全身炎症反应综合征中性白细胞基因表达谱的研究

目的:研究全身炎症反应综合征患者外周血中性白细胞和健康人外周血中性白细胞的基因差异表达。方法:应用基因芯片技术对4例SIRS患者外周血中性白细胞和6例正常人外周血中性细胞的mRNA进行检测。结果:在8400条基因中发现差异表达基因382条, 其中SIRS患者中性白细胞基因122条表达增加, 260条表达减少, 差异表达的基因主要是细胞内信号转导通路基因(35％), 细胞受体基因(22％), DNA结合、转录的各种因子基因(23％)以及细胞因子基因(11％)等。结论:SIRS患者体内存在抗炎和促炎两种不同介质作用, 中性白细胞在该环境中基因表达的改变与血液中多种刺激因素作用结果相一致。基因芯片技术可同时大通量研究基因的表达水平, 是一种可应用于检测炎症反应基因改变的新方法。     

Induction of TLR2 expression by inflammatory stimuli is required for endothelial cell responses to lipopeptides

Human endothelial cells (EC) express Toll-like receptor 4 (TLR4), a receptor for lipopolysaccharides (LPS), but little or no TLR2, a lipopeptide receptor. The aim of this study was to investigate to what extent inflammatory stimuli modify the expression by EC of TLR4 and TLR2, of the TLR2 co-receptors TLR1 and TLR6 and of the TLR2-accessory proteins CD14 and CD36. Stimulation of umbilical vein derived EC with TNF-alpha, LPS or IL-1beta for 24h induced a strong increase in TLR2 mRNA but not in TLR1, TLR4 and TLR6 mRNA. Inflammatory activation had little effect on CD14 mRNA, but decreased the expression of CD36 mRNA. TLR2 antigen was readily detected by flow cytometry on activated EC, but not on resting EC. A significant proportion of TLR2 was found to be located intracellularly. By using specific signalling pathway inhibitors we established that the induction of TLR2 by inflammatory stimuli was dependent on NF-kappaB, p38-MAP kinase and c-Jun kinase. IRAK-1 phosphorylation after treatment with 10mug/ml of lipoteichoic acid (LTA), a TLR2 agonist, was only observed in TNF-alpha-stimulated EC and not in resting EC. Furthermore, LTA potentiated the increase of the inflammatory markers E-Selectin or IL-8 in EC pre-treated with TNF-alpha, LPS or IL-1beta, but not in resting EC. These results imply that the up-regulated TLR2 is functionally active. Interestingly, LTA had no effect on TLR2 expression, nor maintained TLR2 expression, in activated EC. This suggests that lipopeptide responses of EC are dependent on the continued presence of inflammatory cytokines, provided by other cell types, or LPS. In conclusion, inflammatory stimuli induce a high TLR2 expression in EC, which in turn enables the cells to strongly respond to lipopeptides. The up-regulation of TLR2 may be of relevance for the vascular effects of Gram-positive bacteria.     

Intrathecal neuropeptide Y inhibits behavioral and cardiovascular responses to noxious inflammatory stimuli in awake rats

To test the hypothesis that administration of neuropeptide Y (NPY) to the spinal cord reduces inflammatory pain, we evaluated the effects of intrathecal NPY on behavioral and cardiovascular markers of the nociception associated with intraplantar formalin injection in rats. Before the administration of formalin, NPY dose dependently increased blood pressure, an effect that could be prevented with the coadministration of the Y2 antagonist, BIIE0246. This effect lasted only 20 min, and thus was over before initiation of the formalin test. NPY dose dependently inhibited the flinching, licking, pressor, and tachycardia responses associated with formalin injection. The Y1 receptor antagonist BIBO 3304 partially reversed the antinociceptive effect of NPY at a dose that did not by itself have an effect (3 μg). We conclude that intrathecal NPY acts in part via Y1 receptors to inhibit ongoing inflammatory nociception.     

