In this study we used a repeated measures design and univariate analysis of variance to study the respective effects of ISI, spatial attention and stimulus detection on the strengths of the sources previously identified by modelling SEFs during the 200 ms following mentally counted left median nerve stimuli delivered at long and random ISIs (Part I). We compared the SEF source strengths in response to frequent and rare stimuli, both in detection and ignoring conditions. This permitted us to establish a hierarchy in the effects of ISI, attention and stimulus detection on the activation of the cortical network of SEF sources distributed in SI and posterior parietal cortex contralateral to stimulation, and in the parietal operculum (SII) and premotor frontal cortex of both hemispheres. In all experimental conditions the SI and parietal opercular sources were the most active. All sources were more active in response to stimuli delivered at long and random ISIs and the frontal sources were activated only in this condition of stimulation. Driving the subject's attention toward the side stimulated had no detectable effect on the activity of SEF sources at short ISI. At long ISIs mental counting of the stimuli increased the responses of all sources except SI. These results suggest that activation of frontal sources during mental counting could reflect a working memory process, and that of posterior parietal sources a spatial attention effect detectable only at long ISIs.

We describe intracranial local field potentials (LFPs) recorded in the supplementary eye field (SEF) of macaque monkeys performing a saccade countermanding task. The most prominent feature at 90% of the sites was a negative-going polarization evoked by a contralateral visual target. At roughly 50% of sites a negative-going polarization was observed preceding saccades, but in stop signal trials this polarization was not modulated in a manner sufficient to control saccade initiation. When saccades were canceled in stop signal trials, LFP modulation increased with the inferred magnitude of response conflict derived from the coactivation of gaze-shifting and gaze-holding neurons. At 30% of sites, a pronounced negative-going polarization occurred after errors. This negative polarity did not appear in unrewarded correct trials. Variations of response time with trial history were not related to any features of the LFP. The results provide new evidence that error-related and conflict-related but not feedback-related signals are conveyed by the LFP in the macaque SEF and are important for identifying the generator of the error-related negativity.

IL-17, the hallmark cytokine of the Th17 population, mediates immunity to extracellular pathogens and promotes autoimmune immunopathology. The signaling mechanisms triggered by the IL-17 receptor (IL-17RA) and related receptors are strikingly different from other cytokine subclasses. Namely, IL-17Rs contain a conserved SEF/IL-17R (SEFIR) subdomain that engages Act1, leading to activation of TRAF6, NF-κB, and other events. Although the SEFIR is critical for signaling, the molecular details of the functional subdomains within IL-17RA remain poorly characterized. Here, we provide a detailed structure-function analysis delineating the C-terminal boundary of the SEFIR-containing region of IL-17RA. We show that functionality of this domain requires a large extension to the previously identified SEFIR motif. In contrast to the SEFIR, this extension is not conserved among IL-17R family members. Surprisingly, Act1 recruitment is not sufficient for downstream signaling activation, whereas ubiquitination of TRAF6 correlates tightly with functional receptors. We further demonstrate that IL-17RA exhibits signaling properties that are nonredundant with other IL-17R family members. Finally, we report that IL-17 signals synergistically with lymphotoxin-α3, using the same signaling motifs within IL-17RA. These studies provide new insight into the structure-function relationships of IL-17RA and reveal distinct signaling differences among IL-17R family members.

Efferents from the frontal eye fields (FEF) to the ipsilateral frontal lobe were studied by autoradiography of tritiated tracers (leucine, proline, and fucose) in seven macaque monkeys that were used previously to describe subcortical connections. In four of the cases, tracer injection sites were confirmed by low thresholds for the electrical elicitation of saccadic eye movements. Cases were grouped as lFEF of sFEF cases according to large or small saccades that were characteristic of the injection site. Projections from the FEF terminated in five frontal regions: 1) area FD on the dorsomedial convexity; 2) area FC (containing SEF) medial to the upper limb of the arcuate sulcus; 3) areas FD and FD delta along the walls of the principal sulcus; 4) area FCBm on the deep, posterior wall of the arcuate sulcus inferior to the sulcal spur; and 5) the inferolateral cortex (area FDi) on the convexity and lateral two thirds of the anterior wall of the arcuate sulcus. Projections in sFEF cases tended to be confined to medial parts of dorsomedial FD and FC and the lateral wall of the principal sulcus and inferolateral convexity. Neither lFEF nor sFEF appeared to project to the SMA or pericingulate cortex. Label in these areas was found only in the cases in which tracer spread into non-FEF areas. FEF projections terminated in column-like patches of about 500-600 microns in diameter. Labeled axons and terminals were seen in all cortical layers regardless of location in the frontal lobe.

