Effect of isatin on nitric oxide-stimulated soluble guanylate cyclase from human platelets

Isatin, an endogenous indole, has previously been shown to inhibit atrial natriuretic peptide (ANP)-stimulated particulate guanylate cyclase activity. Here, it was shown that it can be transported to human platelets where it inhibited nitric oxide (NO)-stimulated soluble guanylate cyclase activity obtained from human platelets. The effect was most pronounced at 10(-8)M isatin and is the most potent effect of isatin yet observed. The dose response curve was bell shaped with higher doses becoming less effective. The maximal inhibition observed was of 40%. Isatin had no effect on protoporphyrin IX-stimulated guanylate cyclase. Isatin-dependent regulation of ligand-stimulated guanylate cyclases is suggested to promote a stress-induced switch in metabolism.     

The relationship between hodological and cytoarchitectonic organization in the vestibular complex of the 11-day chicken embryo

To understand the relationship between structure and function in specific brain regions, it is necessary to ascertain which anatomical features are physiologically relevant. Physiological studies of brain function traditionally have been set in the context of anatomical features based on cytoarchitectonics and myeloarchitectonics, but the relationship between structure and function in this context can be complex. Alternative schemes of anatomical organization, such as that based on hodology (the mapping of projections) may provide greater insight. Here, we make a direct comparison of the hodological and the cytoarchitectonic organization of the vestibular complex in the mid-term chicken embryo, using retrograde tracing and three-dimensional reconstruction. In one set of experiments, vestibulospinal and vestibulo-ocular neuron groups were selectively labeled with biotin dextran-amines and aligned with the cytoarchitectonically defined vestibular nuclei in alternating sections that were then combined into intercalated three-dimensional models. This allowed a semiquantitative analysis of the apportionment of individual hodological groups among cytoarchitectonic nuclei. In another set of experiments, vestibulospinal and vestibulo-ocular neuron groups were labeled differentially with fluorescent dextran-amines, three-dimensionally reconstructed, and subjected to a quantitative analysis of spatial overlap. Our results provide the first three-dimensional representation and quantitative analysis of the hodological compartmentalization of the vestibular complex (the "hodological mosaic"). They also show directly how each hodologically defined neuron group relates to the conventional vestibular nuclei, underscoring the fact that the units of the hodological mosaic do not bear a one-to-one correspondence to the cytoarchitectonic nuclear divisions. Some hodologically defined groups are localized to restricted portions of a nucleus, whereas others overlap multiple nuclei. Thus, hodology and cytoarchitectonic features appear to be separately regulated in the vestibular complex of the chicken embryo, possibly through different sets of positional specification mechanisms. The three-dimensional representations we present here provide a foundation for integrating anatomical, physiological, developmental, and evolutionary studies of the vestibular system.     

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.     

Optic ataxia as a deficit specific to the on-line control of actions

Optic ataxia is characterized by inaccuracies in body movements under visual control, and is a common consequence of damage to the posterior parietal lobes in humans. It is argued here that optic ataxia can be characterized as a deficit in the visual on-line guidance of actions, with action planning remaining relatively intact. This contrasts with the common view of optic ataxia as representing a deficit in the transformations that take place between visual inputs and motor outputs. Evidence in support of the planning-control view comes from the pattern of spared and disrupted behaviors in patients with optic ataxia. It is shown that spared behaviors are those that emphasize planning, whereas disrupted behaviors are those that emphasize control. In particular, recent studies have highlighted the inability of a patient with optic ataxia to make on-line adjustments to targets that change position during the movement. Taken in sum, the data from patients with optic ataxia is more consistent with the planning-control interpretation of optic ataxia than with the visuomotor transformation interpretation.     

Basic restrictions in EMF exposure guidelines

Different bodies have set guidelines restricting exposure to electric and magnetic fields. The limits at power frequencies recommended by these guidelines and the scientific basis and rationale for setting them have been reviewed, starting with the WHO Environmental Health Criteria 69 on Magnetic Fields, published in 1987. These guidelines are all designed to limit the induced current density to 10 mA m(-2), sometimes reduced by an additional safety factor of five for the general public. While published guidelines have, to date, universally adopted a restriction based upon induced current density, the internal electric field is the more fundamental quantity in determining biological effects. It is recommended that consideration be given to using the internal electric field rather than current density in future guidelines. Those who are responsible for setting guidelines need good scientific information on which to be able to set their limits. While there is already a significant weight of scientific evidence upon which exposure restrictions can be based, there is a need for more research to reduce uncertainties and to enable greater precision in the setting of limits. Some suggestions for future research directions, particularly aimed at further understanding of the interaction of electric fields with the nervous system, are suggested in this paper and are developed more widely in the following papers covering the proceedings of the EPRI Guidelines Science Workshop held in Brussels in June 2000.     

