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PubMed2004

Specific and nonspecific effects of transcranial magnetic stimulation on picture-word verification.

Repetitive transcranial magnetic stimulation (rTMS) can temporarily impair or improve performance, including language processing. It remains unclear, however, (i) which scalp sites are most appropriate to achieve the desired effects and (ii) which experimental setups produce facilitation or inhibition of language functions. We assessed the effects of TMS at different stimulation sites on picture-word verification in healthy volunteers. Twenty healthy volunteers with left language lateralization, as determined by functional transcranial Dopplersonography, performed picture-word verification prior to and after rTMS (1 Hz for 600 s at 110% of subjects' resting motor thresholds). Stimulation sites were the classical language areas (Broca's and Wernicke's), their homolog brain regions of the right hemisphere, and the occipital cortex. Additionally, sham stimulation over Broca's area was applied in a subsample of 11 subjects. As a control task, 10 volunteers performed a colour-tone matching task under the same experimental conditions. There was a general nonspecific arousal effect for both verum and sham TMS for both the picture-word verification and for the control task. However, superimposed there were opposite effects on picture-word verification for stimulation of Wernicke's area and Broca's area, namely a relative inhibition in the case of Wernicke's area and a relative facilitation in the case of Broca's area. These results demonstrate that low frequency rTMS has both general arousing effects and domain-specific effects.

Adult↗
PubMed1984

Effect of lead intoxication on calcium homeostasis and calcium-mediated cell function: a review.

The interaction between lead and essential metals is a complex, well recognized, but poorly understood phenomenon. Dietary deficiencies or excesses of certain essential metals may alter the absorption, elimination, or dose response of lead. Lead, in turn, may alter the homeostasis and function of essential metals. This review will be limited to the effect of lead on calcium, an essential metal with elaborate systemic and cellular homeostatic mechanisms and innumerable second messenger and coupling-factor functions. Lead may ultimately perturb calcium-regulated or calcium-mediated functions (a) directly by interfering with calcium transport or storage processes, e.g., Ca2+ transport proteins, calcium gates, etc.; (b) indirectly by altering cell functions required for calcium homeostasis, e.g., energy production, plasma membrane permeability, etc.; (c) by substitution of Pb2+ for Ca2+ at functionally important calcium binding sites, e.g., calmodulin. While any individual study may not provide adequate experimental verification of the causal role of perturbations of calcium metabolism and function as the primary toxic lesion of lead intoxication, the collective observations of many studies do strongly support lead-calcium interactions as an important functional lesion in lead intoxicated organelles, cells, tissues, and organ systems.

Animals↗
PubMed1992

Chronic reduction of myocardial ischemia does not attenuate coronary collateral development in miniswine.

BACKGROUND: Myocardial ischemia is considered to be a possible stimulus for development of the coronary collateral circulation. We therefore hypothesized that chronic reduction of myocardial oxygen demand to lessen ischemia would attenuate coronary collateral development over an 8-week period using left circumflex coronary artery (LCx) ameroid-induced constriction in pigs. METHODS AND RESULTS: Collateral development was assessed by myocardial blood flow (radioactive microspheres) and left ventricular regional function (sonomicrometer dimension gauges). beta-Adrenoceptor blockade with propranolol (160 or 320 mg b.i.d.p.o.) was initiated in 15 animals 1 day after surgery. Compared with 16 untreated animals, beta-adrenoceptor antagonism was documented in the treated group by 1) pharmacological stimulation with isoproterenol, 2) physiological stimulation during graded treadmill exercise, and 3) repeated long-term biotelemetry recordings of oxygen demand (heart rate and blood pressure) and regional myocardial function. In addition to pharmacological and physiological verification of beta-blockade, biotelemetry showed that, compared with the untreated animals, propranolol significantly reduced the daily number, individual duration, and severity of events representing myocardial dysfunction. This suggests that in the beta-blocked group, little if any ischemia was present throughout the first 5 weeks when collateral growth occurs. Transmural myocardial blood flow (expressed as a ratio of flow in the LCx region to the nonoccluded region of the left ventricle) and systolic wall thickening in the LCx region were determined at rest and during treadmill exercise (240 beats per minute) 31-38 days (5 weeks) and 60-67 days (8 weeks) after surgery. Propranolol was withdrawn 3 days before flow and function determinations and was resumed immediately after testing. Blood flow ratios at 5 weeks decreased similarly from rest to exercise in the untreated (0.83 +/- 0.04 to 0.60 +/- 0.05, p less than 0.05) and beta-blockade group (0.82 +/- 0.09 to 0.57 +/- 0.10, p less than 0.05). Systolic wall thickening from rest to exercise was attenuated to the same degree in the untreated (59 +/- 6% to 38 +/- 6%, p less than 0.05) and beta-blockade group (50 +/- 8% to 30 +/- 5%, p less than 0.05). Similar flow and function responses were observed in both groups at 8 weeks. CONCLUSIONS: We conclude that growth and development of the coronary collateral circulation measured functionally during exercise at 90% of maximal heart rate is unrelated to the extent and duration of myocardial ischemia in this model.

