Behavioral Pharmacology of Dopamine D2 and D3 Receptor Agonists and Antagonists in Rats.

Dopamine D2-like receptors are involved in the regulation of a variety of behaviors, and have proven to be important pharmacologic targets for the treatment of diseases such as Parkinson’s disease, schizophrenia, restless leg syndrome, and depression, however, the receptor(s) responsible for the therapeutic and behavioral effects have yet to be elucidated. Identification of behaviors specifically mediated by the D2 and/or D3 receptors would not only provide insight into the receptor(s) mediating these therapeutic and behavioral effects, but it would also aid in the evaluation of novel D2-like agonists and antagonists. These studies were primarily aimed at the pharmacologic evaluation of the hypothesis that the induction of yawning by D2-like agonists is mediated by a specific activation of the D3 receptor, while the inhibition of yawning observed at higher doses is mediated by a concomitant activation of the D2 receptor. Convergent evidence from the effects of D2-like agonists alone, and in combination with a series of D2-like antagonists support this general hypothesis. All D3-preferring agonists elicited dose-dependent yawning behavior resulting in a characteristic inverted U-shaped dose-response curve. These functions were differentially modulated by D3- and D2-preferring antagonists, with D3-preferring antagonists producing selective rightward shifts of the ascending limb, and D2-preferring antagonists producing selective shifts of the descending limb. The selectivity of these effects was confirmed by a comparison of the relative potencies of D2- and D3-preferring agonists to induce yawning and hypothermia (a well validated D2-mediated effect), as well as the relative potencies of D2- and D3-preferring antagonists to inhibit the induction of yawning and hypothermia by D2-like agonists. Similar comparisons of the effects of D2-like agonists and antagonists on the induction of yawning and penile erection not only provided further support for the differential roles of the D3 and D2 receptors in the regulation of yawning, but suggest that D2-like agonist-induced yawning and penile erection are similarly mediated by the D3 (induction) and D2 (inhibition) receptors in rats. These studies not only provide strong pharmacologic evidence for a specific D3-mediated behavior, but have also allowed for the identification of other D3-mediated behaviors and determinations of in vivo D2/D3 selectivity.Ph.D.PharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60671/1/collinsg_1.pd

Treatment of malignant tumors of the skull base with multi-session radiosurgery

<p>Abstract</p> <p>Objective</p> <p>Malignant tumors that involve the skull base pose significant challenges to the clinician because of the proximity of critical neurovascular structures and limited effectiveness of surgical resection without major morbidity. The purpose of this study was to evaluate the efficacy and safety of multi-session radiosurgery in patients with malignancies of the skull base.</p> <p>Methods</p> <p>Clinical and radiographic data for 37 patients treated with image-guided, multi-session radiosurgery between January 2002 and December 2007 were reviewed retrospectively. Lesions were classified according to involvement with the bones of the base of the skull and proximity to the cranial nerves.</p> <p>Results</p> <p>Our cohort consisted of 37 patients. Six patients with follow-up periods less than four weeks were eliminated from statistical consideration, thus leaving the data from 31 patients to be analyzed. The median follow-up was 37 weeks. Ten patients (32%) were alive at the end of the follow-up period. At last follow-up, or the time of death from systemic disease, tumor regression or stable local disease was observed in 23 lesions, representing an overall tumor control rate of 74%. For the remainder of lesions, the median time to progression was 24 weeks. The median progression-free survival was 230 weeks. The median overall survival was 39 weeks. In the absence of tumor progression, there were no cranial nerve, brainstem or vascular complications referable specifically to CyberKnife^®radiosurgery.</p> <p>Conclusion</p> <p>Our experience suggests that multi-session radiosurgery for the treatment of malignant skull base tumors is comparable to other radiosurgical techniques in progression-free survival, local tumor control, and adverse effects.</p

Variation in climate sensitivity and feedback parameters during the historical period

