Alpha oscillations and stimulus-evoked activity dissociate metacognitive reports of attention, visibility, and confidence in a rapid visual detection task.

Variability in the detection and discrimination of weak visual stimuli has been linked to oscillatory neural activity. In particular, the amplitude of activity in the alpha-band (8-12 Hz) has been shown to impact the objective likelihood of stimulus detection, as well as measures of subjective visibility, attention, and decision confidence. Here we investigate how preparatory alpha in a cued pretarget interval influences performance and phenomenology, by recording simultaneous subjective measures of attention and confidence (experiment 1) or attention and visibility (experiment 2) on a trial-by-trial basis in a visual detection task. Across both experiments, alpha amplitude was negatively and linearly correlated with the intensity of subjective attention. In contrast with this linear relationship, we observed a quadratic relationship between the strength of alpha oscillations and subjective ratings of confidence and visibility. We find that this same quadratic relationship links alpha amplitude with the strength of stimulus-evoked responses. Visibility and confidence judgments also corresponded with the strength of evoked responses, but confidence, uniquely, incorporated information about attentional state. As such, our findings reveal distinct psychological and neural correlates of metacognitive judgments of attentional state, stimulus visibility, and decision confidence when these judgments are preceded by a cued target interval.

An Updated Review of Iclaprim: A Potent and Rapidly Bactericidal Antibiotic for the Treatment of Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Gram-Positive Including Multidrug-Resistant Bacteria.

New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and nosocomial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at -10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at -10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at -10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital-acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. This article will provide an update to the chemistry, preclinical, pharmacology, microbiology, clinical and regulatory status of iclaprim.

Time contracts and temporal precision declines when the mind wanders.

Our perception of time varies considerably from moment to moment, but how this variability relates to endogenous fluctuations in attentional states has been neglected. Here, we tested the hypothesis that perceptual decoupling during spontaneous mind wandering episodes distorts interval timing. In two studies with different visual subsecond interval timing paradigms, participants judged their attentional state on a trial-by-trial basis. Mind wandering states were characterized by underestimation of temporal intervals and a decline in temporal discrimination. Further analyses suggested that temporal contraction during mind wandering, but not the decline in temporal discrimination, could be attributed in part to attentional lapses. By contrast, we did not find any robust evidence that metacognition pertaining to interval timing was altered during mind wandering states. These results highlight the role of transient fluctuations in attentional states in intraindividual variability in time perception and have implications for the perceptual consequences, behavioral markers, and costs and benefits, of mind wandering. (PsycINFO Database Record

Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity.

The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hµrelrat™, Hµreldog™, and Hµrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, "time-based ratios" were determined by dividing the compounds' 24-hour TC50/Cmax values by TC50/Cmax values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies.

Attentional sampling of multiple wagon wheels.

Attending to a periodic motion stimulus can induce illusory reversals of the direction of motion. This continuous wagon wheel illusion (c-WWI) has been taken to reflect discrete sampling of motion information by visual attention. An alternative view is that it is caused by adaptation. Here, we attempt to discriminate between these two interpretations by asking participants to attend to multiple periodic motion stimuli: The discrete attentional sampling account, but not the adaptation account, predicts a decrease of c-WWI temporal-frequency tuning with set size (with a single periodic motion stimulus the c-WWI is tuned to a temporal frequency of 10 Hz). We presented one to four rotating gratings that occasionally reversed direction while participants counted reversals. We considered reversal overestimations as manifestations of the c-WWI and determined the temporal-frequency tuning of the illusion for each set size. Optimal temporal frequency decreased with increasing set size. This outcome favors the discrete attentional sampling interpretation of the c-WWI, with a sampling rate for each individual stimulus dependent on the number of stimuli attended.

Perceptual echoes at 10 Hz in the human brain.

The occipital alpha rhythm (∼10 Hz) is the most prominent electrophysiological activity in the awake human brain, yet its functional role and relation to visual perception are little understood. Transient stimuli normally elicit a short series of positive and negative deflections lasting between 300 and 500 ms: the visual-evoked potential (VEP). Alpha oscillations, on the other hand, are generally suppressed by transient visual input; they only augment in response to periodic ("steady-state") inputs around 10 Hz. Here, we applied reverse-correlation techniques to the visual presentation of random, nonperiodic dynamic stimulation sequences and found that the brain response to each stimulus transient was not merely a short-lived VEP but also included a strong ∼10 Hz oscillation that lasted for more than 1 s. In other words, the alpha rhythm implements an "echo" or reverberation of the input sequence. These echoes are correlated in magnitude and frequency with the observer's occipital alpha rhythm, are enhanced by visual attention, and can be rendered perceptually apparent in the form of ∼10 Hz flicker. These findings suggest a role for the alpha rhythm in the maintenance of sensory representations over time.

Trial-by-Trial Variations in Subjective Attentional State are Reflected in Ongoing Prestimulus EEG Alpha Oscillations.

