Non-supervised spatio-temporal analysis of interictal magnetic spikes: comparison with intracerebral recordings.

OBJECTIVE: Our main goal was to evaluate the accuracy of an original non-supervised spatio-temporal magnetoencephalography (MEG) localization method used to characterize interictal spikes generators. METHODS: MEG and stereotactic intracerebral recordings (stereo-electro-encephalographic exploration, SEEG) data were analyzed independently in 4 patients. MEG localizations were performed with and without anatomical constraints. RESULTS: We analyzed 1326 interictal spikes recorded using MEG. For each patient, 2-3 typical source patterns were described. These source configurations were compared with SEEG. SEEG findings and MEG spatio-temporal localization results were remarkably coherent in our 4 patients. Most of the MEG patterns were similar to interictal SEEG patterns from a spatio-temporal point of view. CONCLUSIONS: We were able to evaluate the usefulness of our non-invasive localization method. This approach described correctly the part of the epileptogenic network involved in the generation of interictal events. Our results demonstrate the potential of MEG in the non-invasive spatio-temporal characterization of generators of interictal spikes.

Spatiotemporal brain imaging of visual-evoked activity using interleaved EEG and fMRI recordings.

Combined analysis of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has the potential to provide higher spatiotemporal resolution than either method alone. In some situations, in which the activity of interest cannot be reliably reproduced (e.g., epilepsy, learning, sleep states), accurate combined analysis requires simultaneous acquisition of EEG and fMRI. Simultaneous measurements ensure that the EEG and fMRI recordings reflect the exact same brain activity state. We took advantage of the spatial filtering properties of the bipolar montage to allow recording of very short (125--250 ms) visual-evoked potentials (VEPs) during fMRI. These EEG and fMRI measurements are of sufficient quality to allow source localization of the cortical generators. In addition, our source localization approach provides a combined EEG/fMRI analysis that does not require any manual selection of fMRI activations or placement of source dipoles. The source of the VEP was found to be located in the occipital cortex. Separate analysis of EEG and fMRI data demonstrated good spatial overlap of the observed activated sites. As expected, the combined EEG/fMRI analysis provided better spatiotemporal resolution than either approach alone. The resulting spatiotemporal movie allows for the millisecond-to-millisecond display of changes in cortical activity caused by visual stimulation. These data reveal two peaks in activity corresponding to the N75 and the P100 components. This type of simultaneous acquisition and analysis allows for the accurate characterization of the location and timing of neurophysiological activity in the human brain.

Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts.

SU101 (leflunomide, N-[4-(trifluoromethyl)-phenyl] 5-methylisoxazole-4-carboxamide), an inhibitor of platelet-derived growth factor receptor signaling, has shown promising clinical activity in Phase I and II studies. Currently, SU101 in combination with cytotoxic agents is in late-stage clinical development for the treatment of cancers. In previous reports, efficacy in vivo versus varied tumor xenografts was observed. As part of the preclinical development of SU101 as a cancer therapy, the combination of SU101 with cytotoxic agents was studied in athymic mice bearing small, established, s.c. human tumor cell xenografts of glioblastoma (SF763T cells), lung (Calu-6 cells), or head and neck (KB cells) origin. In the SF763T model, the combination of SU101 with carmustine resulted in a statistically significant growth inhibition of 74% compared with the vehicle control; this combination was more effective than either agent alone. In the Calu-6 model, the combination of SU101, cisplatin, and etoposide resulted in a growth inhibition of 75% that was statistically greater than that of the vehicle-treated control group and groups treated with one or two agents. In the KB model, the combination of SU101, 5-fluorouracil, and cisplatin resulted in a statistically significant growth inhibition of 69% compared with the vehicle control. Treatment with one or two agents did not significantly inhibit growth in this model. Importantly, in addition to enhanced efficacy resulting from combination therapies, the combination treatments tested were well tolerated, as evidenced by lack of mortality. These data suggest that SU101 in combination with cytotoxic agents may provide clinical benefit and warrant further clinical investigation.

Evaluation of a new MEG-EEG spatio-temporal localization approach using a realistic source model.

