Neural stem cells as tools for understanding retroviral neuropathogenesis

The discovery within the past decade that neural stem cells (NSCs) from the developing and adult mammalian brain can be propagated, cloned, and genetically manipulated ex vivo for ultimate transfer back into the CNS has opened the door to a novel means for modifying the CNS environment for experimental and therapeutic purposes. While a great deal of interest has been focused on the properties and promise of this new technology, especially in regard to cellular replacement and gene therapy, this minireview will focus on the recent use of NSCs to study the neuropathogenesis of the murine oncornaviruses. In brief, the use of this NSC-based approach has provided a means for selective reconstitution within the brain, of specific retroviral life cycle events, in order to consider their contribution to the induction of neurodegeneration. Furthermore, by virtue of their ability to disseminate virus within the brain, NSCs have provided a reliable means for assessing the true neurovirulence potential of murine oncornaviruses by directly circumventing a restriction to virus entry into the CNS. Importantly, these experiments have demonstrated that the neurovirulence of oncornaviruses requires late virus life cycle events occurring specifically within microglia, the resident macrophages of the brain. This initial application of NSC biology to the analysis of oncornavirus-CNS interactions may serve as an example for how other questions in viral neuropathogenesis might be addressed in the future.     

Neural mechanisms of social risk for psychiatric disorders

Mental health and social life are intimately inter-related, as demonstrated by the frequent social deficits of psychiatric patients and the increased rate of psychiatric disorders in people exposed to social environmental adversity. Here, we review emerging evidence that combines epidemiology, social psychology and neuroscience to bring neural mechanisms of social risk factors for mental illness into focus. In doing so, we discuss existing evidence on the effects of common genetic risk factors in social neural pathways and outline the need for integrative approaches to identify the converging mechanisms of social environmental and genetic risk in brain.     

Neural and mechanical factors in eye control

Soft tissue "pulleys" in the orbit alter the paths of the eye muscles in a way that may simplify the brain's work in implementing Listing's law, i.e., in holding ocular torsion at zero. But Listing's law does not apply to some oculomotor systems, such as the vestibuloocular reflex (VOR), which shows a different kinematic pattern. To explain this different pattern, some authors have assumed that the pulleys must adopt a different configuration, retracting along their muscles when the eye switches from Listing's law to VOR mode. The proposed retraction has not so far been observed, although the pulleys do move in other ways. We show that the hypothetical retraction of the pulleys would not in fact explain the full kinematic pattern seen in the VOR. But this pattern can be explained entirely on the basis of pulley positions and motions that have actually been observed. If one takes into account the neural processing within the VOR, specifically the fact that the reflex is weak in the torsional dimension, then a single mode of pulley action can serve both vestibuloocular kinematics and Listing's law.     

Theoretical concepts of modern pathology (a critique of their medical philosophical foundations)

Separation of theoretical pathology into an independent branch of science seems to be justified and creation of the Centre of Theoretical pathology in the Heidelberg Academy of Sciences is due and useful. As W. Doerr truly states, the theoretical pathology seems to be over the pathological physiology and general pathology, exerts additional functions, studies questions of the methodology in pathology, defines more exactly and analyzes the notion of disease, other concepts and terms, clarifies early preclinical and clinical disease manifestations, determines sociological and psychological factors of disease. However, we are not in full agreement with our colleagues from the FRG in the definition of "disease" and in the interpretation of such categories as "spirit", "soul", "psychic". K. Rotschuh' suggestion to consider the disease in terms of "body-soul" appears to be interesting but to be productive, it must be linked with the problems of medical psychology. W. Doerr and his colleagues support the dualistic concepts of human nature which is unacceptable for us; they claim that the understanding of the theoretical pathology essence is possible only on the basis of theleology and spirit (theology). As the highest commencenment on the way of the theoretical pathology recognition W. Doerr's categorical declaration that theoretical pathology based on the "gestalttheorie" returns scientists, as he writes" to their great delight, to the possibility of studying "spiritual essence of the disease". In W. Doerr's opinion, studying the concept of theoretical pathology "from the spiritual point of view" will ensure its brilliant future. Of course, we, Soviet pathologists and philosophers, do not reject the significance of the integrity theory in the meaning of the disease psycophysiological integrity, yet we decidedly reject any idealistic concepts. W. Doeer and his colleagues are right that the theoretical pathology stimulates the search of the approaches to the solution of complex biomedical problems, favours the creation of more precise definitions and terminology. Likewise, W. Doerr is right that he sharply condemns the attempts of some pathologists to substitute qualitative differences in pathological processes by quantitative ones; this may result, in his view, in one-sided erroneous conclusions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Information and redundancy: key concepts in understanding the genetic control of health and intelligence.

