What counts in estimation? The nature of the preverbal system.

It has been proposed that the development of verbal counting is supported by a more ancient preverbal system of estimation, the most widely canvassed candidates being the accumulator originally proposed by Gibbon and colleagues and the analogue magnitude system proposed by Dehaene and colleagues. The aim of this chapter is to assess the strengths and weaknesses of these models in terms of their capacity to emulate the statistical properties of verbal counting. The emphasis is put on the emergence of exact representations, autoscaling, and commensurability of noise characteristics. We also outline the modified architectures that may help improve models' power to meet these criteria. We propose that architectures considered in this chapter can be used to generate predictions for experimental testing and provide an example where we test the hypothesis whether the visual sense of number, ie, ability to discriminate numerosity without counting, entails enumeration of objects.

Nitrapyrin: a scientific advisory group review of the mode of action and carcinogenicity in B6C3F1 mice.

Nitrapyrin has been registered as a nitrogen stabilizer in the United States for many years based on a robust set of regulatory data. These data demonstrated that nitrapyrin was not genotoxic and that there were no tumors elicited in rats or mice that were relevant for human risk assessment. A repeat carcinogenicity study in B6C3F1 mice, conducted at two substantially higher-dose levels (0, 125 or 250 mg/kg/day) than the original study (0, 5, 25 or 75 mg/kg/day) identified liver, stomach, epididymal and Harderian gland tumors. In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The SAG determined that the maximum tolerated dose had been exceeded in mice given 125 or 250 mg/kg/day, based on 26-33% decreased body weight gains (males-250 mg/kg/day), hepatocellular necrosis and compensatory hepatocellular proliferation (males and females-125 and 250 mg/kg/day). The SAG believed that the increased incidences of hepatocellular foci of alteration and hepatocellular neoplasms represented an epigenetic response to hepatocellular necrosis and increased mitogenesis. Increased incidences of proliferative lesions in the forestomach mucosa were likely secondary to the irritant effects of nitrapyrin. Neither the liver nor forestomach effects were interpreted to be a direct carcinogenic effect. Higher incidences of Harderian gland adenomas (females) and undifferentiated sarcomas in the epididymis represented normal biological variations in incidence and were unrelated to nitrapyrin. Therefore, it was the SAG's opinion that nitrapyrin exposure that does not produce target organ toxicity in exposed individuals would not be expected to increase the risk of cancer.

Imaging informational conflict: a functional magnetic resonance imaging study of numerical stroop.

We employed a parametric version of the comparison Stroop paradigm to investigate the processing of numerical magnitude and physical size under task-relevant and -irrelevant conditions to investigate two theoretical issues: (1) What is the neural fate of task-irrelevant information? (2) What is the neural basis of the resolution of the conflict between task-relevant and -irrelevant information? We show in 18 healthy adults that numerical magnitudes of numbers call for higher processing requirements than physical sizes. The enhanced activation elicited by numerical magnitudes is not modulated by task relevance, indicating autonomous processing. Moreover, the normal behavioral distance effect when the numerical dimension is task relevant and reversed distance effect when it is not show that autonomous processing fully encodes numerical magnitudes. Conflict trials elicited greater activation in bilateral inferior frontal gyri, right middle frontal gyri, and right superior frontal gyri. We postulate two sources to the conflict, namely, at cognitive and response levels.

To play 'B' but not to say 'B': selective loss of letter names.

This paper is the first report of an aphasic patient (GT) who shows a selective impairment in naming musical notes and letters in the context of preserved instrumental reading of notes. The ability to orally name notes (which are given the letter names A-G in English) and to play notes from a spoken note name was severely impaired. By contrast, instrumental sightreading and matching of written letters and single notes were both well preserved. This complex pattern of impairments can be explained in terms of a selective deficit in the letter name system.

Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice.

