Exploration of anomalous perceptual experiences in migraine between attacks using the Cardiff Anomalous Perceptions Scale.

Distortions in sensory experiences that precede a migraine attack have been extensively documented, the most well-known being the visual aura. Distortions in the experience of other senses are also reported as part of an aura, albeit less frequently, together with changes in the perception or ownership of the body or body parts. There are many examples of differences in aspects of visual perception between migraine and control groups, between attacks, but not as much on unusual experiences involving other senses, the sense of the body or the experience of the environment. Seventy-seven migraine (33 with aura) and 74 control participants took part. Anomalous perceptions were experienced by both migraine and control groups, but more with migraine experienced them and rated them as more distressing, intrusive and frequent. Associations with reports of visual triggers of migraine and visual discomfort are presented. This study is the first to show relationships between these factors.

First record of recurring reproduction of captive tawny nurse sharks Nebrius ferrugineus.

Between 2008 and 2015, a group of tawny nurse sharks Nebrius ferrugineus reproduced successfully in a captive environment on the central Red Sea coast of Saudi Arabia. Births occurred on an annual basis, except for 2013. Of 12 confirmed birthing events, the most recent (2015) was observed and recorded in detail, which further contributes to the limited reproductive knowledge of this monotypic species.

Visual motion processing in migraine: Enhanced motion after-effects are related to display contrast, visual symptoms, visual triggers and attack frequency.

Background Visual after-effects are illusions that occur after prolonged viewing of visual displays. The motion after-effect (MAE), for example, is an illusory impression of motion after viewing moving displays: subsequently, stationary displays appear to drift in the opposite direction. After-effects have been used extensively in basic vision research and in clinical settings, and are enhanced in migraine. Objective The objective of this article is to assess associations between ( 1 ) MAE duration and visual symptoms experienced during/between migraine/headache attacks, and ( 2 ) visual stimuli reported as migraine/headache triggers. Methods The MAE was elicited after viewing motion for 45 seconds. MAE duration was tested for three test contrast displays (high, medium, low). Participants also completed a headache questionnaire that included migraine/headache triggers. Results For each test contrast, the MAE was prolonged in migraine. MAE duration was associated with photophobia; visual triggers (flicker, striped patterns); and migraine or headache frequency. Conclusions Group differences on various visual tasks have been attributed to abnormal cortical processing in migraine, such as hyperexcitability, heightened responsiveness and/or a lack of intra-cortical inhibition. The results are not consistent with hyperexcitability simply from a general lack of inhibition. Alternative multi-stage models are discussed and suggestions for further research are recommended, including visual tests in clinical assessments/clinical trials.

Attention training normalises combat-related post-traumatic stress disorder effects on emotional Stroop performance using lexically matched word lists.

We examined two groups of combat veterans, one with post-traumatic stress disorder (PTSD) (n = 27) and another without PTSD (n = 16), using an emotional Stroop task (EST) with word lists matched across a series of lexical variables (e.g. length, frequency, neighbourhood size, etc.). Participants with PTSD exhibited a strong EST effect (longer colour-naming latencies for combat-relevant words as compared to neutral words). Veterans without PTSD produced no such effect, t < .918, p > .37. Participants with PTSD then completed eight sessions of attention training (Attention Control Training or Attention Bias Modification Training) with a dot-probe task utilising threatening and neutral faces. After training, participants-especially those undergoing Attention Control Training-no longer produced longer colour-naming latencies for combat-related words as compared to other words, indicating normalised attention allocation processes after treatment.

A Flow Cytometry-Based Method for Assessing CAR Cell Binding Kinetics Using Stable CAR Jurkat Cells.

Chimeric antigen receptors (CARs) are synthetic fusion proteins that can reprogram immune cells to target specific antigens. CAR-expressing T cells have emerged as an effective treatment method for hematological cancers; despite this success, the mechanisms and structural properties that govern CAR responses are not fully understood. Here, we provide a simple assay to assess cellular avidity using a standard flow cytometer. This assay measures the interaction kinetics of CAR-expressing T cells and targets antigen-expressing target cells. By co-culturing stably transfected CAR Jurkat cells with target positive and negative cells for short periods of time in a varying effector-target gradient, we were able to observe the formation of CAR-target cell doublets, providing a readout of actively bound cells. When using the optimized protocol reported here, we observed unique cellular binding curves that varied between CAR constructs with differing antigen binding domains. The cellular binding kinetics of unique CARs remained consistent, were dependent on specific target antigen expression, and required active biological signaling. While existing literature is not clear at this time whether higher or lower CAR cell binding is beneficial to CAR therapeutic activity, the application of this simplified protocol for assessing CAR binding could lead to a better understanding of the proximal signaling events that regulate CAR functionality. Key features • Determines CAR receptor cellular interaction kinetics using a Jurkat cell model. • Can be used for a wide variety of CAR target antigens, including both hematological and solid tumor targets. • Experiments can be performed in under two hours with no staining using a standard flow cytometer. • Requires stable CAR Jurkat cells and target cells with stable fluorescent marker expression for optimal results.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

Color and spatial frequency are related to visual pattern sensitivity in migraine.

