Helicity-Dependent Cross Sections for the Photoproduction of π

The double-polarization observable E and helicity-dependent cross sections σ_{1/2}, σ_{3/2} have been measured for the photoproduction of π^{0} pairs off quasifree protons and neutrons at the Mainz MAMI accelerator with the Crystal Ball/TAPS setup. A circularly polarized photon beam was produced by bremsstrahlung from longitudinally polarized electrons and impinged on a longitudinally polarized deuterated butanol target. The reaction products were detected with an almost 4π covering calorimeter. The results reveal for the first time the helicity- and isospin-dependent structure of the γN→Nπ^{0}π^{0} reaction. They are compared to predictions from reaction models in view of nucleon resonance contributions and also to a refit of one model that predicted results for the proton and for the neutron target. The comparison of the prediction and the refit demonstrates the large impact of the new data.

Signatures of the d

We report a measurement of the spin polarization of the recoiling neutron in deuterium photodisintegration, utilizing a new large acceptance polarimeter within the Crystal Ball at MAMI. The measured photon energy range of 300-700 MeV provides the first measurement of recoil neutron polarization at photon energies where the quark substructure of the deuteron plays a role, thereby providing important new constraints on photodisintegration mechanisms. A very high neutron polarization in a narrow structure centered around E_{γ}∼570 MeV is observed, which is inconsistent with current theoretical predictions employing nucleon resonance degrees of freedom. A Legendre polynomial decomposition suggests this behavior could be related to the excitation of the d^{*}(2380) hexaquark.

Study of η and η' Photoproduction at MAMI.

The reactions γp→ηp and γp→η^{'}p are measured from their thresholds up to the center-of-mass energy W=1.96 GeV with the tagged-photon facilities at the Mainz Microtron, MAMI. Differential cross sections are obtained with unprecedented statistical accuracy, providing fine energy binning and full production-angle coverage. A strong cusp is observed in the total cross section for η photoproduction at the energies in the vicinity of the η^{'} threshold, W=1896 MeV (E_{γ}=1447 MeV). Within the framework of a revised ηMAID isobar model, the cusp, in connection with a steep rise of the η^{'} total cross section from its threshold, can only be explained by a strong coupling of the poorly known N(1895)1/2^{-} state to both ηp and η^{'}p. Including the new high-accuracy results in the ηMAID fit to available η and η^{'} photoproduction data allows the determination of the N(1895)1/2^{-} properties.

Measurement of the transverse target and beam-target asymmetries in η meson photoproduction at MAMI.

We present new data for the transverse target asymmetry T and the very first data for the beam-target asymmetry F in the γ[over →]p[over →]→ηp reaction up to a center-of-mass energy of W=1.9 GeV. The data were obtained with the Crystal-Ball/TAPS detector setup at the Glasgow tagged photon facility of the Mainz Microtron MAMI. All existing model predictions fail to reproduce the new data indicating a significant impact on our understanding of the underlying dynamics of η meson photoproduction. The peculiar nodal structure observed in existing T data close to threshold is not confirmed.

Photoproduction of π0 mesons off neutrons in the nucleon resonance region.

Precise angular distributions have been measured for the first time for the photoproduction of π0 mesons off neutrons bound in the deuteron. The effects from nuclear Fermi motion have been eliminated by a complete kinematic reconstruction of the final state. The influence of final-state-interaction effects has been estimated by a comparison of the reaction cross section for quasifree protons bound in the deuteron to the results for free protons and then applied as a correction to the quasifree neutron data. The experiment was performed at the tagged photon facility of the Mainz Microtron MAMI with the Crystal Ball and TAPS detector setup for incident photon energies between 0.45 and 1.4 GeV. The results are compared to the predictions from reaction models and partial-wave analyses based on data from other isospin channels. The model predictions show large discrepancies among each other and the present data will provide much tighter constraints. This is demonstrated by the results of a new analysis in the framework of the Bonn-Gatchina coupled-channel analysis which included the present data.

Narrow structure in the excitation function of η photoproduction off the neutron.

