Peripheral and parafoveal cueing and masking effects on saccadic selectivity in a gaze-contingent window paradigm.

The present study employed the gaze-contingent window paradigm to investigate parafoveal and peripheral cueing and masking effects on saccadic selectivity in a triple-conjunction visual search task. In the cueing conditions, the information shown outside the gaze-contingent window was restricted to the feature or feature pair shared between the target and a particular distractor type. In the masking conditions, no stimulus features were shown outside the window. Significant cueing and masking effects on saccadic selectivity were observed for saccades directed at items within the window, where all features were visible across experimental conditions. Cueing a particular feature or feature pair biased saccadic selectivity towards this feature or feature pair, while masking generally reduced saccadic selectivity. These findings support the concept of visual guidance being a preattentive process that operates in parallel across the display.

Investigating the visual span in comparative search: the effects of task difficulty and divided attention.

In three experiments, participants' visual span was measured in a comparative visual search task in which they had to detect a local match or mismatch between two displays presented side by side. Experiment 1 manipulated the difficulty of the comparative visual search task by contrasting a mismatch detection task with a substantially more difficult match detection task. In Experiment 2, participants were tested in a single-task condition involving only the visual task and a dual-task condition in which they concurrently performed an auditory task. Finally, in Experiment 3, participants performed two dual-task conditions, which differed in the difficulty of the concurrent auditory task. Both the comparative search task difficulty (Experiment 1) and the divided attention manipulation (Experiments 2 and 3) produced strong effects on visual span size.

Visual span in expert chess players: evidence from eye movements.

The reported research extends classic findings that after briefly viewing structured, but not random, chess positions, chess masters reproduce these positions much more accurately than less-skilled players. Using a combination of the gaze-contingent window paradigm and the change blindness flicker paradigm, we documented dramatically larger visual spans for experts while processing structured, but not random, chess positions. In addition, in a check-detection task, a minimized 3 x 3 chessboard containing a King and potentially checking pieces was displayed. In this task, experts made fewer fixations per trial than less-skilled players, and had a greater proportion of fixations between individual pieces, rather than on pieces. Our results provide strong evidence for a perceptual encoding advantage for experts attributable to chess experience, rather than to a general perceptual or memory superiority.

The perceptual aspect of skilled performance in chess: evidence from eye movements.

Expert and intermediate chess players attempted to choose the best move in five chess positions while their eye movements were monitored. Experts were faster and more accurate than intermediates in choosing the best move. Experts made fewer fixations per trial and greater amplitude saccades than did intermediates, but there was no difference in fixation duration across skill groups. Examining the spatial distribution of the first five fixations for each position by skill group revealed that experts produced more fixations on empty squares than did intermediates. When fixating pieces, experts produced a greater proportion of fixations on relevant pieces than did intermediates. It is argued that expert chess players perceptually encode chess configurations, rather than individual pieces, and, consequently, parafoveal or peripheral processing guides their eye movements, producing a pattern of saccadic selectivity by piece saliency.

Bioavailability study of oral liquid and tablet forms of alpha-difluoromethylornithine.

The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.

Distractor ratio influences patterns of eye movements during visual search.

We examined the flexibility of guidance in a conjunctive search task by manipulating the ratios between different types of distractors. Participants were asked to decide whether a target was present or absent among distractors sharing either colour or shape. Results indicated a strong effect of distractor ratio on search performance. Shorter latency to move, faster manual response, and fewer fixations per trial were observed at extreme distractor ratios. The distribution of saccadic endpoints also varied flexibly as a function of distractor ratio. When there were very few same-colour distractors, the saccadic selectivity was biased towards the colour dimension. In contrast, when most of the distractors shared colour with the target, the saccadic selectivity was biased towards the shape dimension. Results are discussed within the framework of the guided search model.

Score comparability of a state mathematics assessment across students with and without reading accommodations.

This study investigated the factorial invariance of a fourth-grade state mathematics assessment across groups of general education students and students with learning disabilities with and without reading accommodations. Confirmatory factor analysis was used to assess the fit of a 2-factor model to each of the 3 groups. In addition to the overall fit of this model, several levels of constraint were investigated. Invariance across the 3 groups was supported for factor loadings and intercepts. However, invariance of the factor covariances across the general education group and the groups of students with learning disabilities was not supported. Because of the implications for aggregating reported scores, further research is needed into the relationship between the factors in the different groups.

Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day.

