Mechanisms underlying methamphetamine-induced dopamine transporter complex formation.

Repeated, high-dose methamphetamine (METH) administrations cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. In rats, this treatment also causes the formation of high-molecular mass (greater than approximately 120 kDa) dopamine transporter (DAT)-associated complexes, the loss of DAT monomer immunoreactivity, and a decrease in DAT function, as assessed in striatal synaptosomes prepared 24 h after METH treatment. The present study extends these findings by demonstrating the regional selectivity of DAT complex formation and monomer loss because these changes in DAT immunoreactivity were not observed in the nucleus accumbens. Furthermore, DAT complex formation was not a consequence limited to METH treatment because it was also caused by intrastriatal administration of 6-hydroxydopamine. Pretreatment with the D2 receptor antagonist, eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], attenuated METH-induced DAT complex formation. Eticlopride pretreatment also attenuated METH-induced DAT monomer loss and decreases in DAT function; however, the attenuation was much less pronounced than the effect on DAT complex formation. Finally, results also revealed a negative correlation between METH-induced DAT complex formation and DAT activity. Taken together, these data further elucidate the underlying mechanisms and the functional consequences of repeated administrations of METH on the DAT protein. Furthermore, these data suggest a multifaceted role for D2 receptors in mediating METH-induced alterations of the DAT and its function.

Binary and multi-category ratings in a laboratory observer performance study: a comparison.

The authors investigated radiologists, performances during retrospective interpretation of screening mammograms when using a binary decision whether to recall a woman for additional procedures or not and compared it with their receiver operating characteristic (ROC) type performance curves using a semi-continuous rating scale. Under an Institutional Review Board approved protocol nine experienced radiologists independently rated an enriched set of 155 examinations that they had not personally read in the clinic, mixed with other enriched sets of examinations that they had individually read in the clinic, using both a screening BI-RADS rating scale (recall/not recall) and a semi-continuous ROC type rating scale (0 to 100). The vertical distance, namely the difference in sensitivity levels at the same specificity levels, between the empirical ROC curve and the binary operating point were computed for each reader. The vertical distance averaged over all readers was used to assess the proximity of the performance levels under the binary and ROC-type rating scale. There does not appear to be any systematic tendency of the readers towards a better performance when using either of the two rating approaches, namely four readers performed better using the semi-continuous rating scale, four readers performed better with the binary scale, and one reader had the point exactly on the empirical ROC curve. Only one of the nine readers had a binary "operating point" that was statistically distant from the same reader's empirical ROC curve. Reader-specific differences ranged from -0.046 to 0.128 with an average width of the corresponding 95% confidence intervals of 0.2 and p-values ranging for individual readers from 0.050 to 0.966. On average, radiologists performed similarly when using the two rating scales in that the average distance between the run in individual reader's binary operating point and their ROC curve was close to zero. The 95% confidence interval for the fixed-reader average (0.016) was (-0.0206, 0.0631) (two-sided p-value 0.35). In conclusion the authors found that in retrospective observer performance studies the use of a binary response or a semi-continuous rating scale led to consistent results in terms of performance as measured by sensitivity-specificity operating points.

Perceptual Characterization of the Macronutrient Picture System (MaPS) for Food Image fMRI.

Food image fMRI paradigms are used widely for investigating the neural basis of ingestive behavior. However, these paradigms have not been validated in terms of ingestive behavior constructs, engagement of food-relevant neural systems, or test-retest reliability, making the generalizability of study findings unclear. Therefore, we validated the Macronutrient Picture System (MaPS) (McClernon et al., 2013), which includes food images from the six categories represented in the Geiselman Food Preference Questionnaire (FPQ) (Geiselman et al., 1998). Twenty-five healthy young adults (n = 21 female, mean age = 20.6 ± 1.1 years, mean BMI = 22.1 ± 1.9 kg/m2) rated the MaPS images in terms of visual interest, appetitive quality, nutrition, emotional valence, liking, and frequency of consumption, and completed the FPQ. In a second study, 12 individuals (n=8 female, mean age = 25.0 ± 6.5 years, mean BMI = 28.2 ± 8.7 kg/m2) viewed MaPS and control images (vegetables and non-food) during two separate 3T BOLD fMRI scans after fasting overnight. Intuitively, high fat/high sugar (HF/HS) and high fat/high complex carbohydrate (HF/HCCHO) images achieved higher liking and appetitive ratings, and lower nutrition ratings, than low fat/low complex carbohydrate/high protein (LF/LCHO/HP) images on average. Within each food category, FPQ scores correlated strongly with MaPS image liking ratings (p < 0.001). Brain activation differences between viewing images of HF/HS and vegetables, and between HF/HCCHO and vegetables, were seen in several reward-related brain regions (e.g., putamen, insula, and medial frontal gyrus). Intra-individual, inter-scan agreement in a summary measure of brain activation differences in seven reward network regions of interest was high (ICC = 0.61), and was even higher when two distinct sets of food images with matching visual ratings were shown in the two scans (ICC = 0.74). These results suggest that the MaPS provides valid representation of food categories and reliably activates food-reward-relevant neural systems.