We investigate the climate feedback parameter α (W m−2 K−1) during the historical period (since 1871) in experiments using the HadGEM2 and HadCM3 atmosphere general circulation models (AGCMs) with constant preindustrial atmospheric composition and time-dependent observational sea surface temperature (SST) and sea ice boundary conditions. In both AGCMs, for the historical period as a whole, the effective climate sensitivity is ∼2 K (α≃1.7 W m−2 K−1), and α shows substantial decadal variation caused by the patterns of SST change. Both models agree with the AGCMs of the latest Coupled Model Intercomparison Project in showing a considerably smaller effective climate sensitivity of ∼1.5 K (α = 2.3 ± 0.7 W m−2 K−1), given the time-dependent changes in sea surface conditions observed during 1979–2008, than the corresponding coupled atmosphere-ocean general circulation models (AOGCMs) give under constant quadrupled CO2 concentration. These findings help to relieve the apparent contradiction between the larger values of effective climate sensitivity diagnosed from AOGCMs and the smaller values inferred from historical climate change

On the nature of the z=0 X-ray absorbers: I. Clues from an external group

Absorption lines of OVII at redshift zero are observed in high quality Chandra spectra of extragalactic sightlines. The location of the absorber producing these lines, whether from the corona of the Galaxy or from the Local Group or even larger scale structure, has been a matter of debate. Here we study another poor group like our Local Group to understand the distribution of column density from galaxy to group scales. We show that we cannot yet rule out the group origin of z=0 systems. We further argue that the debate over Galactic vs. extragalactic origin of z=0 systems is premature as they likely contain both components and predict that future higher resolution observations will resolve the z=0 systems into multiple components.Comment: Submitted to ApJ

Investigation of the photosensitivity, temperature sustainability and fluorescence characteristics of several Er-doped photosensitive fibers

Three different types of Er doped photosensitive fibers, germanium/erbium (Ge/Er) fiber, tin/germanium/erbium fiber (Sn/Er) and antimony/germanium/erbium fiber (Sb/Er) have been manufactured and studied for use in optical sensor systems. Their characteristics of photosensitivity, the temperature sustainability of fiber Bragg gratings (FBGs) written into these fibers and the fluorescence emission from the Er dopant were investigated and compared. It has been shown in this work that these fibers all show a satisfactory degree of photosensitivity to enable the fabrication of FBGs and a significant level of fluorescence emission within the 1550 nm band for sensor use. The high temperature sustainability of the FBGs written into these fibers was investigated and seen to be quite significant at temperatures as high as 850 ^{\circ}C, in particular for the Sn/Er and Sb/Er fibers. A fiber laser using the Sb/Er fiber as the gain medium was demonstrated, giving evidence of the strong fluorescence emission from the Er dopant. These fibers are all suitable for use in a variety of sensing applications for the simultaneous measurement of temperature and strain by means of monitoring both the fluorescence characteristics and the peak wavelength shift of the FBGs formed in fiber laser sensor application

Isomerization dynamics of a buckled nanobeam

We analyze the dynamics of a model of a nanobeam under compression. The model is a two mode truncation of the Euler-Bernoulli beam equation subject to compressive stress. We consider parameter regimes where the first mode is unstable and the second mode can be either stable or unstable, and the remaining modes (neglected) are always stable. Material parameters used correspond to silicon. The two mode model Hamiltonian is the sum of a (diagonal) kinetic energy term and a potential energy term. The form of the potential energy function suggests an analogy with isomerisation reactions in chemistry. We therefore study the dynamics of the buckled beam using the conceptual framework established for the theory of isomerisation reactions. When the second mode is stable the potential energy surface has an index one saddle and when the second mode is unstable the potential energy surface has an index two saddle and two index one saddles. Symmetry of the system allows us to construct a phase space dividing surface between the two "isomers" (buckled states). The energy range is sufficiently wide that we can treat the effects of the index one and index two saddles in a unified fashion. We have computed reactive fluxes, mean gap times and reactant phase space volumes for three stress values at several different energies. In all cases the phase space volume swept out by isomerizing trajectories is considerably less than the reactant density of states, proving that the dynamics is highly nonergodic. The associated gap time distributions consist of one or more `pulses' of trajectories. Computation of the reactive flux correlation function shows no sign of a plateau region; rather, the flux exhibits oscillatory decay, indicating that, for the 2-mode model in the physical regime considered, a rate constant for isomerization does not exist.Comment: 42 pages, 6 figure