Alternative splicing (AS) is an important regulatory process that leads to the creation of multiple RNA transcripts from a single gene. Alternative transcripts often carry premature termination codons (PTCs), which trigger nonsense-mediated decay (NMD), a cytoplasmic RNA degradation pathway. However, intron retention, the most prevalent AS event in plants, often leads to PTC-carrying splice variants that are insensitive to NMD; this led us to question the fate of these special RNA variants. Here, we present an innovative approach to monitor and characterize endogenous mRNA splice variants within living plant cells. This method combines standard confocal laser scanning microscopy for molecular beacon detection with a robust statistical pipeline for sample comparison. We demonstrate this technique on the localization of NMD-insensitive splice variants of two Arabidopsis thaliana genes, RS2Z33 and the SEF factor. The experiments reveal that these intron-containing splice variants remain within the nucleus, which allows them to escape the NMD machinery. Moreover, fluorescence recovery after photobleaching experiments in the nucleoplasm show a decreased mobility of intron-retained mRNAs compared with fully spliced RNAs. In addition, differences in mobility were observed for an mRNA dependent on its origin from an intron-free or an intron-containing gene.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive fibroblastic neoplasm composed of cords of epithelioid cells embedded in a dense collagenous stroma. The reported immunophenotype of SEF is nonspecific. Some SEF cases show morphologic and molecular overlap with low-grade fibromyxoid sarcoma (LGFMS), suggesting a relationship between these tumor types. MUC4 has recently been identified as a sensitive and specific marker for LGFMS; MUC4 expression was also observed in 2 tumors with hybrid features of SEF and LGFMS. We investigated MUC4 expression in SEF and other epithelioid soft tissue tumors to determine (1) the potential diagnostic utility of MUC4 for SEF and (2) the association between MUC4 expression and FUS rearrangement in SEF. Whole sections of 180 tumors were evaluated: 41 cases of SEF (including 29 "pure" SEF and 12 hybrid LGFMS-SEF), 20 epithelioid sarcomas, 11 clear cell sarcomas, 11 metastatic melanomas, 10 perivascular epithelioid cell tumors, 10 alveolar soft part sarcomas, 10 epithelioid angiosarcomas, 10 epithelioid hemangioendotheliomas, 10 epithelioid gastrointestinal stromal tumors, 10 myoepithelial carcinomas, 17 ossifying fibromyxoid tumors, 10 leiomyosarcomas, and 10 biphasic synovial sarcomas. Immunohistochemical analysis was performed after antigen retrieval using a mouse anti-MUC4 monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed on 33 SEF cases using FUS break-apart probes. A subset of cases was also evaluated for EWSR1 and CREB3L2/L1 rearrangements by FISH. Strong diffuse cytoplasmic staining for MUC4 was observed in 32 of 41 (78%) cases of SEF, including all 12 hybrid tumors. FUS rearrangement was detected in 8 of 21 (38%) MUC4-positive cases of SEF with successful FISH studies. The prevalence of FUS rearrangement was similar in hybrid LGFMS-SEF (2 of 6; 33%) and SEF without an LGFMS component (6 of 15; 40%). FUS rearrangement was not detected in any cases of MUC4-negative SEF. Two hybrid tumors had both EWSR1 and CREB3L1 rearrangements. MUC4 expression was also seen in 9 of 10 (90%) biphasic synovial sarcomas, predominantly in the glandular component. All other tumor types were negative for MUC4, apart from focal reactivity in 5 ossifying fibromyxoid tumors, 2 epithelioid gastrointestinal stromal tumors, and 1 myoepithelial carcinoma. MUC4 is a sensitive and relatively specific marker for SEF among epithelioid soft tissue tumors. MUC4 expression occurs more frequently than FUS rearrangement in SEF. The finding of EWSR1 and CREB3L1 rearrangements in 2 cases of hybrid LGFMS-SEF suggests that SEFs are genetically heterogenous. MUC4-positive SEFs with FUS rearrangement are likely closely related to LGFMS. MUC4-positive SEFs that lack FUS rearrangement may be related to LGFMS but could have alternate fusion partners, including EWSR1. SEF without MUC4 expression may represent a distinct group of tumors. MUC4 expression correlates with glandular epithelial differentiation in biphasic synovial sarcoma and is very limited in other epithelioid soft tissue tumors.