The prevalence effect in a laboratory environment: Changing the confidence ratings.

RATIONALE AND OBJECTIVES: We sought to assess whether or not prevalence levels affected the confidence ratings of readers during the interpretation of cases in a laboratory receiver operating characteristic-type observer performance study. MATERIALS AND METHODS: We reanalyzed a previously conducted observer performance study that included 14 readers and 5 different levels of prevalence. The previous study yielded the observation that in the laboratory we could not detect a "prevalence effect" in terms of differences in areas under the receiver operating characteristic curves. The detection ratings (for presence or absence) of lung nodules, interstitial disease, and pneumothorax for the five prevalence levels were compared, and a test for trend in averaged ratings as a function of abnormality prevalence was performed within a mixed-model setting that accounts for different sources of variability and correlations induced by the study design. RESULTS: The ratings of the cases in terms of confidence that the specific abnormality in question is present tend, on average, to be larger when actual disease prevalence is lower. The rate of the increase of the average confidence ratings with the decreasing prevalence of a specific abnormality is very similar for actually positive and actually negative cases for every considered abnormality. The observed trend in the changes of the average confidence ratings as a function of prevalence levels was statistically significant (p < 0.01). CONCLUSION: Expectations of disease prevalence in the case mix during a laboratory observer performance study may systematically affect the behavior of observers in terms of their actual confidence ratings.

The effect of image display size on observer performance an assessment of variance components.

RATIONALE AND OBJECTIVE: Our goal was to investigate the effect of the displayed image size on variance components during the performance of an observer performance study to detect masses on abdominal computed tomography (CT) examinations. MATERIALS AND METHODS: A previously performed receiver operating characteristic (ROC) study with eight observers to detect abdominal masses on 166 CT examinations was reanalyzed to assess variance components when comparing two similar modes with displayed image sizes varying by a factor of 2. Case, mode, and reader-related variance components were estimated for the group of eight observers and subsets of readers after excluding each of the participants. RESULTS: There was no significant difference in the average area under the ROC curves between the two modes using the two image sizes (P > .05). Reader and reader-by-case variability were substantially larger for the mode displaying enlarged images for the group and all subsets formed by excluding a single reader. Reader variability was affected by one observer who actually performed better with the enlarged images. CONCLUSION: Sequential viewing of enlarged CT images for the detection of abdominal masses did not improve performance and increased reader variability.

Variability in observer performance studies experimental observations.

RATIONALE AND OBJECTIVES: The aim of the study is to assess variance components in observer performance studies and the possible impact on study results and conclusions. MATERIALS AND METHODS: Two previously performed retrospective receiver operating characteristic-type observer performance studies to evaluate the performance of seven radiologists in detecting interstitial disease on conventional posteroanterior chest films and nine radiologists in detecting interstitial disease on a high-resolution workstation were reanalyzed by using the Beiden, Wagner, and Campbell nine-component model to estimate the different variance components. We estimated case-, reader-, and mode-related components of the variance for the group as a whole and after excluding (round robin) each reader. Overall variance was evaluated, and the effect of individual readers on overall study conclusions was assessed. RESULTS: Overall results and conclusions of the reanalysis agreed with the original one in that, as a group, radiologists performed significantly better when using conventional films (P < .05) in both studies. Reader variability was large compared with all other components, and in one study, it was substantially larger for the workstation reading mode. Reader variability was affected substantially by one observer in each study, and in one study, reader-by-mode variability was affected by another reader who performed better on the workstation. CONCLUSION: Estimates of variance components can shed light on the appropriateness of study design, as well as the sensitivity of results to the inclusion (or exclusion) of individual observers.

Impact of the new density reporting laws: radiologist perceptions and actual behavior.

RATIONALE AND OBJECTIVES: To assess radiologists' perceptions of how the new Breast Density Notification Act (BDNA) of Pennsylvania would affect their breast density reporting and their actual reporting patterns after implementation. MATERIALS AND METHODS: Under an institutional review board-approved protocol, we surveyed 21 radiologists about how they believe the new law affected their breast density reporting patterns and analyzed actual changes for 16 respondents before and after the law took effect. Three hundred consecutive reports were assessed for each radiologist before and after the effective date. The distributions of reported density Breast Imaging Reporting and Data System (BI-RADS) (1-4) were compared using a type III test in the context of an ordinal mixed model accounting for between-reader variability and adjusting for age (PROC GLIMMIX, SAS, version 9.3) using a two-sided .05 significance level. RESULTS: Seventeen radiologists responded to the survey; however, one retired shortly after responding. Of the 16 respondents, 56% (nine of 16) did not favor the law, 13% (two of 16) were in favor, and 31% (five of 16) were neutral. The fraction perceived that after implementation, they rated more, equally, or less frequently breasts as scattered fibroglandular densities (BI-RADS 2) versus heterogeneously dense rating (BI-RADS 3) was 50% (eight of 16), 44% (seven of 16), and 6% (one of 16), respectively. In practice, 44% (seven of 16) performed differently than their survey answers. Fourteen of 16 radiologists increased the frequency of reported BI-RADS 2 scores after BDNA implementation with seven having statistically significant (P < .05) increases after adjusting for age differences. CONCLUSIONS: Radiologists' reporting patterns changed, at least for a short duration, after the new density reporting law and for some of the radiologists in an unexpected way.