Parieto-occipital electroencephalogram (EEG) alpha power and subjective reports of attentional state are both associated with visual attention and awareness, but little is currently known about the relationship between these two measures. Here, we bring together these two literatures to explore the relationship between alpha activity and participants' introspective judgments of attentional state as each varied from trial-to-trial during performance of a visual detection task. We collected participants' subjective ratings of perceptual decision confidence and attentional state on continuous scales on each trial of a rapid serial visual presentation detection task while recording EEG. We found that confidence and attentional state ratings were largely uncorrelated with each other, but both were strongly associated with task performance and post-stimulus decision-related EEG activity. Crucially, attentional state ratings were also negatively associated with prestimulus EEG alpha power. Attesting to the robustness of this association, we were able to classify attentional state ratings via prestimulus alpha power on a single-trial basis. Moreover, when we repeated these analyses after smoothing the time series of attentional state ratings and alpha power with increasingly large sliding windows, both the correlations and classification performance improved considerably, with the peaks occurring at a sliding window size of approximately 7 min worth of trials. Our results therefore suggest that slow fluctuations in attentional state in the order of minutes are reflected in spontaneous alpha power. Since these subjective attentional state ratings were associated with objective measures of both behavior and neural activity, we suggest that they provide a simple and effective estimate of task engagement that could prove useful in operational settings that require human operators to maintain a sustained focus of visual attention.

Visual perceptual load induces inattentional deafness.

In this article, we establish a new phenomenon of "inattentional deafness" and highlight the level of load on visual attention as a critical determinant of this phenomenon. In three experiments, we modified an inattentional blindness paradigm to assess inattentional deafness. Participants made either a low- or high-load visual discrimination concerning a cross shape (respectively, a discrimination of line color or of line length with a subtle length difference). A brief pure tone was presented simultaneously with the visual task display on a final trial. Failures to notice the presence of this tone (i.e., inattentional deafness) reached a rate of 79% in the high-visual-load condition, significantly more than in the low-load condition. These findings establish the phenomenon of inattentional deafness under visual load, thereby extending the load theory of attention (e.g., Lavie, Journal of Experimental Psychology. Human Perception and Performance, 25, 596-616, 1995) to address the cross-modal effects of visual perceptual load.

Human and environmental health challenges for the next decade (2010–2020).

The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.

A data-based assessment of alternative strategies for identification of potential human cancer hazards.

The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.

Load induced blindness.

Although the perceptual load theory of attention has stimulated a great deal of research, evidence for the role of perceptual load in determining perception has typically relied on indirect measures that infer perception from distractor effects on reaction times or neural activity (see N. Lavie, 2005, for a review). Here we varied the level of perceptual load in a letter-search task and assessed its effect on the conscious perception of a search-irrelevant shape stimulus appearing in the periphery, using a direct measure of awareness (present/absent reports). Detection sensitivity (d') was consistently reduced with high, compared to low, perceptual load but was unaffected by the level of working memory load. Because alternative accounts in terms of expectation, memory, response bias, and goal-neglect due to the more strenuous high load task were ruled out, these experiments clearly demonstrate that high perceptual load determines conscious perception, impairing the ability to merely detect the presence of a stimulus--a phenomenon of load induced blindness.

Applying mechanisms of chemical toxicity to predict drug safety.

Toxicology can no longer be used only as a science that reacts to problems but must be more proactive in predicting potential human safety issues with new drug candidates. Success in this area must be based on an understanding of the mechanisms of toxicity. This review summarizes and extends some of the concepts of an American Chemical Society ProSpectives meeting on the title subject held in June 2006. One important area is the discernment of the exact nature of the most common problems in drug toxicity. Knowledge of chemical structure alerts and relevant biological pathways are important. Biological activation to reactive products and off-target pharmacology are considered to be major contexts of drug toxicity, although defining exactly what the contributions are is not trivial. Some newer approaches to screening for both have been developed. A goal in predictive toxicology is the use of in vitro methods and database development to make predictions concerning potential modes of toxicity and to stratify drug candidates for further development. Such predictions are desirable for several economic and other reasons but are certainly not routine yet. However, progress has been made using several approaches. Some examples of the application of studies of wide-scale biological responses are now available, with incorporation into development paradigms.

The toxicology of HMG-CoA reductase inhibitors: prediction of human risk.

The discovery that 3-hydroxy-3-methyglutaryl coenzyme A reductase was a rate-determining step in the biosynthesis of cholesterol led to the discovery of inhibitors of this enzyme. To support the development of these agents (statins) as potential hypocholesterolemic drugs, a variety of preclinical studies were conducted in several animal species. Not unexpectedly due to the central role played by mevalonic acid and its products including cholesterol in development and maintenance of cellular homeostasis, administration of high dosage levels of these agents led to the expression of a broad variety of adverse effects in many different tissues. Using the tools of toxicologic pathology and classical risk assessment, these varied toxicities were evaluated by many groups relative to the conditions of use in human therapy and a perspective was developed on potential human risk. These approaches of mechanism-based risk assessment predicted that most of the adverse effects observed in animals would not be seen under conditions of human use and supported the successful introduction of one of the most important classes of human medicines.