Bromodichloromethane (BDCM) is a common municipal drinking water disinfection by-product, resulting in widespread trace human exposure via ingestion and inhalation. The present studies were designed to define organ-specific, BDCM-induced toxicity in wild type (p53(+/+)) and heterozygous (p53(+/-)) mice on both the FVB/N and C57BL/6 genetic backgrounds. Mice were exposed to BDCM vapor daily for 6 h/day and 7 days/week at concentrations of 0, 1, 10, 30, 100, or 150 ppm for 1 week and at 0, 0.3, 1, 3, 10, or 30 ppm for 3 weeks. In the 1-week exposure study, dose-dependent mortality and morbidity were observed at concentrations of 30 ppm and above and were as high as 100% at 150 ppm. In the 3-week exposure study, mortality and morbidity were found only in the 30-ppm exposure groups and were 0, 17, 67, and 33% for the wild-type C57BL/6, p53(+/-) C57BL/6, wild-type FVB/N, and p53(+/-) FVB/N mice, respectively. BDCM was a particularly potent kidney cytotoxicant. Dose-dependent tubular degeneration, necrosis, and associated regenerative cell proliferation greater than 10-fold over controls were seen at concentrations as low as 10 ppm in the kidneys of all strains at 1 week. Similar dose-dependent increases in hepatic necrosis, degeneration, and regenerative cell proliferation were observed but were induced only at concentrations of 30 ppm and higher. Pathological changes were more severe in the FVB/N compared to the C57BL/6 mice and were more severe in the heterozygotes compared to the wild-type mice. However, recovery and return of the percentage of kidney cells in S-phase to control levels was seen at 3 weeks. The estimated maximum tolerated dose for longer-term exposures was 15 ppm, based on mortality, induced kidney pathology, and regenerative cell proliferation. A one-year cancer bioassay was initiated with doses of 0, 0.5, 3, 10, and 15 ppm, based on this information. No pathological changes in the livers were found at the 13-week time point of that study. At 13 weeks, the kidney lesions and regenerative cell proliferation seen at the 1-week time point at doses of 10 ppm and above had resolved, and the cell proliferation rates had returned to baseline. Differences in toxicity indicate that caution be used in substituting wild-type mice for transgenic mice for range-finding studies to select doses for p53(+/-) cancer studies. Resolution of the kidney lesions indicates that periods of very high regenerative cell proliferation, potentially important in the carcinogenic process, may not be observed if measurements are taken only at 3 weeks of exposure or later.

Branchial elimination of superhydrophobic organic compounds by rainbow trout (Oncorhynchus mykiss).

The branchial elimination of pentachloroethane and four congeneric polychlorinated biphenyls by rainbow trout was measured using a fish respirometer-metabolism chamber and an adsorption resin column. Branchial elimination was characterized by calculating a set of apparent in vivo blood:water partition coefficients (P(BW)). Linear regression was performed on the logarithms of P(BW) estimates and the log K(OW) value for each compound to give the fitted equation: log P(BW)=0.76 x log K(OW)-1.0 (r(2)=0.98). The linear nature of this relationship provides support for existing models of chemical flux at fish gills and suggests that a near equilibrium condition was established between chemical in venous blood entering the gills, including dissolved and bound forms, and dissolved chemical in expired branchial water. In vivo P(BW) estimates were combined with P(BW) values determined in vitro for a set of lower log K(OW) compounds (Bertelson et al., Environ. Toxicol. Chem. 17 (1998) 1447-1455) to give the fitted relationship: log P(BW)=0.73 x log K(OW)-0.88 (r(2)=0.98). The slope of this equation is consistent with the suggestion that chemical binding to non-lipid organic material contributes substantially to blood:water chemical partitioning. An equation based on the composition of trout blood (water content and the total amount of organic material) was then derived to predict blood:water partitioning for compounds with log K(OW) values ranging from 0 to 8: log P(BW)=log[(10(0.73 log K(ow)) x 0.16)+0.84].

Number-Stroop performance in normal aging and Alzheimer's-type dementia.

The number-Stroop paradigm was used to investigate changes in the inhibitory system and in numerical processing in healthy elderly and individuals with dementia of Alzheimer's type (DAT). The size-congruity effect (i.e., relative to neutral trials, incongruent pairs interfere and/or congruent pairs facilitate either numerical or physical comparison) was found in all groups, though the pattern of interference and facilitation varied across them. Overall, the selective attention breakdown was reflected by the increase in interference shown by the older group and the DAT group. On the other hand, the observation of a standard laterality effect andof automatic numerical processing in all groups suggests that access and retrieval of numerical information is relatively resistant to cognitive deterioration.

Spared numerical abilities in a case of semantic dementia.

We report a case study of a patient (IH) with a progressive impairment of semantic memory affecting all categories of knowledge apart from numbers. Pictorial material was better understood than words, but was still severely impaired. The selective preservation of nearly all aspects of numerical knowledge suggested that this domain might have different neuropsychological status from other aspects of semantic memory.

Category specificity in reading and writing: the case of number words.

In standard models, word meanings contribute to reading words aloud and writing them to dictation. It is known that categories of knowledge and the associated word meanings can be spared or impaired selectively, but it has not been possible to demonstrate that category-specific effects apply to reading and writing. Here we report the case of a neurodegenerative patient with selectively spared numerical abilities whose brain damage left him able to read and write only number words.

