Skin sensitization to linalyl hydroperoxide: support for radical intermediates

In order to better understand the skin sensitization mechanism of allylic hydroperoxides, linalyl hydroperoxide (1) and several of its potential rearrangement products-epoxylinalool (2), epoxynerol (3), epoxygeraniol (4), and furan (5) and pyran (6) derivatives-were synthesized. The sensitizing properties of these molecules have been screened on mice using the local lymph node assay (LLNA) and further evaluated on guinea pigs using the Freund's complete adjuvant test (FCAT). Linalyl hydroperoxide (1) and linalyl epoxide (2) were found to be sensitizers, while the other compounds were classified as mild sensitizers or nonsensitizers. In the guinea pigs, no cross-reactions were observed between skin sensitizers 1 and 2. Radical-trapping experiments were carried out on linalyl hydroperoxide (1) using TTBP as trapping agent and Fe(3+)-TPP as radical inducer. The major reaction taking place is the formation of a furan ring by intramolecular reaction of the oxygen-centered radical with the isoprenyl double bond with the formation of a tertiary radical. Reaction of this intermediate with radicals derived from TTBP gave compounds 10a,b in 25% yield. The second important reaction, accounting for 14%, is taking place on the allylic double bond with the formation of a less stable primary radical which is not trapped by a TTBP-derived radical but by a hydroxy radical to give a mixture of epoxides 3 and 4. These results are in favor of the formation of a carbon-centered reactive radical as intermediate in the skin sensitization to linalyl hydroperoxide.     

Bootstrapping for pharmacokinetic models: visualization of predictive and parameter uncertainty

PURPOSE: We explore use of "bootstrapping" methods to obtain a measure of reliability of predictions made in part from fits of individual drug level data with a pharmacokinetic (PK) model, and to help clarify parameter identifiability for such models. METHODS: Simulation studies use four sets (A-D) of drug concentration data obtained following a single oral dose. Each set is fit with a two compartment PK model, and the "bootstrap" is employed to examine the potential predictive variation in estimates of parameter sets. This yields an empirical distribution of plausible steady state (SS) drug concentration predictions that can be used to form a confidence interval for a prediction. RESULTS: A distinct, narrow confidence region in parameter space is identified for subjects A and B. The bootstrapped sets have a relatively large coefficient of variation (CV) (35-90% for A), yet the corresponding SS drug levels are tightly clustered (CVs only 2-9%). The results for C and D are dramatically different. The CVs for both the parameters and predicted drug levels are larger by a factor of 5 and more. The results reveal that the original data for C and D, but not A and B, can be represented by at least two different PK model manifestations, yet only one provides reliable predictions. CONCLUSIONS: The insights gained can facilitate making decisions about parameter identifiability. In particular, the results for C and D have important implications for the degree of implicit overparameterization that may exist in the PK model. In cases where the data support only a single model manifestation, the "bootstrap" method provides information needed to form a confidence interval for a prediction.     

Alcohol outcome expectancies: Scale construction and predictive utility in higher order confirmatory models.

The goals of this research were to develop a scale to measure alcohol outcome expectancies that incorporated important features suggested by previous research; to examine the psychometric properties of the instrument, with particular attention to item discrimination; and to examine the relationship of positive and negative expectancy to self-reported alcohol use. In Study 1, a preliminary expectancy scale was constructed; factor analysis showed 2 general constructs representing positive and negative consequences of drinking. In Study 2, the scale was refined through tests of item discrimination and was used to predict alcohol use using structural equation modeling. Although negative expectancy was significantly related to alcohol use, positive expectancy was a stronger predictor. These results are consistent with earlier work that proposed a general positive–negative expectancy distinction and suggest that positive expectancy is a more powerful motivator of drinking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Skin sensitization testing: the relevance of rechallenge and pretreatment with sodium lauryl sulfate in the guinea pig maximization test

The guinea pig maximization test is one of the preferred test methods for the identification of skin sensitizers. The OECD/EC test guidelines allow for the conduct of a rechallenge in case doubtful reactions are obtained after challenge. The relevance of rechallenging was investigated by performing multiple challenges (up to four) in the maximization test with four well-known sensitizers of varying strength: nickel sulfate, sulfathiazole, benzocaine, and 1-chloro-2,4-dinitrobenzene. In addition, the effect of sodium lauryl sulfate (SLS)-pretreatment during topical induction with weak sensitizers on rechallenging was investigated. In contrast to what has frequently been hypothesized, rechallenge did not result in an increase of skin reaction as compared with the reactions observed after the first treatment. SLS pretreatment was very effective in increasing the initial challenge response to weak sensitizers. Subsequent rechallenging in these cases however again showed a decrease in sensitivity of the animals.     

