Testing two-step models of negative quantification using a novel machine learning analysis of EEG.

The sentences "More than half of the students passed the exam" and "Fewer than half of the students failed the exam" describe the same set of situations, and yet the former results in shorter reaction times in verification tasks. The two-step model explains this result by postulating that negative quantifiers contain hidden negation, which involves an extra processing stage. To test this theory, we applied a novel EEG analysis technique focused on detecting cognitive stages (HsMM-MVPA) to data from a picture-sentence verification task. We estimated the number of processing stages during reading and verification of quantified sentences (e.g. "Fewer than half of the dots are blue") that followed the presentation of pictures containing coloured geometric shapes. We did not find evidence for an extra step during the verification of sentences with fewer than half. We provide an alternative interpretation of our results in line with an expectation-based pragmatic account.

Evidence accumulation as a model for lexical selection.

We propose and demonstrate evidence accumulation as a plausible theoretical and/or empirical model for the lexical selection process of lexical retrieval. A number of current psycholinguistic theories consider lexical selection as a process related to selecting a lexical target from a number of alternatives, which each have varying activations (or signal supports), that are largely resultant of an initial stimulus recognition. We thoroughly present a case for how such a process may be theoretically explained by the evidence accumulation paradigm, and we demonstrate how this paradigm can be directly related or combined with conventional psycholinguistic theory and their simulatory instantiations (generally, neural network models). Then with a demonstrative application on a large new real data set, we establish how the empirical evidence accumulation approach is able to provide parameter results that are informative to leading psycholinguistic theory, and that motivate future theoretical development.

Perceptual decision neurosciences - a model-based review.

In this review we summarize findings published over the past 10 years focusing on the neural correlates of perceptual decision-making. Importantly, this review highlights only studies that employ a model-based approach, i.e., they use quantitative cognitive models in combination with neuroscientific data. The model-based approach allows capturing latent decision-making processes such as strategic adjustments of response thresholds and relate these to interindividual differences or single-trial blood-oxygenated level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) responses. The review shows that different cortico-subcortical networks are responsive to different latent decision-making processes. More concretely, we show that evidence accumulation is associated with a fronto-parietal network which is partly overlapping with choice bias in perceptual decision making. The setting of decision thresholds is associated with fronto-basal ganglia networks which are also found for choice bias. In sum, we argue that the model-based approach holds great promises to understand the neural correlates of latent cognitive processes.

Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors.

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.

Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors.

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

Safe handling of antineoplastic drugs. Results of a survey.

As research continues to highlight the risks involved in handling antineoplastic drugs, the health services are giving increased attention to safety measures. In order to establish what protective measures nursing staff employ and what they know about antineoplastic drugs, a survey was carried out in The Netherlands. The questions were based on the self-study modules by Dunne and the (American) Oncology Nursing Society. A total of 1,373 questionnaires were distributed in 10 hospitals. Of these, 824 were returned, which represents a response rate of 60%. Over two-thirds (68%) of the nursing staff reported that they were involved, on a daily or weekly basis, in caring for patients being treated with antineoplastic drugs. In the view of 94% of the nurses, protective measures are effective. While administering antineoplastic drugs, 91% of the respondents said that they wore gloves, 21% said that they wore a gown, 18% wore a mask, and 3% used goggles. While handling excreta, fewer nurses applied safety measures. Thirty-nine percent of the respondents knew that latex gloves offer a greater degree of protection than PVC gloves. It appeared that there was not one Dutch hospital whose guidelines for the safe handling of antineoplastic material were completely up-to-date and that nurses do not always follow the guidelines established.