Animals↗
PubMed2003

Aerobic tryptophan degradation pathway in bacteria: novel kynurenine formamidase.

While a variety of chemical transformations related to the aerobic degradation of L-tryptophan (kynurenine pathway), and most of the genes and corresponding enzymes involved therein have been predominantly characterized in eukaryotes, relatively little was known about this pathway in bacteria. Using genome comparative analysis techniques we have predicted the existence of the three-step pathway of aerobic L-tryptophan degradation to anthranilate (anthranilate pathway) in several bacteria. Based on the chromosomal gene clustering analysis, we have identified a previously unknown gene encoding for kynurenine formamidase (EC 3.5.1.19) involved with the second step of the anthranilate pathway. This functional prediction was experimentally verified by cloning, expression and enzymatic characterization of recombinant kynurenine formamidase orthologs from Bacillus cereus, Pseudomonas aeruginosa and Ralstonia metallidurans. Experimental verification of the inferred anthranilate pathway was achieved by functional expression in Escherichia coli of the R. metallidurans putative kynBAU operon encoding three required enzymes: tryptophan 2,3-dioxygenase (gene kynA), kynurenine formamidase (gene kynB), and kynureninase (gene kynU). Our data provide the first experimental evidence of the connection between these genes (only one of which, kynU, was previously characterized) and L-tryptophan aerobic degradation pathway in bacteria.

Aerobiosis↗
PubMed2006

Rapid detection of major depression in epilepsy: a multicentre study.

BACKGROUND: Depression is a common comorbid disorder in epilepsy but is not routinely assessed in neurology clinics. We aimed to create a rapid yet accurate screening instrument for major depression in people with epilepsy. METHODS: We developed a set of 46 items to identify symptoms of depression that do not overlap with common comorbid cognitive deficits or adverse effects of antiepileptic drugs. This preliminary instrument and several reliable and valid instruments for diagnosis of depression on the basis of criteria from the Diagnostic and Statistical Manual IV, depression symptom severity, health status, and toxic effects of medication were applied to 205 adult outpatients with epilepsy. We used discriminant function analysis to identify the most efficient set of items for classification of major depression, which we termed the neurological disorders depression inventory for epilepsy (NDDI-E). Baseline data for 229 demographically similar patients enrolled in two other clinical studies were used for verification of the original observations. FINDINGS: The discriminant function model for the NDDI-E included six items. Internal consistency reliability of the NDDI-E was 0.85 and test-retest reliability was 0.78. An NDDI-E score of more than 15 had a specificity of 90%, sensitivity of 81%, and positive predictive value of 0.62 for a diagnosis of major depression. Logistic regression showed that the model of association of major depression and the NDDI-E was not affected by adverse effects of antiepileptic medication, whereas models for depression and generic screening instruments were. The severity of depression symptoms and toxic effects of drugs independently correlated with subjective health status, explaining 72% of variance. Results from a separate verification sample also showed optimum sensitivity, specificity, and predictive power at a cut score of more than 15. INTERPRETATION: Major depression in people with epilepsy can be identified by a brief set of symptoms that can be differentiated from common adverse effects of antiepileptic drugs. The NDDI-E could enable rapid detection and improve management of depression in epilepsy in accordance with internationally recognised guidelines.

Adult↗
PubMed2000

An intermediate state of the gamma-aminobutyric acid transporter GAT1 revealed by simultaneous voltage clamp and fluorescence.

