Using event-related fMRI, we analyzed the functional neuroanatomy of covert reorienting and inhibition of return (IOR). Covert reorienting to a target appearing within 250 msec after an invalid contralateral location cue elicited increased activation in the left fronto-polar cortex (LFPC), right anterior and left posterior middle frontal gyrus, and right cerebellum, areas that have previously been associated with attentional processes, specifically attentional change. In contrast, IOR, which leads to prolonged response times to targets that appear at the cued location at a stimulus-onset-asynchrony (SOA)>250 msec, was accompanied by increased activation in brain areas involved in oculomotor programming, such as the right medial frontal gyrus (supplementary eye field; SEF) and the right inferior precentral sulcus (frontal eye field; FEF), supporting the oculomotor bias theory of IOR. Pre-SEF and pre-FEF areas were involved both in covert reorienting and IOR. The supramarginal gyri were bilaterally involved in IOR, with the right supramarginal gyrus additionally involved in covert reorienting.

The SWR1/SRCAP complex is a chromatin-remodeling complex that has been shown to be involved in substitution of histone H2A by the histone variant H2A.Z in yeast (Saccharomyces cerevisiae) and animals. Here, we identify and characterize SERRATED LEAVES AND EARLY FLOWERING (SEF), an Arabidopsis (Arabidopsis thaliana) homolog of the yeast SWC6 protein, a conserved subunit of the SWR1/SRCAP complex. SEF loss-of-function mutants present a pleiotropic phenotype characterized by serrated leaves, frequent absence of inflorescence internodes, bushy aspect, and flowers with altered number and size of organs. sef plants flower earlier than wild-type plants both under inductive and noninductive photoperiods. This correlates with strong reduction of FLOWERING LOCUS C and MADS-AFFECTING FLOWERING4 transcript levels and up-regulation of FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 gene expression. The sef phenotype is similar to that of the photoperiod-independent early flowering1 (pie1) and the actin-related protein 6 (arp6) mutants. PIE1 and ARP6 proteins are also homologs of SWR1/SRCAP complex subunits. Analysis of sef pie1 double mutants demonstrates genetic interaction between these two genes. We also show physical interactions between SEF, ARP6, and PIE1 proteins. Taken together, our data indicate that SEF, ARP6, and PIE1 might form a molecular complex in Arabidopsis related to the SWR1/SRCAP complex identified in other eukaryotes.

WGA-HRP was used to examine projections to the brainstem from the supplementary eye field (SEF). The SEF was defined electrophysiologically in awake, behaving monkeys and connections were compared to those of the arcuate frontal eye field (FEF), area 6DC, and primary motor cortex. The SEF was found to have either direct or indirect connections with almost every known pre- and paraoculomotor structure of the brainstem. The SEF was found to project bilaterally to layers I and IV of a tangentially widespread region of the superior colliculus. Terminal label was evident in the pretectal olivary nucleus, nucleus of the optic tract, nucleus raphe interpositus (omnipause region), nucleus prepositus hypoglossi, the perioculomotor cap of the central gray, dorsal central gray, nucleus reticularis tegmenti pontis, nucleus reticularis pontis oralis, and to multiple nuclei of the basis pontis (most densely to the dorsomedial nucleus). Bilateral projections were found in the parvicellular red nucleus. Reciprocal connections were present in the nucleus limitans, the mesencephalic reticular formation, locus coeruleus, and the serotonergic nuclei of the raphe complex (dorsalis and central superior). Overall patterns of connectivity were similar to those of the FEF and markedly different from those of the contiguous dorsocaudal area 6 or primary motor cortex. It was concluded that observed patterns of SEF-brainstem connectivity further justifies viewing this region as a distinct eye field that is likely to serve preparatory and trigger functions in the generation of saccadic eye movements.