Small global-mean cooling due to volcanic radiative forcing

In both the observational record and atmosphere-ocean general circulation model (AOGCM) simulations of the last ∼∼ 150 years, short-lived negative radiative forcing due to volcanic aerosol, following explosive eruptions, causes sudden global-mean cooling of up to ∼∼ 0.3 K. This is about five times smaller than expected from the transient climate response parameter (TCRP, K of global-mean surface air temperature change per W m−2 of radiative forcing increase) evaluated under atmospheric CO2 concentration increasing at 1 % yr−1. Using the step model (Good et al. in Geophys Res Lett 38:L01703, 2011. doi:10.​1029/​2010GL045208), we confirm the previous finding (Held et al. in J Clim 23:2418–2427, 2010. doi:10.​1175/​2009JCLI3466.​1) that the main reason for the discrepancy is the damping of the response to short-lived forcing by the thermal inertia of the upper ocean. Although the step model includes this effect, it still overestimates the volcanic cooling simulated by AOGCMs by about 60 %. We show that this remaining discrepancy can be explained by the magnitude of the volcanic forcing, which may be smaller in AOGCMs (by 30 % for the HadCM3 AOGCM) than in off-line calculations that do not account for rapid cloud adjustment, and the climate sensitivity parameter, which may be smaller than for increasing CO2 (40 % smaller than for 4 × CO2 in HadCM3)

Gravitational collapse in braneworld models with curvature corrections

We study the collapse of a homogeneous braneworld dust cloud in the context of the various curvature correction scenarios, namely, the induced-gravity, the Gauss-Bonnet, and the combined induced-gravity and Gauss-Bonnet. In accordance to the Randall-Sundrum model, and contrary to four-dimensional general relativity, we show in all cases that the exterior spacetime on the brane is non-static.Comment: References adde

Large-scale distributions of tropospheric nitric, formic, and acetic acids over the western Pacific basin during wintertime

We report here measurements of the acidic gases nitric (HNO3), formic (HCOOH), and acetic (CH3COOH) over the western Pacific basin during the February-March 1994 Pacific Exploratory Mission-West (PEM-West B). These data were obtained aboard the NASA DC-8 research aircraft as it flew missions in the altitude range of 0.3–12.5 km over equatorial regions near Guam and then further westward encompassing the entire Pacific Rim arc. Aged marine air over the equatorial Pacific generally exhibited mixing ratios of acidic gases \u3c100 parts per trillion by volume (pptv). Near the Asian continent, discrete plumes encountered below 6 km altitude contained up to 8 parts per billion by volume (ppbv) HNO3 and 10 ppbv HCOOH and CH3COOH. Overall there was a general correlation between mixing ratios of acidic gases with those of CO, C2H2, and C2Cl4, indicative of emissions from combustion and industrial sources. The latitudinal distributions of HNO3 and CO showed that the largest mixing ratios were centered around 15°N, while HCOOH, CH3COOH, and C2Cl4 peaked at 25°N. The mixing ratios of HCOOH and CH3COOH were highly correlated (r2 = 0.87) below 6 km altitude, with a slope (0.89) characteristic of the nongrowing season at midlatitudes in the northern hemisphere. Above 6 km altitude, HCOOH and CH3COOH were marginally correlated (r2 = 0.50), and plumes well defined by CO, C2H2, and C2Cl4 were depleted in acidic gases, most likely due to scavenging during vertical transport of air masses through convective cloud systems over the Asian continent. In stratospheric air masses, HNO3 mixing ratios were several parts per billion by volume (ppbv), yielding relationships with O3 and N2O consistent with those previously reported for NOy