Effects of l-amphetamine sulfate on cognitive function in multiple sclerosis patients.

We evaluated the effects of the levo (l) enantiomer of amphetamine sulfate on cognitive function in multiple sclerosis (MS) patients. Using a counterbalanced within-subjects design, 19 MS patients received four single-dose administrations of placebo, 15 mg, 30 mg, or 45 mg of l-amphetamine. Neuropsychological tests measuring processing speed and memory served as the primary outcomes. Performance on tests of processing speed were improved following the 45 mg condition and the largest effects were observed on the Symbol Digit Modalities Test, which measures visual processing speed and working memory. While episodic memory test effects were in the expected direction, the findings were not statistically significant. These preliminary findings show promise for the use of l-amphetamine for the symptomatic treatment of slowed mental processing in MS. Further placebo-controlled trials are needed to confirm these findings.

The reliability of isokinetic and isometric leg strength measures among individuals with symptoms of mild osteoarthritis.

AIM: The aim of the study is to evaluate the test-retest reliability of measures of isokinetic and isometric leg strength and joint function among individuals exhibiting symptoms of mild osteoarthritis. Reliable procedures are needed to assess the effectiveness of an intervention on osteoarthritic symptoms. METHODS: Test-retest reliability of two leg strength protocols was assessed using the intraclass correlation coefficient (R). Testing was completed on two occasions separated by 7 days. Eighteen subjects (9 male and 9 female; 54.1+/-11 years) completed an isokinetic testing trial, which consisted of a set of 5 maximal repetitions of the quadriceps and hamstrings at 60 deg/s followed by a set of 15 maximal contractions at 180 deg/s with a 2-min rest between sets and an isometric testing trial, which consist of 3 maximal contractions of the quadriceps for 6 s with a 30-s rest between contractions at 30, 45, and 80 degrees of knee flexion for a total of 9 isometric contractions. A 90-s rest occurred between angles. RESULTS: Most of the isokinetic variables showed moderate to high intraclass reliability (ICC). Two of the calculated isokinetic variables (work fatigue at 180 degrees /s for extension and for flexion) showed low intraclass reliability (ICC=0.78, resp. ICC=0.6). All calculated ICC values of the isometric variables were moderate to high. CONCLUSIONS: Test-retest reliability of isokinetic and isometric leg strength was high, allowing the intervention protocol to monitor changes in leg strength and joint function among those exhibiting symptoms of mild osteoarthritis.

Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells.

Epithelial-mesenchymal transition (EMT) is an essential step for tumor progression, although the mechanisms driving EMT are still not fully understood. In an effort to investigate these mechanisms, we observed that heregulin (HRG)-mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail. We then investigated how HER2 induced Slug expression and found, for the first time, that there are four consensus HSF sequence-binding elements (HSEs), the binding sites for heat shock factor-1 (HSF-1), located in the Slug promoter. HSF-1 bound to and transactivated the Slug promoter independent of heat shock, leading to Slug expression in breast cancer cells. Mutation of the putative HSEs ablated Slug transcriptional activation induced by HRG or HSF-1 overexpression. Knockdown of HSF-1 expression by siRNA reduced Slug expression and HRG-induced EMT. The positive association between HSF-1 and Slug was confirmed by immunohistochemical staining of a cohort of 100 invasive breast carcinoma specimens. While investigating how HER2 activated HSF-1 independent of heat shock, we observed that HER2 activation resulted in concurrent phosphorylation of Akt and HSF-1. We then observed, also for the first time, that Akt directly interacted with HSF-1 and phosphorylated HSF-1 at S326. Inhibition of Akt using siRNA, dominant-negative Akt mutant, or small molecule inhibitors prevented HRG-induced HSF-1 activation and Slug expression. Conversely, constitutively active Akt induced HSF-1 phosphorylation and Slug expression. HSF-1 knockdown reduced the ability of Akt to induce Slug expression, indicating an essential role that HSF-1 plays in Akt-induced Slug upregulation. Altogether, our study uncovered the existence of a novel Akt-HSF-1 signaling axis that leads to Slug upregulation and EMT, and potentially contributes to progression of HER2-positive breast cancer.

ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia.

ADL-8-2698 is a novel peripherally restricted opioid antagonist that may selectively prevent opioid-induced gastrointestinal effects without reversing analgesia. Gastrointestinal transit time (lactulose hydrogen breath test) was measured in 14 volunteers with oral and intravenous placebo, oral placebo and intravenous morphine (0.05 mg x kg(-1)), and oral ADL 8-2698 (4 mg) and intravenous morphine (0.05 mg x kg(-1)) in a double blind, cross-over study. Morphine prolonged gastrointestinal transit time from 69 to 103 minutes (P = .005); this was prevented by ADL 8-2698 (P = .004). Postoperatively, 45 patients were randomly assigned in a double-blind fashion to receive ADL 8-2698 (4 mg) or placebo and intravenous morphine (0.15 mg/kg) or to receive oral and intravenous placebo. Analgesia and pupil constriction were measured. Morphine analgesia and pupil constriction were unaffected by ADL 8-2698 and differed from placebo (P < .002). We conclude that ADL 8-2698 prevents morphine-induced increases in gastrointestinal transit time by means of selective peripheral opioid anitagonism without affecting central opioid analgesia.

A proposed approach to study the toxicology of complex mixtures of petroleum products: the integrated use of QSAR, lumping analysis and PBPK/PD modeling.

Mixture toxicity is a topic that has become a matter of concern during the last two decades. One of the major problems with assessing the toxicity of mixtures and the associated human and environmental risk is the large number of possible mixtures, as well as the fact that the actual mixture effect for a given set of constituents might strongly depend on the actual composition of the mixture, i.e., the ratios of the constituent, as well as their nature. This paper presents a possible approach to describe and thereby better understand the pharmacokinetics and dynamics of complex mixtures by combining quantitative structure-activity relationships to predict needed parameters, lumping to reduce the complexity of the problem, and physiologically based pharmacokinetic/pharmacodynamic modeling to integrate all this information into a complete toxicological description of the mixture. It is our hope that by presenting this conceptual approach we might be able to stimulate some criticisms and discussions in the toxicology community regarding this complex and yet very important area of research.

A physiological model for predicting carboxyhemoglobin formation from exposure to carbon monoxide in rats.

A time-dependent simulation model, based on the Coburn-Forster-Kane equation, was written in Advanced Continuous Simulation Language to predict carboxyhemoglobin (HbCO) formation and dissociation in F-344 rats during and after exposure to 500 parts/million CO for 1 h. Blood-gas analysis and CO-oximetry were performed on samples collected during exposure and off-gassing of CO. Volume displacement plethysmography was used to measure minute ventilation (VE) during exposure. CO diffusing capacity in the lung (DLCO) was also measured. Other model parameters measured in the animals included blood pH, total blood volume, and Hb concentration. Comparisons between model predictions using values for VE, DLCO, and the Haldane coefficient cited in the literature and predictions using measured VE, DLCO, and calculated Haldane coefficient for individual animals were made. General model predictions using values for model parameters derived from the literature agreed with published HbCO values by a factor of 0.987 but failed to simulate experimental data. On average, the general model overpredicted measured HbCO level by nearly 9%. A specific model using the means of measured variables predicted HbCO concentration within a factor of 0.993. When experimentally observed parameter fluctuations were included, the specific model predictions reflected experimental effects on HbCO formation.

Toxicant distribution in the Thomas Domes.

Measurement of test article concentration distribution for light gases have been made in the Thomas Dome inhalation chambers at Wright-Patterson Air Force Base, using propane as a test agent. The method used to analyze for inhomogeneities in test article spatial distribution deliberately varies the dome operational parameters rather than requiring extreme operational stability. The variation in test article concentration is analyzed by regression to determine which operational parameters most influence the test agent distribution. Unaccounted concentration variability is assumed to be the inherent spatial variation of the test article in the dome. The propane studies indicated that the spatial variation within the dome was 6.4% of the mean and that room air temperature at the top of the dome, propane analyzer baseline stability, and dome pressure were (listed in order of decreasing importance) the variables influencing the test article distribution.