Only certain serotypes of Salmonella represent 99% of all human clinical isolates. We determined whether the phylogenetic distribution of fimbrial operons would account for the host adaptations observed for Salmonella serotypes. We found that three fimbrial operons, fim, lpf, and agf, were present in a lineage ancestral to Salmonella. While the fim and agf fimbrial operons were highly conserved among all Salmonella serotypes, sequence analysis suggested that the lpf operon was lost from many distantly related lineages. As a consequence, the distribution of the lpf operon cannot be explained easily and may be a consequence of positive and negative selection in different hosts for the presence of these genes. Two other fimbrial operons, sef and pef, each entered two distantly related Salmonella lineages and each is present only in a small number of serotypes. These results show that horizontal gene transfer and deletion events have created unique combinations of fimbrial operons among Salmonella serotypes. The presence of sef and pef correlated with serotypes frequently isolated from common domesticated animals.

Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration as well as differentiation events such as angiogenesis, osteogenesis, and chondrogenesis. Recently, genetic screens in Drosophila and gene expression screens in zebrafish have resulted in the identification of several feedback inhibitors of FGF signaling. One of these, Sef (similar expression to fgf genes), encodes a transmembrane protein that belongs to the FGF synexpression group. Here we show that like zebrafish Sef (zSef), mouse Sef (mSef) interacts with FGFR1 and that the cytoplasmic domain of mSef mediates this interaction. Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser(338), MEK1/2 at Ser(217) and Ser(221), and ERK1/2 at Thr(202) and Tyr(204). Furthermore, mSef inhibits ERK activation mediated by a constitutively activated FGFR1 but not by a constitutively active Ras and decreases FGF but not PDGF-mediated activation of Akt. These results indicate that Sef exerts its inhibitory effects at the level of FGFR and upstream of Ras providing an additional level of negative regulation of FGF signaling.

There are several eye fields in the primate frontal cortex. The number and location of these oculomotor control zones remain controversial, especially in the human brain. In the monkey, the frontal eye field (FEF) is located in the rostral bank of the arcuate sulcus at approximately the level of the posterior end of the sulcus principalis, the supplementary eye field (SEF) is located on the dorsomedial frontal cortex, and the cingulate eye field (CEF) in the dorsal bank of the cingulate sulcus. In the human frontal cortex, the location of the FEF varies depending on the method used, electrical stimulation or functional neuroimaging, to establish it. Some investigators have argued that the SEF is located on the medial wall of the frontal lobe but its presumed location remains controversial. The location of the CEF in the human brain is not known. The present article reviews electrophysiological and functional neuroimaging evidence regarding the location of these frontal oculomotor areas in the macaque monkey and human brains and, in light of new findings in the human brain, attempts to reconcile the differences observed in the location of these eye fields using the different techniques. Together, these data suggest the existence of at least four eye fields in the frontal cortex, i.e. the FEF, the SEF, the CEF, and a premotor eye field, and suggest that their anatomical relationships are preserved from monkey to human brain.

Subcellular compartmentalization has become an important theme in cell signaling such as spatial regulation of Ras by RasGRP1 and MEK/ERK by Sef. Here, we report spatial regulation of Raf kinase by RKTG (Raf kinase trapping to Golgi). RKTG is a seven-transmembrane protein localized at the Golgi apparatus. RKTG expression inhibits EGF-stimulated ERK and RSK phosphorylation, blocks NGF-mediated PC12 cell differentiation, and antagonizes Ras- and Raf-1-stimulated Elk-1 transactivation. Through interaction with Raf-1, RKTG changes the localization of Raf-1 from cytoplasm to the Golgi apparatus, blocks EGF-stimulated Raf-1 membrane translocation, and reduces the interaction of Raf-1 with Ras and MEK1. In RKTG-null mice, the basal ERK phosphorylation level is increased in the brain and liver. In RKTG-deleted mouse embryonic fibroblasts, EGF-induced ERK phosphorylation is enhanced. Collectively, our results reveal a paradigm of spatial regulation of Raf kinase by RKTG via sequestrating Raf-1 to the Golgi apparatus and thereby inhibiting the ERK signaling pathway.