The photoproduction of η mesons off nucleons bound in 2H and 3He has been measured in coincidence with recoil protons and recoil neutrons for incident photon energies from threshold up to 1.4 GeV. The experiments were performed at the Mainz MAMI accelerator, using the Glasgow tagged photon facility. Decay photons from the η→2γ and η→3π0 decays and the recoil nucleons were detected with an almost 4π electromagnetic calorimeter combining the Crystal Ball and TAPS detectors. The data from both targets are of excellent statistical quality and show a narrow structure in the excitation function of γn→nη. The results from the two measurements are consistent, taking into account the expected effects from nuclear Fermi motion. The best estimates for position and intrinsic width of the structure are W=(1670±5) MeV and Γ=(30±15) MeV. For the first time precise results for the angular dependence of this structure have been extracted.

Blockade of the second messenger functions of the glutamate metabotropic receptor is associated with degenerative changes in the retina and brain of immature rodents.

Activation of metabotropic glutamate receptors (mGluR) by Glu or related mGluR agonists triggers phosphoinositide (PI) hydrolysis, intracellular Ca2+ mobilization and protein kinase C activation. These mGluR agonist-stimulated events are inhibited strongly by 2-amino-3-phosphono-L-propionic acid (L-AP3) and L-aspartate-beta-hydroxamate (L-A beta H), and much more weakly by D-AP3 and L-serine-O-phosphate (L-SOP). Daily s.c. administration of DL-AP3 subchronically to infant rodents causes the developing retina and optic nerves to degenerate. In the present study, we describe the evolution of the cytopathological reaction in the developing rodent retina following DL-AP3 treatment and show that DL-AP3 can induce similar cytopathological changes in several regions of the immature rodent brain. In addition, we show that the retinotoxic action of DL-AP3 is mimicked by L-A beta H but not by L-SOP, and that L-AP3 is a much stronger retinotoxin that D-AP3. These observations suggest a possible mechanistic link between the PI-hydrolysis blocking action and retinotoxic action. Our findings are consistent with the hypothesis that under normal physiological circumstances, the Glu metabotropic receptor through its PI-hydrolysis-linked second messenger functions provides vitally important support for developing neurons, and that disruption of this support can cause widespread neuronal degeneration.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

Neuropathologic assessment of chemically induced developmental alterations in the nervous system for regulatory purposes is a multifactorial, complex process. This calls for careful qualitative and quantitative morphologic study of numerous brains at several developmental stages in rats. Quantitative evaluation may include such basic methods as determination of brain weight and dimensions as well as the progressively more complex approaches of linear, areal, or stereologic measurement of brain sections. Histologic evaluation employs routine stains (such as hematoxylin and eosin), which can be complemented by a variety of special and immunohistochemical procedures. These brain studies are augmented by morphologic assessment of selected peripheral nervous system structures. Studies of this nature require a high level of technical skill as well as special training on the part of the pathologist. The pathologist should have knowledge of normal microscopic neuroanatomy/neuronal circuitry and an understanding of basic principles of developmental neurobiology, such as familiarity with the patterns of physiologic or programmed cell de

Prevalence of antibodies to hepatitis E in two rural Egyptian communities.

A population-based serosurvey in two rural Egyptian communities was used to assess age-specific prevalence of antibody to hepatitis E virus (anti-HEV). One community is in the Nile Delta (11,182 inhabitants; 3,997 participants) and the other in Upper Egypt (10,970 inhabitants; 6,029 participants). Samples were tested for anti-HEV with a commercial enzyme-linked immunoassay (ELISA) based on antigens derived from open reading frame (ORF)2 and ORF3. Although there was a clear difference in sensitivity among the lots of the commercial test used, it was still possible to determine the seroprevalence. The seroprevalence of anti-HEV exceeded 60% in the first decade of life, peaked at 76% in the second decade and remained above 60% until the eighth decade. Prevalence of this magnitude is among the highest reported in the world, with an age-specific pattern more similar to hyperendemic hepatitis A virus transmission than generally described. Lot-to-lot variation in the sensitivity of the commercial ELISA kit highlights a problem when comparing seroepidemiologic studies of different populations.

