Comparison of Logarithmic Reading Charts for Visual Assessment in Normally Sighted Participants.

SIGNIFICANCE: Logarithmic reading charts provide standardized measures of reading performance. Here we show that existing charts provide equivalent assessments of visual aspects of reading that are in good agreement with traditional measures of visual acuity and seem uninfluenced by cognitive (linguistic) factors. PURPOSE: The aims of this study were to (1) determine the equivalence of logarithmic charts of sentence and word reading, (2) evaluate the relationship between reading chart performance and more traditional measures of visual assessment, and (3) establish the influence of linguistic factors on reading chart performance. METHODS: In a sample of 82 normally sighted participants, we determined performance on the reading measures (e.g., reading acuity, reading speed, critical print size) of the following logarithmic charts of sentence and word reading: The Colenbrander English Continuous Text Near Vision Card, Radner Reading Chart, Minnesota Reading Acuity Chart, and Smith-Kettlewell Reading Chart. In doing so, we compared performance on reading measures between charts and with performance on more traditional measures of visual assessment (uncrowded and crowded letter acuity, stereoacuity, accommodation) and cognitive measures of word knowledge and ability (Wechsler Adult Intelligence Scale Vocabulary Subtest, National Adult Reading Test). RESULTS: Factor analysis confirmed that performance on the reading measures (reading acuity, reading speed, critical print size) was equivalent across charts. Reading test performance was also related to more traditional measures of vision, the most consistent of which were significant associations between reading acuity and acuity for single-letter optotypes. There were no significant associations between reading chart performance and cognitive measures of word knowledge and ability. CONCLUSIONS: The findings presented here suggest that logarithmic charts composed of sentences and words represent an alternative to traditional letter acuity testing. This is particularly the case for measures of reading acuity.

Selectively reduced contrast sensitivity in high schizotypy.

Deficits in the ability to encode small differences in contrast between adjacent parts of an image (contrast sensitivity) are well documented in schizophrenic patients. In the present study, we sought to determine whether contrast sensitivity deficits reported in schizophrenic patients are also evident in those who exhibit high schizotypy scores in a typical (i.e., non-schizophrenic) population. Using the O-Life Questionnaire, we determined the effects of schizotypy on spatial (0.5, 2 and 8 c/deg) and spatiotemporal (0.5 and 8 c/deg at 0.5 and 8 Hz) contrast sensitivity in 73 young (18-26 years), majority female (n = 68) participants. We found differences in contrast sensitivity that were spatial, spatiotemporal and O-Life subscale specific. Spatial contrast sensitivity was significantly lower in high, compared to low schizotypes at low spatial frequencies (0.5 c/deg) in those who scored highly on the Unusual Experiences and Cognitive Disorganisation O-Life subscales. For moving stimuli, individuals with high scores on the Unusual Experiences subscale exhibited lower spatiotemporal contrast sensitivity for 0.5 and 8 c/deg patterns drifting at 8 Hz. Although the effects reported here were relatively small, this is the first report of reduced contrast sensitivity in schizotypy.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Phase-Dependent Interactions in Visual Cortex to Combinations of First- and Second-Order Stimuli.

A fundamental task of the visual system is to extract figure-ground boundaries between objects, which are often defined, not only by differences in luminance, but also by "second-order" contrast or texture differences. Responses of cortical neurons to both first- and second-order patterns have been studied extensively, but only for responses to either type of stimulus in isolation. Here, we examined responses of visual cortex neurons to the spatial relationship between superimposed periodic luminance modulation (LM) and contrast modulation (CM) stimuli, the contrasts of which were adjusted to give equated responses when presented alone. Extracellular single-unit recordings were made in area 18 of the cat, the neurons of which show responses to CM and LM stimuli very similar to those in primate area V2 (Li et al., 2014). Most neurons showed a significant dependence on the relative phase of the combined LM and CM patterns, with a clear overall optimal response when they were approximately phase aligned. The degree of this phase preference, and the contributions of suppressive and/or facilitatory interactions, varied considerably from one neuron to another. Such phase-dependent and phase-invariant responses were evident in both simple- and complex-type cells. These results place important constraints on any future model of the underlying neural circuitry for second-order responses. The diversity in the degree of phase dependence between LM and CM stimuli that we observed could help to disambiguate different kinds of boundaries in natural scenes. SIGNIFICANCE STATEMENT: Many visual cortex neurons exhibit orientation-selective responses to boundaries defined by differences either in luminance or in texture contrast. Previous studies have examined responses to either type of boundary in isolation, but here we measured systematically responses of cortical neurons to the spatial relationship between superimposed periodic luminance-modulated (LM) and contrast-modulated (CM) stimuli with contrasts adjusted to give equated responses. We demonstrate that neuronal responses to these compound stimuli are highly dependent on the relative phase between the LM and CM components. Diversity in the degree of such phase dependence could help to disambiguate different kinds of boundaries in natural scenes, for example, those arising from surface reflectance changes or from illumination gradients such as shading or shadows.