The superior sector of Brodmann area 6 (dorsal premotor cortex, PMd) of the macaque monkey consists of a rostral and a caudal architectonic area referred to as F7 and F2, respectively. The aim of this study was to define the origin of prefrontal and agranular cingulate afferents to F7 and F2, in the light of functional and hodological evidence showing that these areas do not appear to be functionally homogeneous. Different sectors of F7 and F2 were injected with neural tracers in seven monkeys and the retrograde labelling was qualitatively and quantitatively analysed. The dorsorostral part of F7 (supplementary eye field, F7-SEF) was found to be a target of strong afferents from the frontal eye field (FEF), from the dorsolateral prefrontal regions located dorsally (DLPFd) and ventrally (DLPFv) to the principal sulcus and from cingulate areas 24a, 24b and 24c. In contrast, the remaining part of F7 (F7-non SEF) is only a target of the strong afferents from DLPFd. Finally, the ventrorostral part of F2 (F2vr), but not the F2 sector located around the superior precentral dimple (F2d), receives a minor, but significant, input from DLPFd and a relatively strong input from the cingulate gyrus (areas 24a and 24b) and area 24d. Present data provide strong hodological support in favour of the idea that areas F7 and F2 are formed by two functionally distinct sectors.

Together with the frontal and parietal eye fields, the supplementary eye field (SEF) is involved in the performance and control of voluntary and reflexive saccades and of ocular pursuit. This region was first described in non-human primates and is rather well localized on the dorsal surface of the medial frontal cortex. In humans the site of the SEF is still ill-defined. Functional imaging techniques have allowed investigation of the location and function of the SEF. However, there is great variability with regard to the published standardized coordinates of this area. We used here the spatial precision of functional magnetic resonance imaging (fMRI) in order to better localize the SEF in individuals. We identified as the SEF a region on the medial wall that was significantly activated when subjects executed self-paced horizontal saccades in darkness as compared to rest. This region appeared to be predominantly activated in the left hemisphere. We found that, despite a discrepancy of >2 cm found in the standardized Talairach coordinates, the location of this SEF-region could be precisely and reliably described by referring to a sulcal landmark found in each individual: the upper part of the paracentral sulcus.

OBJECTIVE

Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation.

METHODS

Observational study.

METHODS

Academic medical intensive care unit.

METHODS

Critically ill patients receiving MV and intravenous sedation.

METHODS

Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously.

RESULTS

We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64).

CONCLUSIONS

The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

BACKGROUND

The electroencephalogram (EEG) has been evaluated as a tool for measuring depth of anesthesia, but the use of the EEG monitoring is still controversial. The current study was designed to evaluate the accuracy of three EEG parameters and anesthetic concentration for predicting depth of sedation and anesthesia during sevoflurane anesthesia

METHODS

One low and one high equilibrated concentration ranging from 0.2-1.8% were assigned randomly and administered consecutively to 69 patients. The bispectral index (BIS; version 3.2), 95% spectral edge frequency (SEF), and median power frequency (MPF) were obtained from a bipolar frontomastoid (Fp1-A1, Fp2-A2) montage using an EEG monitor. Sedation was assessed using the responsiveness portion of the observer's assessment of alertness-sedation scale. In the second phase of the study, the 47 patients who were scheduled to have skin incisions were observed for purposeful movement in response to skin incision at sevoflurane concentrations between 1.6% and 2.4%. The relation among BIS, 95% SEF, MPF, sevoflurane concentration, sedation score, and movement or no movement after skin incision, was determined. Prediction probability values for EEG parameters and sevoflurane concentration to predict depth of sedation and anesthesia were also calculated.