We systematically explored the frontal eye field (FEF), the supplementary eye field (SEF), and nearby regions of the frontal cortex to establish the limits of these or possible adjacent eye-movement fields in macaque monkeys. We found a medio-laterally oriented band of saccadic eye-movement sites that extended from the inferior limb of the arcuate sulcus onto the medial surface of the hemisphere and into the dorsal bank of the cingulate sulcus. Two parts of this region may be outside previously described eye-movement areas. We conclude that eye movements are more broadly represented in the frontal lobes than previously described: either the SEF extends into the dorsal bank of the cingulate sulcus and laterally to the arcuate sulcus, or there are more than two frontal eye-movement fields.

We measured somatosensory evoked fields (SEFs) to electric median nerve stimuli from eight healthy subjects with a whole-scalp 122-channel neuromagnetometer in two different conditions: (i) 'rest', with stimuli producing clear tactile sensation without any motor movement, and (ii) 'contraction' with exactly the same stimuli as in 'rest', but with the subjects maintaining sub-maximal isometric contraction in thenar muscles of the stimulated hand. The aim was to study the role of the primary (SI) and secondary somatosensory (SII) cortices in sensorimotor integration. The amplitude of the SI response N20m did not change with coincident isometric contraction, whereas P35m was significantly reduced. On the contrary, activation of contra- and ipsilateral SII cortices was significantly enhanced during the contraction. We suggest that isometric contraction facilitates activation of SII cortices to tactile stimuli, possibly by decreasing inhibition from the SI cortex. The enhanced SII activation may be related to tuning of SII neurons towards relevant tactile input arising from the region of the body where the muscle activation occurs.

Complex goal-directed behaviors extend over time and thus depend on the ability to serially order memories and assemble compound, temporally coordinated movements. Theories of sequential processing range from simple associative chaining to hierarchical models in which order is encoded explicitly and separately from sequence components. To examine how short-term memory and planning for sequences might be coded, we used microstimulation to perturb neural activity in the supplementary eye field (SEF) while animals held a sequence of two cued locations in memory over a short delay. We found that stimulation affected the order in which animals saccaded to the locations, but not the memory for which locations were cued. These results imply that memory for sequential order can be dissociated from that of its components. Furthermore, stimulation of the SEF appeared to bias sequence endpoints to converge toward a location in contralateral space, suggesting that this area encodes sequences in terms of their endpoints rather than their individual components.