Nonlinear responses of simple cells to Mach band stimuli: evidence from early monocularly deprived cats

We have previously shown that, cat simple cells respond linearly to edges of variable blur widths: cells with receptive fields (RFs) of even symmetry respond better to a luminance ramp (where Mach bands are observed); cells with RFs of odd symmetry respond better to a luminance step (where no Mach bands are perceived). Our evidence has also indicated the existence of inhibitory interaction between cells with RFs of even and odd symmetry as predicted by the Tolhurst-Ratliff Mach band model. Since monocular deprivation is known to impair cortical inhibitory mechanisms, we studied the responses of simple cells of adult cats monocularly deprived at the age of 8–10 weeks to Mach band stimuli in order to delineate specific changes in inhibitory interactions caused by monocular deprivation. In pattern-deprived cats, particularly for cells driven by the deprived eye, there were many cells that responded contrary to linear models: odd-symmetric cells responded maximally to blurred edges while even symmetric cells responded maximally to sharp edges. Cells that responded maximally as predicted, responded, similarly to normal cat cells, less than expected at suboptimal widths. All cells in normal and light-deprived cats responded in a linear fashion to sinusoidal stimuli. We conclude, therefore, that intracortical inhibition shapes simple cells' responses to edges. Monocular deprivation impairs this mechanism, thus causing simple cells in monocularly deprived cats to respond nonlinearly to edges. All simple cells responded linearly to gratings since it is not the linear spatiotemporal RF of these simple cells that was impaired under monocular deprivation.     

Defensive responses to phobic stimuli.

Physiological recordings were made while nine females who were afraid of spiders (group P) and nine who were not (group N) viewed a random series of spider and neutral slides. Group P's responses to the spider slides included heart rate (HR) acceleration, cephalic vasoconstriction and an increase in palmer skin conductance (SC), a pattern considered to be part of a defensive response (DR). Group N's responses, on the other hand, were indicative of an orienting response (OR), and included HR deceleration, cephalic vasodilation and an increase in palmar SC. The neutral slides elicited little in the way of responses from group N. However, they elicited the cardiovascular and electrodermal components of an OR from group P, presumably because of their contrast with the feared spider slides. Although the DR pattern observed in group P was often accompanied by increased somatic activity, HR acceleration and cephalic vasoconstriction still occurred even when somatic activity did not appear to increase.     

Competitive dynamics in cortical responses to visual stimuli

Neurons in the visual cortex of the macaque monkey exhibit a variety of competitive behaviors, including normalization and oscillation, when presented with multiple visual stimuli. Here we argue that a biophysically plausible cortical circuit with opponent inhibition, spike-frequency adaptation, and synaptic depression can account for the full range of behaviors. The governing parameter is the strength of inhibition between competing neuronal pools. As the strength of inhibition is increased, the pattern of network behavior shifts from normalization mode to oscillatory mode, with oscillations occurring at progressively lower frequency until, at the extreme, winner-take-all behavior appears.     

Respiratory responses to olfactory stimuli in Parkinson's disease

There are many reports of olfactory impairment in patients with Parkinson's disease (PD) and the impairment can be observed before the appearance of typical PD symptom. Accordingly, olfactory screening tests may predict disease onset and indicates a need for early treatment before classic signs of the disease. Olfaction is dependent on inspiration, and activation of olfactory limbic areas are synchronized with the natural breathing cycle in animals and humans. Subconscious changes in respiratory pattern occur in response to odor stimulation. The use of olfactory stimuli to investigate respiratory pattern could be used to assess olfactory perception and serve as an index for olfactory limbic activation. In this study, we tested olfactory acuity in normal subjects and in patients with PD and recorded V(O2) and respiratory variables during pleasant and unpleasant odor presentation. All subjects were able to detect the odorants; however patients with PD were assigned to one of two groups, group that could recognize odors or the group with impaired odor recognition. Respiratory response toward unpleasant and pleasant odor recognition were weak in PD groups who could recognize odors than normal subject as well as emotional response to odor stimuli. PD group with impaired odor recognition showed no respiratory response toward odor stimuli. PD may experience difficulty in feeling positive emotions toward pleasant odors prior to the unpleasant odor because respiratory responses to pleasant odors may also be related to higher processes including intentional control of breathing pattern as a result of olfactory cortex processing and perceptions or emotions.     

