Expression and Activity of the NF-κB Subunits in Chronic Lymphocytic Leukaemia: A Role for RelB and Non-Canonical Signalling.

BACKGROUND: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour types, we theorised that RelB and p52 may also contribute to the pathology of CLL. METHODS: DNA binding activity of all five NF-kB subunits, p65, p50, RelB, p52, and c-Rel, was quantified using ELISA and correlated to ex vivo chemoresistance, CD40L-stimulated signalling (to mimic the lymph node microenvironment), and clinical data. RESULTS: Importantly, we show for the first time that high basal levels of RelB DNA binding correlate with nuclear RelB protein expression and are associated with del(11q), ATM dysfunction, unmutated IGHV genes, and shorter survival. High levels of nuclear p65 are prevalent in del(17p) cases (including treatment-naïve patients) and also correlate with the outcome. CD40L-stimulation resulted in rapid RelB activation, phosphorylation and processing of p100, and subsequent CLL cell proliferation. CONCLUSIONS: These data highlight a role for RelB in driving CLL cell tumour growth in a subset of patients and therefore strategies designed to inhibit non-canonical NF-κB signalling represent a novel approach that will have therapeutic benefit in CLL.

Illusory edges comingle with real edges in the neural representation of objects.

The visual system must transform a point-by-point biological representation from the photoreceptors into neural representations of separate objects. Even a uniform circular patch of light that slowly modulates in luminance can be segmented into separate central and surrounding areas merely by introducing black lines to outline a central square. The black lines cause brightness induction in the center even though the light inside and outside the square is always identical, as predicted by spatial antagonism between the square central area and its surround. Importantly, illusory Kanizsa lines forming the square are as effective for this brightness induction as real black lines, suggesting a 'form-cue invariant' cortical neural representation that does not distinguish between a central region set off by real or illusory edges. An open question is whether separate subsystems generate objects defined by real versus illusory edges, each providing the same form-cue invariant neural representation of an object, or whether form-cue invariance extends to integrating component pieces that together define an object. Experiments here show object segmentation when subparts of a square are defined by a mixture of real and illusory edges. Subjects adjusted the Michelson contrast of a separate patch to match the perceived modulation depth within the central region of a circular field that slowly oscillated in luminance. A closed, four-sided figure, no matter how constructed, reduced the perceived modulation depth within the central region. This shows that both real and illusory subparts can be integrated to segment center from surround. It supports a strong version of form-cue invariance in which neural mechanisms responsible for object segmentation are impartial to the piecemeal cues that are integrated to define an object.

Prospective Comparative Study of Laparoscopic Narrow Band Imaging (NBI) Versus Standard Imaging in Gynecologic Oncology.

BACKGROUND: Narrow band imaging (NBI) is an optic filtration enhancement for endoscopy that uses two wavelengths of light (415 and 540 nm) to highlight superficial microvascular patterns. It has been successfully utilized to improve identification of lesions with abnormal vasculature, which is associated with endometriosis and endometrial cancer. Case studies suggest it may also facilitate surgical staging of gynecologic cancer, which is critical in determining appropriate adjuvant therapies. A technology that enhances the ability to identify metastatic disease during minimally invasive surgery (MIS) could make an important difference in patient outcomes. METHODS: A prospective comparative study was conducted to evaluate patients with clinical indication for diagnostic or operative laparoscopy. All received white light imaging followed by NBI during the same procedure. Suspicious lesions were examined and photographed, using both modalities, before excision. The two techniques were compared. Positive predictive value, negative predictive value, and diagnostic accuracy in identifying histologically confirmed metastatic lesions were assessed, using appropriate statistical methods. RESULTS: Of 124 patients enrolled in the study, 94 were evaluable; 30 did not undergo MIS and were therefore excluded. A significantly higher number of peritoneal abnormalities were identified with NBI versus white light imaging (P = 0.0239). However, no statistically significant difference (P = 0.18, patient level) was observed in identification of histologically confirmed metastatic disease. CONCLUSIONS: NBI imaging provides a unique contrast between peritoneal surface and microvascular patterns. However, the results of this study suggest that NBI-enhanced laparoscopy does not provide superior detection of peritoneal surface malignancy compared with standard white light high-definition laparoscopy.

Attitudes about race predict individual differences in face adaptation aftereffects.