The rat gamma-aminobutyric acid transporter GAT1 expressed in Xenopus oocytes was labeled at Cys74, and at one or more other sites, by tetramethylrhodamine-5-maleimide, without significantly altering GAT1 function. Voltage-jump relaxation analysis showed that fluorescence increased slightly and monotonically with hyperpolarization; the fluorescence at -140 mV was approximately 0. 8% greater than at +60 mV. The time course of the fluorescence relaxations was mostly described by a single exponential with voltage-dependent but history-independent time constants ranging from approximately 20 ms at +60 mV to approximately 150 ms at -140 mV. The fluorescence did not saturate at the most negative potentials tested, and the midpoint of the fluorescence-voltage relation was at least 50 mV more negative than the midpoint of the charge-voltage relation previously identified with Na(+) binding to GAT1. The presence of gamma-aminobutyric acid did not noticeably affect the fluorescence waveforms. The fluorescence signal depended on Na(+) concentration with a Hill coefficient approaching 2. Increasing Cl(-) concentration modestly increased and accelerated the fluorescence relaxations for hyperpolarizing jumps. The fluorescence change was blocked by the GAT1 inhibitor, NO-711. For the W68L mutant of GAT1, the fluorescence relaxations occurred only during jumps to high positive potentials, in agreement with previous suggestions that this mutant is trapped in one conformational state except at these potentials. These observations suggest that the fluorescence signals monitor a novel state of GAT1, intermediate between the E*(out) and E(out) states of Hilgemann, D.W., and C.-C. Lu (1999. J. Gen. Physiol. 114:459-476). Therefore, the study provides verification that conformational changes occur during GAT1 function.

Animals↗
PubMed2006

Revisiting the prediction of protein function at CASP6.

The ability to predict the function of a protein, given its sequence and/or 3D structure, is an essential requirement for exploiting the wealth of data made available by genomics and structural genomics projects and is therefore raising increasing interest in the computational biology community. To foster developments in the area as well as to establish the state of the art of present methods, a function prediction category was tentatively introduced in the 6th edition of the Critical Assessment of Techniques for Protein Structure Prediction (CASP) worldwide experiment. The assessment of the performance of the methods was made difficult by at least two factors: (a) the experimentally determined function of the targets was not available at the time of assessment; (b) the experiment is run blindly, preventing verification of whether the convergence of different predictions towards the same functional annotation was due to the similarity of the methods or to a genuine signal detectable by different methodologies. In this work, we collected information about the methods used by the various predictors and revisited the results of the experiment by verifying how often and in which cases a convergent prediction was obtained by methods based on different rationale. We propose a method for classifying the type and redundancy of the methods. We also analyzed the cases in which a function for the target protein has become available. Our results show that predictions derived from a consensus of different methods can reach an accuracy as high as 80%. It follows that some of the predictions submitted to CASP6, once reanalyzed taking into account the type of converging methods, can provide very useful information to researchers interested in the function of the target proteins.

Caspase 6↗
PubMed1985

Effect of fluid pressure on the hydraulic conductance of interstitium and fenestrated endothelium in the rabbit knee.