Confidence intervals for the cross-validated multiple correlation in predictive regression models.

Presents improved procedures to approximate confidence intervals for ρ–2 and ρc–2 in both fixed and random predictor models. These approximations require neither point estimates nor variance estimates and are analytically shown to be precise enough for most practical prediction purposes. An application of confidence intervals in regression model development is also given. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization

The lutropin receptor (LHR) is a G protein-coupled receptor in which high affinity ligand binding occurs to the relatively large extracellular N-terminal domain. Various portions of the receptor have been mapped for their relative importance in localization and in hormone-mediated signaling. There is, however, a paucity of information available on the intracellular loops (ICL), where, along with the C-terminal cytoplasmic tail, G protein coupling is expected to occur. Site-directed mutagenesis was used to investigate the role of several conserved ionizable groups and one tyrosyl residue in ICLs I-III of the rat LHR. The pSVL expression vector, containing the LHR cDNA (wild-type and mutants), was transiently transfected into COS-7 cells, and human choriogonadotropin (hCG) binding and hCG-mediated cAMP production were determined. Several point mutants of amino acid residues in ICL II were prepared and characterized with the following results: replacements of Lys-455 and of His-460 with Glu gave mutant LHRs that failed to localize or fold properly at the cell surface as evidenced by the lack of significant binding to intact cells, although hCG binding could be detected in broken cell preparations, and a neighboring Arg-459 --> Glu replacement had no apparent effect on receptor trafficking, hCG binding or hCG-mediated cAMP-production. A reversal mutant in ICL II in which Glu-441, at the boundary of transmembrane helix III and ICL II, and His-460, at the interface between ICL II and transmembrane helix IV, were interchanged, exhibited hCG binding to intact cells, but the maximal cAMP level at high concentrations of ligand was less than that obtained with COS-7 cells transfected with wild-type LHR. The total number of cell surface receptors determined with the reversal mutant was less than that found with wild-type LHR. This difference, however, is not believed to be responsible for the reduced signaling, since maximal cAMP responses to hCG were obtained with comparable receptor densities of wild-type and various mutant LHRs. Other single replacements in ICL I, Lys-368 --> Glu and to Gln, and in ICL III, Arg-526 --> Glu and Tyr-528 --> Ser, resulted in mutant LHRs with characteristics of wild-type LHR in trafficking, hCG binding and hCG-mediated cAMP production. These findings suggest an important functional role of several amino acid residues in ICL II of LHR.     

Using predictive models of behavior change to promote evidence-based treatment for PTSD.

While there is a strong evidence base regarding effective treatment of Posttraumatic Stress Disorder (PTSD), and an increased number of treatment guidelines available internationally, research indicates that there is significant variation in clinical practice. This study aimed to identify effective ways to promote adoption of trauma-focused interventions in community services offering mental health care to people who have experienced trauma. The study sought to do so by identifying factors influencing the uptake of evidence-based practice at both an individual and organizational level, and trialing competency training and support strategies based on these factors across 6 community trauma services. The effectiveness of the training and support strategies was investigated using self-report surveys and prospective recording of clinicians' treatment planning for PTSD clients. The study found that while lack of skills and confidence were identified as significant barriers to the uptake of trauma-focused interventions, expectations about treatment outcomes and organizational factors also influenced clinical behavior. This finding highlighted the importance of considering factors other than knowledge and skills when developing training and other interventions to support the implementation of evidence-based practice. Furthermore, it was found that a training and implementation process tailored to organizational and individual barriers, and based on currently recognized theories of behavior change, led to a significant increase in the use of imaginal exposure in the treatment plans of clients assessed as having PTSD. This change was maintained 6 months following training. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Uncertainty analysis methods for comparing predictive models and biomarkers: A case study of dietary methyl mercury exposure

