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Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome.

The single-minded (sim) gene encodes a transcriptional regulator that functions as a key determinant of central nervous system (CNS) midline development in Drosophila. We report here the identification of two murine homologs of sim, Sim1 and Sim2, whose products show a high degree of sequence conservation with Drosophila SIM in their amino-terminal halves, with each containing a basic helix-loop-helix domain as well as a PAS domain. Sim1 maps to the proximal region of mouse chromosome 10, whereas Sim2 maps to a portion of the distal end of chromosome 16 that is syntenic to the Down syndrome critical region of human chromosome 21. Recent exon-trapping studies have identified in the critical region several exons of a human sim homolog which appears to be the homolog of murine Sim2; this has led to the hypothesis that increased dosage of this sim homolog in cases of trisomy 21 might be a causal factor in the pathogenesis of Down syndrome. We have examined the expression patterns of the Sim genes during embryogenesis. Both genes are expressed in dynamic and selective fashion in specific neuromeric compartments of the developing forebrain, and the expression pattern of Sim2 provides evidence for early regionalization of the diencephalon prior to any overt morphological differentiation in this region. Outside the CNS, Sim1 is expressed in mesodermal and endodermal tissues, including developing somites, mesonephric duct, and foregut. Sim2 is expressed in facial and trunk cartilage, as well as trunk muscles. Both murine Sim genes are also expressed in the developing kidney. Our data suggest that the Sim genes play roles in directing the regionalization of tissues where they are expressed. Moreover, the expression pattern documented for Sim2 may provide insights into its potential roles in Down syndrome.

Amino Acid Sequence↗

Social behaviour in pervasive developmental disorders: effects of informant, group and "theory-of-mind".

Theory of mind skills and a range of social behaviour in everyday life were assessed in a sample of 21 children with pervasive developmental disorders and 22 normally-developing preschoolers. Parents, teachers and therapists were interviewed using the Vineland Adaptive Behaviour Scales and a new supplementary scale, the "Echelle d'Adaptation Sociale pour Enfants" (EASE). Teachers and therapists were able to differentiate subtle forms of social problems in everyday life between subgroups of children diagnosed later to have either autism (n = 13) or PDDNOS (n = 8), according to DSM-III-R (1) criteria. This study offers a (small) cross-cultural replication of recent work suggesting that differences in the mentalising skills of children with autism are reflected in the everyday social behaviour of this group. A significant effect of informant was found for the PDD group, and this effect was particularly pronounced when children with autism were considered separately. The implications of informant differences are discussed.

Activities of Daily Living↗

Neuropsychological impairments and deficits in theory of mind and emotion recognition in a non-autistic boy.

A 9-year-old non-autistic boy revealed marked deficits in visuo-spatial and visuo-motor skills, in planning and organizational capacities and in impulse inhibition. Particular strengths were his verbal comprehension and reasoning abilities. This neuropsychological pattern of assets and deficits fitted the nonverbal learning disability syndrome as described by Rourke (1989). On a battery of Theory of Mind (TOM) and emotion recognition tests he performed rather poor on several first-order TOM tasks and on all second-order TOM and emotion-matching tasks, compared to samples of autistic and normal subjects. It is suggested that his visuo-spatial and cognitive shifting deficits account for his social cognitive failures, while his superior verbal skills protect him from severe social handicaps.

Affect↗

"Mind control" and the battering of women.

This paper describes one variation in the battering phenomenon which was initially observed among low-income women. The strategies of coercion and deception utilized by the abusive male in these relationships are described and compared with similar strategies of "mind control" utilized in more traditional "cultic" systems. The debilitating effects of these techniques on the battered female are described, as is the battering male's own separation reaction, and the probable dynamics of the men and women involved in this pathological family system. Some preliminary assessment and treatment guidelines are offered.

Dominance-Subordination↗

Is the mind-body interface microscopic?

This paper puts forward the hypothesis that consciousness might be linked to matter in a way which is more sophisticated than the traditional macroscopic Cartesian hypothesis suggests. Advances in the biophysics of the nervous system, not only on the level of its macroscopic functioning but also on the level of individual ion channels, have made the question of 'how finely' consciousness is tied to matter and its dynamics more important. Quantum mechanics limits the attainable resolution and puts into doubt the idea of an infinitely fine-woven attachment. A recent approach to physics rekindles such a rationalist hope. 'Endophysics' focuses on the global implications of microscopic computer simulations of chemical and biophysical processes. A complete 'artificial universe' can be set up in the computer. It produces non-classical and nonlocal effects inside--on the 'interface' that exists between an internal observer ('fluid neuron') and the rest of the world. This interface is finer than any brain property to which the status of the mind-body interface has been attributed hitherto. A new class of experiments becomes possible in the artificial world and, by analogy, in the real world. Magnetic resonance imaging experiments, routinely performed under open-loop conditions, can be repeated under psychophysical (closed-loop) conditions--in search for microscopically induced changes in the perceived and measured structure of the world.

