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Conducting exposure treatment in multiple contexts can prevent relapse.

The acquisition of anxiety disorders (e.g., phobias) is often thought to be mediated by classical conditioning processes (e.g., Wolpe, 1958, Psychotherapy by reciprocal inhibition Wolpe and Rowan, 1989, Behaviour Research and Therapy, 27, 583-585). Thus, the success of exposure therapy is possibly a consequence of extinction, and factors affecting extinction in Pavlovian conditioning are potentially relevant to clinicians who administer exposure therapy. The present experiments investigated the effects of conducting extinction in multiple contexts using rats as subjects in a conditioned suppression paradigm. In Experiment 1, subjects received conditioned stimulus (CS) and unconditioned stimulus (US) pairings in one context followed by extinction of that CS in one or three other contexts. When tested in an associatively neutral context (i.e., different from those of conditioning or extinction), rats that had received extinction in three contexts exhibited less responding to the CS than rats that had received extinction in one context. In Experiment 2, CS-US training occurred in either one or three contexts, followed by extinction of that CS in three other contexts. Testing in a neutral context revealed that rats conditioned in multiple contexts showed greater responding to the CS than rats trained in a single context. The results are discussed in the framework of memory retrieval, and the clinical implications are explored.

Animals↗

Another possible precipitating factor in multiple sclerosis: the exposure to organic solvents.

Recent clinical observations seem to indicate that a possible correlation may exist between the appearance of inflammatory diseases of the nervous system and exposure to organic solvents. In certain cases the patients could not be distinguished, either from the clinical or laboratory point of view, from typical cases of multiple sclerosis. These observations raise the problem of a possible action of organic solvents on the immunological responses, already described in different pathological conditions as a further possible precipitating factor in MS.

Adult↗

Lead exposure enhances virus multiplication and pathogenesis in mice.

Suppression of the immune system by environmental xenobiotics may cause increased susceptibility of the host towards a variety of microbial pathogens an result in a life-threatening state. We investigated whether lead exposure would enhance susceptibility to Semliki Forest Virus (SFV). Mice orally exposed to lead acetate (62.5, 125, 250 or 500 mg/kg bw) exhibited increased mortality and decreased mean survival time compared to untreated animals on challenge with SFV. The mortality was associated with enhancement of high virus titer and earlier appearance of virus in lead-exposed mice. Histopathological studies observed enhancement of viral pathogenesis in a dose dependent pattern in the lead-dosed group challenged with SFV. The results indicate that exposure to lead enhanced susceptibility to viral infection. Environmental metal contamination and subsequent infection by pathogenic microbes points necessitate studies on the interaction of environmental pollutants on the immune system.

Alphavirus Infections↗

Tolerance to the miotic effect of sarin vapor in rats after multiple low-level exposures.

Inhibition of acetylcholinesterase (AChE) by the organophosphorous compound sarin (GB) results in the accumulation of acetylcholine and excessive cholinergic stimulation. There are few data in the literature regarding the effects of multiple low-level exposures to GB and other organophosphorous compounds via relevant routes of exposure. Therefore, the present study was undertaken, and is the first, to investigate the effect of low-level repeated whole-body inhalation exposures to GB vapor on pupil size and cholinesterase activity in the eyes and blood. Male Sprague-Dawley rats were exposed to 4.0 mg/m3 of GB vapor for 1 h on each of 3 consecutive days. Pupil size and cholinesterase activities were determined at various points throughout the exposure sequence. The results demonstrate that multiple inhalation exposures to GB vapor produce a decrease in the miotic potency of GB in rats. This tolerance developed at a dose of GB that produced no overt signs of intoxication other than miosis. AChE and butyrylcholinesterase activity did not increase throughout the exposure sequence, suggesting that the tolerance cannot be attributed to a reduced inhibitory effect of GB. A decrease in the amount of GB present in the eye occurred after the third exposure. However, this change is insufficient to explain the tolerance, as there was no corresponding increase in AChE activity. Thus, the mechanism mediating the miotic tolerance observed after multiple inhalation exposures to the nerve agent GB remains uncertain, although several possibilities can be excluded based on the results of the present study.

Acetylcholinesterase↗

Oxidative metabolism in platelets, platelet aggregation, and hematology in patients undergoing multiple hyperbaric oxygen exposures.

