KIR/HLA gene combinations influence susceptibility to B-cell chronic lymphocytic leukemia and the clinical course of disease.

The aim of this study was to analyze the association between gene polymorphisms of killer-cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) and the clinical course of disease. The distribution of individual KIR genes in 197 B-CLL patients and 200 controls was similar, except for a tendency for lower frequencies of the KIR2DS3 and KIR2DL5 genes among B-CLL patients (26.9% vs 35.5%, P = 0.06, 46.2% vs 55.5%, P = 0.06). The associations between KIR2DS3 and B-CLL reached statistical significance in women (P = 0.05). Moreover, we found a trend toward a lower frequency of genotypes with the presence of five or six activating KIR genes in B-CLL patients compared to controls (20.8% vs 29.0%, P = 0.06), and a significantly higher frequency of individuals possessing genotypes with a prevalence of inhibitory over activating KIR genes (ratio < 0.71) among B-CLL patients (P = 0.04). The HLA-Bw4 specificity was significantly reduced among B-CLL patients (48.7% vs 63.0%, P = 0.005), which resulted from a decreased frequency of HLA-Bw4(Thr80) (21.6% vs 32.0%, P = 0.02). Moreover, among HLA-Bw4-positive individuals, progression-free survival (PFS) tended to be higher in the presence of KIR3DS1 (77% ± 9% vs 39% ± 13%, P = 0.07). However, in B-CLL patients, the presence of HLA-C2 was associated with decreased PFS (49% ± 9% vs 75% ± 7%, P = 0.02), and among HLA-C2-positive patients, the probability of PFS was significantly reduced in the absence of KIR2DS1 (34% ± 11% vs 77% ± 7%, P = 0.007). Our results indicate that the pattern of inhibitory/activating KIR genes, together with their HLA ligands, is associated with susceptibility to B-CLL and affects the clinical course of this disease.

Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population.

Abnormal expression of the costimulatory molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), CD28, and inducible co-stimulator (ICOS) leads to disturbances of immune response and an increased risk of cancer. An extended study was undertaken to evaluate the association among the polymorphisms CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CD28c.17+3T>C, and ICOSc.1554+4GT(8_15) and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) in the Polish population. The study revealed increased frequency of the CTLA-4g.319C>T [T] allele and the CTLA-4g.319C>T [T] phenotype in B-CLL patients compared with healthy controls (p = 0.003, odds ratio [OR] = 1.73; and p = 0.009, OR = 1.74, respectively). The presence of the CD28c.17+3T>C [C] allele and the CD28c.17+3T>C [C] phenotype increased the OR of B-CLL to 1.59 (p = 0.007) and 1.74 (p = 0.007), respectively. Either CTLA-4g.319C>T or CD28c.17+3T>C was associated with time to Rai stage progression. The distributions of the alleles and genotypes of the ICOS gene significantly differed between patients and controls (p = 0.0009 and p = 0.006, respectively). Individuals possessing short alleles were 2.02 times more prone to B-CLL than others (p = 0.001), whereas carriers of long alleles were protected from B-CLL (p = 0.02, OR = 0.62). The haplotype association study and multivariate analysis confirmed the association of CTLA-4g.319C>T and ICOSc.1554+4GT(8_15) gene polymorphisms with B-CLL. The polymorphic sites CTLA-4c.49A>G and CTLA-4g.*642AT(8_33) did not correlate with B-CLL. Our results are the first in the literature to report that gene polymorphism of the costimulatory molecules CTLA-4, CD28, and ICOS contributes to susceptibility to B-CLL.

Rapid extraction of emotional expression: evidence from evoked potential fields during brief presentation of face stimuli.

Although the emotional expression of faces is believed to be accessed rapidly, previous ERP studies hardly found correlates of these processes. Here, we report findings from a study that investigated dichoptic binocular interaction using emotional face stimuli. Thirty-one subjects were briefly presented with schematic normal and scrambled faces (of neutral, positive, or negative expression) that occurred simultaneously in the left and right visual fields. Stimuli for both eyes could be congruent (control) or incongruent (dichoptic). Subjects decided which of the superimposed images in both hemi-fields appeared more "face-like" and during this task, the EEG was recorded from 30 channels. VEPs were analysed topographically according to the influence of the different experimental conditions (defined by presentation form, emotional expression, and location). Behavioural responses to the ambiguous dichoptic stimuli demonstrated a functional eye dominance not related to visual acuity and conventional eye preference. Electrophysiological data revealed three components with mean latencies of 85, 160, and 310 ms. Topography of the second component (equivalent to the face-related N170) differed in left-right and anterior-posterior direction compared with simple checkerboard stimuli. Dichoptic presentation caused reduced field strength of all three, and increased latency of the first component. Faces with negative expression yielded largest field strength of the second and third components. Besides that, emotional expression affected topography not only of late, but also the first component. This provides new evidence about the timing of perceptual processes related to facial expression, indicating that already VEP components occurring at 80-90 ms are sensitive to emotional content.