RESULTS

The BIS and sevoflurane concentration correlated closely with the sedation score. Both 95% SEF and MPF changed significantly but biphasically with increasing sedation. The prediction probability values for BIS and sevoflurane concentration were 0.966 and 0.945, respectively, indicating a high predictive performance for depth of sedation. No EEG parameters predicted movement after skin incision better than chance alone.

CONCLUSIONS

Parameters derived from EEG, such as BIS, and 95% SEF are reliable guides to the depth of sedation, but not to the adequacy of anesthesia level for preventing movement during sevoflurane anesthesia.

Neuronal activities were recorded in the supplementary eye field (SEF) of 3 macaque monkeys trained to perform antisaccades pseudorandomly interleaved with prosaccades, as instructed by the shape of a central fixation point. The prosaccade goal was indicated by a peripheral stimulus flashed anywhere on the screen, whereas the antisaccade goal was an unmarked site diametrically opposite the flashed stimulus. The visual cue was given immediately after the instruction cue disappeared in the immediate-saccade task, or during the instruction period in the delayed-saccade task. The instruction cue offset was the saccade gosignal. Here we focus on 92 task-related neurons: visual, eye-movement, and instruction/fixation neurons. We found that 73% of SEF eye-movement-related neurons fired significantly more before anti-saccades than prosaccades. This finding was analyzed at 3 levels: population, single neuron, and individual trial. On individual antisaccade trials, 40 ms before saccade, the firing rate of eye-movement-related neurons was highly predictive of successful performance. A similar analysis of visual responses (40 ms astride the peak) gave less-coherent results. Fixation neurons, activated during the initial instruction period (i.e., after the instruction cue but before the stimulus) always fired more on antisaccade than on prosaccade trials. This trend, however, was statistically significant for only half of these neurons. We conclude that the SEF is critically involved in the production of antisaccades.

The expression of the alpha' and beta subunit genes of beta-conglycinin is differentially regulated during soybean embryo development. Although both are expressed solely in developing seeds during mid to late stages of embryo development, the alpha' subunit is expressed more highly on a per gene basis, and alpha' subunit mRNA begins to accumulate three to five days earlier than beta subunit mRNA. In cultured cotyledons, beta subunit gene(s) respond to changes in methionine or abscisic acid levels, whereas expression of the alpha' subunit gene(s) is unaffected by these changes. To investigate the mechanisms by which these genes are transcriptionally regulated, we examined the interactions of nuclear proteins with upstream sequences from the alpha' and beta subunit genes. Four distinct DNA binding factors were identified in nuclear extracts from developing soybean seeds. These factors are termed Soybean Embryo Factors (<em>SEF</em>) 1 through 4. <em>SEF</em> binding sites are distributed non-uniformly between the alpha' and beta subunit genes, and the amount of protein binding is modulated over the course of embryo development. DNA footprinting revealed the sequences recognized by three of these factors. Factors which behave in a manner similar to that of <em>SEF</em>3 were also identified in nuclear extracts from developing tobacco and sunflower seeds.

Cortical motor areas are thought to contribute "higher-order processing," but what that processing might include is unknown. Previous studies of the smooth pursuit-related discharge of supplementary eye field (SEF) neurons have not distinguished activity associated with the preparation for pursuit from discharge related to processing or memory of the target motion signals. Using a memory-based task designed to separate these components, we show that the SEF contains signals coding retinal image-slip-velocity, memory, and assessment of visual motion direction, the decision of whether to pursue, and the preparation for pursuit eye movements. Bilateral muscimol injection into SEF resulted in directional errors in smooth pursuit, errors of whether to pursue, and impairment of initial correct eye movements. These results suggest an important role for the SEF in memory and assessment of visual motion direction and the programming of appropriate pursuit eye movements.