Myoblasts produce IL-6 in response to inflammatory stimuli

Muscle fibers are the target of T cell-mediated cytotoxic reactions in polymyositis and inclusion body myositis, while the success of myoblast transplantation depends on the absence of an immune rejection against the myofibers. In order to study the behaviour of muscle cells in an inflammatory milieu, we investigated the production of IL-6 and its modulation, including the second messenger pathways controlling it, in in vitro highly purified human myoblast cultures. We found that IL- 1beta, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) stimulated myoblast IL-6 secretion in a dose- and time-dependent manner, whereas forskolin and cholera toxin did not. HA1004 at 10 microM did not significantly affect the IL-1beta- and TNF-alpha-induced IL-6 secretion, suggesting that cAMP and protein kinase A are not sufficient to stimulate this process. To investigate the role of protein kinase C (PKC) in this signal transduction, we employed the inhibitor calphostin C, and the activators phorbol-12-myristate-13- acetate (PMA) and calcium ionophore A23187. Calphostin C blocked IL-6 secretion, PMA had a small stimulatory effect and A23187 had no effect; moreover, PKC down-regulation by PMA did not inhibit IL-1beta stimulation, while it reduced TNF-alpha stimulation. These data indicate that different PKC isoforms may be involved in TNF-alpha and IL-1beta signal transduction. Such a difference can distinguish the action of two traditionally 'overlapping' inflammatory cytokines. Our data suggest that muscle cells, like myoblasts, satellite cells and in vivo regenerating myofibers, may discriminate between different stimuli and produce IL-6 when activated in response to muscle injury.      

Expectation enhances event-related responses to affective stimuli

How the expectation of forthcoming emotional events influences individuals’ behaviors and brain responses to such events remains controversial. The present study addressed this issue using event-related potentials (ERPs) to overcome limitations in research techniques. In addition, a no cue condition was adopted as the unexpected condition to make the research paradigm closer to real life situations for ecological validity. Behavioral results showed that positive stimuli were experienced more pleasantly and negative ones were experienced more unpleasantly during the expected condition than the unexpected one. ERPs results also displayed larger P2, N2 and LPP amplitudes in the expected condition, regardless of stimulus valence. The finding that expected emotional events evoke enhanced behavioral and brain responses than the unexpected ones do provides a strong piece of evidence for the effect of expectation on emotion processing.     

Event-related potential responses to love-related facial stimuli

In event-related potential (ERPs) studies, emotional stimuli usually elicit an enhanced late positive potential (LPP), which is assumed to reflect motivated attention. However, whether a stimulus elicits emotional responses may depend on the individual's state, such as experiencing romantic love. It has been suggested that stimuli that are related to someone's beloved will elicit increased attention in that infatuated individual. In this study, participants who were in love viewed faces of their beloved, their friend, and of an unknown, beautiful person. The friend was included to control for familiarity, and the unknown person for perceived beauty. As expected, the LPP was larger in response to the face of the beloved than to the other two emotionally significant faces. Interpreting the LPP as reflecting motivated attention, this implies that romantic love is accompanied by increased attention for the face of one's beloved.     

Foveal attention modulates responses to peripheral stimuli

When attending to a visual object, peripheral stimuli must be monitored for appropriate redirection of attention and gaze. Earlier work has revealed precentral and posterior parietal activation when attention has been directed to peripheral vision. We wanted to find out whether similar cortical areas are active when stimuli are presented in nonattended regions of the visual field. The timing and distribution of neuromagnetic responses to a peripheral luminance stimulus were studied in human subjects with and without attention to fixation. Cortical current distribution was analyzed with a minimum L1-norm estimate. Attention enhanced responses 100-160 ms after the stimulus onset in the right precentral cortex, close to the known location of the right frontal eye field. In subjects whose right precentral region was not distinctly active before 160 ms, focused attention commonly enhanced right inferior parietal responses between 180 and 240 ms, whereas in the subjects with clear earlier precentral response no parietal enhancement was detected. In control studies both attended and nonattended stimuli in the peripheral visual field evoked the right precentral response, whereas during auditory attention the visual stimuli failed to evoke such response. These results show that during focused visual attention the right precentral cortex is sensitive to stimuli in all parts of the visual field. A rapid response suggests bypassing of elaborate analysis of stimulus features, possibly to encode target location for a saccade or redirection of attention. In addition, load for frontal and parietal nodi of the attentional network seem to vary between individuals.