Perceptual learning: psychophysical thresholds and electrical brain topography.

We studied perceptual learning by determining psychophysical discrimination thresholds for visual hyper acuity targets (vernier stimuli) as a function of stimulus orientation. One aim was to relate perceptual improvements to changes of electrophysiological activity of the human brain. A group of 43 healthy adults participated in a psychophysical experiment where vernier thresholds for vertical and horizontal vernier targets were compared. In 16 subjects thresholds were measured for each orientation twice at an interval of 25 min. Between threshold estimations, evoked brain activity was recorded from 30 electrodes over the occipital brain areas while the subjects observed appearance and disappearance of supra-threshold vernier offsets. Mean evoked potentials were computed for the first and second 600 stimulus presentations, and the scalp topography of electrical brain activity was analyzed. Vertically oriented stimuli yielded significantly better performance than horizontal targets, and thresholds were significantly lower in the second half of the experiment, i.e. after prolonged viewing of stimuli. The improvements in discrimination performance were specific for stimulus orientation and did not generalize. Learning effects were also observed with electrical brain activity, and field strength of the potentials increased significantly as a function of time. Scalp topography of the evoked components was significantly affected indicating a shift of activation between different neuronal elements induced by perceptual learning.

Associative learning in humans--conditioning of sensory-evoked brain activity.

A classical conditioning paradigm was employed in two experiments performed on 35 human volunteers. In nine subjects, the presentation of Landolt rings (conditioned stimuli, CS + ) was paired with an electric stimulus (unconditioned stimuli, UCS) applied to the left median nerve. Neutral visual control stimuli were full circles (CS -) that were not paired with the UCS. The skin conductance response (SCR) was determined in a time interval of 5 s after onset of the visual stimuli, and it was measured in the acquisition and test phase. Associative learning was reflected by a SCR occurring selectively with CS +. The same experiment was repeated with another group of 26 adults while electroencephalogram (EEG) was recorded from 30 electrodes. For each subject, mean evoked potentials were computed. In 13 of the subjects, a conditioning paradigm was followed while the other subjects served as the control group (non-contingent stimulation). There were somatosensory and visual brain activity evoked by the stimuli. Conditioned components were identified by computing cross-correlation between evoked somatosensory components and the averaged EEG. In the visual evoked brain activity, three components with mean latencies of 105.4, 183.2, and 360.3 ms were analyzed. Somatosensory stimuli were followed by major components that occurred at mean latencies of 48.8, 132.5, 219.7, 294.8, and 374.2 ms latency after the shock. All components were analyzed in terms of latency, field strength, and topographic characteristics, and were compared between groups and experimental conditions. Both visual and somatosensory brain activity was significantly affected by classical conditioning. Our data illustrate how associative learning affects the topography of brain electrical activity elicited by presentation of conditioned visual stimuli.

Learning to see 3-D: psychophysics and brain electrical activity.

We investigated human perceptual learning with stereoscopic stimuli presented below threshold. Different visual patterns were shown as dynamic random dot stereograms in a forced-choice design in order to determine the psychophysical thresholds of 16 adults. Brain electrical activity was recorded from 30 electrodes over parieto-occipital areas while stereograms were presented with horizontal disparities below threshold. During the observation of sub-threshold stimuli, we tested repeatedly whether implicit perceptual learning occurred. More than half of the subjects learned to see stereoscopic targets. This was accompanied by topographic changes in the pattern of activation of neural assemblies in the visual cortex where the center of activity shifted towards the right hemisphere. Subjects who did not improve in perception, displayed no such effects.

Scalp distribution components of brain activity evoked by visual motion stimuli.