We report 25 cases of a peculiar sclerosing epithelioid variant of fibrosarcoma (SEF) simulating an infiltrating carcinoma. The tumors occurred primarily in the deep musculature and were frequently associated with the adjacent fascia or periosteum. The patients' ages were 14 to 87 years (median, 45). Fourteen were male and 11 female. The tumors were located in the lower extremities and limb girdles (12 cases), trunk (9), upper limb girdles (2), and neck (2). They measured 2 to 14.5 cm in greatest dimension (median size, 7 cm) and were gray to white and firm. Histologically, the lesions were characterized by a proliferation of rather uniform, small, slightly angulated, round to ovoid epithelioid cells with sparse, often clear cytoplasm arranged in distinct nests and cords. In all cases there was prominent hyaline sclerosis, sometimes reminiscent of osteoid or cartilage and foci of conventional fibrosarcoma. Occasional myxoid zones with cyst formation and foci of hyaline cartilage, calcification, and metaplastic bone were also seen. Mitotic figures were generally scarce. Vimentin was detected in 13 of 14 cases, epithelial membrane antigen in seven, S100 protein in four, and neuron-specific enolase in two. Cytokeratins were detected with AE1/AE3 and CAM 5.2 in two cases. Leukocyte common antigen, CD68 antigen, HMB45, desmin, and alpha-smooth muscle actin were negative in all cases. In 13 of 14 cases, 75% or more of the cells stained for proliferating cell nuclear antigen (PCNA). Ki67 immunostaining with MIB 1 showed low proliferative activity in all cases, averaging 5% of tumor cells or less. In all cases, p53 was detected by immunohistochemical methods; bcl-2, an antiapoptosis marker, was detected in more than 90% of the cells in 11 of 12 cases. Ultrastructurally, both the epithelioid and spindled tumor cells had features of fibroblasts. Follow-up in 16 cases ranging from 13 months to 17 years 3 months (median, 11 years 4 months) revealed persistent disease or local recurrences in 53% of patients and metastases in 43%. The metastases were to the lungs (4 cases), skeleton (3), chest wall/pleura (3), pericardium (1), and brain (1). Four patients died of disease, four were alive with disease, two were known to be alive but disease status unknown, and six had no evidence of further disease at last follow-up. The data suggest that SEF is a relatively low-grade fibrosarcoma; yet it is fully malignant despite the presence of histologically benign-appearing foci. The proliferation markers PCNA and Ki67 did not correlate with prognosis.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE

A neural system matching action observation and execution seems to operate in the human brain, but its possible role in processing sensory inputs reaching the cortex during movement observation is unknown.

METHODS

We investigated somatosensory evoked potentials (SEPs), somatosensory evoked fields (SEFs) and the temporal spectral evolution of the brain rhythms (approximately 10 and approximately 20 Hz) following electrical stimulation of the right median nerve in 15 healthy subjects, during the following randomly intermingled conditions: a pure cognitive/attentive task (mental calculation); the observation of a motoric act (repetitive grasping) with low cognitive content ('Obs-grasp'); and the observation of a complex motoric act (finger movement sequence), that the subject had to recognize later on, therefore reflecting an adjunctive cognitive task ('Obs-seq'). These conditions were compared with an absence of tasks ('Relax') and actual motor performance.

RESULTS

The post-stimulus rebound of the approximately 20 Hz beta magnetoencephalographic rhythm was reduced during movement observation, in spite of little changes in the approximately 10 Hz rhythm. Novel findings were: selective amplitude increase of the pre-central N(30) SEP component during both 'Obs-grasp' and 'Obs-seq', as opposed to the 'gating effect' (i.e. amplitude decrease of the N(30)) occurring during movement execution. The strength increase of the 30 ms SEF cortical source significantly correlated with the decrease of the approximately 20 Hz post-stimulus rebound, suggesting a similar pre-central origin.

CONCLUSIONS

Changes took place regardless of either the complexity or the cognitive content of the observed movement, being related exclusively with the motoric content of the action. It is hypothesized that the frontal 'mirror neurons' system, known to directly facilitate motor output during observation of actions, may also modulate those somatosensory inputs which are directed to pre-central areas. These changes are evident even in the very first phases (i.e. few tens of milliseconds) of the sensory processing.

