Consumer Voices for Coverage: Advocacy Evaluation Toolkit

Offers step-by-step guidance on evaluating advocacy projects, including developing a logic model, collecting evaluation data, and using focus groups and interviews to evaluate or inform program performance. Includes surveys on RWJF's advocacy initiative

Building Advocacy Capacity: Where Grantees Started

Describes the baseline levels of core advocacy capacities of groups participating in Consumer Voices for Coverage, a twelve-state initiative to build consumer organizations' network and advocacy capacity. Discusses lessons learned and recommendations

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies

CHANG-ES VI: Probing Supernova Energy Deposition in Spiral Galaxies Through Multi-Wavelength Relationships

How a galaxy regulates its SNe energy into different interstellar/circumgalactic medium components strongly affects galaxy evolution. Based on the JVLA D-configuration C- (6 GHz) and L-band (1.6 GHz) continuum observations, we perform statistical analysis comparing multi-wavelength properties of the CHANG-ES galaxies. The high-quality JVLA data and edge-on orientation enable us for the first time to include the halo into the energy budget for a complete radio-flux-limited sample. We find tight correlations of $L_{\rm radio}$ with the mid-IR-based SFR. The normalization of our $I_{\rm 1.6GHz}/{\rm W~Hz^{-1}}-{\rm SFR}$ relation is $\sim$2-3 times of those obtained for face-on galaxies, probably a result of enhanced IR extinction at high inclination. We also find tight correlations between $L_{\rm radio}$ and the SNe energy injection rate $\dot{E}_{\rm SN(Ia+CC)}$, indicating the energy loss via synchrotron radio continuum accounts for $\sim0.1\%$ of $\dot{E}_{\rm SN}$, comparable to the energy contained in CR electrons. The integrated C-to-L-band spectral index is $\alpha\sim0.5-1.1$ for non-AGN galaxies, indicating a dominance by the diffuse synchrotron component. The low-scatter $L_{\rm radio}-{\rm SFR}$/$L_{\rm radio}-\dot{E}_{\rm SN (Ia+CC)}$ relationships have super-linear logarithmic slopes at $\sim2~\sigma$ in L-band ($1.132\pm0.067$/$1.175\pm0.102$) while consistent with linear in C-band ($1.057\pm0.075$/$1.100\pm0.123$). The super-linearity could be naturally reproduced with non-calorimeter models for galaxy disks. Using Chandra halo X-ray measurements, we find sub-linear $L_{\rm X}-L_{\rm radio}$ relations. These results indicate that the observed radio halo of a starburst galaxy is close to electron calorimeter, and a galaxy with higher SFR tends to distribute an increased fraction of SNe energy into radio emission (than X-ray).Comment: 16 pages, 6 figures, 1 table, MNRAS in pres

Continuum Halos in Nearby Galaxies -- an EVLA Survey (CHANG-ES) -- I: Introduction to the Survey

We introduce a new survey to map the radio continuum halos of a sample of 35 edge-on spiral galaxies at 1.5 GHz and 6 GHz in all polarization products. The survey is exploiting the new wide bandwidth capabilities of the Karl G. Jansky Very Large Array (i.e. the Expanded Very Large Array, or EVLA) in a variety of array configurations (B, C, and D) in order to compile the most comprehensive data set yet obtained for the study of radio halo properties. This is the first survey of radio halos to include all polarization products. In this first paper, we outline the scientific motivation of the survey, the specific science goals, and the expected improvements in noise levels and spatial coverage from the survey. Our goals include investigating the physical conditions and origin of halos, characterizing cosmic ray transport and wind speed, measuring Faraday rotation and mapping the magnetic field, probing the in-disk and extraplanar far-infrared - radio continuum relation, and reconciling non-thermal radio emission with high-energy gamma-ray models. The sample size allows us to search for correlations between radio halos and other properties, including environment, star formation rate, and the presence of AGNs. In a companion paper (Paper II) we outline the data reduction steps and present the first results of the survey for the galaxy, NGC 4631.Comment: 17 pages, 1 figure, accepted to the Astronomical Journal, Version 2 changes: added acknowledgement to NRA

Highly localized interactions between sensory neurons and sprouting sympathetic fibers observed in a transgenic tyrosine hydroxylase reporter mouse