We analyzed the scalp distribution of electrical brain activity elicited by visual motion stimuli in 14 healthy adults. Stimuli were square-wave gratings of high or low contrast moving with a velocity of 4.9 deg/s on a computer monitor. Adaptation to motion was varied by changing the so-called duty cycle of stimulus presentation (i.e., the relation of motion to total presentation time) in order to enhance motion-related activity. Data obtained with motion stimuli were compared with checkerboard pattern reversal evoked activity. Spatial principal components analysis revealed four latent topographical components that accounted for 92.05% of the variance. Two components showed occipital extreme values surrounded by steep potential gradients while another two components displayed lateralized activity. Analysis of the contribution of these spatial components to the observed potential fields revealed significant differences between activity evoked by pattern reversal and that evoked by motion. The topographical patterns of cortical activation changed rapidly within 240 ms after motion onset. Our results confirm the sequential and parallel activation of different neuronal generators selectively sensitive to physical stimulus parameters of motion stimuli. The converging evidence of specialized quality-specific streams of sensory processing stemming from single-unit recordings in monkeys and imaging methods is supplemented by our electrophysiological results reflecting the activation of different brain areas.

Functional perimetry combined with topographical VEP analysis.

The processing of visual input depends on the position of the visual stimuli in the visual field. Based on the anatomical structure of the retina and the cortex, the function and perception vary with the location in the visual field. Due to the low signal-to-noise ratio, electrophysiological recordings in human subjects commonly have to use large stimuli and, therefore, yield poor spatial resolution. The combination of the method of quasi-simultaneous stimulation of many small (1.5 degrees x 1.5 degrees squares) visual field elements by binary m-sequences and topographical recordings allowed us to reconstruct the potential maps elicited at each of 54 visual field locations independently. Twenty-two normal subjects participated in the experiments and observed monocularly a stimulation field of 13.5 degrees x 9 degrees filled with the 54 squares. Mean luminance was 6.5 cd/m2 and contrast was 95%. The EEG was recorded in 30 channels with a dense array of electrodes over the occipital brain areas. Individual noise levels of the subjects were estimated and significant signals were analyzed quantitatively. We determined three components between 90 ms and 220 ms latency. Both global field power (GFP) and topography of the components were affected by retinal stimulus location, showing a significant decline of GFP with retinal eccentricity. Our data demonstrate that even small retinal targets may evoke brain activity which can be recorded simultaneously. Scalp field topography depends critically on the exact stimulus location within the foveal and parafoveal retinal areas while response strength mainly depends on eccentricity.

Local luminance and pattern reversal stimuli yield different visual evoked potential topography.

We studied how the stimulation of quadrants of the visual field affect brain potential topography, and we compared activity elicited by conventional pattern reversal or by local luminance stimuli. The method of quasi-simultaneous stimulation of many small visual field elements by binary m-sequences allowed us to reconstruct the potentials evoked at each of 54 visual field locations independently. Data from all field elements within each quadrant and in the whole stimulation field were summed and compared to those elicited by checkerboard reversal stimuli presented in the four quadrants or as full field stimuli. In twenty-two healthy adults evoked brain activity was recorded in 30 channels with an electrode array densely spaced over the occipital brain areas. With local flash stimuli as well as with checkerboard reversal the topographical distributions of cortical activation changed significantly with retinal stimulus location. Analysis of three components occurring between 50 and 240 ms revealed significant differences between pattern reversal and local luminance evoked brain activity. Reversal stimuli yielded not only larger amplitudes but also a completely different component structure and topography. Our results illustrate that different neuronal generators are activated by pattern reversal and local luminance stimuli although visual field location of the stimuli was identical indicating that the same retinal and cortical structures respond in a different way depending on stimulation mode.

Sensory thresholds and neurophysiological correlates of human perceptual learning.

The repeated presentation of visual targets yields significant improvements of psychophysical thresholds, and in the present paper corresponding alterations in neurophysiological activity of the human brain are reported. A group of 23 healthy adults was investigated in a psychophysical experiment in which hyperacuity thresholds were determined repeatedly for up to about 25 min with vertically and horizontally oriented targets. Evoked brain activity was recorded during the same experimental session from 30 electrodes over the occipital brain areas. For each subject mean potentials were computed offline for two conditions corresponding to "before learning' (i.e. the first half of the experiment) and "after learning' (i.e. the second half of the experiment), and visual evoked brain activity was compared between these conditions. In the psychophysical experiments vernier thresholds decreased significantly with time, and this improvement in performance could be confirmed in a control session after an interval of 9 weeks. All changes in discrimination performance were specifically bound to stimulus orientation. Learning effects were also observed in electrical brain activity, which displayed significantly smaller component latencies and larger amplitudes as a function of training time. In addition, learning affected the topography of the evoked potential fields suggesting that cortical neurons are activated in a different way before and after perceptual learning.