Hepatitis C in a community in Upper Egypt: I. Cross-sectional survey.

The prevalence of antibody to hepatitis C virus (anti-HCV) was determined in a cross-sectional survey in a village in Upper Egypt. Exposure and demographic characteristics were obtained through a questionnaire. Antibody to hepatitis C virus was assessed using a second generation enzyme immunoassay, and the presence of HCV RNA was tested using a reverse transcriptase-polymerase chain reaction. Collection of blood samples was targeted at those > or = 5 years old, and obtained from 62.8%. This report describes the community, the HCV infection characteristics of the subjects, and evaluates some factors associated with presence of anti-HCV. Of the 6,031 participants, 522 (8.7%) were anti-HCV positive. Prevalence was higher among males than females (11.3% versus 6.5%; P < 0.001). It was greater among those > 30 years of age than among those < or = 30 years of age (20.0% versus 3.6%; P < 0.001). Those who were less educated, farmed, provided health care, and were currently married had a significantly higher anti-HCV prevalence than those who were not; however, these associations were not significant after adjusting for age. Although active infections with Schistosoma haematobium were not associated with anti-HCV, a history of past infection was (age-adjusted risk ratio [RR] = 2.1, 95% confidence interval [CI] = 1.8, 2.4); 134 persons who had a history of receiving parenteral anti-schistosomal therapy had a higher age-adjusted RR (3.0; 95% CI = 2.5, 3.7) for anti-HCV than those who did not. Hepatitis C virus RNA was detected in 62.8% of the anti-HCV positive subjects, without significant variation by age, gender, education, or marital status. The prevalence of anti-HCV in Upper Egypt is high, albeit lower than in Lower Egypt, with continuing but limited transmission indicated by the lower prevalence in residents < or = 30 years old.

Three independent yearly analyses of the spectrum and potency of metronidazole: a multicenter study of 1,108 contemporary anaerobic clinical isolates.

To comply with ongoing United States Food and Drug Administration (FDA) recommendations about the validation of prescribing information, in each of three years (1994, 1996, 1997) at six medical centers, metronidazole was tested against > or = 50 strains of a range of contemporary anaerobic clinical bacteria. Species having > or = 90% susceptibility (MIC, < or = 8 microg/ml) to metronidazole (fulfilling FDA requirements) included Bacteroides fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus, Fusobacterium spp. and Clostridium spp. Only Eubacterium spp. and anaerobic Gram-negative cocci failed to achieve the required proportion of susceptibility throughout the 3 year period. Metronidazole appears to remain highly active versus anaerobic species associated with strict anaerobic organisms.

Emerging elevated mupirocin resistance rates among staphylococcal isolates in the SENTRY Antimicrobial Surveillance Program (2000): correlations of results from disk diffusion, Etest and reference dilution methods.

Staphylococci cause one-third of all serious invasive infections in the SENTRY Antimicrobial Surveillance Program including bacteremias and lower respiratory tract infections. Staphylococci are also commensals of the skin and nasal passages; therefore, topical agents active against these organisms are valuable in preventing infections or transfer of the organisms between patients and/or health care workers. Mupirocin is a potent topical anti-staphylococcal compound, but its effectiveness has been compromised by emerging resistance. In early 2000, the SENTRY Program detected 302 mupirocin-resistant isolates (131 Staphylococcus aureus, and 171 coagulase-negative staphylococci [CoNS]) from the United States (19/25 medical centers), Canada (4/5), Latin America (3/9) and Europe (7/18). One hundred sixty-eight mupirocin-resistant and 59 susceptible isolates were tested further by reference MIC, Etest (AB BIODISK, Solna, Sweden) and disk diffusion (5-microg) methods. Mupirocin resistance rates for blood stream infections varied by geographic area: for S. aureus from 1.9 to 5.6%, and for CoNS from 12.8 to 39.9%. Using elevated mupirocin MIC results, two resistant populations were noted: low-level resistance at 8-128 microg/mL and high-level resistance at > or = 1024 microg/mL. Acceptable correlation was observed between Etest and disk diffusion results (r = 0.84) without serious intermethod interpretive errors. High-level resistant isolates had heavy growth with no visible zone around the disk; low-level resistant isolates produced hazy zones of inhibition, and susceptible strains had clear zones of inhibition at > or = 17 mm. As mupirocin resistance can be plasmid-mediated, the prudent and appropriate use of this topical agent is important to minimize the ongoing development of resistance. Local surveillance for emerging mupirocin resistance appears warranted particularly in the United States and Canada, pragmatically using a disk diffusion test screening. Where more precise data are needed, the Etest is a very accurate method for distinguishing mupirocin low-level from high-level resistance patterns.

