Attenuating the 'attentional white bear' effect enhances suppressive attention.

Trying to ignore an object can bias attention towards it - a phenomenon referred to as the 'attentional white bear' (AWB) effect. The mechanisms behind this effect remain unclear. On one hand, the AWB may reflect reactive, 'search and destroy' distractor suppression, which directs attention toward irrelevant objects in order to suppress further attention to them. However, another possibility is that the AWB results from failed proactive distractor suppression - attempting to suppress attention to an irrelevant object from the outset may inadvertently result in an attentional shift towards it. To distinguish these two possibilities, we developed a categorical visual search task that addresses limitations present in prior studies. In five experiments (Ntotal = 96), participants searched displays of naturalistic stimuli cued only with distractor categories (targets were unknown and unpredictable). We observed an AWB and later attenuated it by presenting a pre-search stimulus, likely disrupting guidance from distractor templates in working memory. We conclude that the AWB resulted from a failure of proactive suppression rather than a search and destroy process.

Improved X-ray baggage screening sensitivity with 'targetless' search training.

When searching for a known target, mental representations of target features, or templates, guide attention towards matching objects and facilitate recognition. When only distractor features are known, distractor templates allow irrelevant objects to be recognised and attention to be shifted away. This is particularly true in X-ray baggage search, a challenging real-world visual search task with implications for public safety, where targets may be unknown, difficult to predict and concealed by an adversary, but distractors are typically benign and easier to identify. In the present study, we draw on basic principles of distractor suppression and rejection to investigate a counterintuitive 'targetless' approach to training baggage search. In a simulated X-ray baggage search task, we observed significant benefits to target detection sensitivity (d') for targetless relative to target-based training, but no effects of performance-contingent rewards or the inclusion of superordinate semantic categories during training. The benefits of targetless search training were most apparent for stimuli involving less spatial overlap (occlusion), which likely represents the difficulty and greater individual variation involved in searching more visually complex images. Together, these results demonstrate the effectiveness of a counterintuitive targetless approach to training target detection in X-ray baggage search, based on basic principles of distractor suppression and rejection, with potential for use as a real-world training tool.

Autocrine/paracrine modulation of baroreceptor activity after antidromic stimulation of aortic depressor nerve in vivo.

Activation of the sensory nerve endings of non-myelinated C-fiber afferents evokes release of autocrine/paracrine factors that cause localized vasodilation, neurogenic inflammation, and modulation of sensory nerve activity. The aims of this study were to determine the effect of antidromic electrical stimulation on afferent baroreceptor activity in vivo, and investigate the role of endogenous prostanoids and hydrogen peroxide (H2O2) in mediating changes in nerve activity. Baroreceptor activity was recorded from the left aortic depressor nerve (ADN) in anesthetized rats before and after stimulating the ADN for brief (5­20 s) periods. The rostral end of the ADN was crushed or sectioned beforehand to prevent reflex changes in blood pressure. Antidromic stimulation of ADN using parameters that activate both myelinated A-fibers and non-myelinated C-fibers caused pronounced and long-lasting (> 1 min) inhibition of baroreceptor activity (n = 9, P < 0.05), with the magnitude and duration of inhibition dependent on the duration of the stimulation period (n = 5). Baroreceptor activity was only transiently inhibited after selective stimulation of A-fibers. The inhibition of activity after antidromic stimulation of A and C fibers was prolonged after administration of the cyclooxygenase inhibitor indomethacin (5 mg/kg, IV, n = 7) and abolished after administration of PEG-catalase (104 units/kg, IV, n = 7), an enzyme that catalyzes the decomposition of H2O2 to water and oxygen. The results demonstrate a long-lasting inhibition of baroreceptor activity after antidromic stimulation of ADN and suggest that endogenous prostanoids and H2O2 oppose and mediate the inhibition, respectively. These mechanisms may contribute to rapid baroreceptor resetting during acute hypertension and be engaged during chronic baroreceptor activation therapy in patients with hypertension.

Unconscious priming of task-switching generalizes to an untrained task.

Evidence suggests that subliminal stimuli can influence ostensibly volitional, executive processes but it is unclear whether this is highly task-specific. To address this we used a set-switching task. Volunteers saw a word pair and reported either if both words had the same number of syllables or if both were concrete. Task selection was random and instructed by a hexagon/triangle preceding the words. A subliminally-presented square or diamond reliably preceded each of these consciously perceived instruction-shapes. Significant congruency effects were observed in a subsequent Test Phase in which primes no longer reliably predicted the task (and in which high/low tones now served as conscious instructions). The Generalization Phase required novel phonological (rhyme) or semantic (category) judgments. Remarkably, unconscious priming congruency effects carried over in those participants who had shown priming in the Test Phase, the degree correlating across the two conditions. In a final phase of the study, participants were asked to discriminate between the two originally presented prime shapes. Those participants whose discriminations were more accurate showed reduced priming relative to participants with less accurate discriminations. The results suggest that, rather than being highly task specific, priming can operate at the level of a generalizable process and that greater awareness of primes may lessen their impact on behavior.

The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-ΔF508, is misprocessed, although the in vivo consequences of this mutation remain uncertain. To better understand the effects of the ΔF508 mutation in vivo, we produced CFTR(ΔF508/ΔF508) pigs. Our biochemical, immunocytochemical, and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro predictions. They also indicated that CFTR(ΔF508/ΔF508) airway epithelia retain a small residual CFTR conductance, with maximal stimulation producing ~6% of wild-type function. Cyclic adenosine 3',5'-monophosphate (cAMP) agonists were less potent at stimulating current in CFTR(Δ)(F508/)(Δ)(F508) epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTR(ΔF508/ΔF508) pigs developed lung disease similar to human CF. These results suggest that this limited CFTR activity is insufficient to prevent lung or gastrointestinal disease in CF pigs. These data also suggest that studies of recombinant CFTR-ΔF508 misprocessing predict in vivo behavior, which validates its use in biochemical and drug discovery experiments. These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics.

Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.

Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes. We now report that, within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. In humans, the temporal and causal relations between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation but were less often sterile than controls. Moreover, after introduction of bacteria into their lungs, pigs with CF failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Our finding that pigs with CF have a host defense defect against bacteria within hours of birth provides an opportunity to further investigate CF pathogenesis and to test therapeutic and preventive strategies that could be deployed before secondary consequences develop.

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs.

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.

Population-based validation of the prognostic model ADJUVANT! for early breast cancer.

PURPOSE: Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated. METHODS: Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared. RESULTS: Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted-observed = 8.6%, 9.6%, and 13.6%, respectively; all P < .001) or with lymphatic or vascular invasion (LVI; predicted-observed = 3.6%, 3.8%, and 4.2%, respectively; all P < .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different. CONCLUSION: Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.