[The Freiburg Stereotest. On assessment of stereovision in automobile driver examination]. / Der Freiburger Stereotest. Zur Beurteilung des Stereosehens bei Führerscheinbewerbern.

BACKGROUND: The "Freiburg Stereotest" is a new instrument where disparate pictures are generated by a computer and displayed on one single high resolution video monitor. In the present work, the Freiburg Stereotest was used to check the stereo qualification for certain categories of driver's licence. For this purpose, a determination of the smallest detectable disparity is not reasonable. Rather, it should be checked whether or not a certain disparity, usually well above threshold, is recognized with a sufficient reliability. We have chosen a disparity of 100 arcsec; this value is considered to be an acceptable requirement for certain categories of driver's licence. SUBJECTS AND METHODS: 6 strabismic subjects were examined binocularly and 10 normal subjects were examined both binocularly and monocularly. Two targets ("busses"), side by side and different in depth by a disparity of 100 arcsec, were presented 78 times and, in a two-alternative forced-choice procedure, a minimum of 66 hits was required to pass the test. Monocular cues were excluded by a systematic variation of the lateral distance between the two targets. RESULTS: The strabismic subjects and the monocularly occluded normal subjects reached random scores only. With both eyes open, 8 of the 10 normal subjects reached scores near 100%, while 2 of them passed the test only when the lateral distance between the two targets was 15 minarc or less. For a lateral distance between the two targets of more than 15 minarc, these 2 subjects showed a learning effect. CONCLUSIONS: The Freiburg Stereotest allows to determine with statistical significance whether or not a proband can recognize a certain disparity which may be required for a driver's licence.

[The Freiburg Vision Test. A computer-assisted procedure with sequential strategy]. / Der Freiburger Visustest. Ein computergesteuertes Verfahren mit Eingabelungsstrategie.

Single Landolt Cs were presented in one of four positions on a monitor. Subjects responded by pressing one of four buttons (forced choice). A computer selected the size of the Landolt Cs on a logarithmic scale using the "Best PEST" algorithm (Best Parameter Estimation by Sequential Testing), a modern procedure to measure psychophysical thresholds. For comparison, conventional measurements according to DIN 58220 (Deutsche Industrie Norm) were performed with Landolt Cs projected in eight positions, using three out of five correct responses as the threshold criterion. Examination of 23 patients (most of them with senile cataract) did not show any significant difference between the two tests in either visual acuity or reproducibility on two consecutive days. The coefficients of variation between sessions were 22% for the Freiburg test and 26% for the DIN test and 18% between the two tests, pooled over two sessions. The Freiburg acuity test thus appears to be numerically equivalent to the DIN 58220 procedure. In addition, it has a number of advantages: (1) examiner-dependent variability is reduced; therefore, the test can be used by inexperienced examiners; (2) the forced choice technique is used rigorously; (3) mistakes in confounding oblique directions are largely avoided; (4) the procedure is about twice as fast.

Reserpine ulcers in morphine dependent and withdrawal rats.

Reserpine ulcers were produced in dependent and withdrawal rats. The reactivity of isolated duodenum and colon to morphine and papaverine was tested in both groups of animals. Chronic administration of morphine decreases the development of post reserpine gastric ulcers, while in withdrawal rats it increases their occurrence. Relaxation and contraction responses of duodenum taken from the dependent rats showed tolerance. On the other hand, withdrawal rats displayed increased responses as compared with placebo group. Colon of dependent rats showed stronger responses to morphine and papaverine which indicates the lack of tolerance to morphine or enhanced receptors sensitivity. Stronger responses of colon in both dependent and withdrawal rats suggest the lack of tolerance in this segment of the gut. In withdrawal rats which obtained reserpine and placebo responses to papaverine were similar. It is suggested that reserpine decreased the sensitivity of mu receptor to morphine.