Aging effects in cueing tasks as assessed by the ideal observer: peripheral cues.

Previous aging and cueing studies suggest that automatic orienting driven by peripheral cues is preserved with aging; however, inconsistencies can be found. One issue might be the use of response times (RT) to assess cueing effects (invalid RT--valid RT), which, in many cases, may not have clear quantitative predictions. We propose an ideal observer (IO) analysis of accuracy estimating participants' internal value of cue validity, or weight, which should equal the actual cue validity. The weight measures the use of information provided by the cue and is insensitive to variations in set size and difficulty, thus potentially providing advantages to RT. Older (n = 54) and younger (n = 58) participants performed a yes/no detection task of a two-dimensional (2-D) Gaussian (60 ms). Square peripheral precues (150 ms) indicated likely target locations (70% valid) across two or six locations (set sizes). For cueing effects, (valid--invalid hit rates), younger participants had set-size effects (larger cueing effects for set size 6), while older participants did not. The opposite pattern was found for weights (younger: no set-size effects, older: set-size effects) due to the IO predicting larger cueing effects for larger set sizes. Comparisons to the ideal weight (cue validity) suggested that older participants used the cue information effectively with set size 2 (as or more so than younger participants), but not with set size 6. These results suggest that attentional deficits from aging in peripheral cueing tasks may only arise as difficulty increases, such as larger set sizes.

Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia.

Although expressed in several haematological lineages and involved in multiple different signalling pathways, Bruton tyrosine kinase (BTK) plays an indispensible role in B cells in signalling from the B cell receptor (BCR) for antigen. Many B cell malignancies remain dependent on constitutive BCR signalling, making BTK a functional therapeutic target. Several BTK inhibitors (BTKi) with different kinomes and modes of action are being assessed clinically. This review documents the efficacy and toxicity of BTKi in chronic lymphocytic leukaemia (CLL). Clinically, the furthest in development is ibrutinib (trade name, Imbruvica), an irreversible BTKi, which has shown spectacular preliminary efficacy, with rapid reductions in lymph nodes accompanied by peripheral blood lymphocytosis. The lymphocytosis resolves slowly and most patients do not enter a complete remission. Nevertheless, it is possible to maintain many CLL patients, even those with adverse cytogenetic features, on drug for many months with minimal toxicities, thus potentially transforming the therapeutic paradigms for CLL. The efficacy, lack of toxicity and oral administration of BTKi will ensure their adoption in a wide range of B cell malignancies. An outstanding challenge is to incorporate BTKi with other precision medicines in a mechanism-based manner in order to dispense with conventional chemotherapy.

Monocyte-derived dendritic cells from chronic myeloid leukaemia have abnormal maturation and cytoskeletal function that is associated with defective localisation and signalling by normal ABL1 protein.

OBJECTIVES: Mature dendritic cells (DCs) may be derived from the BCR/ABL1 expressing monocytes in chronic myeloid leukaemia. These cells have potential therapeutic applications, but are recognised to have defective function. In normal DCs, activation and maturation depend on ABL1 dependent signals. We therefore tested the hypothesis that in the DCs of chronic myeloid leukaemia, the presence of the BCR/ABL1 molecule disrupts normal ABL1 signal pathways, and contributes to the observed functional defects of the cells. METHODS: We employed in vitro culture of clinical samples, combining microscopic and biochemical techniques with a phosphoproteomic approach to compare and characterise DCs from normal individuals and chronic myeloid leukaemia patients. RESULTS AND CONCLUSIONS: We identified an altered intracellular localisation for ABL1 within DCs derived from the monocytes of chronic myeloid leukaemia. The protein was found in the perinuclear region co-distributed with the adapter-protein CRKL and the BCR/ABL1 protein. This altered distribution was associated with defective generation of ABL1-dependent maturation signals, and a dislocation of ABL1 from the F-actin cytoskeleton. We suggest that abnormal ABL1-dependent signals contribute to the recognised functional defects affecting chronic myeloid leukaemia DCs.