Palilalia and repetitive speech: two case studies.

Palilalia, a disorder of speech characterized by compulsive repetitions of utterances has been found in various neurological and psychiatric disorders. It has commonly been interpreted as a defect of motor speech. This article describes palilalia and other variants of verbal repetitive behavior, such as monosyllabic iterations and conduite d'approche. The clinical features of palilalia, its prevalence in different language tasks, and the individual patterns of verbal repetitive behavior are illustrated in two patients with a long-standing cerebrovascular disease. An attempt is made to locate the origin of different forms of verbal repetitions in a standard model of speech production (Butterworth, 1980a; Garrett, 1980; Levelt, 1989) by analysis of their morphology and correlation with impairments of lexical or phonological processes. From these observations it is suggested that palilalia results from control malfunctions at the level of the Articulator, whereas other variants of pathological verbal iterations result from an impairment of the Formulator or from malfunctions of both the Articulator and the Formulator.

Dietary uptake kinetics of 2,2',5,5'-tetrachlorobiphenyl in rainbow trout.

The disposition of [UL-(14)C]2,2',5,5'-tetrachlorobiphenyl (TCB) in rainbow trout (Oncorhynchus mykiss) was studied in acute dietary exposures using TCB-contaminated fathead minnows (Pimephales promelas). Trout were sampled at several postfeeding time points and TCB-derived radioactivity was measured in gut contents and selected tissues. Gastric evacuation was exponential with time and was 95% complete within 36 h of feeding. The ratio of activity in upper intestinal tissue to that in blood declined between 6 and 48 h, as did the lumenal contents/tissue ratio. Stomach content lipid declined between 0 and 24 h, while the lipid content of chyme remained relatively constant. These observations are consistent with liquid phase emptying of lipid and TCB to the upper intestine followed by rapid coassimilation. Tissue/blood activity ratios for the stomach, lower intestine, muscle, liver, and kidney were constant and probably represented near equilibrium conditions. The fat/blood activity ratio increased through 96 h, indicating that TCB was redistributing to fat. The lower intestinal tissue/feces activity ratio increased between 6 and 24 h and then declined rapidly. Fecal lipid content also increased between 6 and 24 h, but the amount of this increase was insufficient to explain observed changes in the distribution of TCB-derived activity. A small amount of 3-hydroxy TCB was detected in feces. Generally, however, metabolism had little or no impact on the uptake, distribution or elimination of TCB. Measured assimilation efficiencies exceeded 90% and are the highest ever reported in fish feeding studies with TCB.

The preparation of anthraquinone used in the National Toxicology Program cancer bioassay was contaminated with the mutagen 9-nitroanthracene.

Commercial anthraquinone (AQ) (9,10-anthracenedione) is produced by at least three different production methods worldwide: oxidation of anthracene (AQ-OX), Friedel-Crafts technology (AQ-FC) and by Diels-Alder chemistry (AQ-DA), with the final product varying in color and purity. AQ-OX begins with anthracene produced from coal tar and different lots can contain various contaminants, particularly the mutagenic isomers of nitroanthracene. AQ has been reported to be negative in a variety of genotoxicity tests including numerous Ames Salmonella mutagenicity assays. In addition, we report that AQ-DA is negative in the Salmonella-Escherichia coli reverse mutation assays, the L5178Y mouse lymphoma forward mutation assay, for inducing chromosomal aberrations, polyploidy or endoreduplication in Chinese hamster ovary cells, and in the in vivo mouse micronucleus assay. Further, a previous 18 month bioassay conducted with AQ administered to male and female B6C3F(1) and (C57BL/6xAKR)F(1) mice reported no induction of cancer. Thus, it was somewhat unexpected that in a long-term study conducted by the National Toxicology Program (NTP) AQ-OX induced a weak to modest increase in tumors in the kidney and bladder of male and female F344/N rats and a strong increase in the livers of male and female B6C3F(1) mice. In the studies reported here, a sample of the AQ-OX used in the NTP bioassay was shown to be mutagenic in the Ames tester strains TA98, TA100 and TA1537. Addition of an S9 metabolic activation system decreased or eliminated the mutagenic activity. In contrast, the purified NTP AQ-OX as well as the technical grade samples AQ-FC and AQ-DA were not mutagenic in the Ames test. The chemical structure of AQ does not suggest that the parent compound would be DNA reactive. Therefore, a mutagenic contaminant was present in the NTP bioassay sample that is either directly mutagenic or can be activated by bacterial metabolism. Analytical studies showed that the primary contaminant 9-nitroanthracene (9-NA) was present in the NTP AQ-OX at a concentration of 1200 p.p.m., but not in the purified material. The 9-NA and any other contaminants that might have been present in the NTP AQ-OX induced measurable mutagenicity at 9-NA concentrations as low as 0.15 microg/plate in tester strain TA98, indicating potent mutagenic activity. On the basis of revertants per microgram, 9-NA was more potent than benzo[a]pyrene (B[a]P) and was about equally as potent as the 2-nitrofluorene run concurrently as positive controls. TD(50) quantitative carcinogenicity potency estimates indicate that a carcinogen of a potency in the range between B[a]P and dimethylnitrosamine would be required to produce the observed carcinogenic response at the levels of the contaminants found in the test sample. While recognizing that there are limitations in extrapolating mutagenic potency to potential carcinogenic potency, these estimates do indicate that it is plausible that the 9-NA contaminant might have been responsible for all of the tumor induction observed in the NTP study. In fact, in the absence of reliable cancer data, the genetic toxicology profile indicates that AQ would not be a genotoxic carcinogen. Thus, no conclusion as to the carcinogenic activity of AQ can be made at this time.