This study examined whether category boundaries between Black and White faces relate to individual attitudes about race. Fifty-seven (20 Black, 37 White) participants completed measures of explicit racism, implicit racism, collective self-esteem (CSE), and racial centrality. Category boundaries between Black and White faces were measured in three separate conditions: following adaptation to (1) a neutral gray background, a sequence of (2) Black or (3) White faces. Two additional conditions measured category boundaries for facial distortion to investigate whether attitudes relate to mechanisms of racial identity alone, or to more global mechanisms of face perception. Using a two-alternative forced-choice staircase procedure, participants indicated whether a test image appeared to be Black or White (or contracted or expanded). Following neutral adaptation, participants with higher CSE showed category boundaries shifted toward faces with a higher percentage of Black features. In addition, the strength of short-term sensitivity shifts following adaptation to Black and White faces was related to explicit and implicit attitudes about race. Sensitivity shifts were weaker when participants scored higher on explicit racism, but were stronger when participants scored higher on implicit but lower on explicit racism. The results of this study indicate that attitudes about race account for some individual differences in natural category boundaries between races as well as the strength of identity aftereffects following face adaptation.

Practical considerations in the selection of seed strength for prostate implants.

There are advantages in using lower numbers of higher activity seeds for prostate seed implants. This work investigated the use of higher strength seeds for our manually optimized prostate implants. Following a planning study using a range of seeds strengths between 0.4 U and 0.7 U, a series of patients were implanted using seeds of strength ~ 0.7 U. Twenty consecutive patients were selected for this study; ten patients were implanted with 0.4 U seeds and the next ten patients implanted with 0.7 U seeds. Postimplant dosimetry for the target volume, urethra, and rectal wall was compared between the two groups. Our data showed a small and insignificant decrease in the total theatre time when implanting seeds of higher strength. The mean number of seeds required per implant decreased by over 30% for the 0.7 U implants, and the mean number of needles decreased by eight needles. The mean D90 (%) was marginally lower for the 0.7 U group, and spread over a wider range of values. Doses to the rectal wall were slightly higher for the 0.7 U group. At six years postimplant, the symptom scores for urinary and rectal toxicity and erectile function were similar to those reported before brachytherapy, with little differences between the 0.4 U and 0.7 U groups. Our experiences and practical advice in the selection of seed strength for prostate implants are reported in this paper.

Scotopic hue percepts in natural scenes.

Traditional trichromatic theories of color vision conclude that color perception is not possible under scotopic illumination in which only one type of photoreceptor, rods, is active. The current study demonstrates the existence of scotopic color perception and indicates that perceived hue is influenced by spatial context and top-down processes of color perception. Experiment 1 required observers to report the perceived hue in various natural scene images under purely rod-mediated vision. The results showed that when the test patch had low variation in the luminance distribution and was a decrement in luminance compared to the surrounding area, reddish or orangish percepts were more likely to be reported compared to all other percepts. In contrast, when the test patch had a high variation and was an increment in luminance, the probability of perceiving blue, green, or yellow hues increased. In addition, when observers had a strong, but singular, daylight hue association for the test patch, color percepts were reported more often and hues appeared more saturated compared to patches with no daylight hue association. This suggests that experience in daylight conditions modulates the bottom-up processing for rod-mediated color perception. In Experiment 2, observers reported changes in hue percepts for a test ring surrounded by inducing rings that varied in spatial context. In sum, the results challenge the classic view that rod vision is achromatic and suggest that scotopic hue perception is mediated by cortical mechanisms.

Perceived segmentation of center from surround by only illusory contours causes chromatic lateral inhibition.

When a light and also its surrounding context slowly oscillate in chromaticity over time, the color appearance of the light depends on the relative phase of center and surround. The influence of the surround is generally accounted for by retinotopic center-surround organization, with the surround inhibiting signals from the center. The traditional neural account, however, cannot rule out lateral inhibition due to cortical mechanisms sensitive to object segmentation cues. Experiments here reveal that illusory contours are sufficient to separate a center from its surround. Observers adjusted the Michelson contrast of a matching disk to equal the perceived modulation depth of a central area within a surround. Both the central test and matching disk were maintained at constant luminance and modulated in-phase at 2Hz along one chromatic axis (L/(L+M) or S/(L+M)). The center was perceptually segmented from the surround by either a physical (retinotopic separation) or illusory (cortically represented) triangle contour. Segmentation of center from surround by the illusory contour strongly attenuated the perceived modulation depth for both chromatic axes. Further, the strength of attenuation was consistently greater with the illusory than the physically segmenting triangle. This cannot be accounted for by retinal center-surround antagonism; instead it points to a cortical neural representation of contours, with lateral inhibition following neural mechanisms sensitive to object segmentation cues.