Age-related differences in saccadic indices of top-down guidance via short-term memory during visual search.

Aging has been associated with significant declines in the speed and accuracy of visual search. These effects have been attributed partly to low-level (bottom-up) factors including reductions in sensory acuity and general processing speed. Aging is also associated with changes in top-down attentional control, but the impact of these on search is less well-understood. The present study investigated age-related differences in top-down attentional control by comparing the speed and accuracy of saccadic sampling in the presence and absence of top-down information about target color in young (YA) and older (OA) observers. Displays contained an equal number of red and blue Landholt stimuli. Targets were distinguished from distractors by a unique orientation, and observers reported the direction of the target's gap on each trial. Single-target cues signaled the color of the target with 100% validity. Dual-target cues indicated the target could be present in either colored subgroup. The results revealed reliable group differences in the benefits associated with top-down information on single-target cues compared to dual-target cues. On single-target searches, OA made significantly more saccades than YA to stimuli in the uncued color subset. Single-target cues also produced a smaller advantage in the time taken to fixate the target in OA compared to YA. These results support an age-related decline in observers' use of top-down information to restrict sequences of saccades to a task-relevant subset of objects during visual search. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cue competition effects in the planarian.

The learning abilities of planarian worms (Dugesia tigrina) were assessed by using a number of Pavlovian conditioning paradigms. Experiment 1 showed that planaria were susceptible to basic conditioning in that they readily developed a conditioned response to a change in ambient luminance when it was consistently paired with an electric shock over a number of trials. In Experiment 2, the change in luminance was presented in a compound with a vibration stimulus during conditioning. Subsequent tests revealed poor conditioning of the elements compared with control groups in which the animals were conditioned in the presence of the elements alone, an instance of overshadowing. In Experiment 3, pre-training of one of the elements before compound conditioning resulted in blocking of learning about the other element. These results add to other studies that have reported cue competition effects in animal species belonging to different phyla (chordate, mollusk, arthropod), suggesting that learning in these phyla could be ruled by similar principles. The results are discussed adopting an evolutionary-comparative approach.

Characterising eye movement dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: People who suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report that their eye movements are sluggish and that they have difficulties tracking moving objects. However, descriptions of these visual problems are based solely on patients' self-reports of their subjective visual experiences, and there is a distinct lack of empirical evidence to objectively verify their claims. This paper presents the first experimental research to objectively examine eye movements in those suffering from ME/CFS. METHODS: Patients were assessed for ME/CFS symptoms and were compared to age, gender, and education matched controls for their ability to generate saccades and smooth pursuit eye movements. RESULTS: Patients and controls exhibited similar error rates and saccade latencies (response times) on prosaccade and antisaccade tasks. Patients showed relatively intact ability to accurately fixate the target (prosaccades), but were impaired when required to focus accurately in a specific position opposite the target (antisaccades). Patients were most markedly impaired when required to direct their gaze as closely as possible to a smoothly moving target (smooth pursuit). CONCLUSIONS: It is hypothesised that the effects of ME/CFS can be overcome briefly for completion of saccades, but that continuous pursuit activity (accurately tracking a moving object), even for a short time period, highlights dysfunctional eye movement behaviour in ME/CFS patients. Future smooth pursuit research may elucidate and improve diagnosis of ME/CFS.

Patterns of abnormal visual attention in myalgic encephalomyelitis.

PURPOSE: To experimentally assess visual attention difficulties commonly reported by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). METHODS: Twenty-nine ME/CFS patients and 29 controls took part in the study. Performance was assessed using the Useful Field of View (UFOV), a spatial cueing task and visual search. RESULTS: Patients and controls performed similarly on the processing speed subtest of the UFOV. However, patients exhibited marginally worse performance compared with controls on the divided attention subtest and significantly worse performance on the selective attention subtest. In the spatial cueing task, they were slower than controls to respond to the presence of the target, particularly when cues were invalid. They were also impaired, relative to controls, on visual search tasks. CONCLUSIONS: We have provided experimental evidence for ME/CFS-related difficulties in directing visual attention. These findings support the subjective reports of those with ME/CFS and could represent a potential means to improve diagnosis.