Prolonged survival of Islet- allo- and xenografts can be induced following implantation of the islets into the abdominal testis of diabetic rats. We previously showed that a factor released by Sertoli cells appears to be responsible for the protection of the intratesticular islet allo- and xenografts against rejection. The aim of this study was to examine whether an immunologically privileged site can be established in an organ site in vivo, other than the testis, such as the renal, subcapsular space, to make feasible the grafting of female recipients as well. A total of 36 male and 21 female, diabetic, PVG rats were divided into six different treatment groups: 1) Six male rats were grafted with islets from Sprague-Dawley (S-D) donor rats only. 2) Ten male rats were grafted with islets from (S-D) donors and were then given a short course of cyclosporine (CsA) posttransplantation. 3) Ten male rats were grafted with islets from (S-D) donors and with Sertoli cell-enriched fractions (SEF) from PVG donors but without CsA. 4) Ten male rats were grafted with a combination of islets from (S-D) and SEF from (PVG), donors, respectively, and CsA. 5) Ten female rats were given an identical combination of cells and CsA as depicted for group 5. 6) Ten female rats were grafted with a combination of islets and SEF, both cell types from S-D donors, and CsA. The results showed that 70% to 100% of the grafted rats in groups 1, 2, and 3 remained hyperglycemic.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study evaluated the effect of context on behavior and brain activity during saccade tasks. FMRI and eye movement data were collected while 36 participants completed three runs in a block design: (1) fixation alternating with pro-saccades, (2) fixation alternating with anti-saccades, and (3) pro- alternating with anti-saccades. Two task-related data-driven regressors, identified using independent component analysis, were used in GLM analyses. Brain activity associated with anti- and pro-saccades were compared under both single (runs 1 and 2) and mixed saccade (run 3) conditions. Brain areas consistently associated with anti-saccades in previous studies, including striatum, thalamus, cuneus, precuneus, lateral and medial frontal eye fields (FEF), supplementary eye fields (SEF), and prefrontal cortex (PFC) showed significantly greater percent signal change during the fixation/anti- compared with the fixation/pro-saccade run. During the pro/anti run, however, only precuneus, SEF and FEF showed greater activation during the anti-saccade trials. This is a clear demonstration that the saccade-related neural circuitry is affected by context. Behavioral results suggest that performance on saccade tasks is also affected by context. Participants made more direction errors on pro-trials that followed anti-trials than on pro-trials that followed fixation. Results from this study indicate that precuneus, SEF and FEF, which showed anti-saccade-related activity during both comparisons, may be more important for supporting this complex behavioral response. Other brain regions, such as PFC, however, which showed anti-saccade-related activity during only the single task comparison, may be more involved in response selection and/or context updating.

We recorded somatosensory evoked magnetic fields (SEFs) by a whole head magnetometer to elucidate cortical receptive areas involved in pain processing, focusing on the primary somatosensory cortex (SI), following painful CO(2) laser stimulation of the dorsum of the left hand in 12 healthy human subjects. In seven subjects, three spatially segregated cortical areas (contralateral SI and bilateral second (SII) somatosensory cortices) were simultaneously activated at around 210 ms after the stimulus, suggesting parallel processing of pain information in SI and SII. Equivalent current dipole (ECD) in SI pointed anteriorly in three subjects whereas posteriorly in the remaining four. We also recorded SEFs following electric stimulation of the left median nerve at wrist in three subjects. ECD of CO(2) laser stimulation was located medial-superior to that of electric stimulation in all three subjects. In addition, by direct recording of somatosensory evoked potentials (SEPs) from peri-Rolandic cortex by subdural electrodes in an epilepsy patient, we identified a response to the laser stimulation over the contralateral SI with the peak latency of 220 ms. Its distribution was similar to, but slightly wider than, that of P25 of electric SEPs. Taken together, it is postulated that the pain impulse is received in the crown of the postcentral gyrus in human.

