Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome.

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

Epileptic seizures can be anticipated by non-linear analysis.

Epileptic seizures are a principal brain dysfunction with important public health implications, as they affect 0.8% of humans. Many of these patients (20%) are resistant to treatment with drugs. The ability to anticipate the onset of seizures in such cases would permit clinical interventions. The view of chronic focal epilepsy now is that abnormally discharging neurons act as pacemakers to recruit and entrain other normal neurons by loss of inhibition and synchronization into a critical mass. Thus, preictal changes should be detectable during the stages of recruitment. Traditional signal analyses, such as the count of focal spike density, the frequency coherence or spectral analyses are not reliable predictors. Non-linear indicators may undergo consistent changes around seizure onset. Our objective was to follow the transition into seizure by reconstructing intracranial recordings in implanted patients as trajectories in a phase space and then introduce non-linear indicators to characterize them. These indicators take into account the extended spatio-temporal nature of the epileptic recruitment processes and the corresponding physiological events governed by short-term causalities in the time series. We demonstrate that in most cases (17 of 19), seizure onset could be anticipated well in advance (between 2-6 minutes beforehand), and that all subjects seemed to share a similar 'route' towards seizure.

Onset and offset of brain events as indices of mental chronometry.

Analysis of single-trial electroencephalogram waveforms in a reaction time task demonstrated that the onset and offset values of event-related potentials can be used as indices of the duration of information processing. Two negative waves have been identified which peak at different times in different regions of the scalp, with the second overlapping the last part of the first. These waves are related in different ways to the duration of perceptual processing.

K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions.

We studied K-ras and p53 gene mutations in a panel of 57 primary pancreatic cancers including ductal and nonductal tumors. DNAs were obtained from formalin-fixed, paraffin-embedded material. Target sequences were amplified by polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis and sequencing. Both K-ras and p53 genes were frequently mutated in ductal cancers (25 of 35, 71.4%; 18 of 35, 51.4%, respectively). K-ras mutations were confined to the second position of codon 12 where base transitions and transversions were equally observed. p53 changes were mainly missense mutations. Transitions and transversions were found equally with a prevalence of G:C-->A:T changes among transitions. No gene alterations were present in the 6 exocrine nonductal tumors and (with one exception) in the 12 endocrine tumors analyzed. Our results indicate that mutated K-ras and p53 genes can cooperate in the establishment of ductal pancreatic cancers, whereas other genetic events have to be present in nonductal tumors. Moreover, K-ras alterations may represent an early event in ductal tumorigenesis, as suggested both by the high gene mutation frequency and by the presence of mutations in low-grade tumors. On the contrary, p53 gene changes seem to represent an event required for the malignancy progression of ductal tumors from lower to higher grades.

Base transitions are the most frequent genetic changes at P53 in gastric cancer.

We searched for P53 mutations in gastric carcinoma by analyzing tumor DNAs from 29 patients. We detected 13 different somatic mutations in 15 patients (52%) and a biallelic polymorphism in exon 6 (5 heterozygous subjects). The somatic mutations were mainly localized in the sequences corresponding to the highly conserved domains of the protein. Twelve samples showed a single base change: 11 missense and 1 nonsense mutations. Three samples showed deletions leading to a frame shift, to the in-frame loss of 2 amino acids, and to the deletion of a splicing site. All point mutations, except one, were transitions, and 91% of them were G:C-->A:T changes. We previously analyzed this panel of tumors for allelic loss at the 17p13 chromosomal region, where the P53 gene had previously been located: the results showed an increasing incidence of allelic loss in late-stage tumors. On the contrary, in the present study no trend between P53 mutations and tumor stages was found. This observation indicates that mutation events precede allelic loss in gastric cancer. Half (54%) of the mutations occurred in samples without allelic loss, suggesting that specific mutated alleles, acting in a dominant negative fashion, can alter in vivo the P53 protein function.

Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract.