Vasoconstrictors in facial plastic surgery.

The effectiveness of local anesthetics is improved by the addition of a vasoconstrictor with an increased duration of action and the ability to decrease both systemic toxic reactions and local bleeding. Epinephrine, the standard drug for vasoconstriction, has some limitations due to potential cardiac and local toxic effects. Using an animal model, we compared the effects of various concentrations of epinephrine and two other vasoconstrictors, phenylephrine hydrochloride and felypressin, on local blood flow. We also examined the local effects of bupivacaine hydrochloride and ropivacaine hydrochloride, a new local anesthetic. We found that felypressin was as effective a vasoconstrictor as epinephrine, with fewer potential toxic reactions. Phenylephrine (Neo-Synephrine), on the other hand, was less effective, with a shorter duration of action. As expected, bupivacaine produced vasodilation, while ropivacaine was found to have vasoconstrictive properties.

Effects of repeated exposure of rats to JP-5 or JP-8 jet fuel vapor on neurobehavioral capacity and neurotransmitter levels.

The U.S. Naval Service is anticipating transition from the nearly exclusive use of JP-5 jet fuel to predominant use of JP-8, consistent with the primary utilization by the U.S. Army, U.S. Air Force, and the militaries of most NATO countries. To compare the relative risk of repeated exposure to JP-5 versus JP-8 vapor, groups of 32 male Sprague-Dawley rats each were exposed for 6 h/d, 5 d/wk for 6 wk (180 h) to JP-8 jet fuel vapor (1,000 +/- 10% mg/m3), IP-5 vapor (1,200 +/- 10% mg/m3), or room air control conditions. Following a 65-d rest period, rats completed 10 tests selected from the Neurobehavioral Toxicity Assessment Battery (NTAB) to evaluate changes in performance capacity. Repeated exposure to JP-5 resulted in significant effects on only one test, forelimb grip strength (FGS), while exposure to JP-8 vapor resulted in a significant difference versus controls on appetitive reinforcer approach sensitization (ARAS). Rats were further evaluated for concentrations of major neurotransmitters and metabolites in five brain regions and in the blood serum. Levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the serotonin metabolite homovanillic acid (HVA) were significantly modulated in various brain regions, as measured 85+ d postexposure. Similarly, serum levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were differentially modulated following JP-8 or JP-5 exposure. Results are compared to previously published research evaluating the neurotoxicity of repeated exposure to other hydrocarbon fuels and solvents.

Effects of repeated exposure to JP-8 jet fuel vapor on learning of simple and difficult operant tasks by rats.

Groups of 16 Sprague-Dawley rats each were exposed by whole-body inhalation methods to JP-8 jet fuel at the highest vapor concentration without formation of aerosol (1,000 +/- 10% mg/m3); to 50% of this concentration (500 +/- 10% mg/m3); or to treated room air (70 +/- 81 L/min) for 6 h/d, 5 d/wk, for 6 wk (180 h). Although two subjects died of apparent kidney complications during the study, no other change in the health status of exposed rats was observed, including rate of weight gain. Following a 65-d period of rest, rats were evaluated for their capacity to learn and perform a series of operant tasks. These tasks ranged in difficulty from learning of a simple food-reinforced lever pressing response, to learning a task in which subjects were required to emit up to four-response chains of pressing three different levers (e.g., press levers C, R, L, then C). It was shown that repeated exposure to 1,000 mg/m3 JP-8 vapor induced significant deficits in acquisition or performance of moderately difficult or difficult tasks, but not simple learning tasks, as compared to those animals exposed to 500 mg/m3. Learning/performance of complex tasks by the 500-mg/m3 exposure group generally exceeded the performance of control animals, while learning by the 1,000-mg/m3 group was nearly always inferior to controls, indicating possible "neurobehavioral" hormesis. These findings appear consistent with some previously reported data for operant performance following acute exposure to certain hydrocarbon constituents of JP-8 (i.e., toluene, xylenes). There has, however, been little previously published research demonstrating long-term learning effects for repeated hydrocarbon fuel exposures. Examination of regional brain tissues from vapor-exposed rats indicated significant changes in levels of dopamine in the cerebral cortex and DOPAC in the brainstem, measured as long as 180 d postexposure, as compared to controls.