Winners don't take all: Characterizing the competition for links on the web

As a whole, the World Wide Web displays a striking “rich get richer” behavior, with a relatively small number of sites receiving a disproportionately large share of hyperlink references and traffic. However, hidden in this skewed global distribution, we discover a qualitatively different and considerably less biased link distribution among subcategories of pages—for example, among all university homepages or all newspaper homepages. Although the connectivity distribution over the entire web is close to a pure power law, we find that the distribution within specific categories is typically unimodal on a log scale, with the location of the mode, and thus the extent of the rich get richer phenomenon, varying across different categories. Similar distributions occur in many other naturally occurring networks, including research paper citations, movie actor collaborations, and United States power grid connections. A simple generative model, incorporating a mixture of preferential and uniform attachment, quantifies the degree to which the rich nodes grow richer, and how new (and poorly connected) nodes can compete. The model accurately accounts for the true connectivity distributions of category-specific web pages, the web as a whole, and other social networks.     

Correction of physiologically induced global off-resonance effects in dynamic echo-planar and spiral functional imaging.

In functional magnetic resonance imaging, a rapid method such as echo-planar (EPI) or spiral is used to collect a dynamic series of images. These techniques are sensitive to changes in resonance frequency which can arise from respiration and are more significant at high magnetic fields. To decrease the noise from respiration-induced phase and frequency fluctuations, a simple correction of the "dynamic off-resonance in k-space" (DORK) was developed. The correction uses phase information from the center of k-space and a navigator echo and is illustrated with dynamic scans of single-shot and segmented EPI and, for the first time, spiral imaging of the human brain at 7 T. Image noise in the respiratory spectrum was measured with an edge operator. The DORK correction significantly reduced respiration-induced noise (image shift for EPI, blurring for spiral, ghosting for segmented acquisition). While spiral imaging was found to exhibit less noise than EPI before correction, the residual noise after the DORK correction was comparable. The correction is simple to apply and can correct for other sources of frequency drift and fluctuations in dynamic imaging.     

Outcome of major cardiac injuries at a Canadian trauma center

Background  

Canadian trauma units have relatively little experience with major cardiac trauma (disruption of a cardiac chamber) so injury outcome may not be comparable to that reported from other countries. We compared our outcomes to those of other centers.     

Role of Corticosterone in Immunosuppressive Effects of Acute Ethanol Exposure on Toll-Like Receptor Mediated Cytokine Production

Acute ethanol (EtOH) exposure causes a stress response in humans, nonhuman primates, and rodents. Previous study results indicate that the suppression of some immunological parameters by EtOH is mediated in part or completely by elevated corticosterone concentrations induced by EtOH. However, initial results suggested that corticosterone is not involved in the modulation of cytokine production by macrophages in response to polyinosinic polycytidylic acid (poly I:C). New studies were conducted to further evaluate the role of corticosterone in EtOH-mediated changes in production of interleukin-6 (IL-6), IL-10, and IL-12 in serum and peritoneal fluid in mice treated with poly I:C or lipopolysaccharide (LPS). Suppression of IL-6, but not IL-12, production by EtOH was found to be mediated by corticosterone. However, poly I:C, LPS, and EtOH all caused similar elevations of corticosterone concentrations; thus, it is not clear if EtOH is required to induce levels or durations of corticosterone needed to mediate the observed effects. The situation with IL-10 was more complicated. Inhibition of corticosterone synthesis with aminoglutethimide prevented the increase in IL-10 production caused by EtOH plus poly I:C as compared to poly I:C only. This indicates that this increase is dependent on corticosterone, but exogenous corticosterone plus poly I:C did not increase IL-10 production. Thus, EtOH and corticosterone are required. However, with LPS inhibition of corticosterone synthesis (using aminoglutethimide) or inhibition of its action (using mifepristone) further increased, or did not affect IL-10 concentrations, suggesting fundamental differences in the signaling pathways leading from poly I:C and LPS to IL-10 production.This work was presented at the annual meeting of the Society for Neuroimmune Pharmacology, Santa Fe, NM, April 2006.