A model is proposed in which information from the environment is analysed by complex biological decision-making systems which are highly redundant. A correct response is intelligent behaviour which preserves health; incorrect responses lead to disease. Mutations in genes which code for the redundant systems will accumulate in the genome and impair decision-making. The number of mutant genes will depend upon a balance between the new mutation rate per generation and systems of elimination based on synergistic interaction in redundant systems. This leads to a polygenic pattern of inheritance for intelligence and the common diseases. The model also gives a simple explanation for some of the hitherto puzzling aspects of work on the genetic basis of intelligence including the recorded rise in IQ this century. There is a prediction that health, intelligence and socio-economic position will be correlated generating a health differential in the social hierarchy. Furthermore, highly competitive societies will place those least able to cope in the harshest environment and this will impair health overall. The model points to a need for population monitoring of somatic mutation in order to preserve the health and intelligence of future generations.     

The roots of modern justice: cognitive and neural foundations of social norms and their enforcement

Among animals, Homo sapiens is unique in its capacity for widespread cooperation and prosocial behavior among large and genetically heterogeneous groups of individuals. This ultra-sociality figures largely in our success as a species. It is also an enduring evolutionary mystery. There is considerable support for the hypothesis that this facility is a function of our ability to establish, and enforce through sanctions, social norms. Third-party punishment of norm violations ("I punish you because you harmed him") seems especially crucial for the evolutionary stability of cooperation and is the cornerstone of modern systems of criminal justice. In this commentary, we outline some potential cognitive and neural processes that may underlie the ability to learn norms, to follow norms and to enforce norms through third-party punishment. We propose that such processes depend on several domain-general cognitive functions that have been repurposed, through evolution's thrift, to perform these roles.     

Children's concepts of health and illness: understanding of contagious illnesses, non-contagious illnesses and injuries

This study was designed to provide a more comprehensive picture of children's understanding of illness and injury than previous studies by interviewing 83 children from 4 age groups (4/5 years, 7/8 years, 9/10 years and 11/12 years). They were asked questions about how they defined illness and health as well as questions regarding different features of specific illnesses. First, it was found that definitions of health and illness became more polarized with age. Further, significant effects of age were detected for understanding of the specific illnesses with explanations becoming more sophisticated and accurate with development. This result held for almost every illness and illness feature. Lastly, cross-illness analyses showed that children hold differing levels of understanding for each ailment, e.g. understanding of injuries was higher than illnesses. These results contribute to health psychology literature on children's understanding of specific illnesses.     

The neuroanatomical basis of understanding sarcasm and its relationship to social cognition

The authors explored the neurobiology of sarcasm and the cognitive processes underlying it by examining the performance of participants with focal lesions on tasks that required understanding of sarcasm and social cognition. Participants with prefrontal damage (n=25) showed impaired performance on the sarcasm task, whereas participants with posterior damage (n=16) and healthy controls (n=17) performed the same task without difficulty. Within the prefrontal group, right ventromedial lesions were associated with the most profound deficit in comprehending sarcasm. In addition, although the prefrontal damage was associated with deficits in theory of mind and right hemisphere damage was associated with deficits in identifying emotions, these 2 abilities were related to the ability to understand sarcasm. This suggests that the right frontal lobe mediates understanding of sarcasm by integrating affective processing with perspective taking.     

A novel combinatorial approach for understanding microstructural evolution and its relationship to mechanical properties in metallic biomaterials

The new generation of metallic biomaterials for prosthesis implantation (orthopedic and dental) typically have a Ti base with fully biocompatible alloying additions such as Nb, Ta, Zr, Mo, Fe and Sn. While the binary Ti-Ta and the ternary Ti-Nb-Ta systems are promising, the large composition space afforded by these systems offers tremendous scope in terms of alloy design via optimization of alloy composition and thermomechanical treatment. In the present paper a novel combinatorial approach has been developed for rapidly exploring the microstructural evolution and microstructure-microhardness (or elastic modulus) relationships in these systems. Using directed laser deposition, compositionally graded alloy samples have been fabricated and subsequently heat-treated to affect different microstructures in terms of the volume fraction and distribution of the alpha phase in the beta matrix as a function of composition. Subsequently, composition-specific indentation-based hardness and modulus information has been obtained from these graded samples, and the resulting data have been used to develop relationships between the composition, microstructure and mechanical properties. Such rapid combinatorial assessments can be very useful in optimizing not only the alloy composition but also the desired microstructure for achieving the best combination of properties for specific orthopedic or dental applications.     

The understanding of core pharmacological concepts among health care students in their final semester

Background

The overall aim of the study was to explore health care students´ understanding of core concepts in pharmacology.

Method

An interview study was conducted among twelve students in their final semester of the medical program (n?=?4), the nursing program (n?=?4), and the specialist nursing program in primary health care (n?=?4) from two Swedish universities. The participants were individually presented with two pharmacological clinically relevant written patient cases, which they were to analyze and propose a solution to. Participants were allowed to use the Swedish national drug formulary. Immediately thereafter the students were interviewed about their assessments. The interviews were audio-recorded and transcribed verbatim. A thematic analysis was used to identify units of meaning in each interview. The units were organized into three clusters: pharmacodynamics, pharmacokinetics, and drug interactions. Subsequent procedure consisted of scoring the quality of students´ understanding of core concepts. Non-parametric statistics were employed.