A synovial cavity is separated from plasma by synovial intima in series with capillary endothelium. Because 20% of the intimal surface is bare interstitium, the system is a convenient model for the study of passive transport through serial endothelial and interstitial layers. Here hydraulic flow across the composite barrier was investigated in forty-seven knees of isolated, blood-perfused rabbit hindquarters, at intra-articular pressures between 4 and 30 cmH2O. In order to measure barrier conductance at constant intra-articular pressure, pressure on the opposite side of the barrier was varied, i.e. capillary blood pressure (PC). Capillary pressure was changed by alteration of vascular perfusion pressures, and the resulting changes in rate of absorption of Krebs solution from the synovial cavity (QS) were recorded. Trans-synovial absorption was a negative linear function of PC at each joint pressure, in verification of the applicability of Starling's hypothesis to this system. The hydraulic conductance of the blood-joint barrier was calculated as dQS/dPC. Conductance was independent of intra-articular pressure below 9 cmH2O and was 0.12 +/- 0.015 microliter min-1 mmHg-1 (mean +/- S.E. of mean). Barrier conductance increased as a curvilinear function of intra-articular pressure above 9.4 cmH2O (yield pressure). At 30 cmH2O conductance averaged 0.60 +/- 0.06 microliter min-1 mmHg-1, a 5-fold increase. A hyperbolic curve relating net barrier conductance to joint pressure was predicted from the hypothesis that interstitial conductance increases as a monotonic function of intra-articular pressure above yield pressure (Appendix). The data were in reasonable agreement with the theoretical hyperbola. Interstitial conductivity (3 X 10(-7)-7 X 10(-7) cm4 s-1 N-1 below yield pressure) and mean endothelial conductance (1.1 X 10(-4)-1.4 X 10(-4) cm3 s-1 N-1) were evaluated and compared with values in other tissues. Synovial endothelium contains on average 0.25 fenestrae micron-1 circumference. The conductance of a single fenestra was calculated to be 2.3 X 10(-13) cm5 s-1 N-1. Interstitial resistance accounted for roughly half the total resistance below yield point: therefore dQS/dPC should not be equated with 'capillary filtration capacity' in tissues with dense or fenestrated capillary beds. Large inconsistencies between interstitial conductivity and glycosaminoglycan concentration are noted, and mechanistic explanations of increases in conductivity with joint pressure are offered.

Animals↗
PubMed2005

Mediotemporal contributions to semantic processing: fMRI evidence from ambiguity processing during semantic context verification.

The medial temporal lobe (MTL) is well known to be crucial for various types of memory; however, controversy remains as to which of its substructures contribute to semantic processing and, if so, to what extent. The current study addresses the issue of MTL contributions to semantic processing during lexico-semantic ambiguity processing by using functional magnetic resonance imaging (fMRI) in combination with a context verification task (CVT). The CVT required decisions on the semantic fit of congruent and incongruent target words to the overall meaning of preceding sentential contexts with and without semantic ambiguity. In two of the four experimental conditions (congruent homographic, incongruent homographic), target decisions were critically dependent on the successful processing of prior sentence-final lexico-semantic ambiguity. Semantic context verification per se evidenced bilateral activations of the hippocampus that were part of a functional network including inferior prefrontal and superior parietal cortices. Commonalities in activation differences pertaining to the specific cognitive component of lexico-semantic ambiguity processing were found in a left temporal lobe network that comprised activation foci in the temporal pole, the parahippocampal and fusiform gyri. The present results suggest that the hippocampus may well contribute to semantic processing, namely by a mnemonic function that serves to link the target meaning representation with the meaning of a prior sentence context. Contrary to previous reports from human lesion studies, the present findings further suggest, that the specific cognitive component of lexico-semantic ambiguity processing is neither dependent on the hippocampus nor exclusively subserved by the temporal pole, but also recruits an associative semantic memory function from the parahippocampal gyrus as well as a more general (bottom-up) semantic function from the fusiform gyrus.

Adult↗
PubMed2004

Construction of a non-redundant human SH2 domain database.

Domain database is essential for domain property research. Eliminating redundant information in database query is very important for database quality. Here we report the manual construction of a non-redundant human SH2 domain database. There are 119 human SH2 domains in 110 SH2-containing proteins. Human SH2s were aligned with ClustalX, and a homologous tree was generated. In this tree, proteins with similar known function were classified into the same group. Some proteins in the same group have been reported to have similar binding motifs experimentally. The tree might provide clues about possible functions of hypothetical proteins for further experimental verification.

Amino Acid Sequence↗
PubMed2006

Kinetics and thermodynamics of electron transfer in Debye solvents: an analytical and nonperturbative reduced density matrix theory.

A nonperturbative electron transfer rate theory is developed on the basis of reduced density matrix dynamics, which can be evaluated readily for the Debye solvent model without further approximation. Not only does it recover for reaction rates the celebrated Marcus' inversion and Kramers' turnover behaviors, but the present theory also predicts reaction thermodynamics, such as equilibrium Gibbs free energy and entropy, some interesting solvent-dependent features that are calling for experimental verification. Moreover, a continued fraction Green's function formalism is also constructed, which can be used together with the Dyson equation technique for efficient evaluation of nonperturbative reduced density matrix dynamics.

