Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6mg/kg/day of the PCB mixture dissolved in corn oil vehicle 4 weeks prior to mating and continued through gestation and up until postnatal day (PND) 21. On PND 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200μA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating attenuated focal (amygdala) excitability. A delay in kindling progression in the amygdala stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed animals in response to a an intense auditory stimulus. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that have been reported in the hippocampus of developmentally PCB exposed animals.

Reports of behavioral effects of repeated inhalation of toluene in rats have yielded inconsistent findings. A recent study from this laboratory (Beasley et al., 2010) observed that after 13 weeks of inhaled toluene ("subchronic" exposure scenario), rats showed mild but persistent changes in behavior, primarily involving acquisition of an autoshaped lever-press response. The present experiment sought to systematically replicate these findings, using a 4-week "sub-acute" exposure scenario. Adult male Long-Evans rats inhaled toluene vapor (0, 10, 100, or 1000 ppm) for 6h/day, 5 days/week for 4 weeks. As in the subchronic study, toluene had no effect on motor activity, anxiety-related behavior in the elevated plus-maze, or acquisition of the visual discrimination. However, sub-acute toluene did not affect appetitively-motivated acquisition of the lever-press response, but did reduce accuracy of signal detection at the end of training. Analysis of the deficit in accuracy in the 1000 ppm group by means of manipulations of different task parameters suggested a greater influence of attentional impairment than visual or motor dysfunction as a source for the deficit. These results confirm a pattern of subtle and inconsistent long-term effects of repeated daily exposure to concentrations of toluene vapor of 1000 ppm and below, in contrast to robust and reliable effects of acute inhalation of the solvent at concentrations above 1000 ppm.

