress and trait anxiety on vagal recovery from cognitive challenge

The present study tested the hypothesis that the change in state negative affect (measured as perceived stress) after cognitive challenge moderates the relationship of trait anxiety and anger to vagal recovery from that challenge. Cardiac vagal control (assessed using heart rate variability) and respiratory rate were measured in a sample of 905 participants from the Midlife in the United States Study. Cognitive challenges consisted of computerized mental arithmetic and Stroop color–word matching tasks. Multiple regression analyses controlling for the effects of the demographic, lifestyle, and medical factors influencing cardiac vagal control showed a significant moderating effect of change in perceived stress on the relationship of trait anxiety to vagal recovery from cognitive challenges (Beta = .253, p = .013). After adjustment for respiratory rate, this effect became marginally significant (Beta = .177, p = .037). In contrast, for the relationship of trait anger to vagal recovery, this effect was not significant either before (Beta = .141, p = .257) or after (Beta = .186, p = .072) adjusting for respiratory rate. Secondary analyses revealed that among the individuals with higher levels of trait anxiety, greater reductions in perceived stress were associated with greater increases in cardiac vagal control after the challenge. In contrast, among the individuals with lower levels of trait anxiety, changes in perceived stress had no impact on vagal recovery. Therefore, change in perceived stress moderates the relationship of trait anxiety, but not trait anger, to vagal recovery from cognitive challenge

Targeting choroid plexus epithelia and ventricular ependyma for drug delivery to the central nervous system

Background: Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS.Methods: A peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity.Results: Three peptides, identified after four rounds of screening, were analyzed for specific and dose dependant binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles.Conclusion: These data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain