The strength and duration of intracellular signals must be precisely regulated, since inappropriate signaling can cause disease. Negative feedback mechanisms provide an effective means of controlling growth factor-mediated signaling, either by restricting the incoming signal or by inducing counter-regulatory mechanisms affecting signal propagation. Sef proteins represent a new class of feedback antagonists capable of regulating receptor tyrosine kinase signaling. The involvement of Sef in development, as well as in other biological processes, was demonstrated by biochemical and genetic approaches.

Carcinomas are tumors of epithelial origin accounting for over 80% of all human malignancies. A substantial body of evidence implicates oncogenic signaling by receptor tyrosine kinases (RTKs) in carcinoma development. Here we investigated the expression of Sef, a novel inhibitor of RTK signaling, in normal human epithelial tissues and derived malignancies. Human Sef (hSef) was highly expressed in normal epithelial cells of breast, prostate, thyroid gland and the ovarian surface. By comparison, substantial downregulation of hSef expression was observed in the majority of tumors originating from these epithelia. Among 186 primary carcinomas surveyed by RNA in situ hybridization, hSef expression was undetectable in 116 cases including 72/99 (73%) breast, 11/16 (69%) thyroid, 16/31 (52%) prostate and 17/40 (43%) ovarian carcinomas. Moderate reduction of expression was observed in 17/186, and marked reduction in 40/186 tumors. Only 13/186 cases including 12 low-grade and one intermediate grade tumor retained high hSef expression. The association of hSef downregulation and tumor progression was statistically significant (P<0.001). Functionally, ectopic expression of hSef suppressed proliferation of breast carcinoma cells, whereas inhibition of endogenous hSef expression accelerated fibroblast growth factor and epidermal growth factor-dependent proliferation of cervical carcinoma cells. The inhibitory effect of hSef on cell proliferation combined with consistent downregulation in human carcinoma indicates a tumor suppressor-like role for hSef, and implicates loss of hSef expression as a common mechanism in epithelial neoplasia.

BACKGROUND

In this study, we visualized the eloquent motor system including the somatosensory-motor cortex and corticospinal tract on a neuronavigation system, integrating magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and anisotropic diffusion-weighted MRI (ADWI).

METHODS

Four patients with brain lesions adjacent to the eloquent motor system were studied. Motor-evoked responses (MER) by finger-tapping paradigm were acquired with a 1.5-Tesla MR scanner, and somatosensory-evoked magnetic fields (SEF) by median nerve stimulation were measured with a 204-channel MEG system. In the same fMRI examination, ADWI and anatomic three-dimensional T1-weighted imaging (3-D MRI) were obtained. Activated areas of MER, estimated SEF dipoles, and the corticospinal tract on ADWI were coregistered to 3-D MRI, and the combined MR data were transferred to a neuronavigation system (functional neuronavigation). Intraoperative recording of cortical somatosensory-evoked potentials was performed for confirmation of the central sulcus.

RESULTS

Combination of fMRI and MEG enabled firm identification of the central sulcus. Functional neuronavigation facilitated extensive tumor resection, having the advantage of sparing the motor cortex and corticospinal tract in all cases.

CONCLUSIONS

The proposed functional neuronavigation allows neurosurgeons to perform effective and maximal resection of brain lesions, identifying and sparing eloquent cortical components and their subcortical connections. Potential clinical application of this technique is discussed.

Patterning of the central nervous system is regulated by a signaling center located at the midbrain-hindbrain boundary (MHB), or isthmus organizer. Fibroblast growth factors secreted from the MHB are required and sufficient to direct the ordered growth and regionalization of the midbrain and anterior hindbrain. In an unbiased secretion cloning screen of Xenopus gastrula embryos we identified a novel gene, which we designated as Isthmin (xIsm) due to its prominent expression at the MHB. xIsm encodes a secreted protein of 449 amino acids containing one copy of the thrombospondin type 1 repeat (TSR). We also found orthologous Isthmin genes in human (hIsm) and mouse (mIsm), as well as a gene encoding an Isthmin-like human unknown protein (hIsm-l). The conservation of a unique carboxy-terminal region between hIsm and hIsm-l suggests that Isthmin is the founding member of a new family of secreted proteins. xIsm was strongly expressed maternally in the Xenopus egg and showed zygotic expression in the ventral blastopore lip, notochord, and MHB. Additional expression domains were detected in neural crest, ear vesicle, and developing blood islands. Interestingly, xIsm was co-expressed with Fibroblast growth factor-8 (xFgf-8) at multiple sites including the MHB, indicating that these two genes are part of a synexpression group which also includes sprouty and sef homologs.

OBJECTIVE

Low-grade fibrosarcomas are tumours that mainly affect the extremities and trunk of adults of either sex. Among these, low-grade fibromyxoid sarcoma (FMS), hyalinizing spindle cell tumour with giant collagen rosettes (HST) and sclerosing epithelioid fibrosarcoma (SEF) are well-established entities. In this study, our aim was to describe a group of low-grade fibrosarcomatous tumours, which could not be encompassed by these entities. These low-grade fibrosarcomas, not otherwise specified (FNOS) were provisionally designated as 'fibrosarcoma, low-grade fibroblastic type'.

RESULTS

In the soft tissue tumour registry we found 39 FNOS (46%), 31 FMS (36%), 11 SEF (13%) and four HST (5%). FNOS occurred in older patients than FMS (mean age 56.3 years versus 33.7 years). They mainly showed fibrous features, but myxoid areas could also be seen. While cells tended to be loosely arranged in the myxoid areas, densely packed sheets with a storiform pattern, fascicular arrangements or regions without a defined growth pattern were observed in the fibrous areas. However, neither whirling nor swirling patterns were found. Arcade-like vessels were not visible; pseudolipoblasts did not occur. FNOS exhibited increased atypia and mitotic count compared with the other sarcomas studied [FNOS, mean value 4.6 mitoses/10 high-power field (HPF); FMS, 0.7/10 HPF). Follow-up data were available in 21 FNOS patients. In seven cases (33.3%), local recurrences were reported. Three patients (14.3%) developed metastases and all of them died of tumour.

CONCLUSIONS

The term 'fibrosarcoma, low-grade fibroblastic type' should be used as a diagnosis of exclusion. Further studies should elucidate whether it represents a distinct fibrosarcoma type.

BACKGROUND

Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0)).

METHODS

Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD.

RESULTS

The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05).

CONCLUSIONS

The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.

The features of somatosensory (SEFs), auditory (AEFs), and visual evoked fields (VEFs) in healthy subjects and patients with brain diseases provide the basis for clinical investigations using magnetoencephalography (MEG). The SEFs provide clinically useful information to identify the central sulcus and somatotopic organization of the primary somatosensory cortex. Localization accuracy of the SEFs can be tested by cortical stimulation during surgery. Functional reorganization suggested by SEF studies must be verified by other modalities. The AEFs can localize the auditory cortex in the bilateral temporal lobes. Separation of bilateral activities is much clearer in AEFs than in auditory evoked potentials. Modulation of the interhemispheric differences of latency, amplitude, and source localization of AEFs can be used to evaluate auditory function in patients with intracranial lesions. Pattern reversal VEFs provide stable localization of the primary visual function. Separation of bihemispherical activities is the advantage of VEFs over visual evoked potentials. Investigation of VEFs provides objective evaluation of visual field deficits such as homonymous or bitemporal hemianopsia in patients with intracranial lesions. Evoked magnetic fields can provide useful diagnostic information. Such clinical findings, in turn, provides the opportunity to test the source estimation accuracy of MEG.

OBJECTIVE

To assess the regional systolic function in patients with post myocardial infarction (PMI), using the velocity vector imaging (VVI) technique, a new two-dimensional echocardiographic method.

METHODS

Two-dimensional images of apical four, two chambers and apical long-axis view were obtained in 20 patients with PMI and 15 normal controls. The segmental myocardial systolic peak strain (epsilon), strain rate (SRs), and segmental ejection fraction (SEF) were analyzed with VVI offline software. The result of epsilon in middle segments of the normal control analyzed by VVI was compared with that by tissue Doppler imaging (DTI).

RESULTS

The segmental epsilon, SRs, and SEF were significantly lower in infarct segments than in the corresponding segments of the normal controls. There were significant difference in average epsilon, SRs, and SEF among infarct, noninfarct, and normal control segments. The segmental epsilon, SRs, and SEF did not vary significantly from basal to apical segments in the normal control subjects. There was a good correlation on epsilon in middle segments between VVI and DTI (r = 0.710, P < 0.01). The interobserver variability was 4.6% and the intraobserver variability was 7.0%, respectively.

CONCLUSIONS

The regional systolic function decreased in infarct segments compared with the adjacent noninfarct segments and normal control segments. The systolic function of adjacent noninfarct area was also affected by infarct areas. VVI could recognize and quantify the abnormality of infarct segments and therefore could be a useful tool in assessing the myocardial regional systolic function.

OBJECTIVE

Magnetoencephalography (MEG) signals are, on theoretical grounds, thought to be relatively undistorted by the skull in contrast to electroencephalographic (EEG) signals. This assumption was experimentally tested in an animal preparation with a brain similar to the human brain in many respects.

METHODS

Possible skull effects on MEG were evaluated directly using an in vivo porcine preparation, by measuring the somatic evoked magnetic field (SEF) above the skull with and without the skull under, otherwise, the same condition.

RESULTS

The SEF was virtually undistorted by the skull with no obvious visible change in its waveform and amplitude under these two conditions. However, there was some small, but significant attenuation when the skull was removed, the distortion being greater for deeper sources.

CONCLUSIONS

Our results are consistent with a theoretical expectation that the skull should be virtually 'transparent' to the magnetic fields for shallow sources, but less so for fields generated by deeper sources.

In sclerosing epithelioid fibrosarcoma (SEF), a rare variant of low-grade fibrosarcoma, treatment results and therapeutic options are poorly characterized. We systematically analyzed the data of all 89 patients (43 female, 46 male; mean age, 47 years [range, 14-87 years]) reported in the literature concerning clinical presentation, histopathology, differential diagnosis, treatment, survival rates, and prognosis, and we present an additional case. Information detailing treatment, disease control, and followup was available in 60 (67%), 75 (84%), and 68 patients (76%), respectively. Case history was variable with one-third of patients reporting a painful, enlarging mass. Ten patients (13%) presented with metastases, 23 (31%) had metastases develop after diagnosis, and 28 (37%) had local recurrence. Low cellularity, mild pleomorphy, and sclerotic hyaline matrix of SEF suggest a benign clinical behavior, and cell morphology allows for the wide differential diagnosis of benign, pseudosarcomatous, and malignant proliferations. In addition to surgery, 11 patients (15%) had chemotherapy, 22 (29%) had postoperative radiation therapy, and three (4%) had a combination of both. Twenty-three patients (34%) died from their disease after a mean of 46 months, 24 (35%) were alive with disease, and 20 (31%) were alive without evidence of disease. Patients with SEF of the head and neck had the worst prognosis.

METHODS

Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

BACKGROUND

Behavioural parent training is effective in improving child disruptive behavioural problems in preschool children by increasing parenting competence. The indicated Prevention Programme for Externalizing Problem behaviour (PEP) is a group training programme for parents and kindergarten teachers of children aged 3-6 years with externalizing behavioural problems.

OBJECTIVE

To evaluate the effects of PEP on child problem behaviour, parenting practices, parent-child interactions, and parental quality of life.

METHODS

Parents and kindergarten teachers of 155 children were randomly assigned to an intervention group (n = 91) and a nontreated control group (n = 64). They rated children's problem behaviour before and after PEP training; parents also reported on their parenting practices and quality of life. Standardized play situations were video-taped and rated for parent-child interactions, e.g. parental warmth.

RESULTS

In the intention to treat analysis, mothers of the intervention group described less disruptive child behaviour and better parenting strategies, and showed more parental warmth during a standardized parent-child interaction. Dosage analyses confirmed these results for parents who attended at least five training sessions. Children were also rated to show less behaviour problems by their kindergarten teachers.

CONCLUSIONS

Training effects were especially positive for parents who attended at least half of the training sessions.

BACKGROUND

CBCL: Child Behaviour Checklist; CII: Coder Impressions Inventory; DASS: Depression anxiety Stress Scale; HSQ: Home-situation Questionnaire; LSS: Life Satisfaction Scale; OBDT: observed behaviour during the test; PCL: Problem Checklist; PEP: prevention programme for externalizing problem behaviour; PPC: Parent Problem Checklist; PPS: Parent Practices Scale; PS: Parenting Scale; PSBC: Problem Setting and Behaviour checklist; QJPS: Questionnaire on Judging Parental Strains; SEFS: Self-Efficacy Scale; SSC: Social Support Scale; TRF: Caregiver-Teacher Report Form.

OBJECTIVE

To correlate the phenotypes with the genotypes of 10 Finnish juvenile neuronal ceroid lipofuscinosis (JNCL; late-onset Batten disease) patients who all are compound heterozygotes for the major 1.02-kb deletion in the CLN3 gene.

METHODS

The mutations on the non-1.02-kb deletion chromosomes were screened in 6 patients; in the other 4 patients the mutations were known (one affecting a splice site, two missense mutations, and one deletion of exons 10 through 13). Clinical features were examined, and MRI, MRS, somatosensory evoked magnetic field (SEF), and overnight polysomnography (PSG) studies were performed.

RESULTS

A novel deletion of exons 10 through 13 was found in 6 patients belonging to three families. In the patients carrying the deletions of exons 10 through 13 the clinical course of the disease was fairly similar. Variation was greatest in the time course to blindness. In these patients the mental and motor decline was slower than in classic JNCL, but more severe than in the two patients with missense mutations in exons 11 and 13. MRI showed brain atrophy in 4 patients. One patient had hyperintense periventricular white matter, otherwise brain signal intensities were normal. SEFs were enhanced in patients older than 14 years, whereas in PSG all but the youngest 6-year-old patient showed epileptiform activity in slow-wave sleep.

CONCLUSIONS

JNCL can manifest as at least three different phenotypes: classic, delayed classic, and protracted JNCL with predominantly ocular symptoms. Finnish compound heterozygotes have the delayed classic or the protracted form of JNCL.

Stiffening of the aorta with progressing age leads to decrease of aortic compliance and thus to an increase of pulse pressure amplitude. Using a strain energy function (SEF) which takes into account the composition of the arterial wall, we have studied the evolution of key structural components of the human thoracic aorta using data obtained from the literature. The SEF takes into account the wavy nature of collagen, which upon gradual inflation of the blood vessel is assumed to straighten out and become engaged in bearing load. The engagement of the individual fibers is assumed to be distributed log-logistically. The use of a SEF enables the consideration of axial stretch (lambda(z)) and residual strain (opening angle) in the biomechanical analysis. Both lambda(z) and opening angle are known to change with age. Results obtained from applying the SEF to the measurements of aortic pressure-diameter curves indicate that the changes in aortic biomechanics with progressing age are not to be sought in the elastic constants of elastin and collagen or their volume fractions of the aortic wall but moreover in alterations of the collagen mesh arrangement and the waviness of the collagen fibers. In old subjects, the collagen fiber ensemble engages in load bearing much more abruptly than in young subjects. Reasons for this change in collagen fiber dynamics may include fiber waviness remodeling or cross-linkage by advanced glycation end-products (AGE). The abruptness of collagen fiber engagement is also the model parameter that is most responsible for the decreased compliance at progressed ages.

Murine retrovirus SL3-3 is highly T lymphomagenic. Its pathogenic properties are determined by the transcriptional enhancer of the U3 repeat region which shows preferential activity in T cells. Within the U3 repeats, the major determinant of T-cell specificity has been mapped to binding sites for the AML1 transcription factor family (also known as the core binding factor [CBF], polyomavirus enhancer binding protein 2 [PEBP2], and SL3-3 enhancer factor 1 [SEF-1]). SL3-3 viruses with AML1 site mutations have lost a major determinant of T-cell-specific enhancer function but have been found to retain a lymphomagenic potential, although disease induction is slower than for the SL3-3 wild type. To compare the specificities and mechanisms of disease induction of wild-type and mutant viruses, we have examined lymphomas induced by mutant viruses harboring transversions of three consecutive base pairs critical to AML1 site function (B. Hallberg, J. Schmidt, A. Luz, F. S. Pedersen, and T. Grundström. J. Virol. 65:4177-4181, 1991). Our results show that the mutated AML1 sites are genetically stable during lymphomagenesis and that ecotropic provirus numbers in DNA of tumors induced by wild-type and mutant viruses fall within the same range. Moreover, proviruses were found to be integrated at the c-myc locus in similar proportions of wild-type and mutant SL3-3-induced tumors, and the mutated AML1 sites of proviruses at c-myc are unaltered. In some cases, however, including one c-myc-integrated provirus, a single-base pair change was detected in a second, weaker AML1 binding site. By DNA rearrangement analysis of the T-cell receptor beta-locus, tumors induced by the AML1 site mutants are found to be of the T-cell type. Thus, although the AML1 site mutants have weakened T-cell-specific enhancers they are T-lymphomagenic, and wild-type- and mutant-virus-induced tumor DNAs are similar with respect to the number of overall ecotropic and c-myc-integrated clonal proviruses. The SL3-3 wild-type and AML1 site mutant viruses may therefore induce disease by similar mechanisms.

How supplementary eye field (SEF) contributes to visual search is unknown. Inputs from cortical and subcortical structures known to represent visual salience suggest that SEF may serve as an additional node in this network. This hypothesis was tested by recording action potentials and local field potentials (LFPs) in two monkeys performing an efficient pop-out visual search task. Target selection modulation, tuning width, and response magnitude of spikes and LFP in SEF were compared with those in frontal eye field. Surprisingly, only ∼2% of SEF neurons and ∼8% of SEF LFP sites selected the location of the search target. The absence of salience in SEF may be due to an absence of appropriate visual afferents, which suggests that these inputs are a necessary anatomical feature of areas representing salience. We also tested whether SEF contributes to overcoming the automatic tendency to respond to a primed color when the target identity switches during priming of pop-out. Very few SEF neurons or LFP sites modulated in association with performance deficits following target switches. However, a subset of SEF neurons and LFPs exhibited strong modulation following erroneous saccades to a distractor. Altogether, these results suggest that SEF plays a limited role in controlling ongoing visual search behavior, but may play a larger role in monitoring search performance.

Several areas of the macaque brain are known to be related to the reward during the performance of saccadic eye-movement tasks. Neurons in the supplementary eye field (SEF) have been reported to be involved in the prediction and detection of a reward. We describe a group of neurons in the SEF that became active during the period of reward delivery after saccades toward a specific direction, but showed weaker activity in other directions, although the same amount of reward was given in each direction. Moreover, this directional reward activity was modulated by the reward size. Our results demonstrate that the SEF cells may reflect both reward amount and target positions toward which a movement was rewarded, and suggest that they may play an important role in providing information about the value of each saccade according to the spatial target location.

The development of the vertebrate inner ear depends on the precise expression of fibroblast growth factors. In a mutagenesis screen for zebrafish with abnormalities of inner-ear development and behavior, we isolated a mutant line, ru622, whose phenotypic characteristics resembled those of null mutants for the gene encoding fibroblast growth factor 8 (Fgf8): an inconsistent startle response, circular swimming, fused otoliths, and abnormal semicircular canals. Positional cloning disclosed that the mutant gene encodes the transcriptional corepressor Atrophin2. Both the Fgf8 protein and zebrafish "similar expression to fgf genes" protein (Sef), an antagonist of fibroblast growth factors induced by Fgf8 itself, were found to be overexpressed in ru622 mutants. We therefore hypothesized that an excess of Sef eliminates Fgf8 signals and produces an fgf8 null phenotype in ru622 mutants. In support of this idea, we could rescue larvae whose atrophin2 expression had been diminished with morpholinos by reducing the expression of Sef as well. We propose that Atrophin2 plays a role in the feedback regulation of Fgf8 signaling. When mutation of the atrophin2 gene results in the overexpression of both Fgf8 and Sef, the excessive Sef inhibits Fgf8 signaling. The resultant imbalance of Fgf8 and Sef signals then underlies the abnormal aural development observed in ru622.

We have compared bispectral index (BIS), 95% spectral edge frequency (SEF) and approximate entropy (ApEn) in 37 patients during induction and recovery from a short general anaesthetic. Heart rate variability (HRV) was also compared during induction only. These indices were noted at the start of induction, when a syringe held between the thumb and fingertips was dropped, at insertion of a laryngeal mask or tracheal tube (tube insertion), at incision, at the end of surgery, on return of the gag reflex and when the patient could follow a verbal command. When indices at the start of induction were compared with those at tube insertion, all four decreased significantly. BIS decreased from a mean of 95.38 (SEM 1.02) to 44.22 (1.05), mean SEF from 20.91 (1.19) to 14.14 (0.70) Hz, mean HRV from 37.1 (7.75) to 17.9 (3.6) bpm2 and ApEn from 0.90 (0.06) to 0.65 (0.04). Using logistic regression, the indices were compared both individually and in combination as to the power of distinguishing awake (at pre-induction) from asleep (at tube insertion) states. BIS had the best predictive power, with a sensitivity of 97.3%, specificity 94.4%, positive predictive value 94.7% and negative predictive value 97.1%. A combination of the indices conferred no additional predictive advantage.

Functional and morphological alterations of microvascular endothelial cells (ECs) would lead to microcirculatory disturbances, thereby providing a basis for the development of a disease state. Clinically endotoxemia frequently encountered in a variety of diseases is considered to be a trigger to develop the microcirculatory disorders such as disseminated intravascular coagulation (DIC) and multiple organ failure (MOF), both of which feature the end stage of severe systemic disease. Experimentally intravital microscopy reveals that continuous venous infusion of endotoxin (LPS) causes a low flow state in the rat mesenteric microcirculatory unit. By vital stain with monastral blue B (MBB), the microvascular ECs are focally positive for MBB at the postcapillary venular site, where leukocytes adhere and extravasate. As shown in the histamine-induced diapedesis by transmission electron microscopy, the MBB-positve venular ECs may correspond to the contracted ECs, enabling the polymorphonuclear leukocytes and erythrocytes to extravasate through the widened gaps between the contracted ECs. Actin filaments proven in the microvascular ECs by electron microscopy may play a modulating role in this neutrophil diapedesis. In the process of gastric ulcer formation under restrained stress to the rat, the ECs of microvessels in the gastric mucosa, particularly of the mucosal capillaries and postcapillary venules directly innervated by the cholinergic nerves, are altered by the stress-induced overstimulation of the autonomic nerves, inducing the diapedesis of leukocytes and erythrocytes followed by hemorrhagic and ischemic injuries in the gastric mucosa. Liver cirrhosis also accompanies endotoxemia. The most prominent electron microscopic alterations of hepatic microvasculature are a decrease of hepatic sinusoidal endothelial fenestrae (SEF) both in diameter and in number, and the formation of basement membranes beneath the hepatic sinusoidal ECs. These ultrastructural changes would be induced by a most potent vasoconstrictor endothelin (ET)-1 through the overexpressed ET(A) and ET(B) receptors on the hepatic stellate cells and the sinusoidal ECs, contributing to the development of portal hypertension as well as to the disturbance in excretion of endotoxin into the bile canaliculi via the hepatocytes from the circulating sinusoidal blood to prevent endotoxemia.

Topography of somatosensory evoked magnetic fields (SEFs) following stimulation of the median nerve were investigated in normal subjects. N20m-P30m-N40m-P60m and their counterpart, P20m-N30m-P40m-N60m, were identified in the hemisphere contralateral to the stimulated median nerve. Their equivalent current dipoles (ECDs) were considered to be located in the hand area of area 3b in the primary sensory cortex (SI). Restricted deflections, P25m and N25m, were considered to be generated in area 1 in SI. Therefore, short-latency deflections less than 40 ms were considered to be hybrids of ECDs generated in areas 3b and 1. Middle-latency deflections, N90m-P90m, were considered to be generated in the second sensory cortex (SII), but they were greatly affected by the much stronger fields generated in SI. The N30m deflection, which was a magnetic reflection of the N30 potential of somatosensory evoked potentials (SEPs), were widely recorded in the frontal area. The generator site of N30 of SEPs is considered to be the supplementary motor area (SMA). However, ECDs of N30m were located in SI, and no significant ECD generated in the frontal area including SMA was detected. No significant deflections other than small N90m-P90m in SII were identified in the hemisphere ipsilateral to the stimulated nerve. No significant deflections whose ECDs were generated in the mid-parietal area were identified. In conclusion, short- and middle-latency SEFs are mainly generated in area 3b in SI contralateral to the stimulated median nerve, and responses generated in area 1 of SI and SII affect the SEFs to some degree.

1. We investigated whether neurons in the supplementary eye field (SEF) of macaque monkeys code saccadic eye movements in oculocentric coordinates (relative to the current direction of fixation) or in craniocentric coordinates (relative to the head). Craniocentric coding in SEF had been previously suggested by the convergent appearance of electrically elicited saccades originating at different orbital positions. 2. We primarily studied SEF neurons that started responding before the beginning of saccades because such presaccadic activity is likely related to saccade generation and metrics. Using a memory-saccade task, we classified the presaccadic activity of each neuron as either purely visual related, purely movement related, or both visual and movement related. 3. We then mapped the response fields (receptive fields and movement fields) of SEF neurons from different orbital positions. When mapped relative to a central fixation point, the strongest responses for a given SEF neuron invariably occurred for a particular polar direction with fairly symmetrical declines for departures from that direction. When tested using other fixation point locations, their strongest responses almost always continued to occur for stimuli having the same polar direction relative to each fixation point tested, and thus they appeared to code both stimulus direction and saccade direction in an oculocentric coordinate system. 4. The effect of eye position on SEF presaccadic activity was quantified in two ways by computing, for each neuron, 1) an "intersection distance," the eccentricity of the point where extensions of the neuron's optimal polar directions measured at two eccentric orbital positions converged, and 2) an "orbital perturbation index" such that an index of 0 corresponded to no change in the neuron's optimal polar direction across different orbital positions (i.e., perfectly oculocentric response fields) and an index of 1 corresponded to optimal polar directions that converged to the same craniocentric goal regardless of initial eye position (i.e., perfectly craniocentric response fields). For neurons with both visual and movement responses, these measures were calculated separately for each type of activity using tasks that temporally separated the visual cue presentation and the saccade to it. 5. Almost all of the intersection distances were well beyond the oculomotor range (+/- 50 degrees) of the monkey (38/39 for movement activity and 62/66 for visual activity). The median intersection distance for visual activity was very large (274 degrees), and the median for movement activity was slightly divergent (beyond infinity). Thus SEF neurons rarely showed a conspicuous convergence of response field direction. 6. Likewise, the mean orbital perturbation indexes were very small (-0.04 +/- 0.21, mean +/- SD, for movement activity and 0.09 +/- 0.15 for visual activity), also indicating that SEF neurons code stimuli and saccades in an oculocentric manner. 7. For neurons with both visual and movement activities, the orbital perturbation indexes of the two activities were not significantly correlated (r = 0.16), even though their characteristic directions (optimal polar direction estimated from the center of the screen) were almost the same (circular correlation, r+ = 0.97). The lack of a significant correlation between the visual and movement activity orbital perturbation indexes is consistent with the hypothesis that most of the variation in this index represents statistically independent errors of measurement. Conversely, the strong covariation of visual and movement activity characteristic directions indicates that directional preference is a fundamental functional property of SEF presaccadic activity.(ABSTRACT TRUNCATED)

We show that it is feasible to monitor the synchronized population spikes of the thalamocortical axonal terminals and cortical neurons outside the brain using high-resolution magnetoencephalography (MEG). Electrical stimulation of the snout elicited somatic-evoked magnetic fields (SEFs) above the primary somatosensory cortex (SI) of the piglet. The SEFs contained high-frequency oscillations (HFOs) around 600 Hz similar in many respects to the noninvasively measured HFOs from humans with MEG and electroencephalography (EEG). These HFOs were highly correlated with those in simultaneously measured intracortical somatic-evoked potentials (SEPs) in the snout projection area in SI. Both HFOs in SEFs and SEPs consisted of an initial component insensitive to cortically injected kynurenic acid (Kyna, 20 mM), a nonspecific antagonist of glutamatergic receptors, and a subsequent Kyna-sensitive component. The former was localized in cortical layer IV, indicating that it was due to spikes produced by the specific thalamocortical axonal terminals, whereas the latter was initially localized in layer IV and subsequently in the superficial and deeper layers. These results suggest that it may be possible to study properties of the thalamocortical and cortical spike activities in humans with MEG.

Selenocysteine is the 21st naturally-occurring amino acid. Selenoproteins have diverse functions and many remain uncharacterized, but they are typically associated with antioxidant activity. The incorporation of selenocysteine into the nascent polypeptide chain recodes the TGA stop codon and this process depends upon a number of essential factors including the selenocysteine elongation factor (SEF). The transcriptional expression of SEF did not change significantly in tick midguts throughout the blood meal, but decreased in salivary glands to 20% at the end of the fast feeding phase. Since selenoprotein translation requires this specialized elongation factor, we targeted this gene for knockdown by RNAi to gain a global view of the role selenoproteins play in tick physiology. We found no significant differences in tick engorgement and embryogenesis but detected no antioxidant capacity in tick saliva. The transcriptional profile of selenoproteins in R. parkeri-infected Amblyomma maculatum revealed declined activity of selenoprotein M and catalase and increased activity of selenoprotein O, selenoprotein S, and selenoprotein T. Furthermore, the pathogen burden was significantly altered in SEF-knockdowns. We then determined the global impact of SEF-knockdown by RNA-seq, and mapped huge shifts in secretory gene expression that could be the result of downregulation of the Sin3 histone deacetylase corepressor complex.

Development of a new medium and modification of incubation conditions increased production of toxic shock syndrome marker proteins and enabled detection of small volumes of pyrogenic exotoxin C (PEC) by isoelectric focusing and staphylococcal enterotoxin F (SEF) by a newly developed solid-phase radioimmunoassay. The results were compared with those obtained with previously described methods. The results were identical, and all PEC-positive isolates were SEF positive. In a second study of 262 randomly selected Staphylococcus aureus isolates examined by isoelectric focusing and solid-phase radioimmunoassay but grown in fresh beef heart medium, 47 (17.9%) isolates were PEC and SEF positive; however, 9 (3.4%) were PEC positive and SEF negative, and 3 (1.1%) were SEF positive and PEC negative. When grown in buffered beef heart yeast extract medium, six of the previously PEC-positive and SEF-negative isolates were PEC negative. Autoradiographic analysis of selected isolates demonstrated that PEC- and SEF-positive strains bound SEF antitoxin to the protein at isoelectric point 7.2, suggesting that in staphylococci from patients with toxic shock syndrome, PEC and SEF are the same protein. In screening staphylococci for toxic shock syndrome marker proteins, isoelectric focusing to identify PEC may detect false-positive proteins and may be more susceptible to technical variation than immunological methods to detect SEF.