Biologically based markers (biomarkers) are currently used to provide information on exposure, health effects, and individual susceptibility to chemical and radiological wastes. However, the development and validation of biomarkers are expensive and time consuming. To determine whether biomarker development and use offer potential improvements to risk models based on predictive relationships or assumed values, we explore the use of uncertainty analysis applied to exposure models for dietary methyl mercury intake. We compare exposure estimates based on self-reported fish intake and measured fish mercury concentrations with biomarker-based exposure estimates (i.e., hair or blood mercury concentrations) using a published data set covering 1 month of exposure. Such a comparison of exposure model predictions allowed estimation of bias and random error associated with each exposure model. From these analyses, both bias and random error were found to be important components of uncertainty regarding biomarker-based exposure estimates, while the diary-based exposure estimate was susceptible to bias. Application of the proposed methods to a simple case study demonstrates their utility in estimating the contribution of population variability and measurement error in specific applications of biomarkers to environmental exposure and risk assessment. Such analyses can guide risk analysts and managers in the appropriate validation, use, and interpretation of exposure biomarker information.     

Morphometric grading in breast cancer: thresholds for mitotic counts

Three hundred sixty-four cases of invasive ductal breast cancer diagnosed during the years 1988 to 1991 were analyzed to determine quantitative thresholds for mitotic activity. Mitotic counts were calculated in each sample and expressed as standardized mitotic index (SMI) and mitotic activity index (MAI). Based on Kaplan-Meier curves, univariate and multivariate analysis of Cox's regression, and maximum efficiencies of ROC analysis, optimal thresholds were determined on the basis of survival and recurrence of disease. In our material, with a follow-up time of 5 years 9 months, we found two thresholds--a lower and a higher--for both SMI (17 mitoses/mm2 and 32 mitoses/mm2) and MAI (13 mitoses/10 HPF and 35 mitoses/10 HPF). The thresholds were the same in the whole material and in subgroups divided according to the patients' age and axillary lymph node status at the time of diagnosis, and tumor size. The thresholds clearly separated patients with favorable, intermediate, and unfavourable outcome of disease. In our material, the risk of breast cancer death associated with the determined thresholds (ranging from 4.7 to 3.8) clearly exceeded those of menopausal status, axillary lymph node status and tumor size. The risk of breast cancer death associated with the determined thresholds was still emphasized in the groups of premenopausal and axillary lymph node-negative patients, and with tumor size less than 2 cm in diameter (risk ratios, 11.8, 6.0, and 6.7, respectively). The results suggest that the presented quantitative thresholds could be applied in grading of invasive ductal breast cancer.     

Covert sensitization: Conditioning or suggestion?

Using 39 female college students, assessed the strength of the underlying theoretical basis of covert sensitization. A covert sensitization group of overweight Ss was compared with a placebo control (suggestion) group and a no-treatment control group. Results show no differential weight change among groups; however, while the control group reported no change in the palatability of any foods, both the covert-sensitization and the placebo-suggestion group reported significant decreases in their "liking" for favorite foods after treatment, while their liking for other foods did not change. The data imply that the effects of covert sensitization may be the result of factors such as suggestion and attention. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nodal metastases: predictive factors

Squamous cell carcinoma of the upper respiratory and digestive tract has a high risk for neck metastasis, which reduces the probability of regional control and survival. We analyzed the literature and our own experience to review the possible risk factors for the occurrence of metastasis. The most significant risk factors were: tumor site and size, grade of histologic differentiation, tumor thickness (tongue and floor of mouth carcinoma), vascular embolization, and perineural infiltration. A series of biomarkers has been studied over the last 10 years, but no one has proved to be significant enough for clinical use. Based on several multivariate analysis, it is recommended elective treatment of the neck for high-risk patients.     