Biophysics↗

An advanced test of theory of mind: understanding of story characters' thoughts and feelings by able autistic, mentally handicapped, and normal children and adults.

Research has suggested that the core handicaps of autism result from a specific impairment in theory of mind (ToM). However, this account has been challenged by the finding that a minority of autistic subjects pass 1st- and even 2nd-order ToM tests while remaining socially handicapped. In the present study, able autistic subjects who failed ToM tasks, those who passed 1st-order, and those who passed 2nd-order tasks were tested with a battery of more naturalistic and complex stories. Autistic subjects were impaired at providing context-appropriate mental state explanations for the story characters' nonliteral utterances, compared to normal and mentally handicapped controls. Performance on the stories was closely related to performance on standard ToM tasks, but even those autistic subjects who passed all ToM tests showed impairments on the more naturalistic story materials relative to normal adult controls.

Adolescent↗

Teaching theory of mind: a new approach to social skills training for individuals with autism.

This study examined the effectiveness of a social skills training program for normal-IQ adolescents with autism. Five boys participated in the 4 1/2-month treatment condition; four boys matched on age, IQ, and severity of autism constituted the no-treatment control group. In addition to teaching specific interactional and conversational skills, the training program provided explicit and systematic instruction in the underlying social-cognitive principles necessary to infer the mental states of others (i.e., theory of mind). Pre- and post-intervention assessment demonstrated meaningful change in the treatment group's performance on several false belief tasks, but no improvement in the control sample. No changes, however, were demonstrated on general parent and teacher ratings of social competence for either group.

Adolescent↗

Theoretical approaches to holistic biological features: Pattern formation, neural networks and the brain-mind relation.

The topic of this article is the relation between bottom-up and top-down, reductionist and holistic approaches to the solution of basic biological problems. While there is no doubt that the laws of physics apply to all events in space and time, including the domains of life, understanding biology depends not only on elucidating the role of the molecules involved, but, to an increasing extent, on systems theoretical approaches in diverse fields of the life sciences. Examples discussed in this article are the generation of spatial patterns in development by the interplay of autocatalysis and lateral inhibition; the evolution of integrating capabilities of the human brain, such as cognition-based empathy; and both neurobiological and epistemological aspects of scientific theories of consciousness and the mind.

Body Patterning↗

The mind-heart connection in coronary artery disease.

Mind and heart are connected by neurocardiologic pathways. Psychosocial risk factors produce sympathetic activation, resulting in mortality in coronary artery disease. Aspirin, exercise, and psychosocial and spiritual supports are important resources in protecting the heart against these risk factors.

Coronary Disease↗

Selective neurotoxins, chemical tools to probe the mind: the first thirty years and beyond.

For centuries, starting with the advent of the microscope, cytotoxins have been known to non-selectively destroy nerves and other tissue cells. However, neurotoxins restricted in effect to one kind of neuron are an invention of the 20th century. One might reasonably trace the origins of this field to 1960 when the Nobel Laureates, R. Levi- Montalcini and S Cohen, showed that an antibody to nerve growth factor effectively prevented development of sympathetic nerves in the absence of overt changes in dorsal root ganglia and other neural and non-neural tissues. The year 1967 marks discovery of 6-hydroxydopamine, the first of dozens of chemically-selective neurotoxins. As stated by the physiologist W.B. Cannon, neural function can be deduced by denoting absence-deficits. A wealth of knowledge in neuroscience has been realized through use of neurotoxins. In the 21st century we foresee neurotoxins for virtually all neurochemically-identifiable or receptor-specific neurons, acting at/via functional proteins or characteristic DNA sites. These tools will provide us with a better means to probe the mind and thereby lead to a fuller understanding of the intricate roles of identifiable neuronal systems in integrative neuroscience.

Journal Article↗

A state of mind.

This essay traces the personal odyssey of a pediatric neurosurgeon from the time of the 'second generation' of subspecialty (the 1960s) to the present. The capture and appreciation of the ethos of the neurosurgical care of children is described and emphasized. It is not possible to overstate the importance of certain role models in this process, a process that does, indeed, induce a lasting 'state of mind.' Concerns for some current trends are raised.

Canada↗

Impairment of theory of mind in patients in remission following first episode of schizophrenia.

The aim of this study was to investigate theory of mind (ToM) ability in patients in remission after the first episode of schizophrenia. A ToM task which contained four pictures was given to 30 patients with schizophrenia in remission and 30 matched healthy controls. Patients with schizophrenia in remission showed statistically significant impairment in the ToM tasks. ToM impairment was not correlated with psychiatric symptoms. Thus, ToM deficit in schizophrenia may be a trait marker.

Adult↗

Theory of mind and unawareness of illness in schizophrenia: is poor insight a mentalizing deficit?