Cardiopulmonary compromise after use of topical and submucosal alpha-agonists: possible added complication by the use of beta-blocker therapy.

We report the specifics of 12 cases of severe hypertension after the intraoperative use of topical phenylephrine, submucosal epinephrine, or both. Ten of these 12 patients also developed severe pulmonary edema. Seven of the twelve were treated with beta blockers; 3 of whom suffered cardiac arrest. We propose a common mechanism: the vasoconstrictors caused systemic hypertension, increased left ventricular afterload, decreased left ventricular compliance, and decreased cardiac output. In those patients treated with beta blockers, decreased contractility and inability to increase heart rate further compromised cardiopulmonary function.

Effects of inhaled nitrogen dioxide and diesel exhaust on developing lung.

This study examined age-related differences in the physiological responses of rats to inhaled automotive emissions. Previous reports suggested that lung development of animals exposed to oxidant gases early in life might be impaired, or that developing lungs might be more susceptible than adult lungs to inhaled toxicants. There were no previous comparisons in developing and adult lungs of the effects of atmospheres containing particles. The hypothesis tested in this study was that rats exposed to chronically inhaled nitrogen dioxide (NO2) or diesel exhaust during lung development were more susceptible to lung injury than rats that were exposed to these atmospheres as adults. Rats were exposed either throughout the period of lung development or as adults, and health effects in the two groups were compared at the end of exposure. Rats were exposed seven hours per day, five days per week for six months to NO2 at 9.5 ppm, to whole diesel exhaust diluted to a soot concentration of 3.5 mg/m3, or to filtered air as controls. These concentrations were selected to produce mild effects in adults. The younger group (developing) was conceived in the exposure atmospheres and exposed during gestation and through the age of six months, and the older group (adult) was exposed between six and twelve months of age. Health effects were evaluated at the end of six months' exposure and some measurements were repeated six months after the cessation of exposure. Measurements included respiratory function, pulmonary immune responses, lung clearance of radiolabeled particles, airway fluid enzymes, protein and cytology, lung tissue collagen and proteinases, lung burdens of diesel soot, lung morphometry and histopathology. Nitrogen dioxide slightly reduced body weight and altered airway fluid enzymes of both age groups, with a greater number of statistically significant differences detectable in the enzyme levels of animals exposed as adults. Normal lung development, as reflected in the size and functional efficiency at adulthood, was not affected by NO2 in this study. Diesel exhaust altered the airway fluid constituents as well as lung tissue collagen and proteinases of both age groups. Particularly striking was an almost sixfold increase in the percentage of neutrophils, a class of highly phagocytic leukocytes, in the airway fluids of adults after six months of exposure. Exhaust-exposed adults had increased numbers of cells in pulmonary lymph nodes, delayed clearance of both diesel soot and 134Cs-labeled particles, and increased lung weight. These changes did not occur in the rats exposed during development.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of acoustic cue discrimination in children.

Three groups of twelve subjects each, ages four, five and six years, respectively, made same-different judgments on six speech discrimination tests. On each test, a single acoustic cue signaled a phonemic difference in minimal pairs which were otherwise acoustically identical. On three of the tests, the independent variable was a spectral cue and on three others a temporal cue was manipulated. With one exception, all subjects passed tests involving a spectral cue, however, significant developmental differences were apparent on tests in which a temporal cue signaled a phonemic difference. The probable contribution of these cues to the perception of speech in young children is discussed.