Repeated hyperbaric oxygen (HBO2) treatments at 2.2 ATA for 90 minutes each are used to treat chronically ill patients with problem wounds, but there are concerns about the cytotoxicity of oxygen to blood cells and platelet function during prolonged HBO2 therapy. We recruited 31 consenting patients scheduled for multiple HBO2 treatments to evaluate oxidative metabolism in platelets, platelet aggregation, and hematology (mean age +/- standard error, 61 +/- 2.6 years, 20 males, 11 females). Venous blood was collected before and after the 1st and 20th HBO2 treatments. No effect of HBO2 was observed on red cell counts, hematocrit, hemoglobin, mean red cell volume (MCV), platelet counts, basal levels of lactate production by platelets, ferric reducing ability of plasma (FRAP), or plasma protein. The capacity for oxidative metabolism (lactate ratio) in platelets was not affected by HBO2, except in smokers where it increased by the 20th HBO2 treatment. Mean lymphocyte count was increased by 38% after the 20th treatment. There was also a 23% increase in platelet protein content, and a 24% increase in arachidonic acid-dependent platelet activation. Collagen-dependent platelet aggregation was unaffected. Blood glucose showed HBO2-dependent variability, but remained in the normal range. Plasma lactate levels decreased significantly from 3.2 to 2.5 mmol/l by the end of the study. Overall, we found no evidence that 20 HBO2 sessions caused adverse effects on platelet aggregation or oxidative metabolism in platelets, red or white cell counts, or total antioxidant status of the plasma.

Acetaminophen↗

Generation of halothane-induced immune response in a guinea pig model of halothane hepatitis.

A guinea pig model of halothane hepatitis was used to explore the humoral immune response induced by multiple halothane exposures and the potential role this response might play in contributing to liver damage. Three different strains of guinea pigs (Strain 2, Amana, and Hartley) were exposed to 1% halothane under either 21 or 80% oxygen for 4 hr at 2-week intervals. In each strain, halothane induced the appearance of an antibody cross-reactive with trifluoroacetylated guinea pig serum albumin (TFA-GSA). Three of six Strain 2 guinea pigs demonstrated an association between antibody titer and serum glutamate pyruvate transaminase levels. However, the possible cause and effect relationship between these two factors requires more investigation. Hartley guinea pigs had a 4- to 11-fold higher level of anti-TFA antibody than the other two strains because of either a "higher responder" genetic background or exposure conditions that favored oxidative metabolism of halothane. Immunization of Amana guinea pigs with TFA-GSA evoked a specific anti-TFA antibody response. However, the presence of this antibody before halothane exposure did not potentiate the transient liver damage induced by exposure. Thus, these results demonstrate that in guinea pigs multiple exposures to halothane induce the formation of an antibody that recognizes a reactive intermediate of halothane formed during the anesthetic's metabolism.

Animals↗

An application of hierarchical regression in the investigation of multiple paternal occupational exposures and neuroblastoma in offspring.

BACKGROUND: We used hierarchical regression to study the effects of 46 paternal occupational exposures on the incidence of neuroblastoma in offspring. METHODS: The study population included 405 cases and 302 controls. The effect of each exposure was estimated using both conventional maximum likelihood and hierarchical regression. RESULTS: Using hierarchical regression, overall precision was greatly enhanced compared to the conventional analysis. In addition, adjustment of effect estimates based on prespecified prior distributions of the true effect parameters allowed a more consistent interpretation across the entire panel of exposures. Estimates for several metals and solvents were shrunk close to the null value, whereas estimates for several thinner solvents, diesel fuel, solders, wood dust, and grain dust remained moderately elevated. CONCLUSIONS: Hierarchical regression may mitigate some of the problems of the conventional approach by controlling for correlated exposures, enhancing the precision of estimates, and providing some adjustment of estimates based on prior knowledge.

Adult↗

Simultaneous determination of urinary hydroxylated metabolites of naphthalene, fluorene, phenanthrene, fluoranthene and pyrene as multiple biomarkers of exposure to polycyclic aromatic hydrocarbons.