Individual and age-related variation in chromatic contrast adaptation.

Precortical color channels are tuned primarily to the LvsM (stimulation of L and M cones varied, but S cone stimulation held constant) or SvsLM (stimulation of S cones varied, but L and M cone stimulation held constant) cone-opponent (cardinal) axes, but appear elaborated in the cortex to form higher-order mechanisms tuned to both cardinal and intermediate directions. One source of evidence for these higher-order mechanisms has been the selectivity of color contrast adaptation for noncardinal directions, yet the degree of this selectivity has varied widely across the small sample of observers tested in previous studies. This study explored the possible bases for this variation, and in particular tested whether it reflected age-related changes in the distribution or tuning of color mechanisms. Observers included 15 younger (18-22 years of age) and 15 older individuals (66-82), who adapted to temporal modulations along one of four chromatic axes (two cardinal and two intermediate axes) and then matched the hue and contrast of test stimuli lying along eight different directions in the equiluminant plane. All observers exhibited aftereffects that were selective for both the cardinal and intermediate directions, although selectivity was weaker for the intermediate axes. The degree of selectivity increased with the magnitude of adaptation for all axes, and thus adaptation strength alone may account for much of the variance in selectivity among observers. Older observers showed a stronger magnitude of adaptation thus, surprisingly, more conspicuous evidence for higher-order mechanisms. For both age groups the aftereffects were well predicted by response changes in chromatic channels with linear spectral sensitivities, and there was no evidence for weakened channel tuning with aging. The results suggest that higher-order mechanisms may become more exposed in observers or conditions in which the strength of adaptation is greater, and that both chromatic contrast adaptation and the cortical color coding it reflects remain largely intact in the aging visual system.

Response normalization and blur adaptation: data and multi-scale model.

Adapting to blurred or sharpened images alters perceived blur of a focused image (M. A. Webster, M. A. Georgeson, & S. M. Webster, 2002). We asked whether blur adaptation results in (a) renormalization of perceived focus or (b) a repulsion aftereffect. Images were checkerboards or 2-D Gaussian noise, whose amplitude spectra had (log-log) slopes from -2 (strongly blurred) to 0 (strongly sharpened). Observers adjusted the spectral slope of a comparison image to match different test slopes after adaptation to blurred or sharpened images. Results did not show repulsion effects but were consistent with some renormalization. Test blur levels at and near a blurred or sharpened adaptation level were matched by more focused slopes (closer to 1/f) but with little or no change in appearance after adaptation to focused (1/f) images. A model of contrast adaptation and blur coding by multiple-scale spatial filters predicts these blur aftereffects and those of Webster et al. (2002). A key proposal is that observers are pre-adapted to natural spectra, and blurred or sharpened spectra induce changes in the state of adaptation. The model illustrates how norms might be encoded and recalibrated in the visual system even when they are represented only implicitly by the distribution of responses across multiple channels.

Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia.

Defects in the DNA damage response pathway [e.g. del(17p)] are associated with drug-resistant B-cell chronic lymphocytic leukaemia (CLL). We previously demonstrated that over-expression of DNA-dependent protein kinase (DNA-PK) correlates with chemo-resistance and that inhibition of DNA-PK sensitizes CLL cells to chemotherapeutics. Here, we investigated expression of DNA-PK and other proteins that impact on drug resistance, and evaluated the effects of a DNA-PK inhibitor (NU7441) on mitoxantrone-induced cytotoxicity in CLL cells. NU7441 sensitized cells from 42/49 CLL samples to mitoxantrone, with sensitization ranging from 2- to 200-fold Co-culture of CLL cells in conditioned stromal medium increased chemoresistance but did not reduce sensitization by NU7441. Mitoxantrone treatment induced γH2AX foci and NU7441 increased their longevity (24 h). NU7441 prevented mitoxantrone-induced autophosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser 2056, confirming that DNA-PK participates in repair of mitoxantrone-induced DNA damage. del(17p) cases were more resistant to mitoxantrone than del(13q) cases, but were resensitized (7-16 fold) by co-incubation with NU7441. Expression of DNA-PKcs, Ku80, P-glycoprotein and topoisomerase IIß were significantly higher in del(17p) cases. PRKDC mRNA levels correlated with DNA-PKcs protein expression, which predicted shorter survival. These data confirm the potential of DNA-PK as a therapeutic target in poor prognosis CLL.