In a search for mutations of the type I transforming growth factor beta receptor (TbetaR-I), we mapped the gene to 9q22 and found a common polymorphism [TbetaR-I(6A)] and a rare variant [TbetaR-I(10A)] of TbetaR-I, causing an in-frame deletion of three alanines and an in-frame insertion of one alanine, respectively, in the receptor's extracellular domain. The biological relevance of the polymorphism TbetaR-I(6A) was investigated. When TbetaR-I(6A) was transiently transfected into TbetaR-I-deficient cells, the growth-inhibitory effects of transforming growth factor beta were restored. TbetaR-I(6A) and TbetaR-I(10A) frequency were assessed in 108 tumor samples and 80 nontumor samples from patients with a diagnosis of cancer, as well as in 118 normal blood donors of comparable ethnic composition. The frequency of TbetaR-I(6A) heterozygotes was fairly similar in normal blood donors (8%), in nontumor DNA of patients with a diagnosis of cancer (10%), and in tumor samples (14%). However, the frequency of TbetaR-I(6A) homozygotes among nontumor (4%) and tumor (8%) samples obtained from patients with a diagnosis of cancer was higher than that predicted by the Hardy-Weinberg law. The clinical and biological significance of TbetaR-I(6A) homozygosity needs to be further investigated.

Heterogeneity of information-processing alterations according to dimensions of depression: an event-related potentials study.

To identify alterations in elementary cognitive operations according to dimensions of depression, two stages of information processing, namely the response choice and the motor preparation stages, were explored using an event-related potential paradigm in two subgroups of depressed patients (retarded and blunted affect versus anxious-agitated and impulsive) compared to controls. Two results are common to all depressed patients: a slow encoding of stimuli (P1 wave) and a prolonged processing of stimulus-response compatibility (after P3b). This is compensated by a global velocity increase in stimulus evaluation or decision making (P3b) in anxious-agitated patients or, on the contrary, cumulated with its velocity decrease in retarded-blunted-affect patients. Such results could provide an explanation for the massive retardation observed in blunted-affect patients, contrary to anxious-agitated patients, whose normal reaction times may come from a very high energetical involvement at the P3b level. Results as a whole suggest that impairments in blunted-affect patients concern effort mechanisms, whereas those in anxious-agitated patients concern perceptual processes.

Depression as a dynamical disease.

Mathematical models are helpful in the understanding of diseases through the use of dynamical indicators. A previous study has shown that brain activity can be characterized by a decrease of dynamical complexity in depressive subjects. The present paper confirms and extends these conclusions through the use of recent methodological advances: first episode and recurrent patients strongly differ in their dynamical response to therapeutic interventions. These results emphasize the need for clinical follow-ups to avoid recurrence and the necessity of specific therapeutic intervention in the case of recurrent patients.

p53 gene mutations and protein nuclear accumulation are early events in intestinal type gastric cancer but late events in diffuse type.

We screened for p53 alterations in 71 early gastric cancers of differing histological types and growth patterns, 18 advanced cancers of diffuse type, 19 dysplastic lesions, and 12 extensive intestinal metaplasia cases. Tumors were investigated for gene mutations (exons 5-8) with PCR-based denaturing gradient gel electrophoresis and sequencing techniques, and for protein accumulation with immunohistochemical methods. Nontumor samples were studied with immunohistochemistry alone. Of the early cancers, intestinal tumors showed a much higher p53 mutation frequency (41%) than did diffuse cancers (4%). When comparing early and advanced tumors of the same type, we observed a similarity in mutation frequency (41 versus about 50%) for intestinal tumors, and a significant increase for diffuse tumors (from 4 to 33%). Immunopositive case distribution between tumor types and stages paralleled that of mutated cases. Immunohistochemical and genetic analysis gave concordant results for all samples with gene mutations. Eighteen of the 65 (28%) nonmutated tumors displayed significant immunoreactivity. Early tumors that massively penetrated the submucosa, i.e., the early tumors for which prognosis is worst, showed the highest frequency both of p53 gene mutation and of nonmutated protein accumulation. Twelve of 19 dysplastic lesions showed significant immunoreactivity, whereas intestinal metaplasias proved unreactive in all but a few cells. Our results yield two implications: that p53 alterations have a crucial and early role in gastric carcinogenesis of intestinal type, likely acting at the transition step between metaplasia and dysplasia; and that the alterations are mainly associated with tumor progression in cancer of diffuse type.