A method is presented for determining monohydroxy polycyclic aromatic hydrocarbons (OHPAHs) having 2-, 3- and 4-rings in human urine by using high-performance liquid chromatography with fluorescence detection. A urine sample containing conjugates of OHPAHs was hydrolysed in the presence of beta-glucuronidase/aryl sulfatase and the solution was cleaned up with a solid-phase extraction (C(18) and silica). Eight OHPAHs, namely 1- and 2-hydroxynaphthalenes, 2-hydroxyfluorene, 2-, 3- and 4-hydroxyphenanthrenes, 3-hydroxyfluoranthene and 1-hydroxypyrene, were separated and 1- and 9-hydroxyphenanthrenes co-eluted on an alkylamide-type reversed-phase column with fluorimetric detection. The urinary concentrations of OHPAHs were quantified by using deuterated 1-hydoxypyrene as an internal standard. The method showed good repeatability for inter- and intra-day precisions as well as good linearity of calibration curves (r (2) ranged from 0.996 to 0.999). The limits of detection (S/N=3) were in the range from 2.3 fmol to 2.2 pmol per injection. This method was successfully applied to urine samples from non-smoking taxi drivers, traffic policemen and rural villagers of Chiang Mai, Thailand. The results showed higher urinary concentrations of OHPAHs in rural villagers, consistent with higher respiratory exposure to PAHs.

Adult↗

DNA damage in multiple organs after exposure to chlorhexidine in Wistar rats.

Since chlorhexidine is effective against microorganisms, it is widely recommended in dentistry. However, studies have provided evidence that chlorhexidine is toxic for a variety of cell types. In order to identify potential genotoxins in different cell types, the purpose of this study was to investigate whether chlorhexidine digluconate is able to cause, in terms of DNA damage, alterations in leukocytes, liver, kidney and urinary bladder by the single cell gel (comet) assay. Ten male Wistar rats were divided into two groups: a negative control and the experimental group treated with 3ml of 0.12% chlorhexidine digluconate by gavage once a day for 8 days. Statistically significant increases of DNA damage was observed in leukocytes and kidney cells of the chlorhexidine digluconate treated group as depicted by the mean tail moment. Taken together, the data indicate that leukocytes and kidney cells are potential targets for primary DNA damage following oral exposure to chlorhexidine digluconate as detected by single cell gel (comet) assay.

Animals↗

A conceptual framework for modeling aggregate and cumulative exposures to chemicals.

Computer simulation programs have been identified as useful tools for characterizing uncertainty and variability in longitudinal exposures to multiple sources by multiple routes of exposures. This paper provides a conceptual framework for such programs that separates and appropriately models the processes that determine uncertainty, inter- and intraindividual variability, as well as the processes that determine the relationships between the individuals and sources of exposure. The framework is based on a series of four nested loops. These are: the exposure event loop that models the route-specific doses to a person from one or more sources at one point in time; the time step loop that moves a person through time updating the sources and the person's characteristics, the interindividual variation loop that determines the initial characteristics of each person modeled, and finally the uncertainty loop that characterizes the uncertainty from model and parameter uncertainties. This framework provides a flexible and internally consistent approach for the design of simulation software.

Computer Simulation↗

Effect of nondifferential misclassification on estimates of odds ratios with multiple levels of exposure.

Nondifferential misclassification of exposure status with a dichotomous exposure will produce biased estimates of odds ratios such that the misclassified odds ratio is always biased toward the null value. However, when an exposure classification has more than two levels, empirical data indicate that the direction of bias is less predictable. Analysis of an algebraic model of multi-level exposure misclassification reveals that all odds ratios based on the misclassified data are constrained between the nonmisclassified odds ratio for the most extreme category and the inverse of this value. This implies that the misclassified odds ratio for the most extreme exposure level will be biased toward the null but that odds ratios for intermediate levels of exposure could be biased away from the null value. Further, the amount of bias depends not only on the misclassification rates but also on the distribution of subjects across exposure levels. If it is assumed that misclassification is likely to occur only between adjacent categories, the range of possible misclassified odds ratios is reduced but is still sufficient to permit serious distortion of an exposure-response relation. In general, biases away from the null occur only for intermediate levels of exposure. Reversal of an exposure-response relation is more likely to occur when misclassification rates are high (especially between nonadjacent levels) and when the number of exposure levels is low.

Bias↗

Phenotypic resistance of Staphylococcus aureus, selected Enterobacteriaceae, and Pseudomonas aeruginosa after single and multiple in vitro exposures to ciprofloxacin, levofloxacin, and trovafloxacin.