Storage and retrieval of addition facts: the role of number comparison.

It is proposed that arithmetical facts are organized in memory in terms of a principle that is unique to numbers--the cardinal magnitudes of the addends. This implies that sums such as 4 + 2 and 2 + 4 are represented, and searched for, in terms of the maximum and minimum addends. This in turn implies that a critical stage in solving an addition problem is deciding which addend is the larger. The COMP model of addition fact retrieval incorporates a comparison stage, as well as a retrieval stage and a pronunciation stage. Three tasks, using the same subjects, were designed to assess the contribution of these three stages to retrieving the answers to single-digit addition problems. Task 3 was the addition task, which examined whether reaction times (RTs) were explained by the model; Task 1 was a number naming task to assess the contribution of the pronunciation stage; Task 2 was a magnitude comparison task to assess the contribution, if any, of the comparison stage. A regression equation that included just expressions of these three stages was found to account for 71% of the variance. It is argued that the COMP model fits not only the adult RT data better than do alternatives, but also the evidence from development of additional skills.

Repetitive speech phenomena in Parkinson's disease.

OBJECTIVES: Repetitive speech phenomena are morphologically heterogeneous iterations of speech which have been described in several neurological disorders such as vascular dementia, progressive supranuclear palsy, Wilson's disease, and Parkinson's disease, and which are presently only poorly understood. The present, prospective study investigated repetitive speech phenomena in Parkinson's disease to describe their morphology, assess their prevalence, and to establish their relation with neuropsychological and clinical background data. METHODS: Twenty four patients with advanced Parkinson's disease and 29 subjects with mid-stage, stable idiopathic disease were screened for appearance, forms, and frequency of repetitive speech phenomena, and underwent a neuropsychological screening procedure comprising tests of general mental functioning, divergent thinking and memory. Patients with advanced Parkinson's disease had a significantly higher disease impairment, longer disease duration, and an unstable motor response to levodopa with frequent on-off fluctuations. Both groups were well matched as to their demographical, clinical, and cognitive background. Perceptual speech evaluation was used to count and differentiate forms of repetitive speech phenomena in different speech tasks. To compare the effect of the motor state, the appearance of repetitive speech phenomena was also assessed in a subgroup of patients with advanced Parkinson's disease during the on versus the off state. RESULTS: Speech repetitions emerged mainly in two variants, one hyperfluent, formally resembling palilalia, and one dysfluent, stuttering-like. Both forms were present in each patient producing repetitive speech phenomena. The repetitive speech phenomena appeared in 15 patients (28.3 %), 13 of whom belonged to the advanced disease group, indicating a significant preponderance of repetitive speech phenomena in patients with a long term, fluctuating disease course. Repetitive speech phenomena appeared with almost equal frequency during the on and the off state of patients with advanced Parkinson's disease. Their distribution among different variants of speech was disproportional, with effort demanding speech tasks producing a significantly higher number of repetitive speech phenomena over semiautomatic forms of speech. CONCLUSIONS: In idiopathic Parkinson's disease repetitive speech phenomena seem to emerge predominantly in a subgroup of patients with advanced disease impairment; manifest dementia is not a necessary prerequisite. They seem to represent a deficit of motor speech control; however, linguistic factors may also contribute to their generation. It is suggested that repetitions of speech in Parkinson's disease represent a distinctive speech disorder, which is caused by changes related to the progression of Parkinson's disease.

