NH3 is a thyroid hormone receptor (TR) antagonist that inhibits binding of thyroid hormones to their receptor and that inhibits cofactor recruitment. It was active in a tadpole tail resorption assay, with partial agonist activity at high concentrations. We determined the effect of NH3 on the cholesterol-lowering, thyroid stimulating hormone (TSH)-lowering, and tachycardic action of thyroid hormone (T 3 ) in rats. Cholesterol-fed, euthyroid rats were treated for 7 days with NH3, and a dose response (46.2-27,700 nmol/kg/day) was determined. We also determined the effect of two doses of T 3 on the NH3 dose-response curve. NH3 decreased heart rate modestly starting at 46.2 nmol/kg/day, but the effect was lost at Ͼ2920 nmol/kg/day. At 27,700 nmol/kg/day, tachycardia was seen, suggesting partial agonist activity. NH3 increased plasma cholesterol to a maximum of 27% at 462 nmol/kg/day. At higher doses, cholesterol was reduced, suggesting partial agonist activity. Plasma TSH was increased from 46.2 to 462 nmol/kg/day NH3, but at higher doses, this effect was lost, and partial agonist effects were apparent. T 3 at 15.4 and 46.2 nmol/kg/day increased heart rate, reduced cholesterol, and reduced plasma TSH. NH3 inhibited the cholesterol-lowering, TSH-lowering and tachycardic effects of 15.4 nmol/kg/day T 3 , but much of the effect was lost at Ͼ924 nmol/kg/day doses. NH3 had no effect on the cholesterollowering action of 46.2 nmol/kg/day T 3 , but it inhibited the tachycardic and TSH suppressant effects up to the 924 nmol/ kg/day dose. Single doses of 462 and 27,700 nmol/kg caused no TR inhibitory effects. In conclusion, NH3 has TR antagonist properties on T 3 -responsive parameters, but it has partial agonist properties at higher doses.

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Repeated traumatic brain injuries (TBIs) cause debilitating effects. Without understanding the acute effects of repeated TBIs, treatment options to halt further degeneration and damage cannot be developed. This study sought to examine the acute effects of blood-brain barrier (BBB) dysfunction, edema, inflammation and behavioral changes after either a single or double TBI using a C57BL/6 mouse model. We examined the effects of one or two TBIs, of either a mild or moderate severity. Double injuries were spaced 7 days apart, and all analysis was performed 24 h post-injury. To examine edema and inflammation, protein levels of glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B, interleukin-6, and matrix metallopeptidase 9 (MMP9) were analyzed. Aquaporin-4 (AQP4) and zonula occludens-1 (ZO-1) were analyzed to observe BBB dysfunction. Ionized calciumbinding adapter molecule 1 (IBA1) was analyzed to observe microglial activation. Rotarod, beam walking, and grip strength tests were used to measure changes in physical behavior post-injury. A sample size of ‡5 was used for all analysis. Double injuries led to an increase in BBB breakdown, as indicated by altered MMP-9, AQP4, and ZO-1 protein expression. Single injuries showed an increase in microglial activation, astrocyte activation, and BBB breakdown. Behavioral tasks showed no significant differences between injured and control groups. Based on our findings, we suggest that behavioral studies should not be used as the sole clinical indicator on brain tissue recovery. Analysis of markers such as IBA1, GFAP, MMP-9, AQP4, and ZO-1 provide valuable insight on pathophysiological response to injury.

Senior author-presenter: Stella M. Papa. Coauthors: Pierre J. Blanchet, Italo Linfante, and Thomas N. ChaseObjectiue. To evaluate the effect of NMDA receptor antagonists on dyskinesias complicating the response to long-term levodopa therapy.Background. Dopaminergic mechanisms are influenced by the extensive glutamatergic innervation of the basal ganglia; blockade of NMDA receptors may thus affect both the antiparkinsonian effects and the dyskinetic complications of levodopa.Methods. Six monkeys (Macaca mulatta and fascicularis) vere given MPTP intravenously until stable parkinsonism was attained. Animals were then treated with oral levodopa daily until dyskinesias appeared. LY235959, a competitive NMDA antagonist, was administered subcutaneously in 0.5, 1-, 3-, and 5-mg/kg doses, each three times, in combination with the minimal subcutaneous dose of levodopahenserazide that induced moderate dyskinesias. Vehicle combined with levodopa served as the control. Animals were scored every 20 minutes by direct examination and subsequent videotape analysis by a blinded examiner.Results. LY235959 (3 mg/kg) abolished oral dyskinesias and diminished by 70% choreic and dystonic limb dyskinesias 0, < 0.01) induced by levodopa. The quality of "on" states was unchanged compared with levodopa plus vehicle. Lower doses of LY235959 failed to significantly affect levodopa-induced dyskinesias; the highest dose (5 mg/kg) increased dystonic movements.Conclusions. Blockade of NMDA receptors may improve motor responses to levodopa during long-term therapy, ameliorating dyskinetic complications while maintaining the beneficial effects on parkinsonian symptoms. CorrectionsIn the 47th Annual Meeting Program of the American Academy of Neurology (Neurology 1995;45[suppl 41), abstract number 1011P was mistakenly withdrawn. It is printed below. In abstract number 335P, an error appeared in the title. The abstract, with the corrected title, is reprinted below. The editors apologize for the errors. I P Anti-Ri Paraneoplastic Syndrome in Association With Primary Lung Carcinoma C.P. Gennaula and B.H. Eidelman, Pittsburgh, PAObjectiue. To describe the first case of paraneoplastic antiRi antibody syndrome in association with a primary lung tumor.Background. Anti-Ri is an anti-neuronal nuclear antibody associated with a paraneoplastic syndrome usually including opsoclonus and ataxia. It has most often been described in association with breast and gynecological malignancies.Methods. A previously healthy 65-year-old woman presented with a 4-month history of progressive gait ataxia, opsoclonus, and startle myoclonus. Initial brain imaging, cerebrospinal fluid studies, and systemic malignancy screen were negative. Paraneoplastic antibody studies yielded a 1:7,680 anti-Ri antibody titer. Serial screens for systemic malignancy were performed.Results. Nine months after the onset of symptoms, a chest CT showed a small right hilar mass. Open biopsy revealed a non-small-cell lung carcinoma. Chemotherapy was initiated and the patient's neurological symptoms imp...

The pathological effects of repeated traumatic brain injuries (TBIs) are largely unknown. To gain a detailed understanding of the cortical tissue acute biological response after one or two TBIs, we utilized RNA-sequencing and protein mass spectrometry techniques. Using our previously validated C57Bl/6 weight-drop model, we administered one or two TBIs of a mild or moderate severity. Double injury conditions were spaced 7 days apart, and cortical tissue was isolated 24 h after final injury. Analysis was carried out through functional gene annotation, utilizing Gene Ontology, for both the proteome and transcriptome. Major themes across the four different conditions include: neurogenesis; inflammation and immune response; cell death; angiogenesis; protein modification; and cell communication. Proteins associated with neurogenesis were found to be upregulated after single injuries. Transcripts associated with angiogenesis were upregulated in the moderate single, mild double, and moderate double TBI conditions. Genes associated with inflammation and immune response were upregulated in every condition, with the moderate single condition reporting the most functional groups. Proteins or genes involved in cell death, or apoptosis, were upregulated in every condition. Our results emphasize the significant differences found in proteomic and transcriptomic changes in single versus double injuries. Further, cortical omics analysis offers important insights for future studies aiming to deepen current knowledge on the development of secondary injuries and neurobehavioral impairments after brain trauma.