The phenotypic resistance of selected organisms to ciprofloxacin, levofloxacin, and trovafloxacin was defined as a MIC of > or =4 microg/ml. The dynamics of resistance were studied after single and sequential drug exposures: clinical isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa were utilized. After a single 48-h exposure of a large inoculum to four times the initial MIC for the organism, the frequency of selection of resistant mutants of MSSA was greater for trovafloxacin than levofloxacin (P = 0.008); for E. cloacae, the frequency was highest for ciprofloxacin and lowest for levofloxacin and trovafloxacin; for S. marcescens, the frequency was highest for trovafloxacin and lowest for ciprofloxacin (P = 0.003). The results of serial passage experiments were analyzed both by the Kaplan-Meier product-limited method as well as by analysis of variance of mean inhibitory values. By both methods, MSSA and MRSA expressed mutants resistant to ciprofloxacin after fewer passages than were required for either levofloxacin or trovafloxacin. For the aerobic gram-negative bacilli, two general patterns emerged. Mutants resistant to trovafloxacin appeared sooner and reached higher mean MICs than did mutants resistant to levofloxacin or ciprofloxacin. Mutants resistant to ciprofloxacin appeared later and reached mean MICs lower than the MICs of the other two drugs studied. Even though individual strain variation occurred, the mean MICs were reproduced when the serial passage experiment was repeated using an identical panel of E. coli isolates. In summary, the dynamic selection of fluoroquinolone-resistant bacteria can be demonstrated in experiments that employ serial passage of bacteria in vitro.

Anti-Infective Agents↗

Consistent effects of TSG101 genetic variability on multiple outcomes of exposure to human immunodeficiency virus type 1.

Tumor susceptibility gene 101 (TSG101) encodes a host cellular protein that is appropriated by human immunodeficiency virus type 1 (HIV-1) in the budding process of viral particles from infected cells. Variation in the coding or noncoding regions of the gene could potentially affect the degree of TSG101-mediated release of viral particles. While the coding regions of the gene were found to lack nonsynonymous variants, two polymorphic sites in the TSG101 5' area were identified that were associated with the rate of AIDS progression among Caucasians. These single-nucleotide polymorphisms (SNPs), located at positions -183 and +181 relative to the translation start, specify three haplotypes termed A, B, and C, which occur at frequencies of 67%, 21%, and 12%, respectively. Haplotype C is associated with relatively rapid AIDS progression, while haplotype B is associated with slower disease progression. Both effects were dominant over the intermediate haplotype A. The haplotypes also demonstrated parallel effects on the rate of CD4 T-cell depletion and viral load increase over time, as well as a possible influence on HIV-1 infection. The data raise the hypothesis that noncoding variation in TSG101 affects the efficiency of TSG101-mediated release of viral particles from infected cells, thereby altering levels of plasma viral load and subsequent disease progression.

Acquired Immunodeficiency Syndrome↗

Multiple cold air exposures change oral triiodothyronine kinetics in normal men.

The influence of cold exposure on triiodothyronine (T3) kinetics was studied in 16 men before, during (biweekly), and after 80 (10/wk) cold (4 degrees C) air exposures. We used serum values before and up to 24 h after a pharmacological oral (o) dose of T3 [76.8 nmol (50 micrograms)] to calculate noncompartmental kinetic parameters. To assess the role of thyroxine (T4) and thyrotropin (TSH), we administered a replacement dose of T3 [46.0 nmol/day (30 micrograms)] to eight men (+T3 group) and placebo to eight others (-T3 group) for the 2-mo study. There was no group effect of T3 treatment (+T3) on oral total volume of distribution (TVdo), metabolic clearance rate (MCRo), or disposal rate (DRo). TVdo was not changed over the study. Cold increased MCRo by 5.4 +/- 2.0 l.day-1.m-2. DRo increased with cold by 10.2 +/- 4.4 nmol.day-1.m-2. Although serum TSH, total T4, and free T4 decreased by approximately 50% in the +T3 group, the changes in MCRo and DRo with cold were not different from those in -T3. We describe that human T3 kinetics are changed with brief repeated exposures to cold air and that these increases in MCRo and DRo do not appear to be dependent on TSH or T4.

Administration, Oral↗