Serum amyloid A (SAA) is a major acute-phase protein synthesized and secreted mainly by the liver. In response to acute inflammation, its expression may be induced up to 1,000-fold, primarily as a result of a 200-fold increase in the rate of SAA gene transcription. We have previously demonstrated that a 350-bp promoter fragment from the mouse SAA3 gene was necessary and sufficient to confer liver-specific and cytokine-induced expression. Deletion studies identified a distal response element that is responsible for the cytokine response and has properties of an inducible transcriptional enhancer. In this study, we further analyzed the distal response element and showed that it consists of three functionally distinct elements: the A element constitutes a weak binding site for C/EBP family proteins, the B element also interacts with C/EBP family proteins but with a much higher binding affinity, and the C element interacts with a novel constitutive nuclear factor, SEF-1. Site-specific mutation studies revealed that all three elements were required for maximum promoter activity. C/EBP alpha, C/EBP beta, and C/EBP delta were capable of interacting with elements A and B. Under noninduced conditions, C/EBP alpha was the major binding factor; however, upon cytokine stimulation C/EBP beta- and C/EBP delta-binding activities were dramatically increased and became the predominant binding factors. Consistent with these binding studies were the cotransfection experiments in which C/EBP beta and C/EBP delta were shown to be potent transactivators for the SAA3 promoter. Moreover, the transactivation required an intact B element despite the presence of other functional C/EBP-binding sites. Interestingly, although element C did not interact with C/EBP directly, it was nevertheless required for maximum transactivation by C/EBP delta. Our studies thus demonstrate that both C/EBP family proteins and SEF-1 are required to transactivate the SAA3 gene.

We examined the location and spatial distribution of prefrontal cortical (PF) cells projecting to the supplementary eye field (SEF) and presupplementary motor area (pre-SMA) using a double retrograde-labeling technique in monkeys (Macaca fuscata). The SEF and pre-SMA were physiologically identified based on the findings of intracortical microstimulation and single cell recordings. Two fluorescent tracers, diamidino yellow and fast blue, were injected into the SEF and pre-SMA of each monkey. Retrogradely labeled cells in the PF were plotted with an automated plotting system. The cells projecting to the SEF and pre-SMA were mainly distributed in the upper and lower banks of the principal sulcus (area 46), with little overlap. Cells projecting to the SEF, but not to the pre-SMA, were observed in areas 8a, 8b, 9, 12, and 45. These findings suggest that the SEF and pre-SMA receive different sets of information from the PF cells.

Subcellular trafficking of key oncogenic signal pathway components is likely to be crucial for neoplastic transformation, but little is known about how such trafficking processes are spatially controlled. In this study, we show how Ras activation causes aberrant nuclear localization of phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) MEK1/2 to drive neoplastic transformation. Phosphorylated MEK1/2 was aberrantly located within the nucleus of primary colorectal tumors and human colon cancer cells, and oncogenic activation of Ras was sufficient to induce nuclear accumulation of phosphorylated MEK1/2 and ERK1/2 in intestinal epithelial cells. Enforced nuclear localization of MEK1 in epithelial cells or fibroblasts was sufficient for hyperactivation of ERK1/2, thereby driving cell proliferation, chromosomal polyploidy, and tumorigenesis. Notably, Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef, the reexpression of which was sufficient to restore normal MEK1/2 localization and a reversal of Ras-induced proliferation and tumorigenesis. Taken together, our findings indicate that Ras-induced downregulation of Sef is an early oncogenic event that contributes to genetic instability and tumor progression by sustaining nuclear ERK1/2 signaling.

The supplementary eye field (SEF) is a region within medial frontal cortex that integrates complex visuospatial information and controls eye-head gaze shifts. Here, we test if the SEF encodes desired gaze directions in a simple retinal (eye-centered) frame, such as the superior colliculus, or in some other, more complex frame. We electrically stimulated 55 SEF sites in two head-unrestrained monkeys to evoke 3D eye-head gaze shifts and then mathematically rotated these trajectories into various reference frames. Each stimulation site specified a specific spatial goal when plotted in its intrinsic frame. These intrinsic frames varied site by site, in a continuum from eye-, to head-, to space/body-centered coding schemes. This variety of coding schemes provides the SEF with a unique potential for implementing arbitrary reference frame transformations.