Porcine toxicology studies of SCH 58500, an adenoviral vector for the p53 gene.

Adenoviral vectors are being actively investigated for their potential utility in gene therapy. SCH 58500, a replication-deficient adenoviral vector, carries the normal p53 tumor suppressor gene, which is frequently mutated or absent in several human cancers. To assess the potential toxicity associated with adenoviral use, Yorkshire pigs were dosed by intravenous, intrahepatic, or local routes (subcutaneous and intradermal) to support a variety of potential clinical indications. Porcine cells were shown to support replication of wild-type human adenovirus. The nonlethal and asymptomatic dose in pigs following dosing via the intrahepatic route was greater than 3 x 10(8) plaque-forming units (pfu)/kg (2.2 x 10(11) particles/kg), but less than 2.1 x 10(9) pfu/kg (1.5 x 10(12) particles/kg). By the intravenous route it was 1 x 10(8) pfu/kg, and by the ip route it was greater than or equal to 3 x 10(8) pfu/kg. In a multicycle intraperitoneal study in pigs, the high dose of 3 x 10(8) pfu/kg caused an increased antibody and/or an inflammatory response. By the intravenous route, plaque-forming units were present in most pigs at 5 min postdose, but only in a few at 10 min postdose. No expression was found in gonadal tissue approximately 3 weeks after a single intravenous injection of 3 x 10(8) pfu/kg. At high intrahepatic doses (about 1.5 x 10(12) particles/kg), acute cardiovascular and hemodynamic effects were found, which in subsequent studies were also present at high doses by intravenous administration. Based on these findings, careful evaluation of hemodynamic parameters in patients receiving systemic doses of SCH 58500 is warranted.

Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene.

SCH 58500 is a replication-defective recombinant adenoviral vector containing the cloned human wild-type (normal) tumor suppressor gene p53. SCH 58500 is in trials to evaluate potential clinical utility. A series of toxicology studies in rats and mice were conducted via multiple routes of exposure to support these programs. The nonlethal and asymptomatic dose in rats following a 14-day observation period was equal to 7.5 x 10(7) plaque-forming units (pfu)/kg (5.6 x 10(10) particles/kg) by intravenous or intraperitoneal route and was similar by the ip route, following 4 weeks of dosing. The high dose of 1.5 x 10(9) pfu/kg (1.1 x 10(12) particles/kg) was lethal by the i.v. route and inflammatory to the peritoneal cavity by the ip route. SCH 58500 was rapidly cleared from the systemic circulation in rats (serum t(1/2) of 7 to 9 min) following iv administration. Administration by other routes resulted in no (sc) or delayed (ip) serum levels. Since most rats in the i.v. rat study died within 24 h postdose, another study to evaluate potential mechanisms of toxicity in rats was designed in which rats were killed at intervals following a single i.v. dosing. A single high i.v. dose of SCH 58500 (1.1 x 10(12) pfu/kg) was associated with lethargy, soft feces, a ruffled-hair coat, and death within 1 h postdose. Potential mechanisms of toxicity appeared to include a mild coagulopathy and/or vasculopathy, resulting in consumption of platelets and clotting factors, leakage or loss of intravascular fluid, hemoconcentration, electrolyte and/or fluid shifts, a moderate stress and/or inflammatory response, and a mild, direct or indirect toxic effect on liver and/or kidney tissue. These findings suggest a multifocal cause for acute lethality following i.v. dosing in rats.

Toxicity and carcinogenicity studies of chlorpromazine hydrochloride and p-cresidine in the p53 heterozygous mouse model.

The carcinogenic potential of chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygous mouse assay. In a 4-week dose range finding study in p53 wild-type mice, doses of 20,40, 60, and 80 mg/kg were poorly tolerated because of mortality secondary to the severe sedative and hypotensive effects of chlorpromazine. Based on 40% mortality at a dose of 20 mg/kg in the dose-range finding study, a high dose of 10 mg/kg was chosen for the 26-week carcinogenicity study in p53 heterozygous mice. Doses of 2.5, 5, and 10 mg/kg chlorpromazine hydrochloride were well tolerated in the 26-week study. The administration of chlorpromazine hydrochloride at dose levels up to and including 10 mg/kg to p53 heterozygous and wild-type mice did not result in a dose-related increase in tumor incidence or in the type of tumors seen in comparison to controls. Findings related to the administration of chlorpromazine in the 26-week study were limited to minimal uterine and ovarian atrophy in p53 wild-type mice dosed with 10 mg/kg chlorpromazine hydrochloride. However, p53 heterozygous mice administered 400 mg/kg p-cresidine, a genotoxic carcinogen commonly used as a positive control for this model, developed urinary bladder tumors. Administration of p-cresidine also resulted in a regenerative anemia, splenic and hepatic hemosiderosis, renal findings, and ovarian and uterine atrophy. This study demonstrated that chlorpromazine hydrochloride, at the doses tolerated, was not carcinogenic in the p53 heterozygous mouse assay.