This study investigates the impact of theory of mind (ToM) deficits on poor insight in schizophrenia. The scale for unawareness of mental disorder (SUMD) was administered to 58 stable outpatients with schizophrenia. First and second order false belief tasks, the Eyes test and a battery of nonToM cognitive measures were administered. The Second order false belief task was the best predictor of each global insight and symptom attribution scores of the SUMD. ToM tasks explained the substantial amount of the variance (ranging from 22.5% to 29.9%) for the insight scores and classified the significant amount of the patients who were aware of the illness correctly. WCST perseveration scores did not contribute to insight scores beyond that contributed by second order false belief tasks. The Second order ToM tasks seems to have critical importance for the awareness of the disorder. Beyond more direct self-evaluation, the awareness of the disorder and its consequences may also require the ability to evaluate the self from the perspective of others. "Understanding the others' belief about another person" may be conceptually very similar to "understanding the others' belief about self" (instead of another person).

Adult↗

Agents of the mind.

The higher order circuitry of the brain is comprised of a large-scale network of cerebral cortical areas that are individually regulated by loops through subcortical structures, particularly through the basal ganglia and cerebellum. These subcortical loops have powerful computational architectures. Using, as an example, the relatively well-understood processing that occurs in the cortical/basal ganglionic/cerebellar distributed processing module that generates voluntary motor commands, I postulate that a network of analogous agents is an appropriate framework for exploring the dynamics of the mind.

Brain↗

Snail is required for Delta endocytosis and Notch-dependent activation of single-minded expression.

In the Drosophila embryo, the mesectoderm corresponds to a single row of cells abutting the mesoderm. It is specified by the expression of the single-minded (sim) gene. The information that precisely positions the sim-expressing cells along the dorso-ventral axis is incompletely understood. Previous studies have shown that Dorsal and Twist activate sim expression in a large ventral domain, while two negative regulators, Snail (Sna) and Suppressor of Hairless [Su(H)], repress sim expression in the mesoderm and neuroectoderm, respectively. Repression by Su(H) is relieved in the presumptive mesectoderm by Notch signaling. In this paper, we show that Sna also has a positive regulatory function on sim expression in the presumptive mesectoderm. This positive effect of Sna depends on the Su(H)-binding sites within the sim promoter, suggesting that Sna regulates Notch signaling. In addition, we find that Delta is endocytosed together with the extracellular domain of Notch. The endocytosis of Delta is only seen in the mesoderm and requires the activity of the sna and neuralized (neur) genes. Interestingly, the Neur-mediated endocytosis of Delta has recently been shown to be sufficient for the non-autonomous activation of Notch target genes in wing imaginal discs. We therefore propose a novel model in which Sna positions the mesectoderm via its dual regulatory activity. In this model, Sna cell-autonomously represses sim expression in the mesoderm and relieves Su(H)-dependent repression in a cell non-autonomous fashion by promoting the Neur-dependent endocytosis of Delta in the mesoderm.

Animals↗

Single-minded, Dmef2, Pointed, and Su(H) act on identified regulatory sequences of the roughest gene in Drosophila melanogaster.

Roughest (Rst) is a cell adhesion molecule of the immunoglobulin superfamily that has multiple and diverse functions during the development of Drosophila melanogaster. The pleiotropic action of Rst is reflected by its complex and dynamic expression during the development of Drosophila. By an enhancer detection screen, we previously identified several cis-regulatory modules that mediate specific expression of the roughest gene in Drosophila developmental processes. To identify trans-regulators of rst expression, we used the Gal4/UAS system to screen for factors that were sufficient to activate Rst expression when ectopically expressed. By this method we identified the transcription factors Single-minded, Pointed.P1, and Su(H)-VP16. Furthermore, we showed that these factors and, in addition, Dmef2 are able to ectopically activate rst expression via the previously described rst cis-regulatory modules. This fact and the use of mutant analysis allocates the action of the transcription factors to specific developmental contexts. In the case of Sim, we could show that it regulates rst expression in the embryonic midline, but not in the optic lobes. Mutagenesis of Sim consensus binding sites in the regulatory module required for rst expression in the embryonic midline, abolished rst expression; indicating that the regulation of rst by Sim is direct.

Animals↗

Factors to keep in mind when introducing virtual microscopy.

Digitization of glass slides and delivery of so-called virtual slides (VS) emulating a real microscope over the Internet have become reality due to recent improvements in technology. We have implemented a virtual microscope for instruction of medical students and for continuing medical education. Up to 30,000 images per slide are captured using a microscope with an automated stage. The images are post-processed and then served by a plain hypertext transfer protocol (http)-server. A virtual slide client (vMic) based on Macromedia's Flash MX, a highly accepted technology available on every modern Web browser, has been developed. All necessary virtual slide parameters are stored in an XML file together with the image. Evaluation of the courses by questionnaire indicated that most students and many but not all pathologists regard virtual slides as an adequate replacement for traditional slides. All our virtual slides are publicly accessible over the World Wide Web (WWW) at http://vmic.unibas.ch . Recently, several commercially available virtual slide acquisition systems (VSAS) have been developed that use various technologies to acquire and distribute virtual slides. These systems differ in speed, image quality, compatibility, viewer functionalities and price. This paper gives an overview of the factors to keep in mind when introducing virtual microscopy.

Education, Medical, Continuing↗