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Summary: Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma. : Bankar et al. show that acylsulfonamides produce analgesic activity at low multiples of the IC50 for inhibition of NaV1.7, in contrast to studies with arylsulfonamides that required >10 times the IC50. The improvement correlates with longer residency time on the target channels. Keywords: pain, sodium channel, inherited erythromelalgia, diabetic neuropathy, residence time

Two Diesel particulate matter emission control devices; the continuously regenerating trap ( CRT TM ) and the catalyzed continuously regenerating trap ( CCRT TM ) were evaluated using a mobile emissions laboratory. The source of emissions was the lab's engine that was fueled with 15 ppm sulfur fuel, and specially formulated, low sulfur (1300 ppm) lubrication oil. The objective was to characterize performance using real-time aerosol instrumentation, real-world dilution, and on-road driving conditions. The devices when combined with low S fuel and lube oil effectively removed Diesel particulate matter. The CRT produced large quantities of nuclei mode particles, the quantity of which increased as a function of exhaust temperature. The CCRT reduced the exhaust particle number concentration to levels not detectable above background storage sites, thus eliminating precursors that form nuclei mode particles. Use of low S fuel and lubrication oil prolongs the storage process. Over time it is expected that this material would be released.

The primary objective was to characterize exhaust aerosols from a small group of in-use, light-duty, spark ignition (SI) vehicles operated on-road, and on a chassis dynamometer. A significant particle signature above background was not measured at highway cruise condition. Number emissions were much higher during acceleration, at high-speed cruise, and during cold–cold starts. Group average fuel-specific number emissions range from 3.9 × 10 14 to 1.0 × 10 17 particles/kg of fuel. Cold–cold start temperatures, driving cycles and vehicular condition influence SI emissions. Elemental carbon was a major contributor to mass emissions measured in chassis dynamometer Unified Driving Cycle (UDC) tests averaging 64% and 34% of the mass emissions for cold–cold and hot start cycles, respectively. Average ratios of cold–cold to hot start emissions were 3.3, 7.6, and 22 for CPC number, filter mass and SMPS volume, respectively. Apportionment results showed that on a weekly weighted basis and on weekdays, the majority of observed particle number was attributed to heavy-duty diesel traffic. Weekend production of particles was attributable to light-duty automobiles. On a per vehicle basis, heavy-duty vehicles produced substantially greater number concentrations. On a fuel-specific basis, heavy-duty vehicles produce slightly higher concentrations of particles than light-duty vehicles. The relative contribution of light-duty vehicles to particle number emissions increased as particle size decreased, for the smallest particles apportioned number emissions were 1.3 × 10 16 and 7.1 × 10 15 particles/kg of fuel for heavy-duty and light-duty vehicles, respectively. Comparison of on-road chase and apportionment results with chassis dynamometer tests in a certification type facility suggests that the latter may underestimate real-world number emissions.

The objective was to characterize diesel exhaust aerosols on road and to duplicate the results in the laboratory without altering the physical characteristics of the nuclei mode. On-road emissions from four, heavy-duty diesel truck engines were measured. The same engines were reevaluated in the manufacturers’ laboratories. For highway cruise and acceleration conditions, all engines produced bimodal size distributions with the nuclei mode ranging in size from 6 to 11 nm and the accumulation mode from 52 to 62 nm. On-road size distribution measurements nearly always showed a nuclei mode while laboratory measurements showed a nuclei mode under many, but not all conditions. Laboratory studies showed that nuclei mode particles consisted mainly of heavy hydrocarbons. More than 97% of the volume of 12 and 30 nm particles disappeared on heating to 400 °C. The volatility resembled that of C24–C32 n -alkanes implying a significant contribution from lubricating oil.

The objective of this study was to evaluate the response of a suite of portable, real-time aerosol instruments to Diesel exhaust aerosol with and without a catalytic stripper (CS) to determine the change in response as a function of particle size and volatility. The response of the photoemission aerosol sensor (PAS) was strongly influenced by the physical and chemical nature of Diesel aerosol. The presence of a large, predominantly volatile nuclei mode, and/or the presence of volatile material on the surface of the solid carbonaceous agglomerates in the accumulation mode suppressed the PAS response. Removal of the volatile material by passage of the aerosol through the CS enhanced the response, and improved correlations between the PAS, the diffusion charger (DC) and the scanning mobility particle sizer (SMPS). Data on aerosol size distributions, number, volume, and surface area concentrations with and without the CS in the sample stream are reported.