Reduced Vision-Related Quality of Life in Dementia: A Preliminary Report.

BACKGROUND: Despite experimental evidence for concurrent dementia and visual impairment, there are no currently validated vision-related quality of life measures for use in this population. OBJECTIVE: To establish the extent to which individuals with mild to moderate dementia self-report visual impairment and determine the efficacy of established vision-related quality of life measures for use in a dementia population. METHODS: We compared vision-related quality of life in participants with mild-moderate dementia to healthy (dementia-free) older adults using two existing questionnaire measures already validated for use in older adults. These were the Visual Activities Questionnaire (VAQ) and the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). RESULTS: Responses on both the VAQ and VFQ-25 revealed a significant effect of dementia on self-reported vision-related quality of life. Visual impairment in dementia was identified in the domains of color discrimination, disability glare, light/dark adaption, acuity/spatial vision, depth perception, peripheral vision, visual search, and visual processing speed. Factor analysis of the data suggested that existing vision-related quality of life measures, designed for use in older adult populations, are likely to provide a robust means of assessing vision-related quality of life in older adults with dementia. This is particularly true of the VAQ, for which one latent factor emerged for both dementia and dementia-free samples. CONCLUSION: Using existing measures designed for use in older adult populations, we have shown that people with dementia experience reduced vision-related quality of life.

Ribosome-associated nucleophosmin 1: increased expression and shuttling activity distinguishes prognostic subtypes in chronic lymphocytic leukaemia.

Two distinct groups of chronic lymphocytic leukaemia (CLL) are distinguished by the presence or absence of somatic hypermutation of the immunoglobulin heavy-chain gene. CLL without somatic hypermutation has an adverse outcome, but the precise biological differences that underlie this more aggressive clinical-course are unclear. Using a proteomic approach, we found that the two prognostic forms of CLL were consistently distinguished according to their protein expression pattern. The most important difference observed related to the different expression of nucleophosmin 1 between the two forms of CLL. This different expression was not related to apoptosis, proliferation or gene mutation. However, co-immunoprecipitation experiments identified an association between nucleophosmin 1 and ribosomal proteins. Using immunocytofluorescence, nucleophosmin 1 expression was identified in the nucleoli and nucleoplasm of all cells, but in a proportion of cells, nucleophosmin had been transferred from the nucleoplasm to the cytoplasm. Both the fluorescent intensity, and the frequency of cytoplasmic nucleophosmin 1 expression, was higher in CLL without somatic hypermutation. We propose therefore, that nucleophosmin 1, in association with ribosomal proteins, undergoes nucleo-cytoplasmic shuttling in CLL. This process is most prominent in un-mutated CLL and may signify altered protein biosynthesis.

The role of contrast sensitivity in global motion processing deficits in the elderly.

This study compared the effects of age on the perception of translational, radial, and rotational global motion patterns. Motion coherence thresholds were measured for judging the direction of each motion type as a function of contrast (visibility) and temporal sampling rate in young and elderly participants. Coherence thresholds decreased as dot contrast increased asymptoting at high dot contrasts but were higher in elderly compared to young participants. This equated to global motion impairment in the elderly of a factor of around 2, characterized by a shift of the threshold vs. contrast function along the horizontal axes (dot contrast). The effect of contrast interacted with the temporal sampling rate. Old participants were deleteriously affected by reduced temporal sampling particularly at low contrasts. The findings suggest that age-related changes in global motion perception may be driven principally by deficits in contrast encoding, rather than by deficits in motion integration and suggest a role for increased internal noise in the older visual system.

Visual adaptation reveals asymmetric spatial frequency tuning for motion.