Development of tolerance to Clara cell necrosis with repeat administration of coumarin.

Coumarin was identified as a mouse-lung carcinogen following oral gavage administration in a chronic bioassay, and was shown to cause the selective necrosis of terminal bronchiolar Clara (non-ciliated bronchiolar epithelial) cells in the mouse lung after acute administration. After oral gavage, a similar effect was not observed in the terminal bronchioles of rats, suggesting that coumarin-mediated Clara cell toxicity is a species-specific effect. Using coumarin dosages (50 and 200 mg/kg) and a dosing schedule modeled after the chronic bioassay, the current study examined the effects of repeated coumarin administration in mouse lung. A single dosage of coumarin (200 mg/kg) caused swelling of Clara cells and necrosis in mouse-lung terminal bronchioles. However, after 5 consecutive oral doses of coumarin (200 mg/kg), the mouse lung became tolerant to coumarin, and although areas of bronchiolar epithelial flattening and hyperplasia were noted, Clara cell necrosis was not observed. After 10 doses of coumarin, mouse lungs appeared nearly normal. Coumarin-mediated Clara cell injury is thought to result from the cytochrome P450-catalyzed formation of coumarin 3,4-epoxide and Western analysis of whole mouse lung microsomal P450 content indicated that, commensurate with Clara cell necrosis, many P450s were decreased. However, P450 levels appeared qualitatively normal in lung microsomes from tolerant mice. Similarly, coumarin epoxidation and 7-hydroxylation rates in whole lung microsomes from tolerant animals were similar to controls. To determine if animals tolerant to coumarin were tolerant to other Clara cell toxicants, a single toxic dose of naphthalene (200 mg/kg) was administered to coumarin-tolerant mice. Coumarin pretreatment reduced naphthalene-mediated Clara cell toxicity, supporting the hypothesis that tolerance may result from general biochemical and molecular changes and not exclusively from alterations in chemical metabolism.

Quantitative analysis of factors influencing neuronal necrosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex.

A single dose of the non-competitive NMDA receptor antagonist MK-801 (dizocilpine maleate) induces neuronal necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of adult rats. The present studies further characterized this effect and evaluated several variables that affect its expression. Male and female rats of two strains (Sprague-Dawley and Fischer 344) and two ages (70 and 127 days) were given a single subcutaneous injection of vehicle (water) or MK-801 (0.5, 1.0 or 5.0 mg/kg). A simple behavioral response (recumbency) and number of necrotic neurons in the PC/RS cortex were evaluated. MK-801 induced dose-dependent recumbency which was more severe and of longer duration in females of either strain or age. In addition, female rats (regardless of strain, dose, or age) consistently had significantly more necrotic PC/RS neurons than male rats. In a second study, a high dose of MK-801 was given intraperitoneally (10 mg/kg) to male and female Sprague-Dawley rats (90-120 days of age). Necrotic neuron counts were determined at 5 separate rostrocaudal levels of the PC/RS cortex. At levels where neuronal necrosis occurred, the magnitude of the effect was significantly greater in females than males and the number of necrotic neurons increased along a rostral to caudal gradient. Our findings indicate that (1) MK-801 dose dependently induces recumbency and necrosis of PC/RS cortical neurons in both Sprague-Dawley and Fischer 344 rats, (2) female rats of either strain are more sensitive than their male counterparts, and (3) the extent of necrosis of PC/RS cortical neurons increases along a rostral to caudal gradient.

MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning.

Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any species.

Neonatal exposure to D,L-2-amino-3-phosphonopropionate (D,L-AP3) produces lesions in the eye and optic nerve of adult rats.

Metabotropic glutamate receptors are a recently described receptor class with emerging importance in synaptic plasticity and brain development. Activation of metabotropic glutamate receptors results in several cellular secondary messenger events that are especially important during postnatal development. This study characterized the effects of D,L-2-amino-3-phosphonopropionate (D,L-AP3), an aspartic acid analog with agonist and antagonist activity at the metabotropic receptor, on the postnatal development of the rat eye and optic nerve. Sprague-Dawley rat pups were treated daily (i.p.) with saline or 500 mg/kg D,L-AP3 on postnatal days (PND) 4-10 or 10-14. After making clinical and ophthalmoscopic examinations, rats were necropsied between 65 and 70 days of age and light microscopic evaluations were made of eyes and optic nerves. Between postnatal days 10-20, all treated rats exhibited motor tremors, circling, and head tilt. Ophthalmoscopic lesions were more severe in rats treated on days 4-10 than days 10-14 and included decreased retinal vasculature, cataracts, and retinal dysplasia, hypoplasia, and detachment. All rats treated on days 4-10 had severe optic nerve atrophy/hypoplasia grossly and severe retinal atrophy, retinal detachment, and cataracts histologically. Seven of eight rats treated on days 10-14 had qualitatively similar but less severe lesions. Overall, rats treated with D,L-AP3 on PND 4-10 had earlier and more severe retinal and optic nerve lesions when compared to rats treated on PND 10-14. These data characterize the morphologic effects in adult rats exposed to D,L-AP3 as neonates and suggest a possible role for the metabotropic receptor in the postnatal development of retina and optic nerve.

Intracerebral 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) produces limbic seizures that are not blocked by ionotropic glutamate receptor antagonists.

The functional role of metabotropic glutamate receptor (mGluR) activation was investigated following intracerebral administration of 1S,3R-ACPD in mice. Injections of 1S,3R-ACPD (50-800 nmol in 5 microliters) into the thalamus produced a dose-dependent increase in limbic seizures. These effects were stereoselective since 1R,3S-ACPD, did not elicit seizure activity. Pharmacologically, limbic seizures were attenuated by the mGluR partial agonist/antagonist L-2-amino-3-phosphonopropionate (L-AP3) and dantrolene, an inhibitor of intracellular calcium mobilization, but not by D-AP3 or ionotropic glutamate receptor antagonists (MK-801 or GYKI-52466). Thus, activation of mGluRs by 1S,3R-ACPD in mice, induces limbic seizures that may involve the mobilization of intracellular calcium stores.

Comparative antimicrobial spectrum and activity of BMS284756 (T-3811, a desfluoroquinolone) tested against 656 Enterobacteriaceae, including preliminary in vitro susceptibility test comparisons and development.

BMS284756 (T-3811), a novel des-F(6)-quinolone, was evaluated using isolates of Enterobacteriaceae from the SENTRY Antimicrobial Surveillance Program tested by Etest (AB BIODISK, Solna, Sweden), reference broth microdilution and disk diffusion (5-microg) methods. Ciprofloxacin, levofloxacin, gemifloxacin and gatifloxacin were also tested by broth microdilution as comparator antimicrobial agents within the same drug class. The 656 isolate collection included species from the genera Citrobacter, Enterobacter, Escherichia, Hafnia, Klebsiella, Morganella, Pantoea, Proteus, Providencia, Salmonella, and Serratia. BMS284756 was slightly less active than comparison fluoroquinolones against these isolates (MIC(90), 4 mg/l versus 0.06-2 mg/l). However, at a proposed susceptible breakpoint of < or =4 mg/l, 90.7% of the isolates processed were susceptible to BMS284756, demonstrating an equivalent spectrum of activity to all other agents except gemifloxacin (86.6%). In general, isolates requiring >4 mg/l of BMS284756 for inhibition of growth were also less susceptible to the comparators suggesting cross-resistance is common between des-F(6)- and fluoro-quinolones. Excellent correlation was observed between broth microdilution MIC results and 5-microg disk zone diameters (r=0.94), and between broth microdilution dilution and Etest MIC values (r=0.96). In conclusion, BMS284756 has an activity and spectrum similar to contemporary fluoroquinolones and in vitro test methods (NCCLS, Etest) appear accurate and reproducible