The oblique effect has an optical component: orientation-specific contrast thresholds after correction of high-order aberrations.

Most of the high-order aberrations of the eye are not circularly symmetric. Hence, while it is well known that human vision is subject to cortically based orientation preference in cell tuning, the optics of the eye might also introduce some orientational anisotropy. We tested this idea by measuring contrast sensitivity at different orientations of sine-wave gratings when viewing through a closed-loop adaptive optics phoropter. Under aberration-corrected conditions, mean contrast sensitivity improved for all observers by a factor of 1.8× to 5×. The detectability of some orientations improved more than others. As expected, this orientation-specific effect varied between individuals. The sensitivity benefits were accurately predicted from MTF model simulations, demonstrating that the observed effects reflected the individual's pattern of high-order aberrations. In one observer, the orientation-specific effects were substantial: an improvement of 8× at one orientation and 2× in another orientation. The experiments confirm that, for conditions that are not diffraction limited, the optics of the eye introduce rotational asymmetry to the luminance distribution on the retina and that this impacts vision, inducing orientational anisotropy. These results suggest that the traditional view of meridional anisotropy having an entirely neural origin may be true for diffraction-limited pupils but that viewing through larger pupils introduces an additional orientation-specific optical component to this phenomenon.

Circulating levels of matrix proteases and their inhibitors in pregnant women with and without a history of recurrent pregnancy loss.

BACKGROUND: We have recently shown that serum relaxin-2 levels are attenuated in women with a history of recurrent pregnancy loss (RPL). We sought to determine whether a history of RPL is also associated with changes in serum matrix metalloproteases (MMPs) and tissue inhibitors of matrix metalloproteases (TIMP) -1 and -2. METHODS: We obtained serum from 20 pregnant women with a history of RPL and 20 age-matched pregnant women with no history of RPL (NRPL) at 6-8, 10-12, 20, and 34 weeks gestation, and from cord blood. We quantified total serum concentrations of MMP-1, MMP-3, MMP-9 and TIMP-1 and TIMP-2 by ELISA. We determined whether these serum marker levels were associated with a history of RPL and delivery before 37 weeks gestation. RESULTS: There was no difference in the rates of miscarriage, preterm birth or prelabour rupture of fetal membranes between RPL and NRPL. However babies born to RPL were lighter than those born to NRPL. Serum MMP-1, 9, and TIMP-1 did not differ between RPL and NRPL but MMP-3 was higher in RPL vs. NRPL at 6-8 weeks (P < 0.05). Serum TIMP-2 levels were higher in RPL women at all gestations (P < 0.01). The ratio of RLX-2 (reported previously) to TIMP-2 at 10-12 weeks gestation was more strongly associated with a history of RPL than either peptide separately - area under the ROC curves for RLX-2 0.79 (95% CI 0.57 to 0.92), TIMP-2 0.83 (95% CI 0.63 to 0.95), and for RLX-2:TIMP-2 ratio 0.92 (95% CI 0.74 to 0.99). CONCLUSIONS: Women with a history of RPL demonstrate increased serum TIMP-2 and reduced RLX-2 during a subsequent viable pregnancy. Determination of both markers in early pregnancy enhances the discrimination of women with a history of RPL. These observations suggest roles for these two peptides in early implantation and placental development. Whether these may prove to be reliable early predictive markers for subsequent pregnancy loss in the index pregnancy is unknown and will require further studies.

Age-related changes in contrast gain related to the M and P pathways.

Neural contributions to the age-related reduction in spatial vision are incontrovertible. Whether there are differential age-related changes in the magnocellular (M) and parvocellular (P) pathways across the life span has not been tested extensively. We studied psychophysically the contrast gain signature of the M and P pathways for 13 younger and 13 older observers. Two separate paradigms thought to separate the M and P pathways based on their contrast gain (J. Pokorny & V. C. Smith, 1997) signature were used. A four-square array was presented as an increment or decrement on a background of 115 Td for 35 ms, with one test square presented at a slightly higher or lower retinal illumination. Using a four-alternative forced-choice procedure, the observer's task was to choose the unique square. The two paradigms differed only in the pretrial adaptation and inter-stimulus array. Data were fitted with models of contrast discrimination derived from the unique contrast gain signatures. The fitted models indicate a change in the discrimination functions with age for both the M and P pathways, revealing a shift in the contrast gain slope. Results indicate that both M and P pathways undergo age-related changes, but functional losses appear greater for the P pathway under the conditions tested.

Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester.

OBJECTIVES: Defective implantation is a mechanism for recurrent pregnancy loss (RPL). We sought to determine whether the serum expression of human relaxin-2 (RLX) is impaired in women with a history of RPL. STUDY DESIGN: Employing a prospective case-controlled design we studied 20 pregnant women with a history of RPL and 20 age-matched women with no history of RPL (NRPL). We measured serum relaxin-2 levels by ELISA at 6-8, 10-12, 20, and 34 weeks gestation and in cord blood, and maternal uterine artery Doppler resistance index (RI) at >or=10 weeks gestation. RESULTS: Relaxin rose to a peak at 12 weeks, and gradually declined towards term. At all gestations, women with a history of RPL had lower RLX levels than women without. At 10-12 weeks gestation, uterine artery RI correlated with serum RLX for both RPL and NRPL. In the NRPL group at 10-12 weeks the presence of a notched waveform was associated with higher RLX levels than the absence of a notch (mean 2.1 ng/ml vs. 1.3 ng/ml, P<0.05) and also at 20 weeks (2.1 ng/ml vs. 0.95 ng/ml, P<0.05) but no such difference was seen in the RPL group. Umbilical venous RLX was 4-fold higher in the RPL group than the NRPL group. CONCLUSION: Women with a history of RPL demonstrate attenuated levels of serum RLX across all pregnancy trimesters. How dysregulated RLX metabolism may contribute to adverse pregnancy outcome in RPL requires further investigation.

Spherical aberration yielding optimum visual performance: evaluation of intraocular lenses using adaptive optics simulation.

PURPOSE: To evaluate the influence of spherical aberration on contrast sensitivity using adaptive optics. SETTING: Vision Science and Advanced Retinal Imaging Laboratory, Department of Ophthalmology & Vision Science, University of California, Davis Medical Center, Sacramento, California, USA. METHODS: Contrast sensitivity at 8 cycles per degree was evaluated using an adaptive optics system that permitted aberrations to be measured with a Hartmann-Shack wavefront sensor and controlled by a 109 actuator continuous-surface deformable mirror that was at a plane conjugate to the observer's pupil. Vertical Gabor patches were viewed through a 6.3 mm diameter pupil conjugate aperture. Contrast sensitivity was measured with the deformable mirror set to produce 1 of 5 spherical aberration profiles (-0.2 to +0.2 microm). Contrast sensitivity over the range of spherical aberration was fitted with a polynomial function. RESULTS: Three subjects (age 21 to 24 years) participated. The measured total mean spherical aberration resulting from the spherical aberration profiles produced by the deformable mirror was between -0.15 microm and +0.25 microm. The peak contrast sensitivity of this function for the 3 subjects combined occurred at +0.06 microm of spherical aberration. The peak contrast sensitivity was also achieved with positive spherical aberration for each subject's data fitted individually (mean 0.09). CONCLUSION: There was intersubject variability in the measurements; however, the mean visual performance was best with the introduction of a small positive spherical aberration.

Role of high-order aberrations in senescent changes in spatial vision.

The contributions of optical and neural factors to age-related losses in spatial vision are not fully understood. We used closed-loop adaptive optics to test the visual benefit of correcting monochromatic high-order aberrations (HOAs) on spatial vision for observers ranging in age from 18 to 81 years. Contrast sensitivity was measured monocularly using a two-alternative forced-choice (2AFC) procedure for sinusoidal gratings over 6 mm and 3 mm pupil diameters. Visual acuity was measured using a spatial 4AFC procedure. Over a 6 mm pupil, young observers showed a large benefit of AO at high spatial frequencies, whereas older observers exhibited the greatest benefit at middle spatial frequencies, plus a significantly larger increase in visual acuity. When age-related miosis is controlled, young and old observers exhibited a similar benefit of AO for spatial vision. An increase in HOAs cannot account for the complete senescent decline in spatial vision. These results may indicate a larger role of additional optical factors when the impact of HOAs is removed, but also lend support for the importance of neural factors in age-related changes in spatial vision.

Selenite induces topoisomerase I and II-DNA complexes in K562 leukemia cells.