Journal Article↗
PubMed2000

Should we create a niche or fall in line? Identity negotiation and small group effectiveness.

A prospective study of 423 MBA students examined the interplay of identity negotiation and group functioning. The findings revealed that self-verification effects (through which group members brought others to see them as they saw themselves) heightened participants' feelings of connection to their groups (i.e., more identification and social integration and less emotional conflict) and improved group project grades on creative tasks (tasks that benefit from divergent perspectives). Appraisal effects (through which groups brought members to see themselves as the group saw them) facilitated group project grades on computational tasks (tasks that require deriving one correct answer). In addition, self-verification effects were more prevalent than appraisal effects. The authors discuss the implications of these findings for understanding the links among self-verification, self-categorization, and group outcomes.

Adult↗
PubMed2001

Analysis of TSC2 stop codon variants found in tuberous sclerosis patients.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations to the TSC1 and TSC2 tumour suppressor genes. We detected two sequence changes involving the TSC2 stop codon and investigated the effects of these changes on the expression of tuberin, the TSC2 gene product, and on the binding between tuberin and the TSC1 gene product, hamartin. While elongation of the tuberin open reading frame by 17 amino acids did not interfere with tuberin-hamartin binding, a longer extension prevented this interaction. Our data illustrate how functional protein assays can assist in the verification and characterisation of disease-causing mutations.

Animals↗
PubMed1981

Characteristics of human large granular lymphocytes and relationship to natural killer and K cells.

Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcgammaR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcgammaR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.

Adsorption↗
PubMed1998

Surgical and implantation reconstruction in a patient with giant-cell central reparative granuloma.

The giant-cell central reparative granuloma, unlike other giant-cell neoplasias, is mainly found in maxillary bones, particularly in the mandible. We report a patient study of giant-cell central reparative granuloma in the mandible extending from dental elements 34 to 44. The patient underwent excision of a neoplasm and reconstruction of the mandible via an autologous bone graft of the iliac crest. To restore fully, functionally, and aesthetically the masticatory apparatus after verification of graft stability, four osseointegrated implants were fixed, and an "overdenture" prosthesis was then applied, thus finally solving the problem.

Adult↗
PubMed1998

Lung cancer: intermittent irradiation synchronized with respiratory motion--results of a pilot study.

PURPOSE: To test the feasibility of a system for intermittent irradiation synchronized with respiratory motion in a clinical setting. MATERIALS AND METHODS: A newly developed gate pulse controller that starts and stops irradiation at a chosen phase of the respiratory cycle by controlling a linear accelerator was used in six patients with lung cancer. A laser displacement sensor was used for the detection of respiratory motion. Three patients underwent radiation therapy during the cycles between 50% expiration and 50% inspiration (step 1), and three patients underwent radiation therapy during the cycles between 70% expiration and 30% inspiration (step 2). RESULTS: The system functioned well; irradiation was verified with portal verification radiography in all six patients. The range of the tumor position during synchronized irradiation was detectable with fast portal localization radiography. The treatment times for steps 1 and 2 were 1.38-1.71 and 2.03-2.18 times longer, respectively, than those for conventional irradiation. CONCLUSION: Synchronized irradiation with the authors' system allowed convenient and reliable reduction of the target volume. Further study is needed to standardize the system for clinical use.

Clinical Protocols↗
PubMed2006

Surface analysis.

Surface analysis techniques are important tools to use in the verification of surface cleanliness and medical device functionality. How these techniques can be employed and some example applications are described.

Biocompatible Materials↗
PubMed1980

Stimulus-rule interactions in concept verification.

The difficulty of learning a conceptual rule has been shown to depend upon the stimulus attributes which that rule conjoins. For what appear to be separable attributes, the disjunctive rule is easier than the conjunctive. In contrast, for what appear to be integrable attributes, the conjunctive rule is easier. This paper reports six experiments designed to determine whether the integrality of stimulus attributes affects the speed of verification of the stimulus, as positive or negative, with respect to a given conjunctive or disjunctive concept. The pattern of reaction times is not consistent with the result of rule-learning experiments and does not support an integrality hypothesis. Verification times seem to be more a function of the perceptual salience of the relevant attributes of the concept. Thus, a perceptual-integrality hypothesis is an unlikely explanation of rule learning results.

Color Perception↗