Reactive gliosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex: GFAP evaluation by sandwich ELISA and immunocytochemistry.

MK-801 (dizocilpine maleate) and certain other related antagonists of the N-methyl-D-aspartate receptor produce vacuolization and necrosis of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex of rats. Neuronal necrosis initiates an astrocytic and microglial reaction. The present studies evaluated the astrocyte response with a sandwich format enzyme-linked immunosorbant assay (ELISA) for glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes. In all cases, Sprague Dawley rats (age 60-70 days) were given single subcutaneous doses of MK-801 and detergent-based sample homogenates were subjected to GFAP ELISA. Initially, female rats receiving vehicle or 0.1, 1.0, or 10 mg/kg MK-801 were sacrificed on 3, 5, 9, or 16 days postdose (DPD). Fresh brain samples included PC/RS (target) and frontal (non-target) cortices. A significant, dose-dependent increase in GFAP occurred in the PC/RS cortex (highest in the 10 mg/kg group at 9 DPD). A second study with both sexes (10 mg/kg; 9 DPD) showed increased GFAP, but there was no difference by sex. Finally, punch samples from PC/RS, occipital, temporal, and entorhinal cortex (females; 10 mg/kg; 9 DPD) revealed a highly significant increase in GFAP confined to the PC/RS cortex. The localized increase in GFAP was confirmed by immunocytochemistry. These biochemical and immunocytochemical data demonstrate a localized astrocytic response to neuronal necrosis that is restricted to the PC/RS cortical target area. Our findings are consistent with previous data showing that chemical-induced injury of the CNS results in dose- and time-dependent increases in GFAP that are restricted to the sites of damage.

Quantification of the hindlimb extensor thrust response in rats.

This report describes a procedure for measuring the extensor thrust response (ETR) and summarizes the results of initial validation experiments using adult Long-Evans rats. The ETR can be quickly elicited and the force measured by pressing against the hindlimb footpads with a small rectangular plate or bar attached to a digital force gauge. Output of the force gauge is analyzed and displayed with commercially available hardware and software. The first experiment compared the acute effects of i.p. injection of chlorpromazine (CPZ; 1, 4, or 7 mg/kg) or amphetamine (AMP; 0.3, 1, or 3 mg/kg) on the ETR and forelimb/hindlimb grip strength (FL/HL-GS) in male and female rats. CPZ decreased both ETR and FL/HL-GS values. Both 1 and 3 mg/kg AMP increased grip strength values but decreased ETR values. A second experiment compared the evolution of changes in ETR, FL/HL-GS, and peripheral neurophysiological measures during 8 weeks of daily oral dosing of 10 mg/kg acrylamide (ACR) monomer. ACR-treated rats exhibited a progressive decrease in ETR beginning after 3 weeks of dosing, whereas a reduction of HL-GS was observed beginning much later, after 7 weeks of dosing. The deficit in ETR progressed in the absence of any changes in spontaneous or evoked electrophysiological abnormalities in neuromuscular function, but was accompanied by a decrease in peripheral nerve conduction velocity. Taken together, the results indicate that the ETR can be used to characterize functional effects in both single dose and repeated dose experiments. The data also indicate that the ETR does not merely duplicate the information provided by FL/HL-GS, and suggest a hypothesis that the ETR may be sensitive to neurotoxicant-induced changes in somatosensory function.