Vol. 117, No. 6 PerspectivesOpen AccessDevelopmental Perchlorate Exposure: Gilbert Responds Mary E. Gilbert Mary E. Gilbert Search for more papers by this author Published:1 June 2009https://doi.org/10.1289/ehp.0800532RAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit I welcome the opportunity to respond to the comments of Mavis and DeSesso regarding our article on the developmental effects of perchlorate exposure on brain function (Gilbert and Sui 2008). Although couched in strong terms, their criticisms are not pertinent to the underlying physiologic processes that we investigated, and many of the points they raised were addressed in our original article. The comments of Mavis and De Sesso alter neither the significance of our study nor the integrity of our conclusions.Mavis and DeSesso opine that the “evidence for ‘thyroid hormone insufficiency’ is questionable.” They base this opinion on two points. First, they argue that there is no “dose–response” effect of perchlorate, and second, they focus on serum triiodothyronine (T3) as the biologically active hormone. They completely ignore the effect of perchlorate in the dams, and they do not acknowledge that circulating levels of T3 do not reflect thyroid function. More than 80% of serum T3 is derived from peripheral deiodination of thyroxine (T4) and is not tightly linked to thyroid hormone action in the developing brain. Tissue (not serum) concentration of T3, as well as the critical window over which the T3 is required, dictates the nuclear action of thyroid hormone. Different tissues, including brain, can be deficient in T3 while serum levels of this hormone are unchanged. In addition T4 and other iodo thyronines interact with membrane-bound hormone receptors and can directly affect, through non nuclear actions, the biological activity in the cells of many tissues. Mavis and DeSesso also inaccurately limit the discussion of thyroid hormones and tissue function to circulating serum levels of T3 in developing pups.Mavis and DeSesso confuse analytical variability of the hormone measures with biological effect size: One characterizes the precision and accuracy of the specific assay (inter- and intra-assay variation); the other characterizes the variation among animals attributable to treatment. The performance of the T3 and T4 assays we reported (Gilbert and Sui 2008) fall well within the manufacturer’s recommended limits, and variation between replicate samples was typically < 3%. Although thyroid-stimulating hormone (TSH) assays are inherently more variable, performance also fell within acceptable limits (9–12%). These sources of variance, as Mavis and DeSesso portend, do not under lie the reported effects on serum hormones in pups.The consequences of small reductions in serum T4 on brain development in pups and dams are not trivial and should not be dismissed (for review, see Zoeller and Rovet 2004). Unless perchlorate is acting through a non thyroidal mechanism, our study fully supports recent data indicating that small changes in maternal and/or neonatal serum thyroid hormone can impact brain development.We are perplexed by Mavis and DeSesso’s erroneous characterization of in vivo field potentials as “electrophysiologic anomalies.” This seems to reflect a misconception of the value of these measures as functional indices of integrated physiologic responses in an intact neural circuit. These end points are widely acknowledged to reflect the functional integrity of the hippocampus. Our data (Gilbert and Sui 2008) go beyond the more commonly reported acute response in an isolated hippocampal brain slice to reveal impairments in the fundamentals of neuronal communication in living animals, and the changes were demonstrated months after exposure to perchlorate had ceased. Certainly a permanent impairment in the synaptic function of any brain structure must be considered an adverse neurotoxicologic insult. Input/output (I/O) functions [Figure 4 (Gilbert and Sui 2008)] reflect the ability of a population of neurons to transmit signals across a monosynaptic connection. Synaptic plasticity, the ability to adapt to stimuli, tested in the form of paired pulse (PP) depression and facilitation measure the influence of local circuit neurons to modulate that synaptic output [Figure 5 (Gilbert and Sui 2008)]. The clear relationship between increasing stimulus strength and increases in the amplitude of the physiologic response, evident in both the I/O and PP data, validates the high degree of experimental control maintained over these biological responses. Contrary to the allegations of Mavis and DeSesso, both sets of meas ures demonstrate dose-dependent perturbations as a function of perinatal perchlorate exposure and represent important contributions to a literature largely lacking examinations of dose–response relationships. Furthermore, these findings are in complete agreement with observations using graded levels of the known goitrogen propylthiouracil (PTU) over a similar dosing regimen.Mavis and DeSesso state that electrophysiologic anomalies are not evidence of neurologic impairment as they occurred in the absence of behavioral changes (Gilbert and Sui 2008). As discussed in our article, the neuroscience literature holds many instances where molecular, neurochemical, anatomical, and electro physiologic indices do not correlate with apical behavioral measures. This does not negate the significance of these downstream observations, but rather reveals the relative bluntness of some of the behavioral tools available to assess cognitive function in rodent models. Attempts to evaluate subtle perturbations of the thyroid axis will require further refinement of existing paradigms to increase sensitivity or the utilization of more sophisticated evaluations of behavioral dysfunction. This paradigm shift is not dissimilar from what was necessary in the behavioral evaluation of developmental lead exposure two decades ago.Mavis and DeSesso state that the concentrations used in our study (Gilbert and Sui 2008) bear no relevance to the human health risk assessment for perchlorate. However, the purpose of our study was not to emulate human exposures to perchlorate. Rather, percholorate was used to disrupt the thyroid axis via a mechanism distinct from standard model compounds (i.e., PTU and methimazole) to examine the impact of mild perturbations of the thyroid axis on neurodevelopment. Nonetheless, the results revealed a significant reduction in synaptic function at a dose (30 ppm = 4.5 mg/kg body weight per day) consistent with the lowest observable adverse effect levels identified from the review of all available animal data and summarized in the U.S. Environmental Protection Agency’s perchlorate risk assessment document (U.S. EPA 2002). As such, these findings corroborate previous findings and add additional weight to the existing evidence from animal studies on the negative impact of perchlorate on brain development.Finally, according to Mavis and DeSesso, the rat model is questionable for sensitivity of the human thyroid system to perchlorate because of differences in thyroid hormone storage. The hypothalamic–pituitary–thyroid axis is very similar in its chemistry and its function in rodents and humans, and rodent models have provided important information on the fundamental biology of endocrine systems informing medical practice and public health protection. Although differences in thyroid hormone economy of adult rats make rodents less than ideal for the assessment of thyroid tumors, the dependence of the fetus on the maternal supply for thyroid hormone makes the rat a suitable model for neurodevelopment. In humans, differences in the capacities and the relative immaturity of compensatory mechanisms of the fetus and neonate increase the vulnerability of these life stages and have significant implications for tolerance to perturbations of the thyroid axis. Rather than detracting from the utility of the model, the limited storage capacities of the rodent offer a reasonable parallel to the immature human.In conclusion, the comments of Mavis and DeSesso are not consistent with current thinking in the fields of thyroid endocrinology or neuroscience. Their critique does not effectively challenge the veracity of our observations or the soundness of our conclusions.ReferencesGilbert ME, Sui L. 2008. Developmental exposure to perchlorate alters synaptic transmission in hippo campus of the adult rat. Environ Health Perspect 116:752-76018560531. Link, Google ScholarU.S. EPA. 2002. Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization (2002 External Review Draft) NCEA-1-0503 Washington, DCU.S. Environmental Protection AgencyAvailable http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=24002[accessed 7 May 2009]. Google ScholarZoeller RT, Rovet J. 2004. Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol 16(10):809-81815500540. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 117, No. 6 June 2009Metrics About Article Metrics Publication History Originally published1 June 2009Published in print1 June 2009 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. 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Tetramethylenedisulfotetramine (tetramine, TETS, TMDT) is a seizure-producing neurotoxic chemical formed by the condensation of sulfamide and formaldehyde. Serendipitously discovered through an occupational exposure in 1949, it was promoted as a rodenticide but later banned worldwide due to its danger to human health. However, exceptional activity of the agent against rodent pests resulted in its clandestine manufacture with large numbers of inadvertent, intentional, and mass poisonings, which continue to this day. Facile synthesis, extreme potency, persistence, lack of odor, color, and taste identify it as an effective food adulterant and potential chemical agent of terror. No known antidote or targeted treatment is currently available. In this review we examine the origins of tetramethylenedisulfotetramine, from its identification as a neurotoxicant 70 years ago, through early research, to the most recent findings including the risk it poses in the post-911 world. Included is the information known regarding its in vitro pharmacology as a GABAA receptor channel antagonist, the toxic syndrome it produces in vivo, and its effect upon vulnerable populations. We also summarize the available information about potential therapeutic countermeasures and treatment strategies as well as the contribution of clinical development of TMDT poisoning to our understanding of epileptogenesis. Finally we identify gaps in our knowledge and suggest potentially fruitful directions for continued research on this dangerous, yet intriguing compound.