Methylphenidate administration alters vesicular monoamine transporter-2 function in cytoplasmic and membrane-associated vesicles.

In vivo methylphenidate (MPD) administration increases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity, VMAT-2-mediated dopamine (DA) transport, and DA content in a nonmembrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction purified from rat striatum: a phenomenon attributed to a redistribution of VMAT-2-associated vesicles within nerve terminals. In contrast, the present study elucidated the nature of, and the impact of MPD on, VMAT-2-associated vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles). Results revealed that, in striking contrast to the cytoplasmic vesicles, DA transport velocity versus substrate concentration curves in the membrane-associated vesicles were sigmoidal, suggesting positive cooperativity with respect to DA transport. Additionally, DA transport into membrane-associated vesicles was greater in total capacity in the presence of high DA concentrations than transport into cytoplasmic vesicles. Of potential therapeutic relevance, MPD increased DA transport into the membrane-associated vesicles despite rapidly decreasing (presumably by redistributing) VMAT-2 immunoreactivity in this fraction. Functional relevance was suggested by findings that MPD treatment increased both the DA content of the membrane-associated vesicle fraction and K(+)-stimulated DA release from striatal suspensions. In summary, the present data demonstrate the existence of a previously uncharacterized pool of membrane-associated VMAT-2-containing vesicles that displays novel transport kinetics, has a large sequestration capacity, and responds to in vivo pharmacological manipulation. These findings provide insight into both the regulation of vesicular DA sequestration and the mechanism of action of MPD, and they may have implications regarding treatment of disorders involving abnormal DA disposition, including Parkinson's disease and substance abuse.

Screening mammography: do women prefer a higher recall rate given the possibility of earlier detection of cancer?

PURPOSE: To prospectively survey women undergoing screening mammography to assess their attitudes toward and preference for the level of recall rates given the possibility that an increase in recall rates may result in earlier detection of cancer. MATERIALS AND METHODS: This HIPAA-compliant survey was performed with an institutional review board-approved protocol. Women who arrived for their routine screening mammographic examination from November 2004 to March 2005 were informed before they consented to participate. The distribution of responses for each survey question was summarized, and proportions for the entire group and different subgroups were computed. The z score statistic was used to assess significant differences between subgroups. RESULTS: Fifteen hundred seventy anonymized questionnaires were collected; 1171 (75%) were from women between 40 and 59 years of age. Of 1528 respondents, 1486 (97%) believed that a false-positive result would not deter them from continuing with regular screening, and most would have been willing to be recalled more often for either a noninvasive (86% [1308 of 1519 respondents]) or an invasive (82% [1248 of 1515 respondents]) procedure if it might increase the chance of detecting a cancer (if present) earlier. Compared with respondents undergoing their initial screening mammographic examination, women who had undergone at least one prior screening examination reported that they were more likely to continue with screening if they had received a previous false-positive result (P = .02). Women younger than 60 years and those previously recalled were more willing to be called back more often for a noninvasive or, when indicated, an invasive procedure (P < .05). CONCLUSION: A substantial fraction of women in this study would have preferred the inconvenience of and anxiety associated with a higher recall rate if it resulted in the possibility of detecting breast cancer earlier.

Prescreening mammography by technologists: a preliminary assessment.

OBJECTIVE: We assessed the ability of technologists to accurately classify screening mammograms as either showing negative findings or requiring follow-up. SUBJECTS AND METHODS: In a prospective study, 33 technologists at a central facility and five satellite breast imaging facilities recorded whether mammograms obtained during 3019 examinations showed negative findings or findings that indicated that additional procedures were required. The technologists were not specifically trained for the experiment. The technologists' interpretations were compared with radiologists' interpretations. RESULTS: Technologists and radiologists agreed in 82% of the cases (77% negative findings and 5% requiring follow-up). Of the 175 cases recommended for follow-up by only the radiologists, 17 were ultimately biopsied and two were found to be malignant. CONCLUSION: Even without undergoing additional training, technologists can perform at reasonable levels of accuracy in classifying screening mammograms. The possibility of using technologists to group cases after the technologists have undergone training is an interesting concept that should be explored further.