This paper introduces a new technique for the localization of brain electromagnetic activity: a spatio-temporal fit (SPTF). This algorithm uses some properties of the principal component analysis and makes no assumptions about the number of sources to be located. It was applied to both simulated and real MEG/EEG signals and was compared to the well-known moving dipole fit (MDF) technique. For the simulations, we constructed extended sources, rather than single dipoles, that respected realistic anatomical and temporal properties. From these, we generated, under different noise conditions, MEG and EEG signals from which localization was performed. The real signals were auditory evoked fields. Firstly, it appeared that the SPTF was able to separate simultaneously activated sources even on strongly noisy signals while, most of the time, the MDF failed to give a clear description of the source configuration. Secondly, although we used the same head model to both generate the signals and locate the sources, localization for EEG was inferior to that for MEG. In conclusion, since in all test conditions the SPTF is found to be far superior to MDF, we suggest the use SPTF for the localization of equivalent dipoles.

Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide.

Many reports have cited coexpression of platelet-derived growth factor (PDGF) and its receptors by tumor cells or cells supporting tumor growth, suggesting both autocrine and paracrine mechanisms for PDGF-mediated tumor growth. We found that a small organic molecule, N-[4-(trifluoromethyl)phenyl] 5-methylisoxazole-4-carboxamide (SU101, leflunomide), inhibited PDGF-mediated signaling events, including receptor tyrosine phosphorylation, DNA synthesis, cell cycle progression, and cell proliferation. SU101 inhibited PDGF-stimulated tyrosine phosphorylation of PDGF receptor (PDGFR) beta in C6 (rat glioma) and NIH3T3 cells engineered to overexpress human PDGFRbeta (3T3-PDGFRbeta). SU101 blocked both PDGF- and epidermal growth factor (EGF)-stimulated DNA synthesis. Previously, this compound was shown to inhibit pyrimidine biosynthesis by interfering with the enzymatic activity of dihydroorotate dehydrogenase. In the current study, EGF-stimulated DNA synthesis was restored by the addition of saturating quantities of uridine, whereas PDGF-induced DNA synthesis was not, suggesting that the compound demonstrated some selectivity for the PDGFR pathway that was independent of pyrimidine biosynthesis. Selectivity was further demonstrated by the ability of the compound to block the entry of PDGF-stimulated cells into the S phase of the cell cycle, without affecting cell cycle progression of EGF-stimulated cells. In cell growth assays, SU101 selectively inhibited the growth of PDGFRbeta-expressing cell lines more efficiently than it inhibited the growth of PDGFRbeta-negative cell lines. SU101 inhibited the s.c., i.p., and intracerebral growth of a panel of cell lines including cells from glioma, ovarian, and prostate origin. In contrast, SU101 failed to inhibit the in vitro or s.c. growth of A431 and KB tumor cells, both of which express EGF receptor but not PDGFRbeta. SU101 also inhibited the growth of D1B and L1210 (murine leukemia) cells in syngeneic immunocompetent mice, without causing adverse effects on the immune response of the animals. In an i.p. model of tumor growth in syngeneic immunocompetent mice, SU101 prevented tumor growth and induced long-term survivors in animals implanted with 7TD1 (murine B-cell hybridoma) tumor cells. Because PDGFRbeta was detected on most of the tumor cell lines in which in vivo growth was inhibited by SU101, these data suggest that SU101 is an effective inhibitor of PDGF-driven tumor growth in vivo.

Practical screening procedures for sulfamethazine and N4-acetylsulfamethazine in milk at low parts-per-billion levels.

Relatively simple and inexpensive procedures for screening milk for sulfamethazine (SMZ) and one of its metabolites, N4-acetylsulfamethazine (ASMZ), are detailed. Both methods detect at the low parts-per-billion level and are suitable for both field and laboratory use. Milk is passed over Chromosorb 102, which adsorbs SMZ. The drug is eluted and purified by direct passage of the effluent over small beds of buffered anion-exchange resins and alumina and is finally isolated and detected colorimetrically. For ASMZ, the procedure is modified so that SMZ is removed in the purification steps. The isolated ASMZ is then hydrolyzed to SMZ for detection. Application of the methods 5 years apart (1988 and 1993) shows that SMZ is still being used but to a lesser extent in 1993. Of over 250 samples screened in the 2 studies, only 2 were estimated to contain SMZ at 10 ppb, and the majority contained SMZ at 1 ppb. ASMZ was detected in a number of samples that were negative for SMZ.

Formation of oxo- and hydroxyfatty acids in irradiated chickens.

Finely ground chicken skin and subcutaneous fat exposed to gamma radiation from (137)Cs at 0-2°C for up to 10 kGy generated oxofatty acids (OFA) and hydroxyfatty acids (HFA) in the glycerides. Both classes were determined as colored derivatives; OFA as 2,4-dinitrophenylhydrazones, and HFA as esters of pyruvic acid 2,6-dinitrophenylhydrazone. The concentration of OFA increased with increasing irradiation dose but not always linearly. Variations in the concentration of both classes were noted and some chicken lipids failed to form both classes. In the samples where OFA were generated in significant quantities, the absorption maximum of the derivatives shifted toward a higher wavelength with increasing dose due ostensibly to the formation of double bond(s) in conjugation with the oxo group. This shift in absorption maximum was initially considered to be a means for detecting irradiation as well as indicating the dose received with fair accuracy. However, in several instances irradiation of a chicken sample did not result in the formation of significant increases in OFA and therefore this method cannot be used as a definitive test.

Quantitation of sulfamethazine in pork tissue by thin-layer chromatography.

Our earlier method to detect and quantitate sulfamethazine (SMZ) in milk at the 10 ppb level was modified to quantitate SMZ in pork tissue. Sulfabromomethazine (SBZ) is added to the tissue as an internal standard. SMZ and SBZ are extracted from the tissue into water as the supernatant of a centrifuged, aqueous homogenate and are cleaned up and concentrated by a series of solid-phase extractions. The sulfonamide-containing eluate is then separated on a silica gel thin-layer chromatographic plate. SBZ and SMZ are derivatized with fluorescamine, and their fluorescence is quantitated with a scanning densitometer. The limit of detection was estimated at 0.25 ppb (signal-to-noise ratio, 3:1). The average accuracy over the analysis range (0.54-21.8 ppb [micrograms/kg]) was 95.6% (standard deviation = 29.4%, n = 54).

A 100-year average recurrence interval for the san andreas fault at wrightwood, california.

Evidence for five large earthquakes during the past five centuries along the San Andreas fault zone 70 kilometers northeast of Los Angeles, California, indicates that the average recurrence interval and the temporal variability are significantly smaller than previously thought. Rapid sedimentation during the past 5000 years in a 150-meter-wide structural depression has produced a greater than 21-meter-thick sequence of debris flow and stream deposits interbedded with more than 50 datable peat layers. Fault scarps, colluvial wedges, fissure infills, upward termination of ruptures, and tilted and folded deposits above listric faults provide evidence for large earthquakes that occurred in A.D. 1857, 1812, and about 1700, 1610, and 1470.

Thin-layer chromatographic detection of zeranol and estradiol in fortified plasma and tissue extracts with Fast Corinth V.

In an attempt to improve sensitivity of thin-layer chromatographic (TLC) analysis and selectivity of visualizing agents for detection of estrogenic anabolic hormones, several dyes were screened for their chromogenic interactions with estrone, estradiol, diethylstilbestrol (DES), zeranol (zearalanol), zearalanone, and mycotoxins, zearalenone and zearalenol. Fast Corinth V salt was selected for its relatively high sensitivity. These anabolic compounds were separated by TLC and visualized with Corinth V and the results compared to iodine and starch visualization. Fortified bovine plasma and tissues (kidney, liver and muscle) and chicken muscles were analyzed after a clean-up procedure using solid-phase dual columns of alumina and anion-exchange resin. Iodine-starch clearly detected 4 ng of estradiol and DES while zeranol and zearalenone were detected at higher levels (10 ng). Fast Corinth V showed distinct spots with 2 ng of zeranol and 4 ng of zearalenone while faint spots were observed with estradiol and estrone standards. DES was not detectable at these levels. Less background interference was observed with Corinth V than with iodine-starch. The former confirmed spots detected by iodine-starch. This study suggests its selectivity for detection of zeranol and its metabolite, zearalanone, in the presence of steroidal compounds.

Effects of bis homoallylic and homoallylic hydroxyl substitution on the olefinic 13C resonance shifts in fatty acid methyl esters.

Substitution of a hydroxyl group at the bis homoallylic position (OH group located three carbons away from the olefinic carbon) in C18 unsaturated fatty acid esters (FAE) induces a 0.73 +/- 0.05 ppm upfield and a 0.73 +/- 0.06 ppm downfield shift on the delta and epsilon olefinic 13C resonances relative to the unsubstituted FAE, respectively. If the hydroxyl group is located on the carboxyl side of the double bond of the bis homoallylic hydroxy fatty acid esters (BHAHFA), the olefinic resonances are uniformly shifted apart by [formula: see text] where delta delta dbu represents the absolute value of the double bond resonance separation in the unsubstituted FAE and 1.46 ppm is the sum of the absolute values of the delta and epsilon shift parameters. With hydroxyl substitution on the terminal methyl side of the double bond, the olefinic shift separation is equal to [formula: see text] In homoallylic (OH group located two carbons away from the olefinic carbon) substituted FAE the gamma and delta induced hydroxyl shifts for the cis double bond resonances are +3.08 and -4.63 ppm, respectively while the trans double bond parameters are +4.06 and -4.18 ppm, respectively. The double bond resonance separation in homoallylic hydroxy fatty acid esters (HAHFA) can be calculated from the formula [formula: see text] for cis and [formula: see text] for the trans case when the OH substitution is on the carboxyl side of the double bond. Conversely, when the OH resides on the terminal methyl side, the double bond shift separations for cis and trans isomers are [formula: see text] and [formula: see text] respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychosis and adolescence. The relation of intrapsychic structure formation and change to action and task.

This article is an exploration of intrapsychic structure formation and change from the point of view of a psychoanalytic concept of action. It compares the normal development of intrapsychic structure with that involved in psychotic disorganization as individuals encounter adolescence and its developmental tasks and requirements for action. The flexible complexity of intrapsychic structure and available action in a normally developing adolescent and the contrasting fixed simplicity of intrapsychic structure and its repertory of action in psychotic patients are highlighted. Four different environmental life occasions, all of which are associated with intrapsychic change, are examined against this background. The first of these involves little initial action on the part of the ego, although lasting change does occur. The last three involve both inner and outer developmental actions that can be central to growth and may be the occasion of psychosis. The first environmental life occasion is "trauma," in which the person's action, potentialities, and intrapsychic structure are disrupted by the world's destructive action and are thereby changed. The second is "intimacy," in which newly evolved actions and interaction are sought, often with little regard for or knowledge of the accompanying necessities of intrapsychic change. In the third --"success"--new intrapsychic change and altered necessities of action can surprisingly affect both the sense of continuity within one's inner world and the nature of one's relationship to the action of the outer world. The fourth occasion is "analytic" therapy, in which the regularities of one's intrapsychic structure and its stereotypies of action are often disrupted by the very "therapeutic" processes that allow these to be observed and examined in the course of promoting progressive development. All of these exciting and dangerous occasions mark out a separate, autonomous, individual, chosen act. The attempt to explicate the role of action in intrapsychic structural change during analytic work with a psychotic patient defines the analyst's actions as interferences and disruptions of that inner structure. His actions are noted, felt, represented, and organized into a part of that reformed, newly organized inner structure. Those analytic actions are represented by the patient as "having an impact" upon the patient and do indeed affect the patient. In that regard it is asserted that for a full, psychoanalytic conception of the ego, what is required is not only a central "body ego," but the integration of action in the formation and function of that ego's intrapsychic structure--an "action ego." Clarification of the complex relationship of conceptions of "fantasy" and action are re-examined in this context.(ABSTRACT TRUNCATED AT 400 WORDS)

A multi-residue TLC screening procedure for anabolic oestrogens and detection of oestradiol, DES or zeranol in chicken muscle tissue extracts.

A multi-residue HETLC (High Efficiency Thin Layer Chromatography) screening procedure for 17 beta-oestradiol, diethylstilboesterol (DES), zearalanol (zeranol), zearalenone and their metabolites oestrone, zearalanone, and zearalenol is described. The anabolic oestrogens were analyzed on HETLC plates coated with silica gel and were developed in methylene chloride:methanol: 2-propanol (97:1:2 v/v). The spots were visualized by exposure to iodine vapours and subsequently sprayed with 1% starch solution. Analysis of standards by HETLC at 4 degrees C as a seven-component mixture showed six discrete bands with mean Rfs of 0.37 (oestrone), 0.35 (zearalanone and zearalenone), 0.26 (t-DES), 0.23 (oestradiol), 0.17 (zearalenol and zearalanol), and 0.15 (c-DES). Chicken muscle tissues (1, 2.5, or 5 g) were extracted with 95% acetone. Extracts were then fortified with 50-250 ng each of the anabolic oestrogens, purified in alumina and ion-exchange columns and analyzed by HETLC. Oestradiol, zeranol or DES in fortified tissue extracts were clearly detected when an equivalent of 4 ng were analyzed by HETLC after purification in alumina and ion-exchange columns. The intensity of their bands suggested near quantitative recovery when compared to intensity of bands of known amounts of standards. The described extraction, purification, and TLC procedures can be used to screen these oestrogens at low ppb amounts in chicken muscle tissues and should be applicable to screen tissues of cattle and sheep.

The development of a Somatic Amplification Rating Scale for low-back pain.

The development of a new scale, the Somatic Amplification Rating Scale (SARS), for the quantification of exaggerated (nonorganic) motor, sensory, and pain responses occurring during a standardized physical examination is described. This 13-item scale, partially based on a measure of nonorganic physical signs developed by Waddell et al, was administered to 127 low-back pain patients at an outpatient pain center. It was determined that the 13-item scale could be shortened to seven items with improved ease of administration and little loss of reliability and validity. Interrater reliability of the finalized seven-item scale was excellent (R = 0.93). Finally, it was determined that patients with high SARS scores were significantly more likely to be receiving workers' compensation benefits and to endorse physical symptoms with greater intensity on psychologic testing (Symptom Checklist 90).

Cognitive and somatic item response pattern of pain patients, psychiatric patients, and hospital employees.

Standard psychological tests generally provide a single global score that reflects multidimensional constructs, such as depression and anxiety. This single score, however, integrates a range of item contents, including cognitive/affective, somatic, and behavioral characteristics of these multidimensional constructs. The present study was designed to compare the pattern of item endorsement among chronic pain patients (N = 50), psychiatric inpatients (N = 50), and hospital employees (N = 50) on the SCL-90-R (Derogatis, Rickels, & Rock, 1976). Pain patients reported the highest SCL-90 scale level of Somatization, while the psychiatric inpatients reported the highest level of Anxiety and Depression. Additionally, the within-scale pattern of item responses on the Anxiety and Depression scales differed among groups. Although psychiatric inpatients endorsed equivalent levels of somatic and cognitive items, the pain patients' reports of psychological distress were limited primarily to somatic signs of anxiety and depression. Thus, the interpretation of pain patients' psychological profiles and subsequent treatment recommendations may be inappropriate if based on normative data obtained from psychiatric and/or normal populations.

Influence of personal and universal failure on the subsequent performance of persons with type A and type B behavior patterns.

We conducted this experiment to compare the task performance of Type A and Type B persons following failure on a task in which no one succeeded (universal failure) versus failure on a task in which others had succeeded (personal failure). Postfailure performance was measured in terms of speed of completion of anagrams. Initial analyses indicated that the failure manipulation was effective in influencing the subjects' perceived cause of their failures, and that subjects were more anxious and depressed following personal failure than universal failure. More important, we found that Type A subjects performed better following personal rather than universal failure, whereas type of failure had no effect on the performance of Type B subjects. The results suggest that contrary to what is usually thought, Type A persons do not struggle for success indiscriminately. The results are discussed in terms of need for control and self-esteem.

Practical screening procedure for sulfathiazole in honey.

A simple, inexpensive procedure is described for rapidly screening small samples of honey for sulfathiazole (ST), a drug formerly used but not approved in the United States for the prophylactic treatment of American foulbrood disease of bees. The method uses 2 plastic tubes arranged in tandem. The upper tube contains a bed of alumina, which removes some interfering pigments. The lower tube contains a very small bed of anion exchange resin in the HSO4- form, which traps the ST. The drug is eventually eluted and detected using the Bratton-Marshall diazotization-coupling reagents. Honey containing 0.1 ppm ST can be readily detected. An optional dye concentration step permits the detection of as little as 25 ppb ST.