<p>Abstract</p> <p>Background</p> <p>Sprouting of sympathetic fibers into sensory ganglia occurs in many preclinical pain models, providing a possible anatomical substrate for sympathetically enhanced pain. However, the functional consequences of this sprouting have been controversial. We used a transgenic mouse in which sympathetic fibers expressed green fluorescent protein, observable in live tissue. Medium and large diameter lumbar sensory neurons with and without nearby sympathetic fibers were recorded in whole ganglion preparations using microelectrodes.</p> <p>Results</p> <p>After spinal nerve ligation, sympathetic sprouting was extensive by 3 days. Abnormal spontaneous activity increased to 15% and rheobase was reduced. Spontaneously active cells had Aαβ conduction velocities but were clustered near the medium/large cell boundary. Neurons with sympathetic basket formations had a dramatically higher incidence of spontaneous activity (71%) and had lower rheobase than cells with no sympathetic fibers nearby. Cells with lower density nearby fibers had intermediate phenotypes. Immunohistochemistry of sectioned ganglia showed that cells surrounded by sympathetic fibers were enriched in nociceptive markers TrkA, substance P, or CGRP. Spontaneous activity began before sympathetic sprouting was observed, but blocking sympathetic sprouting on day 3 by cutting the dorsal ramus in addition to the ventral ramus of the spinal nerve greatly reduced abnormal spontaneous activity.</p> <p>Conclusions</p> <p>The data suggest that early sympathetic sprouting into the sensory ganglia may have highly localized, excitatory effects. Quantitatively, neurons with sympathetic basket formations may account for more than half of the observed spontaneous activity, despite being relatively rare. Spontaneous activity in sensory neurons and sympathetic sprouting may be mutually re-enforcing.</p

Navβ4 regulates fast resurgent sodium currents and excitability in sensory neurons

BACKGROUND: Increased electrical activity in peripheral sensory neurons including dorsal root ganglia (DRG) and trigeminal ganglia neurons is an important mechanism underlying pain. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons and are essential for the upstroke of action potentials. A unique type of VGSC current, resurgent current (INaR), generates an inward current at repolarizing voltages through an alternate mechanism of inactivation referred to as open-channel block. INaRs are proposed to enable high frequency firing and increased INaRs in sensory neurons are associated with pain pathologies. While Nav1.6 has been identified as the main carrier of fast INaR, our understanding of the mechanisms that contribute to INaR generation is limited. Specifically, the open-channel blocker in sensory neurons has not been identified. Previous studies suggest Navβ4 subunit mediates INaR in central nervous system neurons. The goal of this study was to determine whether Navβ4 regulates INaR in DRG sensory neurons. RESULTS: Our immunocytochemistry studies show that Navβ4 expression is highly correlated with Nav1.6 expression predominantly in medium-large diameter rat DRG neurons. Navβ4 knockdown decreased endogenous fast INaR in medium-large diameter neurons as measured with whole-cell voltage clamp. Using a reduced expression system in DRG neurons, we isolated recombinant human Nav1.6 sodium currents in rat DRG neurons and found that overexpression of Navβ4 enhanced Nav1.6 INaR generation. By contrast neither overexpression of Navβ2 nor overexpression of a Navβ4-mutant, predicted to be an inactive form of Navβ4, enhanced Nav1.6 INaR generation. DRG neurons transfected with wild-type Navβ4 exhibited increased excitability with increases in both spontaneous activity and evoked activity. Thus, Navβ4 overexpression enhanced INaR and excitability, whereas knockdown or expression of mutant Navβ4 decreased INaR generation. CONCLUSION: INaRs are associated with inherited and acquired pain disorders. However, our ability to selectively target and study this current has been hindered due to limited understanding of how it is generated in sensory neurons. This study identified Navβ4 as an important regulator of INaR and excitability in sensory neurons. As such, Navβ4 is a potential target for the manipulation of pain sensations

CHANG-ES IV: Radio continuum emission of 35 edge-on galaxies observed with the Karl G. Jansky Very Large Array in D-configuration, Data Release 1