Coherent oscillations of neurons in the primary motor cortex (M1) have been shown to be involved in the corticospinal control of muscle activity. This interaction between M1 and muscle can be measured by the analysis of corticomuscular coherence in the beta-frequency range (beta-CMCoh; 14-30 Hz). Largely based on magnetoencephalographic (MEG) source-modeling data, it is widely assumed that beta-CMCoh reflects direct coupling between M1 and muscle. Deafferentation is capable of modulating beta-CMCoh, however, and therefore the influence of reafferent somatosensory signaling and corresponding neuronal activity in the somatosensory cortex (S1) has been unclear. We present transcranial magnetic stimulation (TMS) and MEG data from three adult patients suffering from congenital hemiparesis due to pre- and perinatally acquired lesions of the pyramidal tract. In these patients, interhemispheric reorganization had resulted in relocation of M1 to the contralesional hemisphere, ipsilateral to the paretic hand, whereas S1 had remained in the lesioned hemisphere. This topographic dichotomy allowed for an unequivocal topographic differentiation of M1 and S1 with MEG (which is not possible if M1 and S1 are directly adjacent within one hemisphere). In all patients, beta-CMCoh originated from the contralesional M1, in accordance with the TMS-evoked motor responses, and in contrast to the somatosensory evoked fields (SEFs) for which the sources (N20m) were localized in S1 of the lesioned hemisphere. These data provide direct evidence for the concept that beta-CMCoh reflects the motorcortical efferent drive from M1 to the spinal motoneuron pool and muscle. No evidence was found for a relevant contribution of neuronal activity in S1 to beta-CMCoh.

The bottom-up processing of visual information is strongly influenced by top-down signals, at least part of which is thought to be conveyed from the frontal cortex through the frontal eye field (FEF) and the lateral intraparietal area (LIP). Here we investigated the architecture of multisynaptic pathways from the frontal cortex to the middle temporal area (MT) of the dorsal visual stream and visual area 4 (V4) of the ventral visual stream in macaques. In the first series of experiments, the retrograde trans-synaptic tracer, rabies virus, was injected into MT or V4. Three days after rabies injections, the second-order (disynaptically connected) neuron labeling appeared in the ventral part of area 46 (area 46v), along with the first-order (monosynaptically connected) neuron labeling in FEF and LIP. In the MT-injection case, second-order neurons were also observed in the supplementary eye field (SEF). In the next series of experiments, double injections of two fluorescent dyes, fast blue and diamidino yellow, were made into MT and V4 to examine whether the frontal inputs are mediated by distinct or common neuronal populations. Virtually no double-labeled neurons were observed in FEF or LIP, indicating that separate neuronal populations mediate the frontal inputs to MT and V4. The present results define that the multisynaptic frontal input to V4 arises primarily from area 46v, whereas the input to MT arises from not only area 46v but also SEF, through distinct FEF and LIP neurons. Segregated pathways from the frontal cortex possibly carry the functionally diverse top-down signals to each visual stream.

BACKGROUND

The Shannon entropy is a standard measure for the order state of sequences. It quantifies the degree of skew of the distribution of values. Increasing hypnotic drug concentrations increase electroencephalographic amplitude. The probability density function of the amplitude values broadens and flattens, thereby changing from a skew distribution towards equal distribution. We investigated the dose-response relation of the Shannon entropy of the electroencephalographic amplitude values during desflurane monoanesthesia in comparison with previously used electroencephalographic parameters.

METHODS

Electroencephalographic records previously obtained in 12 female patients during gynecologic laparotomies were reanalyzed. Between opening and closure of the peritoneum, desflurane vapor settings were varied between 0.5 and 1.6 minimum alveolar concentration. Electroencephalographic Shannon entropy, approximate entropy, median electroencephalographic frequency, SEF 95, total power, log total power, and Bispectral Index were determined, and their correlations with the desflurane effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modeling, were compared.

RESULTS

The electroencephalographic Shannon entropy increased continuously over the observed concentration range of desflurane. The correlation of the Shannon entropy (R2 = 0.84+/-0.08, mean +/- SD) with the desflurane effect compartment concentrations is similar to approximate entropy (R2 = 0.85+/-0.12), SEF 95 (R2 = 0.85+/-0.10), and Bispectral Index (R2 = 0.82+/-0.13) and is more statistically significant than median frequency (R2 = 0.72+/-0.17), total power (R2 = 0.67+/-0.18), and log total power (R2 = 0.80+/-0.09).

