Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins.

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1-1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7.

A multiphase CFD model of DAF process.

A Eulerian-Eulerian multiphase CFD model is employed for the air/water flow. A 3D structure grid is used to incorporate the air nozzle and tank geometry. The fixed frictionless wall boundary approximating the free surface acts as a sink to allow the air bubbles to escape. The air/water volume fraction in the flotation tank is evaluated to determine the effective air/water fluid density. The floc particle is then introduced and is tracked in the air/water fluid using a disperse Lagrangean model. Fate of these flocs depends on their sizes and density. Flocs therefore can either escape through the top water surface, settles in the main tank or breakthrough under the outlet weir. The CFD model is developed for a full scale DAF tank to predict the flow dynamic, particle removal and settled solid profile. The general flow pattern is compared with flow visualisation using the underwater camera. Comparison of average fluid velocities is carried out using acoustic Doppler velocimetry ADV measurement.

Emergence of Lyme disease in Hunterdon County, New Jersey, 1993: a case-control study of risk factors and evaluation of reporting patterns.

Reported cases of Lyme disease in Hunterdon County, New Jersey, increased almost 200% from 75 (67/100,000 population) in 1992 to 216 (193/100,000 population) in 1993. For evaluation of risk factors for Lyme disease and for determination of the cause of this increase, a case-control study was conducted, and the reporting practices of physicians' offices were evaluated. For cases reported in 1993, age and sex distribution, month of disease onset, and proportion of cases with erythema migrans rash were within expected limits. Analysis of age-matched case-control data showed that rural residence; clearing periresidential brush during spring and summer months; and the presence of rock walls, woods, deer, or a bird feeder on residential property were associated with incident Lyme disease. A review of physician reporting patterns suggested that the increase in reported cases in 1993 was due to improved reporting as well as to an increase in the numbers of patients diagnosed with Lyme disease. In addition, substantial underreporting of Lyme disease by physicians' offices was found.

Prevalence of tick-borne pathogens in Ixodes scapularis in a rural New Jersey County.

To assess the potential risk for other tick-borne diseases, we collected 100 adult Ixodes scapularis in Hunterdon County, a rapidly developing rural county in Lyme disease endemic western New Jersey. We tested the ticks by polymerase chain reaction for Borrelia burgdorferi, Babesia microti, and the rickettsial agent of human granulocytic ehrlichiosis (HGE). Fifty-five ticks were infected with at least one of the three pathogens: 43 with B. burgdorferi, five with B. microti, and 17 with the HGE agent. Ten ticks were coinfected with two of the pathogens. The results suggest that county residents are at considerable risk for infection by a tick-borne pathogen after an I. scapularis bite.

Benefits and costs of using an orally absorbed vaccine to control rabies in raccoons.

In November 1989, the epizootic of rabies affecting raccoons in the mid-Atlantic states reached New Jersey. An economic evaluation was conducted in 2 counties first affected by the epizootic to estimate the costs of the epizootic and to assess the costs and benefits of orally administering a newly developed recombinant rabies vaccine to prevent further spread of the disease. Data on expenditures associated with prevention of rabies in human beings and domestic animals and laboratory testing of suspect animals were collected and analyzed for 1988 (before the epizootic) and 1990 (first full year of the epizootic). Benefit-cost ratios were calculated and used to evaluate the economic advisability of the vaccine at various vaccination program alternatives. Two indices of capital investment analysis, payback period and net present value, were used to evaluate the economic benefits of the rabies vaccine. Expenditures were estimated to be $1,952,014 in 1990 (primarily for pet animal vaccinations), compared with $768,488 in 1988. Benefit-cost ratios ranged from 2.21 for the most expensive vaccination program alternative to 6.80 for the least expensive alternative. The payback period varied from 0.69 to 2.11 years, and the net present value ranged from $2,105,453 to $4,877,452. The high costs of this epizootic necessitated the reallocation of scarce public health resources to various rabies prevention activities, particularly the vaccination of dogs. This study also demonstrated the usefulness of benefit-cost analysis in developing public health strategies. Although the mass application of this recombinant vaccine was found to be economically beneficial, other qualitative considerations must be used to supplement these findings.