Field potentials from area CA1 evoked by stimulation of the Schaffer collaterals were compared in dorsal and ventral hippocampal slices of rat brain. Responses were categorized into 5 response types on the basis of their morphology, ranging from simple (single spike component) to complex (multiple spike components). A higher percentage of ventral slices, compared to dorsal slices, responded with a complex morphology under normal and increased K+ concentrations. Thus, there was a significantly greater tendency for cells within the ventral hippocampus to generate burst responses.

The influence of cue type and cue configuration on radial-maze performance in rats was examined in two experiments. In the first experiment, it was found that rats provided with both salient intramaze and extramaze cues acquired the task faster than rats given only one set of cues. No difference in acquisition was found between a group trained with intramaze cues alone and a group trained with extramaze cues alone. In a cue-preference test, it was found that groups that had been trained with extramaze cues, intramaze cues, or both sets of cues relied on extra-maze cues to avoid visited arms when given both types of cues concurrently. When all groups were transferred to intramaze-cue-alone trials, only the group that had been originally trained with extramaze cues alone showed any disruption. Also, during the second half of the intramaze-cue-alone trials, the arrangement of these cues was randomly changed on each trial. This disruption in cue configuration did not deleteriously affect performance in any of the three groups; all remained above chance performance, although the performance of the group originally trained with extramaze cues alone was inferior to that of the other two groups. In Experiment 2, groups of rats were trained on daily alternating trials under intramaze-cue-alone and extramaze-cue-alone conditions. For one group, the configuration of intramaze cues was altered randomly on each trial; the other group had intramaze cues always presented in the same configuration over trials. It was found that acquisition was more rapid on intramaze trials in the group given static configurations. Also, acquisition of the extramaze task was faster than the intramaze task in the group given variable intramaze cue configurations. No difference was found between the intramaze and extramaze conditions in the group given static intramaze cue configurations. These data suggest that a static cue configuration may influence radial maze performance, but is not a necessary condition for such performance.

German Life and LettersVolume 18, Issue 4 p. 264-269 SIMPLEX AND THE BATTLE OF WITTSTOCK Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author First published: July 1965 https://doi.org/10.1111/j.1468-0483.1965.tb00079.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume18, Issue4July 1965Pages 264-269 RelatedInformation

German Life and LettersVolume 11, Issue 2 p. 102-111 SOME OBSERVATIONS ON HOFMANNSTHAL'S TWO ‘NOVELLEN’ REITERGESCHICHTE AND DAS ERLEBNIS DES MARSCHALLS VON BASSOMPIERRE Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author First published: January 1958 https://doi.org/10.1111/j.1468-0483.1958.tb01178.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume11, Issue2January 1958Pages 102-111 RelatedInformation

Other| September 01 1956 Carolus Stuardus Andreas Gryphius and Hugh Powell. Leicester: University College, 1955. Pp. cxli + 132. 30s. Richard F. Wilkie Richard F. Wilkie Search for other works by this author on: This Site Google Modern Language Quarterly (1956) 17 (3): 278. https://doi.org/10.1215/00182702-17-3-278 Cite Icon Cite Share Icon Share Twitter Permissions Search Site Citation Richard F. Wilkie; Carolus Stuardus. Modern Language Quarterly 1 September 1956; 17 (3): 278. doi: https://doi.org/10.1215/00182702-17-3-278 Download citation file: Zotero Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search Books & JournalsAll JournalsModern Language Quarterly Search Advanced Search The text of this article is only available as a PDF. Copyright © 1956 by Duke University Press1956 Article PDF first page preview Close Modal Issue Section: Reviews You do not currently have access to this content.

German Life and LettersVolume 5, Issue 4 p. 255-268 RECENT TRENDS IN THE CRITICISM OF HOFMANNSTHAL Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author First published: July 1952 https://doi.org/10.1111/j.1468-0483.1952.tb01057.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume5, Issue4July 1952Pages 255-268 RelatedInformation

German Life and LettersVolume 3, Issue 2 p. 81-91 Article CAROLUS STUARDUS A CONTEMPORARY TRAGEDY ON THE EXECUTION OF CHARLES I Andreas Gryphius, Andreas GryphiusSearch for more papers by this authorMary E. Gilbert, Mary E. GilbertSearch for more papers by this author Andreas Gryphius, Andreas GryphiusSearch for more papers by this authorMary E. Gilbert, Mary E. GilbertSearch for more papers by this author First published: 01 January 1950 https://doi.org/10.1111/j.1468-0483.1950.tb00047.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume3, Issue2January 1950Pages 81-91 RelatedInformation

German Life and LettersVolume 1, Issue 3 p. 182-193 HUGO VON HOFMANNSTHAL AND ENGLAND Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author Mary E. Gilbert, Mary E. GilbertSearch for more papers by this author First published: April 1937 https://doi.org/10.1111/j.1468-0483.1937.tb01817.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume1, Issue3April 1937Pages 182-193 RelatedInformation