Occupational allergy in greenhouse workers: sensitization to Tetranychus urticae

BACKGROUND: Tetranychus urticae (TU) is a macroscopic mite which is found infesting a large number of plants of economic interest. It has rarely been described as a cause of occupational allergic disease in agricultural workers. OBJECTIVE: To describe TU sensitization in greenhouse workers attending the outpatient allergy unit and its clinical associations, and to characterize the allergens involved. MATERIALS AND METHODS: Twenty-four consecutive carnation greenhouse workers with allergy-related symptoms, referred to our outpatient clinic during a 6-month period, were included. We made the diagnostic extract from carnation leaves heavily infested with TU. Skin-prick test, specific IgE measurement and bronchial provocation test with TU extract were carried out in all subjects. Allergen characterization was achieved by SDS-PAGE (sodium dodecylsulfate-polyacrylamide gel electrophoresis) and immunoblotting. RESULTS: Sixteen patients (66%) presented positive skin-prick test and specific IgE and were diagnosed allergic to TU. Fifteen patients suffered from bronchial asthma, 14 rhinitis and five urticaria. Twelve exhibited positive bronchial provocation test to the TU extract. On RAST-inhibition studies, there was no evidence of crossreactivity between TU extract and D. pteronyssinus. An allergen at 19 kDa was determined in the TU extract by SDS-PAGE immunoblotting studies. CONCLUSION: TU could be an important occupational allergen in greenhouse workers showing allergic symptomatology. There is no crossreactivity between this mite and the house dust mite D. pteronyssinus.     

Amphetamine sensitization: Nonassociative and associative components.

[Correction Notice: An erratum for this article was reported in Vol 117(6) of Behavioral Neuroscience (see record 2007-16849-001). The institutional affiliation for Ying-Chou Wang is incomplete. The correct affiliation is Ching Kuo Institute of Management and Health and National Chung Cheng University.] Rats, pretreated with amphetamine (AMPH, 1 mg/kg) or saline for 2 weeks, were challenged with AMPH (0.5 mg/kg) or saline following 1 week of abstinence, and locomotion was measured. In Experiments 1 and 2, the pretreatment occurred in various contexts (home cage, novel box, test box). Sensitization was observed only when pretreatment context and test context were the same; a context switch abolished sensitization. When rats anesthetized with chloral hydrate were pretreated with AMPH, sensitization was completely dependent on the pretreatment, but independent of context. This "zero context" condition isolated the basal level of excitation attributable to unconditioned neural change to determine the role of contextual input to be a modulator that enhances or inhibits sensitization. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The National Toxicology Program evaluation of genetically altered mice as predictive models for identifying carcinogens

In this study cytoskeletal antigens common to brushtail possum and tammar wallaby spermatozoa were characterised using a monoclonal antibody (PSA-10). Using indirect immunofluorescence, the PSA-10 antibody detected antigens predominantly associated with the midpiece and principal piece of mature, permeabilised marsupial spermatozoa. The principal piece determinant, shared by a variety of other species, was found to arise in the marsupial testis. Midpiece localisation of the PSA-10 epitope was detected only in marsupial spermatozoa and shown to arise in the epididymis. Immunogold labelling demonstrated that the PSA-10 antigens were predominantly associated with the fibrous sheath and midpiece fibre network of both possum and wallaby spermatozoa. Western blotting suggested that two major possum and wallaby sperm polypeptides of 158 and 182 kDa were associated with the midpiece fibre network, a cytoskeletal structure unique to marsupial spermatozoa. A 32 kDa polypeptide was associated with the principal piece fibre network and/or fibrous sheath. The finding that these marsupial sperm cytoskeletal proteins share a common linear epitope suggests that they share some sequence similarity. The midpiece fibre network of marsupial sperm, like the fibrous sheath, has been proposed to have a structural role in providing passive stiffening for the flagellum (Harding et al., 1975, 1979; Olsen, 1975). The PSA-10 monoclonal antibody may provide a tool for comparative studies of mammalian sperm cytoskeletal proteins, particularly the marsupial midpiece fibre network. It may also allow the formation of this unique marsupial cytoskeletal structure, and its fate during the fertilisation process, to be followed by immunological means.