OBJECTIVE: To assess the potential for particular colors to alleviate visual discomfort when people with migraine view repetitive geometric or striped patterns. BACKGROUND: Visual stimuli, such as flicker, glare, or stripes, can trigger migraine and headache. They can also elicit feelings of discomfort and aversion. There are reports that color can be used to decrease the experience of discomfort and reduce migraine frequency. DESIGN/METHODS: Five sets of striped patterns (3, 12 cycles per degree [cpd]) were created using cardinal colors tailored to selectively stimulate the early visual pathways: achromatic (black/white), tritan (black/purple, black/yellow), protan/deutan (black/red, black/green). All had the same high luminance contrast (0.9 Michelson contrast). Twenty-eight migraine (14 migraine with aura, 14 migraine without aura) and 14 control participants rated the discomfort and described the distortions seen in these patterns. They were also assessed for visual migraine/headache triggers, contrast sensitivity, color vision, acuity, stereopsis, visual discomfort from reading, and dyslexia. RESULTS: In the migraine groups, a comparable number of illusions were seen with the 3 and 12 cpd achromatic gratings, whereas in the control group the greatest number was seen with the 3 cpd grating. In the migraine groups only, all 4 colors reduced, to some extent, the number of illusions and 2 decreased the discomfort, particularly for the 12 cpd gratings. There were significant group differences for contrast sensitivity, reported visual migraine/headache triggers, and the visual discomfort scale. There were a few significant correlations between the different measures, notably between the achromatic visual discomfort measures and reports of visual migraine triggers. CONCLUSIONS: Color, independent of luminance or particular color contrasts, can have therapeutic effects for people with visually triggered migraine as it can reduce the number of perceived illusions when viewing stripes or text. The effect was not color-specific and was greatest for the 12 cpd gratings. Given the significant associations between the achromatic discomfort measures and reports of visual triggers, and the lack of significant associations between the chromatic discomfort measures and reports of visual triggers, further research is recommended to explore the potential to reduce the number of visually triggered migraines with color in addition to alleviating visual discomfort.

A simplified function-first method for the discovery and optimization of bispecific immune engaging antibodies.

Bi-specific T-cell engager antibodies (BiTEs) are synthetic fusion molecules that combine multiple antibody-binding domains to induce active contact between T-cells and antigen expressing cells in the body. Blinatumomab, a CD19-CD3 BiTE is now a widely used therapy for relapsed B-cell malignancies, and similar BiTE therapeutics have shown promise for treating various other forms of cancer. The current process for new BiTE development is time consuming and costly, requiring characterization of the individual antigen binding domains, followed by bi-specific design, protein production, purification, and eventually functional screening. Here, we sought to establish a more cost-efficient approach for generating novel BiTE sequences and assessing bioactivity through a function first approach without purification. We generate a plasmid with a bi-modular structure to allow high-throughput exchange of either binding arm, enabling rapid screening of novel tumour-targeting single chain variable (scFv) domains in combination with the well-characterized OKT3 scFv CD3-targeting domain. We also demonstrate two systems for high throughput functional screening of BiTE proteins based on Jurkat T cells (referred to as BiTE-J). Using BiTE-J we evaluate four EGFRvIII-scFv sequenced in BiTE format, identifying two constructs with superior activity for redirecting T-cells against the EGFRvIII-tumour specific antigen. We also confirm activity in primary T cells, where novel EGFRvIII-BiTEs induced T cell activation and antigen selective tumor killing. We finally demonstrate similar exchange the CD3-interacting element of our bi-modular plasmid. By testing several novel CD3-targeting scFv elements for activity in EGFRvIII-targeted BiTEs, we were able to identify highly active BiTE molecules with desirable functional activity for downstream development. In summary, BiTE-J presents a low cost, high-throughput method for the rapid assessment of novel BiTE molecules without the need for purification and quantification.

Motion processing deficits in migraine are related to contrast sensitivity.

BACKGROUND: There are conflicting reports concerning the ability of people with migraine to detect and discriminate visual motion. Previous studies used different displays and none adequately assessed other parameters that could affect performance, such as those that could indicate precortical dysfunction. METHODS: Motion-direction detection, discrimination and relative motion thresholds were compared from participants with and without migraine. Potentially relevant visual covariates were included (contrast sensitivity; acuity; stereopsis; visual discomfort, stress, triggers; dyslexia). RESULTS: For each task, migraine participants were less accurate than a control group and had impaired contrast sensitivity, greater visual discomfort, visual stress and visual triggers. Only contrast sensitivity correlated with performance on each motion task; it also mediated performance. CONCLUSIONS: Impaired performance on certain motion tasks can be attributed to impaired contrast sensitivity early in the visual system rather than a deficit in cortical motion processing per se. There were, however, additional differences for global and relative motion thresholds embedded in noise, suggesting changes in extrastriate cortex in migraine. Tasks to study the effects of noise on performance at different levels of the visual system and across modalities are recommended. A battery of standard visual tests should be included in any future work on the visual system and migraine.

Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation.

Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity.

Visual metacontrast masking in migraine.