We conducted a phase I dose-escalation trial of perillyl alcohol (POH; NSC 641066) given p.o. on a continuous four times a day basis to characterize the maximum tolerated dose, toxicities, pharmacokinetic profile, and antitumor activity. Sixteen evaluable patients with advanced refractory malignancies were treated at the following doses: level 1 (L1), 800 mg/m2/dose; L2, 1200 mg/m2/dose; L3, 1600 mg/m2/dose. POH was formulated in soft gelatin capsules containing 250 mg of POH and 250 mg of soybean oil. The predominant toxicities seen were gastrointestinal (nausea, vomiting, satiety, and eructation), which were dose limiting. There appeared to be a dose-dependent increase in levels of the two main metabolites, perillic acid and dihydroperillic acid. No significant differences were seen whether the drug was taken with or without food. There was a trend toward decreasing metabolite levels on day 29 compared with days 1 and 2. Peak metabolite levels were seen 1-3 h post ingestion. Metabolite half-lives were approximately 2 h. Approximately 9% of the total dose was recovered in the urine in the first 24 h, the majority as perillic acid. Evidence of antitumor activity was seen in a patient with metastatic colorectal cancer who has an ongoing near-complete response of > 2 years duration. Several other patients were on study for > or = 6 months with stable disease. The maximum tolerated dose of POH given continuously four times a day was 1200 mg/m2/dose. Gastrointestinal toxicity was dose limiting, although significant interpatient variability in drug tolerance was seen.

A randomized, placebo-controlled trial of low-dose alpha-difluoromethylornithine in individuals at risk for colorectal cancer.

DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. The goal of this study was to determine the effects of DFMO 0.5 g/m2/day as a single oral dose on polyamine and ODC levels in rectal, rectosigmoidal, and cecal colonic mucosae of individuals at risk for colon cancer because of a personal history of adenomatous polyps of the colon or a family history of colon cancer in at least one first-degree relative. A second goal was to determine toxicity of this treatment given over 1 year. Forty-five randomized subjects had a flexible sigmoidoscopy with no preparation and a colonoscopy after lavage preparation at baseline, a sigmoidoscopy with no preparation after 3 months, and both procedures (as at baseline) after 12 months, with mucosal biopsies taken from the rectosigmoid area (sigmoidoscopy) or rectal and cecal areas (colonoscopy) for evaluations of ODC and polyamine levels. Significantly decreased levels of putrescine and spermidine were found in rectosigmoid colonic mucosae of DFMO-treated (n = 24) compared with placebo (n = 21) subjects at 3 months (P = 0.03 and 0.04) and 12 months (P = 0.005, P = 0.004). Similar trends, none reaching statistical significance, were found for individual polyamine levels in rectal and cecal mucosae. No significant differences in ODC levels were detected marginally. There was evidence of global suppression of ODC and polyamine levels in the treatment group (P = 0.035). Three DFMO recipients (12.5%) developed clinically noticeable and audiologically demonstrated hearing loss, which was reversible and attributed to DFMO after 3 months (two subjects) and 12 months (one subject). The tissue polyamine changes demonstrated in this study are consistent with findings in other studies in colon and other tissues. The ototoxicity findings here suggest that investigation of other DFMO schedules, such as ones with a drug "holiday," will be a necessary step before Phase III chemoprevention studies can be pursued.

Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.

Fixation behavior in observation and imitation of human movement.

This paper describes experiments performed with 40 subjects wearing an eye-tracker and watching and imitating videos of finger, hand, and arm movements. For all types of stimuli, the subjects tended to fixate on the hand, regardless of whether they were imitating or just watching. The results lend insight into the connection between visual perception and motor control, suggesting that: (1) people analyze human arm movements largely by tracking the hand or the end-point, even if the movement is performed with the entire arm, and (2) when imitating, people use internal innate and learned models of movement, possibly in the form of motor primitives, to recreate the details of whole-arm posture and movement from end-point trajectories.

Phase I clinical trial of perillyl alcohol administered daily.

Perillyl alcohol (POH; NSC-641066), a naturally occurring monoterpene, has shown antitumor and preventive activity in preclinical studies in rodent models. Drug-related activities that have been observed include the induction of apoptosis, cell cycle arrest, the inhibition of posttranslational modification of proteins that are involved in signal transduction, and differential gene regulation. We treated 18 patients who had advanced malignancies with POH, which was given on a continuous three-times-a-day schedule at the following doses: (a) level 1 (L1), 800 mg/m2/dose; (b) level 2 (L2), 1600 mg/m2/dose; and (c) level 3 (L3), 2400 mg/m2/dose. The main toxicity, which seemed to be dose related, was gastrointestinal and included nausea and vomiting, anorexia, unpleasant taste, satiety, and eructation. Two heavily pretreated ovarian cancer patients experienced reversible > or =grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The parent drug was not detectable in the plasma. The mean peak plasma levels of the two main metabolites on days 1 and 29 were 175 and 139 microM (L1), 472 and 311 microM (L2), and 456 and 257 microM (L3) for perillic acid (PA) and 7.1 and 9.8 microM (L1), 34.2 and 34.0 microM (L2), and 26.2 and 23.4 microM (L3) for dihydroperillic acid (DHPA). Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA. Metabolite half-lives measured about 2 h for each. POH, PA, and DHPA were detectable in the urine of all patients at L3. About 9% of the total dose was recovered in the first 24 h. The majority was recovered as PA; less than 1% was recovered as POH. Disease stabilization for > or =6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosing schedule.

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin.

Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements. Patients with peak plasma suramin concentrations in excess of 350 mg/liter may be more likely to experience neurotoxicity (P = 0.06), but there was no statistically significant effect of peak suramin concentration or of cumulative dose. Biopsy and autopsy tissue samples demonstrated low penetration of suramin into brain tissue and muscle but good penetration into prostate and other visceral organs. Prospective use of surrogate substrates for CYP1A2, CYP3A3/4, and CYP2D6 showed no consistent effect of suramin on these enzymes. Although a correlation between creatinine clearance and suramin renal clearance was found (r2 = 0.38; P < 0.00005), there was no correlation between creatinine clearance and total suramin clearance (P = 0.21). No suramin dose modification for renal or hepatic dysfunction can be supported at this time. Three of four ovarian cancer patients demonstrated a drop in CA-125 serum concentrations during suramin treatment.

Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.

BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Disambiguating complex visual information: towards communication of personal views of a scene.

Two experiments on the perception and eye-movement scanning of a set of six overtly ambiguous pictures are reported. In the first experiment it was shown that specific perceptual interpretations of an ambiguous picture usually correlate with parameters of the gaze-position distributions. In the second experiment these distributions were used for an image processing of initial pictures in such a way that in regions which attracted less fixations the brightness of all elements was lowered. The preprocessed pictures were then shown to a group of 150 naïve subjects for an identification. The results of this experiment demonstrated that in four out of six pictures it was possible to influence perception of other persons in the predicted way, ie to shift spontaneous reports of naïve subjects in the direction of interpretations that accompanied gaze-position data used for the preprocessing of initial pictures. Possible reasons for a failure of such a communication of personal views in two cases are also discussed.

[Working memory and work with memory: visual-spatial and further components of processing]. / Arbeitsedächtnis und Arbeit mit dem Gedächtnis: Visuell-räumliche und weitere Komponenten der Verarbeitung.

Empirical and theoretical evidence for the concept of working memory is considered. We argue that the major weakness of this concept is its loose connection with the knowledge about background perceptive and cognitive processes. Results of two relevant experiments are provided. The first study demonstrated the classical chunking effect in a speeded visual search and comparison task, the proper domain of a large-capacity very short term sensory store. Our second study was a kind of extended levels-of-processing experiment. We attempted to manipulate visual, phonological, and (different) executive components of long-term memory in the hope of finding some systematic relationships between these forms of processing. Indeed, the results demonstrated a high degree of systematicity without any apparent need for a concept such as working memory for the explanation. Accordingly, the place for working memory is at all the interfaces where our metacognitive strategies interfere with mostly domain-specific cognitive mechanisms. Working memory is simply our work with memory.

Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an attempt at modulation of glutathione.

PURPOSE: A phase I dose-escalation trial of intravenous (IV) L-buthionine-SR-sulfoximine (BSO) with melphalan (L-PAM) was performed to determine the toxicity and biologic activity of BSO, administered as a short infusion every 12 hours, and the combination of BSO plus L-PAM. PATIENTS AND METHODS: Twenty-eight patients with refractory malignancies received 30-minute infusions of BSO every 12 hours for 6 to 10 doses in week 1 followed in week 2 by either IV L-PAM (15 mg/m2) alone or BSO as in week 1 with L-PAM. Patients received the combination in week 5 (course no. 2) if they received L-PAM alone during week 2 and vice versa. BSO doses ranged from 1.5 g/m2 to 13.104 g/m2. RESULTS: The only toxicity observed with BSO infusions was occasional nausea/vomiting. Evaluation of 23 paired courses (L-PAM plus BSO v L-PAM) showed significantly (P < .001) greater leukopenia and thrombocytopenia with L-PAM plus BSO. No other significant toxicity was noted. Measurement of intracellular glutathione (GSH) levels in peripheral mononuclear cells (PBLs) of all patients receiving BSO showed a consistent, non-dose-dependent, linear decrease in GSH with repeated BSO doses. Maximal GSH depletion (40% of baseline values, absolute values 200 to 250 ng/10(6) PBLs) was noted after the sixth BSO dose; extended BSO dosing schedules beyond six total BSO doses did not further deplete GSH. Evaluation of gamma-glutamylcysteine synthetase (GCS) activity showed marked inhibition near the end of each infusion with near complete recovery of GCS activity before the next BSO dose. The pattern of GCS inhibition mirrored the plasma BSO concentrations with peak values (level 6, 4 to 8 mmol/L L,R+L,S BSO) observed at the end of the infusion with a rapid decrease in plasma concentrations with an estimated half-life (t1/2) of less than 2 hours. Differential elimination of the R+S stereoisomers was observed. Analysis of L-PAM pharmacokinetics showed marked interpatient variability and a significant decrease in total-body clearance (P = .01) and volume of distribution (P = .03) in courses with L-PAM plus BSO as compared with L-PAM alone. CONCLUSION: This study shows that BSO alone and in combination with L-PAM can be safely given to patients, but that a schedule of short infusions every 12 hours does not result in GSH depletion less than 30% of baseline values.

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

BACKGROUND: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice. PURPOSE: A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]). METHODS: Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels. RESULTS: In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour. CONCLUSIONS: These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day. IMPLICATIONS: Studies investigating prevention of cancers with DFMO are under consideration.