Brain potentials reveal covert facial recognition in prosopagnosia.

Brain potentials were recorded in a prosopagnosic patient, in response to familiar and unfamiliar faces he was asked to recognize. The amplitude of the P300 component was found to be an inverse function of probability for each category of faces despite the patient's inability to consciously recognize the familiarity of these faces. In addition, P300 latency varied from 700 to 800 msec according to the familiarity of the faces, and P300 scalp location was different as a function of faces probability and overt recognition. The results imply that covert facial recognition may be evidenced in using event-related potentials of the brain. They also demonstrate that automatic and covert processing of face familiarity are preserved, but prolonged in this patient.

N400-like potentials elicited by faces and knowledge inhibition.

Within the theoretical framework of reference, the brain errs in processing complex stimuli, such as faces. Thus, these stimuli not only activate accurate representations but also inaccurate representations corresponding to known persons who resemble the face stimulus, and hence knowledge about these known persons. Since more errors are made in processing unfamiliar than familiar stimuli, these inaccurate activations are assumed to be more frequent, and/or more intense, with unknown than with known faces. Moreover, top-down mechanisms favor representations of stimuli that are congruent with the context, and representations of known persons, even if inaccurate, receive an additional amount of activation in contexts wherein known faces are expected. Inaccurate representations have to be inhibited to achieve accurate recognition. Thus, more inhibition would be required for unknown than for known faces, and in contexts wherein known faces are expected. The aim of the present work is to study the hypothesis that the N400 component of the event-related potentials (ERPs) reflects the inhibition of knowledge, and to see whether this hypothesis accounts for the N400-like potential elicited by faces. To achieve that goal, ERPs to known and unknown faces were recorded while the richness in known faces of each experimental block, and thus the expectancy for known faces, was manipulated. Consistent with the hypothesis, the amplitudes of the N400-like components were greater in conditions where more inhibition was required, i.e. for unknown rather than for known faces, and in the context of the block rich in known faces. This context effect was larger for unknown than for faces, and in the context of the block rich in known faces. This context effect was larger for unknown than for known faces.

A dynamical analysis of oscillatory responses in the optic tectum.

Multi-unit recordings from the optic tectum of an awake pigeon displaying oscillatory behavior evoked by visual stimulus are highly non-stationary and contain a broad band of frequencies under a time-window analysis. Here we extend these observations by a non-linear dynamical analysis of these oscillatory signals (local fields potentials) in successive epochs during background activity and visual responses. Two numerical estimates have been obtained from the original data every 200 ms: (1) correlation dimension and (2) non-linear forecasting of the trajectories. Results from eight different recording sites analyzed are consistent and indicate, in the average, an increase in complexity of the signal during the oscillatory periods.

Brain events related to normal and moderately scrambled faces.

The neural basis of normal and scrambled face processing was investigated by recording evoked potentials from 21 electrodes at standard EEG sites, with respect to a nose reference. Temporal negativities were found that result from two overlapping phenomena: they arise from the polarity reversal on temporal electrodes of the vertex P2, a positive wave peaking about 170-200 ms after the onset of a face stimulus, and also from an overlapping 'processing negativity' of long duration associated with the processing difficulty of the scrambled face stimulus. The comparisons of scalp potential and current density mappings support the proposal that some neuronal networks are active both for faces and scrambled faces and are compatible with the involvement of the superior temporal sulcus, the inferotemporal cortex and the parahippocampal and fusiform gyri, whereas the processing negativity would only involve the deepest generators of this network. Furthermore, the encoding of both faces and scrambled faces seems to take place predominantly in the right hemisphere.