The essential trace element selenium is one of the most promising cancer chemopreventive agents. Data from preclinical studies have revealed that selenite, an inorganic form of selenium, may also be useful in cancer chemotherapy. DNA topoisomerases (topos) are the target of several useful anticancer drugs. These drugs induce DNA complexes with either topo I or topo II; then cellular processing coverts these topo-DNA complexes into permanent DNA strand breaks that ultimately lead to cell death. Previous reports have revealed that selenite can induce apoptosis in cancer cells selectively and that selenite-induced apoptosis is preceded by the formation of DNA strand breaks. In vitro experiments have shown that selenite induces topo II-DNA complexes, which seem to be involved in selenite-induced apoptosis. Using the cell-based assay TARDIS, here we show that selenite induces topo II-DNA complexes (topo IIalpha and topo IIbeta) in K562 leukemia cells; these complexes appeared in a time-dependent manner and correlated with the induction of apoptosis. Cells lacking topo IIbeta were resistant to selenite-induced cell growth inhibition, suggesting that this isoenzyme is a target for selenite. We report for the first time that selenite induces topo I-DNA complexes in K562 cells; the levels of these complexes were high at short exposure times and seem to appear before the induction of apoptosis. Overall, our results show that selenite induces topo-DNA complexes in cells with both topo I and II, and support previous data that suggest that this agent has potential for the treatment of cancer.

DNA-dependent protein kinase is a therapeutic target and an indicator of poor prognosis in B-cell chronic lymphocytic leukemia.

PURPOSE: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL. EXPERIMENTAL DESIGN: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNA-PKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441 on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of gammaH2AX). RESULTS: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser2056. High DNA-PK levels predicted for reduced treatment-free interval. CONCLUSIONS: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.

Aging and blur adaptation.

Color appearance remains remarkably stable in the aging visual system despite large changes in the spectral distribution of the retinal stimulus and losses in chromatic sensitivity (P. B. Delahunt, J. L. Hardy, K. Okajima, & J. S. Werner, 2005; J. S. Werner, 1996). This stability could reflect adaptive adjustments in peripheral or central chromatic mechanisms that compensate for sensitivity losses in senescence. We asked whether similar compensatory adjustments play a role in maintaining spatial vision--and whether the adaptation itself shows changes with aging-by examining the effects of adaptation on judgments of image focus. Perceptual aftereffects following adaptation to a uniform field and blurred or sharpened images were compared between younger adults and older observers. Subjects adapted to a sequence of blurred or sharpened images for 120 s, and a two-alternative forced-choice staircase task was used to vary the filter exponent of the test to define the subjective point of best focus. There was a small but significant difference between younger and older observers in the level perceived as best focused in all three adaptation conditions, possibly reflecting differences in the ambient blur level the groups are routinely exposed to. However, the magnitude of the blur aftereffect did not differ between the two age groups. These results suggest that although there may be small differences in the long-term adaptation to blur, younger and older observers do not differ in the strength of adaptation to transient changes in blur. The neural processes mediating adaptation to blur thus appear to remain largely intact with aging.

Neural adjustments to chromatic blur.

The perception of blur in images can be strongly affected by prior adaptation to blurry images or by spatial induction from blurred surrounds. These contextual effects may play a role in calibrating visual responses for the spatial structure of luminance variations in images. We asked whether similar adjustments might also calibrate the visual system for spatial variations in color. Observers adjusted the amplitude spectra of luminance or chromatic images until they appeared correctly focused, and repeated these measurements either before or after adaptation to blurred or sharpened images or in the presence of blurred or sharpened surrounds. Prior adaptation induced large and distinct changes in perceived focus for both luminance and chromatic patterns, suggesting that luminance and chromatic mechanisms are both able to adjust to changes in the level of blur. However, judgments of focus were more variable for color, and unlike luminance there was little effect of surrounding spatial context on perceived blur. In additional measurements we explored the effects of adaptation on threshold contrast sensitivity for luminance and color. Adaptation to filtered noise with a 1/f spectrum characteristic of natural images strongly and selectively elevated thresholds at low spatial frequencies for both luminance and color, thus transforming the chromatic contrast sensitivity function from lowpass to nearly bandpass. These threshold changes were found to reflect interactions between different spatial scales that bias sensitivity against the lowest spatial grain in the image, and may reflect adaptation to different stimulus attributes than the attributes underlying judgments of image focus. Our results suggest that spatial sensitivity for variations in color can be strongly shaped by adaptation to the spatial structure of the stimulus, but point to dissociations in these visual adjustments both between luminance and color and different measures of spatial sensitivity.