CONCLUSIONS

The Shannon entropy seems to be a useful electroencephalographic measure of anesthetic drug effect.

Two discrete areas in frontal cortex are involved in generating saccadic eye movements--the frontal eye field (FEF) and the supplementary eye field (SEF). Whereas FEF represents saccades in a topographic retinotopic map, recent evidence indicates that saccades may be represented craniotopically in SEF. To further investigate the relationship between these areas, the topographic organization of afferents to FEF from SEF in Macaca mulatta was examined by placing injections of distinct retrograde tracers into different parts of FEF that represented saccades of different amplitudes. Central FEF (lateral area 8A), which represents saccades of intermediate amplitudes, received afferents from a larger portion of SEF than did lateral FEF (area 45), which represents shorter saccades, or medial FEF (medial area 8A), which represents the longest saccades in addition to pinna movements. Moreover, in every case the zone in SEF that innervated lateral FEF (area 45) also projected to medial FEF (area 8A). In one case, a zone in rostral SEF projected to both lateral area 8A from which eye movements were evoked by microstimulation as well as medial area 8A from which pinna movements were elicited by microstimulation. This pattern of afferent convergence and divergence from SEF onto the retinotopic saccade map in FEF is indicative of some sort of map transformation between SEF and FEF. Such a transformation would be necessary to interconnect a topographic craniotopic saccade representation in SEF with a topographic retinotopic saccade representation in FEF.

Somatosensory evoked magnetic fields (SEFs), corresponding with electrical median nerve stimulation, were measured using an MRI-linked, whole-head MEG system. In total 184 hemispheres, SEFs were measured, involving 22 normal volunteers and 70 patients with intracranial lesions. The first SEF peak appeared 20.2 +/- 1.5 msec (mean +/- S.D.) after stimulation. The first peak was followed by a second and third peak, 7.7 +/- 3.2 msec and 14.6 +/- 5.4 msec respectively after the first. Corresponding isofield maps suggested a single current dipole oriented in the anterior direction for the first peak, posterior for the second and either anterior or posterior for the third. Using a spherical model and a single current dipole source, the localization of each peak was estimated and superimposed on individually determined MRI images. On a grand average basis, the first-peak dipole was localized on the posterior surface of the central sulcus, "area 3b." The second-peak dipole was localized 3.7 mm medial (P < 0.001) and 2.0 mm superior (P < 0.001) to the first-peak dipole, on the anterior wall of the central sulcus, "area 4." This study with a large number of subjects was able to statistically distinguish two adjacent cortical sources, located on opposite walls of the central sulcus, and within a few millimeters of each other.

Bispectral index (BIS) and spectral edge frequency (SEF) are used as measures of depth of anesthesia and sedation. We tested whether these signals could predict physiologic sleep stages, by taking processed electroencephalogram measurements and recording full polysomnography through a night's sleep in 10 subjects being investigated for mild sleep apnea/hypopnea syndrome. Computerized polysomnograph signals were analyzed manually according to standard criteria, classifying each 30-s epoch as a specific sleep stage. The BIS and SEF values were taken at the end of each period of sleep when the same stage had lasted for at least 2 min. Before sleep, median values for BIS were 97 +/- 12.1 and for SEF 23 +/- 4.2 Hz. After sleep initiation, the median BIS values for arousal, light, slow wave, and rapid eye movement sleep were 67 +/- 20.2, 50 +/- 16.5, 42 +/- 11.2, and 48 +/- 7.1, respectively, and the median SEF values were 20 +/- 4.7, 15 +/- 3.6, 10 +/- 2.6, and 19 +/- 4.1 Hz, respectively. Although both BIS and SEF decreased with increasing sleep depth, the distribution of values at each sleep depth was considerable, with overlap between each sleep stage. Neither BIS nor SEF reliably indicated conventionally determined sleep stages. In addition, the response of the BIS was slow and patients could arouse with low BIS values, which then took some time to increase.