Fibrosis in the reticular layer beneath the epithelial basement membrane is a feature of airway remodeling in human asthma. We previously reported the presence of subepithelial fibrosis (SEF) in a disease model of atopic asthma in which mice were sensitized and intratracheally challenged with ovalbumin (OVA) (Blyth and colleagues, Am. J. Respir. Cell Mol. Biol. 1996;14:425-438). Here, we describe further studies to quantify the degree of SEF after its induction by repeated exposure of the airways to allergen. The amount of subepithelial reticulin in the airways of animals challenged three times with 80 microg OVA was typically increased 1. 4-fold. The increased amount of reticulin showed no reduction after a 50-d period after the third allergen challenge. A reduction in SEF was achieved by daily treatment with dexamethasone (DEX) for 8 d during the allergen challenge period, or by treatment with anti-interleukin-5 antibody (TRFK5) at the time of allergen challenge. Postchallenge treatment with DEX for 15 d resulted in significant resolution of previously established SEF. Severe nonallergic inflammation during repeated exposure of airways to lipopolysaccharide did not induce SEF. The results indicate that development of SEF is associated with eosinophil infiltration into airways, and may occur only when the inflammatory stimulus is allergic in nature.

OBJECTIVE

A framework for combining bioelectric and biomagnetic data is presented. The data are transformed to signal-to-noise ratios and reconstruction algorithms utilizing a new regularization approach are introduced.

METHODS

Extensive simulations are carried out for 19 different EEG and MEG montages with radial and tangential test dipoles at different eccentricities and noise levels. The methods are verified by real SEP/SEF measurements. A common realistic volume conductor is used and the less well known in vivo conductivities are matched by calibration to the magnetic data. Single equivalent dipole fits as well as spatio-temporal source models are presented for single and combined modality evaluations and overlaid to anatomic MR images.

RESULTS

Normalized sensitivity and dipole resolution profiles of the different EEG/MEG acquisition systems are derived from the simulated data. The methods and simulations are verified by simultaneously measured somatosensory data.

CONCLUSIONS

Superior spatial resolution of the combined data studies is revealed, which is due to the complementary nature of both modalities and the increased number of sensors. A better understanding of the underlying neuronal processes can be achieved, since an improved differentiation between quasi-tangential and quasi-radial sources is possible.

Signal transduction networks allow cells to recognize and respond to changes in the extracellular environment. All eukaryotic cells have MAPK (mitogen-activated protein kinase) pathways that participate in diverse cellular functions, including differentiation, survival, transformation and movement. Five distinct groups of MAPKs have been characterized in mammals, the most extensively studied of which is the Ras/Raf/MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]/ERK cascade. Numerous stimuli, including growth factors and phorbol esters, activate MEK/ERK signalling. How disparate extracellular signals are translated by MEK/ERK into different cellular functions remains obscure. Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1. Scaffolds organize multiprotein signalling complexes. This targets MEK/ERK to specific substrates and facilitates communication with other pathways, thereby mediating diverse functions. The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.

A region of dorsomedial frontal cortex (DMFC) has been implicated in planning and executing saccadic eye movements; hence it has been referred to as a supplementary eye field (SEF). Recently, activity related to executing smooth-pursuit eye movements has been recorded from the DMFC, and microstimulation here has been shown to evoke smooth eye movements. This report documents neuronal activity present in smooth-pursuit tasks where the predictability of target motion was manipulated. The activity of many neurons in the DMFC reached a peak when a predictable change in target motion occurred. Furthermore, the peak activity of some cells was systematically shifted by manipulating the duration of the target event, indicating that the network these neurons were in could learn the temporal characteristics of new target motion. Finally, the activity of most neurons tested was greater when target motion was predictable than when it was unpredictable. The results suggest that the DMFC participates in planning smooth-pursuit eye movements based on past stimulus history.