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Descending control of pain.

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

A positive temperature coefficient is the term which has been used to indicate that an increase in solubility occurs as the temperature is raised, whereas a negative coefficient indicates a decrease in solubility with rise in temperature.

Effect of Temperature

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Immunochemical differences among molecular forms of acetylcholinesterase in brain and blood.

Rapid progress in the past decade with re-engineering of human plasma butyrylcholinesterase has led to enzymes that destroy cocaine so efficiently that they prevent or interrupt drug actions in the CNS even though confined to the blood stream. Over the same time window, improved gene-transfer technology has made it possible to deliver such enzymes by endogenous gene transduction at high levels for periods of a year or longer after a single treatment. This article reviews recent advances in this field and considers prospects for development of a robust therapy aimed at aiding recovering drug users avoid addiction relapse.

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Cocaine hydrolase gene therapy for cocaine abuse.

Can cholinesterase inhibitors affect neural development

The turnover of acetylcholinesterase (AChE) and its molecular forms was measured by following the loss of enzyme activity in the right hemidiaphragms of Sprague-Dawley rats treated with cycloheximide, 20 mg/kg, every 4 h. This treatment inhibited 96% of the incorporation of [3H]leucine into muscle protein. After 8 h of treatment, the total AChE activity of the diaphragm decreased by 17% (P less than 0.01). Assuming first-order exponential kinetics, a half-life of 30 h and an hourly turnover of 180 units were calculated. The measured accumulation of AChE activity at a ligature on the phrenic nerve indicated that axonal transport contributed trivially to this turnover. Sucrose density gradient experiments showed that the cycloheximide-induced low of AChE activity was restricted to the 4S enzyme, which had an apparent half-life of 6.2 h.

Turnover of the molecular forms of acetylcholinesterase in the rat diaphragm.

AIM: To examine the relationship between apoptosis induced by beta-amyloid fragment 25-35 (A beta 25-35) and the activity of acetylcholinesterase (AChE) in AChE over-expresser--SC42 cells. METHODS: Cell survival was measured by microscopy and MTT reduction; DNA laddering was observed by electrophoresis; AChE activity was determined by spectrophotometry. RESULTS: A beta 25-35 1 micromol/L exposure for 24-48 h caused a significant decrease in cell viability, along with changes in morphology and DNA fragmentation. AChE activity was affected in an inverse manner, increasing gradually to a level that was 1.7-fold higher than control at the 48-h time point. No change in the cytotoxicity of A beta 25-35 was observed when the increased AChE activities were effectively inhibited by huperzine A throughout the 48-h exposure period. CONCLUSION: Although A beta 25-35 can induce apoptosis in SC42 cells and simultaneously increase AChE activity, the capacity of AChE to hydrolyze acetylcholine is not involved in this apoptosis model.

Stephen Brimijoin

Papers

Immunochemical differences among molecular forms of acetylcholinesterase in brain and blood.

Cocaine hydrolase gene therapy for cocaine abuse.

Can cholinesterase inhibitors affect neural development

Turnover of the molecular forms of acetylcholinesterase in the rat diaphragm.

Apoptosis induced by beta-amyloid25-35 in acetylcholinesterase-overexpressing neuroblastoma cells.