CONCLUSIONS

Although computer processing of the electroencephalogram can provide an adequate index of depth of anesthesia, the same processing cannot reliably convey depth of natural sleep. At each sleep stage, the output signal has a wide range of possible values.

BACKGROUND

Increasing consultation rates have implications for the organisation of health services, the quality of care, and understanding the decision to consult. Most quantitative studies have concentrated on very high attenders--not those attending five or more times a year, who are responsible for most (60%) consultations--and have assessed neither the role of lifestyle nor patients' attitudes.

OBJECTIVE

To assess associations with higher than average attendance (five or more times ayear).

METHODS

Postal questionnaire sent to a random sample.

METHODS

Four thousand adults (one per household) from six general practices.

METHODS

Data were analysed to identify predictors significantly associated with higher than average attendance.

RESULTS

The response rate was 74%. Sef-reported attendance agreed with the notes (r = 0.80, likelihood ratio for a positive test = 9.4). Higher attendance was independently predicted by the severity of ill health (COOP score = 0-7, 8-9, and 10+; adjusted odds ratios= 1, 1.72, 1.91 respectively; test for trend P<0.001) and the number of reported medical problems (COOP score = 0, 1, 2, and 3+ respectively; adjusted ORs = 1, 2.05, 2.31, 4.29; P<0.001). After controlling for sociodemographic variables, medical problems, the severity of physical ill health, and other confounders, high attendance was more likely in those with medically unexplained somatic symptoms (0, 1-2, 3-5, and 6+ symptoms respectively, ORs = 1, 1.15, 1.48, and 1.62; P<0.001); health anxiety (Whitely Index = 0, 1-5, 6-7 and 8+ respectively, ORs = 1, 1.22, 1.77, and 2.78; P<0.001); and poor perceived health ('very good', 'good', 'poor' respectively, ORs = 1, 1.61, and 2.93; P<0.001). Attendance was less likely in those with negative attitudes to repeated surgery use (OR = 0.61, 95% CI = 0.47-0.78), or to doctors (Negdoc scale <18, 18-20, and 21+ respectively; ORs = 1, 0.87, 0.67; P<0.001), in those usually trying the pharmacy first (OR = 0.61, 95% CI 0.48-0.78), and those consuming alcohol (0, 1, 2, 3+ units/day respectively; ORs = 1, 0.62, 0.41, 0.29; P<0.001). Anxiety or depression predicted perceived health, unexplained symptoms, and health anxiety.

CONCLUSIONS

Strategies to manage somatic symptoms, health anxiety, dealing with the causes of--or treating--anxiety and depression, and encouraging use of the pharmacy have the potential both to help patients manage symptoms and in the decision to consult. Sensitivity to the psychological factors contributing to the decision to consult should help doctors achieve a better shared understanding with their patients and help inform appropriate treatment strategies.

Transient rearrangements of finger representation in primary somatosensory cortex induced by an anesthetic block of the sensory information from adjacent fingers have been shown invasively in animals. Such a phenomenon has been now replicated in seven healthy human volunteers. Somatosensory Evoked Fields (SEFs) have been recorded during separate electrical stimulation of the 1st, 3rd, or 5th finger. Recordings were obtained in control conditions (stage A), following complete ischemic anesthesia of the 4 non-stimulated fingers (stage B), and after regaining sensation (stage C). SEFs were recorded using a 28-channel DC-SQUID magnetometer; a single position of the sensor was enough to identify the source of N20m, P30m and following components using the Equivalent Current Dipole (ECD) model. The amount of afferent input during stages A through C was monitored with surface electrodes placed on the nerve at wrist and elbow. No variation of the nerve compound potential was observed during stages A through C. In stage A, the localizing algorithm was able to discriminate the individual finger representation in accordance with the somatotopic organisation of the sensory homunculus. It was observed that the ECDs responsible for the cortical responses from the unanesthetized finger were significantly changing following a relatively brief period of sensory deprivation from the adjacent fingers. Such changes of the ECDs with respect to the control conditions were characterized by an increase in strength and deepening for the middle finger, and by a shift on the coronal plane for the thumb and the little finger (medial for the former, lateral for the latter). Such changes became progressively evident in stage B, but were persisting in stage C.