Results

The study participants were in general able to define pharmacological concepts, but showed less ability to discuss the meaning of the concepts in depth and to implement these in a clinical context. The participants found it easier to grasp concepts related to pharmacodynamics than pharmacokinetics and drug interactions.

Conclusion

These results indicate that education aiming to prepare future health care professionals for understanding of more complex pharmacological reasoning and decision-making needs to be more focused and effective.

     

Patients' and physicians' understanding of health and biomedical concepts: relationship to the design of EMR systems

OBJECTIVE: The aim of this paper is to examine knowledge organization and reasoning strategies involved in physician-patient communication and to consider how these are affected by the use of computer tools, in particular, electronic medical record (EMR) systems. DESIGN: In the first part of the paper, we summarize results from a study in which patients were interviewed before their interactions with physicians and where physician-patient interactions were recorded and analyzed to evaluate patients' and physicians' understanding of the patient problem. We give a detailed presentation of one of such interaction, with characterizations of physician and patient models. In a second set of studies, the contents of both paper and EMRs were compared and in addition, physician-patient interactions (involving the use of EMR technology) were video recorded and analyzed to assess physicians' information gathering and knowledge organization for medical decision-making. RESULTS: Physicians explained the patient problems in terms of causal pathophysiological knowledge underlying the disease (disease model), whereas patients explained them in terms of narrative structures of illness (illness model). The data-driven nature of the traditional physician-patient interaction allows physicians to capture the temporal flow of events and to document key aspects of the patients' narratives. Use of electronic medical records was found to influence the way patient data were gathered, resulting in information loss and disruption of temporal sequence of events in assessing patient problem. CONCLUSIONS: The physician-patient interview allows physicians to capture crucial aspects of the patient's illness model, which are necessary for understanding the problem from the patients' perspective. Use of computer-based patient record technology may lead to a loss of this relevant information. As a consequence, designers of such systems should take into account information relevant to the patient comprehension of medical problems, which will influence their compliance.     

Progress in understanding electro‐mechanical signalling in the myometrium

In this review, we give a state‐of‐the‐art account of uterine contractility, focussing on excitation–contraction (electro‐mechanical) coupling (ECC). This will show how electrophysiological data and intracellular calcium measurements can be related to more modern techniques such as confocal microscopy and molecular biology, to advance our understanding of mechanical output and its modulation in the smooth muscle of the uterus, the myometrium. This new knowledge and understanding, for example concerning the role of the sarcoplasmic reticulum (SR), or stretch‐activated K channels, when linked to biochemical and molecular pathways, provides a clearer and better informed basis for the development of new drugs and targets. These are urgently needed to combat dysfunctions in excitation–contraction coupling that are clinically challenging, such as preterm labour, slow to progress labours and post‐partum haemorrhage. It remains the case that scientific progress still needs to be made in areas such as pacemaking and understanding interactions between the uterine environment and ion channel activity.     

Neural compensation for mechanical loading of the hand during coupled oscillations of the hand and foot

The role of kinaesthetic afferences in controlling coupling of voluntary oscillation of the hand and foot, both in-phase and anti-phase, was investigated by modifying the mechanical properties of one of the two segments (the hand) with applied inertial or elastic loads. Loads consisted of a lead disk, rotating coaxially with the wrist (total inertial momentum 15 g m²), or in two symmetrical rubber bands (elasticity, 4 g deg^–1) connected 5 cm away from the wrist pivot. Experiments were performed on five male and five female subjects. Both the frequency responses of the hand and foot (i.e. the phase relations between the onset of muscular activation in limb extensors and the onset of the related movement) and the inter-limb phase relations (the phase differences between the hand and foot movement cycles and between the onsets of the electromyographic (EMG) activity in hand and foot extensors) were analysed. The hand frequency-response was fitted with a 2nd-order model, allowing us to describe the loaded and unloaded conditions through the changes in the model response. Inertial loading induced an immediate and steep decay in the frequency response, with a clear-cut reduction of the model resonance frequency, while elastic loading shifted the response to the right and upwards. Inter-limb phase relations were only partially affected by inertial loading of the hand. Despite the fact that the load strongly increased the difference between the frequency-responses of the hand and foot, when hand and foot were oscillated in-phase only about half of this difference remained as an increased phase-lag between hand and foot oscillations. The other half was offset by an advance of the contraction of the hand movers with respect to the foot movers. This compensation mechanism was more effective during anti-phase than during in-phase movements. Elastic loading improved inter-limb synchronisation, since it superimposed the hand frequency-response on that of the foot. In this condition, the requested synchronisation (in-phase or anti-phase) could be achieved by an almost simultaneous (or in strict phase opposition) contraction of the hand and foot movers. In conclusion, the main feedback reaction to the de-coupling effect of hand loading consisted in modifying the timing of activation of the muscles moving the extremities. An advance of hand movers on foot movers is already present in unloaded conditions to compensate for the difference in the natural mechanical properties of the two segments. This advance is enhanced when increasing the inertia of the hand system and attenuated when increasing its elasticity. Electronic Publication