The odd-even effect in multiplication: parity rule or familiarity with even numbers?

This study questions the evidence that a parity rule is used during the verification of multiplication. Previous studies reported that products are rejected faster when they violate the expected parity, which was attributed to the use of a rule (Krueger, 1986; Lemaire & Fayol, 1995). This experiment tested an alternative explanation of this effect: the familiarity hypothesis. Fifty subjects participated in a verification task with contrasting types of problems (even x even, odd x odd, mixed). Some aspects of our results constitute evidence against the use of the parity rule: False even answers were rejected slowly, even when the two operands were odd. We suggest that the odd-even effect in verification of multiplication could not be due to the use of the parity rule, but rather to a familiarity with even numbers (three quarters of products are indeed even).

The development of automaticity in accessing number magnitude.

This study traces developmental changes in automatic and intentional processing of Arabic numerals using a numerical-Stroop paradigm. In Study 1, university students compared the numerical or physical size of Arabic numerals varying along both dimensions. In Study 2, first graders (mean age = 6 years 6 months), third graders (mean age = 8 years 4 months), and fifth graders (mean age = 10 years 3 months) were tested to examine developmental changes in numerical and physical comparisons. In the numerical comparison task, a size congruity effect was found at all ages (i.e., relative to a neutral control, congruent physical sizes facilitated, and incongruent sizes interfered with, the numerical comparison). The pattern of facilitation and interference, however, was modulated by age. In the physical comparison task, the incongruity between physical and numerical size affected only older children and adults. These findings strongly suggest that the automatization in number processing is achieved gradually as numerical skills progress.

Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency.

Elevated and sustained cell replication, together with a decrease in apoptosis, is considered to be the main mechanism of hepatic tumor promotion due to peroxisome proliferators. In contrast, the role of oxidative stress and DNA damage in the carcinogenic mechanism is less well understood. In view of possible induction of DNA damage by peroxisome proliferators, DNA repair mechanisms may be an important factor to consider in the mechanism of action of these compounds. Here, the ability of peroxisome proliferators to induce expression of base excision repair enzymes was examined. WY-14,643, a potent carcinogen, increased expression of several base excision DNA repair enzymes in a dose- and time-dependent manner. Importantly, expression of enzymes that do not repair oxidative DNA damage was not changed. Moreover, less potent members of the peroxisome proliferator group had much weaker or no effects on expression of DNA repair enzymes when compared with WY-14,643. Collectively, these data suggest that DNA base excision repair may be an important factor in peroxisome proliferator-induced carcinogenesis and that induction of DNA repair might provide further evidence supporting a role of oxidative DNA damage by peroxisome proliferators.

Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice.

Chloroform is a nongenotoxic-cytotoxic liver and kidney carcinogen and nasal toxicant in some strains and sexes of rodents. Substantial evidence indicates that tumor induction is secondary to events associated with cytolethality and regenerative cell proliferation. Therefore, pathways leading to toxicity, such as metabolic activation, become critical information in mechanism-based risk assessments. The purpose of this study was to determine the degree to which chloroform-induced cytotoxicity is dependent on the cytochromes P450 in general and P450 2E1 in particular. Male B6C3F(1), Sv/129 wild-type (Cyp2e1+/+), and Sv/129 CYP2E1 knockout (Cyp2e1-/- or Cyp2e1-null) mice were exposed 6 h/day for 4 consecutive days to 90 ppm chloroform by inhalation. Parallel control and treated groups, excluding Cyp2e1-null mice, also received an i.p. injection (150 mg/kg) of the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) twice on the day before exposures began and 1 h before every exposure. Cells in S-phase were labeled by infusion of BrdU via an implanted osmotic pump for 3.5 days prior to necropsy, and the labeling index was quantified immunohistochemically. B6C3F(1) and Sv/129 wild-type mice exposed to chloroform alone had extensive hepatic and renal necrosis with significant regenerative cell proliferation. These animals had minimal toxicity in the nasal turbinates with focal periosteal cell proliferation. Administration of ABT completely protected against the hepatic, renal, and nasal toxic effects of chloroform. Induced pathological changes and regenerative cell proliferation were absent in these target sites in Cyp2e1-/- mice exposed to 90 ppm chloroform. These findings indicate that metabolism is obligatory for the development of chloroform-induced hepatic, renal, and nasal toxicity and that cytochrome P450 2E1 appears to be the only enzyme responsible for this cytotoxic-related metabolic conversion under these exposure conditions.