We present the first part of the observations made for the Continuum Halos in Nearby Galaxies, an EVLA Survey (CHANG-ES) project. The aim of the CHANG-ES project is to study and characterize the nature of radio halos, their prevalence as well as their magnetic fields, and the cosmic rays illuminating these fields. This paper reports observations with the compact D configuration of the Karl G. Jansky Very Large Array (VLA) for the sample of 35 nearby edge-on galaxies of CHANG-ES. With the new wide bandwidth capabilities of the VLA, an unprecedented sensitivity was achieved for all polarization products. The beam resolution is an average of 9.6" and 36" with noise levels reaching approximately 6 and 30 microJy per beam for C- and L-bands, respectively (robust weighting). We present intensity maps in these two frequency bands (C and L), with different weightings, as well as spectral index maps, polarization maps, and new measurements of star formation rates (SFRs). The data products described herein are available to the public in the CHANG-ES data release available at www.queensu.ca/changes. We also present evidence of a trend among galaxies with larger halos having higher SFR surface density, and we show, for the first time, a radio continuum image of the median galaxy, taking advantage of the collective signal-to-noise ratio of 30 of our galaxies. This image shows clearly that a typical spiral galaxy is surrounded by a halo of magnetic fields and cosmic rays.Comment: 70 pages, of which 35 pages present the data of each galax

NF-κB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons

<p>Abstract</p> <p>Background</p> <p>Inflammatory processes play important roles in both neuropathic and inflammatory pain states, but the effects of inflammation <it>per se </it>within the sensory ganglia are not well understood. The cytokine growth-related oncogene (GRO/KC; CXCL1) shows strong, rapid upregulation in dorsal root ganglion (DRG) in both nerve injury and inflammatory pain models. We examined the direct effects of GRO/KC on small diameter DRG neurons, which are predominantly nociceptive. Whole cell voltage clamp technique was used to measure voltage-activated potassium (K) currents in acutely cultured adult rat small diameter sensory neurons. Fluorescently labeled isolectin B4 (IB4) was used to classify cells as IB4-positive or IB4-negative.</p> <p>Results</p> <p>In IB4-negative neurons, voltage-activated K current densities of both transient and sustained components were increased after overnight incubation with GRO/KC (1.5 nM), without marked changes in voltage dependence or kinetics. The average values for the slow and fast decay time constants at 20 mV were unchanged by GRO/KC. The amplitude of the fast inactivating component increased significantly with no large shifts in the voltage dependence of inactivation. The increase in K currents was completely blocked by co-incubation with protein synthesis inhibitor cycloheximide (CHX) or NF-κB inhibitors pyrrolidine dithiocarbamate (PDTC) or quinazoline (6-Amino-4-(4-phenoxypheny lethylamino;QNZ). In contrast, the voltage-activated K current of IB4-positive neurons was unchanged by GRO/KC. GRO/KC incubation caused no significant changes in the expression level of eight selected voltage-gated K channel genes in quantitative PCR analysis.</p> <p>Conclusion</p> <p>The results suggest that GRO/KC has important effects in inflammatory processes via its direct actions on sensory neurons, and that activation of NF-κB is involved in the GRO/KC-induced enhancement of K currents.</p

Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain

Low back pain, a leading cause of disability, is commonly treated by epidural steroid injections that target the anti-inflammatory glucocorticoid receptor (GR). However, their efficacy has been controversial. All currently used epidural steroids also activate the pro-inflammatory mineralocorticoid receptor (MR) with significant potency. Local inflammation of the dorsal root ganglia (DRG), a rat model of low back pain, was used. This model causes static and dynamic mechanical allodynia, cold allodynia and guarding behavior (a measure of spontaneous pain), and activates the MR, with pro-nociceptive effects. In this study, effects of local Dexamethasone (DEX; a glucocorticoid used in epidural injections), and eplerenone (EPL; a second generation, more selective MR antagonist) applied to the DRG at the time of inflammation were examined. Mechanical and spontaneous pain behaviors were more effectively reduced by the combination of DEX and EPL than by either alone. The combination of steroids was particularly more effective than DEX alone or the model alone (3-fold improvement for mechanical allodynia) at later times (day 14). Immunohistochemical analysis of the GR in the DRG showed that the receptor was expressed in neurons of all size classes, and in non-neuronal cells including satellite glia. The GR immunoreactivity was downregulated by DRG inflammation (48%) starting on day 1, consistent with the reduction of GR (57%) observed by Western blot, when compared to control animals. On day 14, the combination of DEX and EPL resulted in rescue of GR immunoreactivity that was not seen with DEX alone, and was more effective in reducing a marker for satellite glia activation/neuroinflammation. The results suggest that EPL may enhance the effectiveness of clinically used epidural steroid injections, in part by enhancing the availability of the GR. Thus, the glucocorticoid-mineralocorticoid interactions may limit the effectiveness of epidural steroids through the regulation of the GR in the DRG