Air quality measurements were made on interstate highways in the Minneapolis metropolitan area. Gas and aerosol concentrations were measured on weekdays and weekends. By exploiting the difference in the relative volumes of heavy duty (HD) diesel and light duty (LD) spark ignition (SI) vehicles on weekdays and weekends, we were able to estimate apportioned fuel specific emissions. The on-road, apportioned, fuel specific particle number emissions factors, estimated from condensation particle counter (CPC) measurements were 1.34±0.2×1016 particles kg−1 for diesels and 7.1±1.6×1015 particles kg−1 for spark ignition vehicles. Estimates from the scanning mobility particle sizer (SMPS) measurements were 2.1±0.3×1015 particles kg−1 for diesels and 3.9±0.6×1014 particles kg−1 for SI vehicles. The difference between CPC and SMPS measurements is mainly due to different lower size detection limits of the instruments, ∼3 and ∼10 nm, respectively. On a weekly weighted basis and on weekdays, the majority of particle number was attributed to HD diesel traffic. Weekend production of particles can be primarily attributed to light duty SI automobiles. On a per vehicle basis, HD vehicles produced substantially greater numbers of particles. On a fuel specific basis, HD vehicles produce slightly higher concentrations of particles than light duty vehicles. The relative contribution of LD vehicles to particle number emissions increased as particle size decreased. The HD apportioned size distributions were similar to size distributions measured during other on-road and laboratory studies. The LD apportioned size distribution was bounded by laboratory and on-road size distributions. Our work is representative of summer, highway cruise conditions. It is likely that under cold start and high load operating conditions LD emissions will increase relative to HD emissions.

The objective of this project was to characterize on-road aerosol on highways surrounding the Minneapolis area. Data were collected under varying on-road traffic conditions and in residential areas to determine the impact of highway traffic on air quality. The study was focused on determining on-road nanoparticle concentrations, and estimating fuel-specific and particle emissions km−1. On-road aerosol number concentrations ranged from 104 to 106 particles cm−3. The highest nanoparticle concentrations were associated with high-speed traffic. At high vehicular speeds engine load, exhaust temperature, and exhaust flow all increase resulting in higher emissions. Less variation was observed in particle volume, a surrogate measure of particle mass. Most of the particles added by the on-road fleet were below 50 nm in diameter. Particles in this size range may dominate particle number, but contribute little to particle volume or mass. Furthermore, particle number is strongly influenced by nucleation and coagulation, which have little or no effect on particle volume. Measurements made in heavy traffic, speeds

We have studied the functional effects of extracellular Cd(2+) on human ether-a-go-go-related gene (HERG) encoded K(+) channels. Low concentrations (10-200 microM) of extracellular Cd(2+) increased outward currents through HERG channels; 200 microM Cd(2+) more than doubled HERG currents and altered current kinetics. Cd(2+) concentrations up to 200 microM did not change the voltage dependence of channel activation, but shifted the voltage dependence of inactivation to more depolarized membrane potentials. Cd(2+) concentrations >or=500 microM shifted the voltage dependence of channel activation to more positive potentials. These results are consistent with a somewhat specific ability of Cd(2+) to destabilize the inactivated state. We tested the hypothesis that channel inactivation is essential for Cd(2+)-induced increases in HERG K(+) currents, using a double point mutation (G628C/S631C) that diminishes HERG inactivation (Smith, P. L., T. Baukrowitz, and G. Yellen. 1996. Nature (Lond.). 379:833-836). This inactivation-removed mutant is insensitive to low concentrations of Cd(2+). Thus, Cd(2+) had two distinct effects on HERG K(+) channels. Low concentrations of Cd(2+) caused relatively selective effects on inactivation, resulting in a reduction of the apparent rectification of the channel and thereby increasing HERG K(+) currents. Higher Cd(2+) concentrations affected activation gating as well, possibly by a surface charge screening mechanism or by association with a lower affinity site.

The early increase in luminal membrane Na+ permeability by aldosterone in Na(+)-reabsorbing epithelia is attributed to an increase in the open probability (and number) of preexisting amiloride-sensitive Na+ channels. Carboxyl methylation reactions are involved, but the mechanism of action is unknown. We report that the 90-95-kDa polypeptide subunit of a purified renal Na+ channel protein can be specifically carboxymethylated and that this biochemical reaction, in the presence of guanosine 5'-3-O-(thio)triphosphate, leads directly to an increase in channel activity. Further, we show that protein kinase A-mediated phosphorylation can synergistically activate these channels. We suggest that renal Na+ channels have multiple biochemical regulatory inputs and that post-translational modifications underlie the increases in luminal membrane Na+ channel activity produced by aldosterone and vasopressin in Na(+)-reabsorbing epithelia.