Internet-based support for bioscience research: a collaborative genome center for human chromosome 12.

This paper describes an approach that provides Internet-based support for a genome center to map human chromosome 12, as a collaboration between laboratories at the Albert Einstein College of Medicine in Bronx, New York, and the Yale University School of Medicine in New Haven, Connecticut. Informatics is well established as an important enabling technology within the genome mapping community. The goal of this paper is to use the chromosome 12 project as a case study to introduce a medical informatics audience to certain issues involved in genome informatics and in the Internet-based support of collaborative bioscience research. Central to the approach described is a shared database (DB/12) with Macintosh clients in the participating laboratories running the 4th Dimension database program as a user-friendly front end, and a Sun SPARCstation-2 server running Sybase. The central component of the database stores information about yeast artificial chromosomes (YACs), each containing a segment of human DNA from chromosome 12 to which genome markers have been mapped, such that an overlapping set of YACs (called a "contig") can be identified, along with an ordering of the markers. The approach also includes 1) a map assembly tool developed to help biologists interpret their data, proposing a ranked set of candidate maps, 2) the integration of DB/12 with external databases and tools, and 3) the dissemination of the results. This paper discusses several of the lessons learned that apply to many other areas of bioscience, and the potential role for the field of medical informatics in helping to provide such support.

Face and shape repetition effects in humans: a spatio-temporal ERP study.

The neural bases of repetition effects for faces and non-significant shapes was studied using Mooneys' faces presented upright (face) or upside down (shape) with a repetition interval of 8 min 30 s-1. Scalp potentials and current density maps on 30 electrodes were compatible with an involvement of the infero-temporal and fusiform gyri (from 50 to at least 250 ms), mainly on the right, for both faces and shapes; the hippocampus and adjacent areas (around 300 ms), specifically for faces; the medial temporal lobes (450-650 ms) again independent of stimulus meaning. These results suggest that the facilitation of perception due to repetition involves both neocortical specialized areas and the medial temporal lobe, with different timings of activation. They further suggest that memory updating takes place more rapidly for faces than for meaningless shapes and that face recognition may be, at least partly, functionally encapsulated.

ERPs and chronometry of face recognition: following-up Seeck et al. and George et al.

Seeck et al. found that event-related potentials (ERPs) evoked by repeated and non-repeated face photographs differ as early as 50-70ms post-onset. They thus suggested that faces are recognized at these latencies, in contrast with current opinions in ERP literature. However, the similar latencies obtained by George et al. for stimuli not perceived as faces suggest that Seeck et al.'s differences could index repetition rather than face recognition per se. To address this issue, we used matched faces of known and unknown persons. We found the earliest differences between the ERPs to these faces between 76 and 130 ms. These results, which are consistent with other data, suggest that the differentiation of faces takes approximately 100 ms of processing time in humans.

Differential processing of part-to-whole and part-to-part face priming: an ERP study.

We provide electrophysiological evidence supporting the hypothesis that part and whole face processing involve distinct functional mechanisms. We used a congruency judgment task and studied part-to-whole and part-to-part priming effects. Neither part-to-whole nor part-to-part conditions elicited early congruency effects on face-specific ERP components, suggesting that activation of the internal representations should occur later on. However, these components showed differential responsiveness to whole faces and isolated eyes. In addition, although late ERP components were affected when the eye targets were not associated with the prime in both conditions, their temporal and topographical features depended on the latter. These differential effects suggest the existence of distributed neural networks in the inferior temporal cortex where part and whole facial representations may be stored.

Decrease of complexity in EEG as a symptom of depression.

Nonlinear dynamic analysis provides new methods for the processing of the electroencephalogram (EEG). We demonstrate here that the EEG dynamics of major depressive subjects is more predictable, that is less complex, than that of control subjects. Moreover, the consequence of treatment upon the EEG dynamics seems to be dependent on the appearance of the illness. Although the specificity of this dynamic signature for different stages of depression is to be confirmed, the assumption of a strong link between a healthy system and a high level of complexity in dynamics is further supported.