OBJECTIVE

To compare the second differential index (SDI) calculated from the auditory evoked potential (AEP) and electroencephalogram (EEG) parameters: median frequency (MF), spectral edge frequency (SEF) and burst suppression rate (BSR) determined at four equivalent minimum alveolar concentrations (MAC) of isoflurane or halothane.

METHODS

Twelve male Wistar rats weighing 418 g (SD +/- 18.4 g).

METHODS

Auditory evoked potentials and EEG responses were recorded in animals implanted with electrodes at established anaesthetic concentrations. Depth of anaesthesia was assessed using the strength of the pedal withdrawal reflex (PWR), and data were analysed using repeated measures anova and paired t-tests.

RESULTS

The SEF tended to decrease with increasing depth of halothane anaesthesia (F = 4.198, p = 0.05), but not with isoflurane. The MF and SDI were significantly higher during halothane than with isoflurane (F = 5.82, p = 0.036 and F = 5.263, p = 0.045, respectively) at equivalent depths of anaesthesia, and EEG burst suppression occurred at deeper planes of isoflurane but not halothane anaesthesia.

CONCLUSIONS

The study demonstrated that EEG and AEP characteristics recorded at MAC equivalent concentrations were suppressed to a greater degree by isoflurane than by halothane. These findings have strong implications for research projects where EEG recordings are collected, and also cast more general doubts upon the value of such parameters for evaluating depth of isoflurane anaesthesia in rats.

The paired domain transcription factor Pax2 is required for the formation of the isthmic organizer (IsO) at the midbrain-hindbrain boundary, where it initiates expression of the IsO signal Fgf8. To gain further insight into the role of Pax2 in mid-hindbrain patterning, we searched for novel Pax2-regulated genes by cDNA microarray analysis of FACS-sorted GFP+ mid-hindbrain cells from wild-type and Pax2-/- embryos carrying a Pax2(GFP) BAC transgene. Here, we report the identification of five genes that depend on Pax2 function for their expression in the mid-hindbrain boundary region. These genes code for the transcription factors En2 and Brn1 (Pou3f3), the intracellular signaling modifiers Sef and Tapp1, and the non-coding RNA Ncrms. The Brn1 gene was further identified as a direct target of Pax2, as two functional Pax2-binding sites in the promoter and in an upstream regulatory element of Brn1 were essential for lacZ transgene expression at the mid-hindbrain boundary. Moreover, ectopic expression of a dominant-negative Brn1 protein in chick embryos implicated Brn1 in Fgf8 gene regulation. Together, these data defined novel functions of Pax2 in the establishment of distinct transcriptional programs and in the control of intracellular signaling during mid-hindbrain development.

Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes encoding inflammatory factors and are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for signaling by either IL-17 or IL-25, and it is recruited to their receptors (IL-17R and IL-25R) through heterotypic interactions between the SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R] domain of Act1 and that of the receptor. SEFIR domains have structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll-like receptors and IL-1R. Whereas the BB' loop of TIR is required for TIR-TIR interactions, we found that deletion of the BB' loop from Act1 or IL-17RA (a common subunit of both IL-17R and IL-25R) did not affect Act1-IL-17RA interactions; rather, deletion of the CC' loop from Act1 or IL-17RA abolished the interaction between both proteins. Surface plasmon resonance measurements showed that a peptide corresponding to the CC' loop of Act1 bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC' loop sequence inhibited IL-17- or IL-25-mediated signaling in vitro, as well as IL-17- and IL-25-induced pulmonary inflammation in mice. Together, these findings provide the molecular basis for the specificity of SEFIR-SEFIR versus TIR-TIR domain interactions and consequent signaling. Moreover, we suggest that the CC' loop motif of SEFIR domains is a promising target for therapeutic strategies against inflammatory diseases associated with IL-17 or IL-25 signaling.