This study investigated the spatial frequency selectivity of the human visual motion system using the technique of adaptation in which motion aftereffect (MAE) duration was taken as an index of aftereffect magnitude. Eight observers adapted to two vertically oriented, oppositely drifting, luminance-defined gratings that were spatially separated in the vertical dimension. The spatial frequency of the adaptation patterns spanned a 3-octave range (0.25 to 2 c/deg) and drifted at 5 Hz. Following adaptation (20 s), two stationary test patterns were presented and MAE duration was measured. The spatial frequency difference between the adaptation and test patterns was varied from -2.5 to 2.5 octaves in 0.5 octave steps. MAE tuning functions at the lowest adaptation frequency (0.25 c/deg) were bandpass and reasonably symmetric. However, as the spatial frequency of the adaptation patterns increased, overall MAE duration decreased and the shape of the tuning functions became markedly asymmetric. This asymmetry was characterized by a MAE peak that was centered approximately 1 octave below the adaptation frequency. The results are consistent with recent masking studies (C. V. Hutchinson & T. Ledgeway, 2007) and may reflect either asymmetric spatial frequency selectivity of underlying motion units or frequency-specific interactions (e.g. inhibition) between motion sensors tuned to different spatial frequencies.

Visual Dysfunction in Huntington's Disease: A Systematic Review.

It is well-documented that patients with Huntington's disease (HD) exhibit specific deficits in visual cognition. A less well-documented literature also exists that suggests people with HD experience a number of disease-related changes to more rudimentary sensory visual processing. Here, we review evidence for the effects of HD on the integrity of the early visual pathways in humans along with changes to low-level visual sensitivity. We find evidence for reduced structural and functional integrity of the visual pathways, marked by retinal thinning, reduced VEP amplitude, and cell loss and thinning in visual cortex. We also find evidence of visual perceptual deficits, particularly for colour and motion. We suggest that future studies with well-defined HD and HD-related groups in appropriate numbers that systematically examine the relationship between structural changes to the visual system, basic visual perceptual deficits and disease stage/severity are therefore likely to yield promising results.

Dual-action CXCR4-targeting liposomes in leukemia: function blocking and drug delivery.

CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

Choice reaction times for identifying the direction of first-order motion and different varieties of second-order motion.

This study sought to quantify the temporal properties of the human visual system by measuring forced-choice reaction times for discriminating the drift direction of first-order motion (luminance-modulated noise) and a variety of second-order motion patterns (modulations of either the contrast, polarity, orientation or spatial length of a noise carrier) over a range of stimulus modulation depths. In general, reaction times for all types of second-order motion were slower than those for first-order motion. Specifically, reaction times were similar for modulations of image contrast, polarity and orientation but were markedly slower for modulations of spatial length. There was also a tendency for reaction times to decrease as stimulus modulation depth increased. The rate of this decrease was shallowest for first-order, luminance-defined patterns. For second-order motion reaction times decreased at a similar rate for contrast, polarity and orientation but this decrease was steepest for spatial length. However, when equated in terms of visibility (multiples of direction-discrimination threshold), the rate at which reaction times decreased as modulation depth increased became comparable for patterns defined by luminance, contrast, polarity and orientation. For patterns defined by spatial length, performance could not be equated in this manner. These findings demonstrate that the time taken to encode the direction of each pattern is not an invariant response metric. The results are consistent with psychophysical and electrophysiological evidence for longer response latencies for second-order motion and may reflect the additional processing stages (e.g. filter-rectify-filter) required for its extraction.

Dissociation of place preference and tolerance responses to sucrose using a dopamine antagonist in the planarian.

In rodents, sucrose has been found to elicit addictive-like behaviours like the development of tolerance and the association with cues present at the time of consumption. Furthermore, the neurochemical response to sucrose binges is equivalent to the one observed in response to the abuse of addictive substances like cocaine. The experiments reported here address the effects of sucrose on an invertebrate model, the Platyhelminth brown planarian. The animals exposed to a 10% sucrose solution in one context developed a conditioned place preference (CPP) which was subsequently extinguished in the absence of the rewarding agent. However, one exposure to sucrose per se sufficed to reinstate the CPP response, suggesting sucrose-induced CPP can be characterised as a standard Pavlovian response. The same training procedure led to the development of context-specific tolerance to the effects of sucrose. However, comparing animals treated with dopamine D1 antagonist (SCH-23390) with control animals showed that the establishment of CPP, but not the development of tolerance, is mediated by the dopamine reward system.