BACKGROUND: In visual metacontrast masking, the visibility of a brief target stimulus can be reduced substantially if it is preceded (forward masking) or followed (backward masking) by a non-overlapping mask. These effects have been attributed to inhibitory processes within the visual system. Two previous studies have used metacontrast masking to assess inhibitory function in migraine and control groups, however, each used different types of masking and obtained different results. SUBJECTS AND METHODS: Forward, backward and combined forward and backward masking were compared in migraine (15 with visual aura, 15 without) and control (n = 15) groups. Baseline trials were also included (target only). RESULTS: For all types of masking, both migraine groups were more accurate than the control group. When performance for the masking trials was expressed relative to baseline, however, there were no significant group differences. Performance in certain conditions nevertheless correlated significantly with migraine frequency and with the recency of the last attack. CONCLUSIONS: The inhibitory processes involved in the masking tasks employed in this study do not appear to be impaired in migraine. Their better overall performance may reflect a sensitivity difference, perhaps as a consequence of a heightened neuronal response, which varies with the migraine cycle.

A Review of Motion and Orientation Processing in Migraine.

Visual tests can be used as noninvasive tools to test models of the pathophysiology underlying neurological conditions, such as migraine. They may also be used to track changes in performance that vary with the migraine cycle or can track the efficacy of prophylactic treatments. This article reviews the literature on performance differences on two visual tasks, global motion discrimination and orientation, which, of the many visual tasks that have been used to compare differences between migraine and control groups, have yielded the most consistent patterns of group differences. The implications for understanding the underlying pathophysiology in migraine are discussed, but the main focus is on bringing together disparate areas of research and suggesting those that can reveal practical uses of visual tests to treat and manage migraine.

A comparison of the effects of the colour and size of coloured overlays on young children's reading.

This study compared the effects of the colour and size of overlays on reading time, reading errors and on the clarity of text with young primary school children. The sample comprised a non-clinical, typical, sample from an East London primary school. One hundred and six children aged between four and seven years were asked to read 11 short passages of text (60 words) either with full page overlays or smaller reading rulers (53 in each group). This sample included younger children than has often been tested before. The 11 short passages allowed an assessment of baseline reading performance (no reading aid) and performance while reading with each of a set of ten coloured reading aids. Two different, yet beneficial, colours were determined: the most effective and the clearest/most comfortable. Both of these measures are not usually recorded. All but four children had reduced reading times with one of the reading aids and all but one reported their aid improved the perceived visual clarity of the text: the size of the reading aid did not affect reading time or visual clarity significantly. The numbers of skipped words and errors/mis-read words also decreased when reading with the most effective and most comfortable reading aid. Near visual acuity was assessed with and without each child's most effective coloured aid. The most effective aid improved acuity in over a third of the children. Acuity has not been assessed in previous studies. As reported previously, different colours helped different children. In conclusion, coloured reading overlays reduced reading times on the reading test employed here and the size of the reading aid was not crucial to facilitate performance. The largest reductions occurred for the youngest readers, suggesting these aids may be particularly effective for early readers.

Spreading photoparoxysmal EEG response is associated with an abnormal cortical excitability pattern.

Photosensitivity or photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an abnormal cortical response to intermittent photic stimulation (IPS). In PPR-positive individuals, IPS induces spikes, spike-waves or intermittent slow waves. The PPR may be restricted to posterior visual areas (i.e. local PPR with occipital spikes only) or spread to anterior non-visual cortical regions (i.e. PPR with propagation). The mechanisms underlying the PPR and causing its spread remain to be clarified. In unmedicated PPR-positive individuals and PPR-negative control participants without any history of previous seizures, we used focal transcranial magnetic stimulation (TMS) to investigate the excitability of the visual or primary motor cortex (M1). In the first experiment [18 healthy control subjects (i.e. without PPR in electroencephalography: 6 females, mean age 26.5 +/- 7.34 years) and 17 healthy participants with PPR (7 females, mean age 25.18 +/- 12.2 years) were studied], occipital TMS was used to elicit phosphenes or to suppress the visual perception of letter trigrams. PPR-positive individuals with propagation had lower phosphene thresholds and steeper stimulus-response curves than individuals without PPR or with occipital spikes only. Occipital TMS also induced a stronger suppression of visual perception in PPR-positive subjects with propagation relative to subjects without PPR or with occipital spikes. In the second experiment, we applied TMS over the right M1 without concurrent IPS and measured the motor threshold, the stimulus response curve, and the duration of the cortical silent period (CSP) in PPR positive individuals with propagation and in PPR-negative control participants [15 right-handed healthy subjects without PPR (3 males, mean age 17.7 +/- 3.6 years) and 14 right-handed healthy individuals showing a PPR with propagation (3 males, mean age 17.4 +/- 3.9 years)]. PPR-positive individuals showed no changes in these excitability measures relative to the PPR-negative control participants. We also measured the modifiability of the CSP by continuous IPS at a frequency of 18 or 50 Hz. While IPS reduced the duration of the CSP in PPR-negative control subjects, IPS had no effect on the duration of the CSP in PPR-positive individuals. Our results provide first time evidence that the propagation of the PPR is associated with increased excitability of the occipital but not the motor cortex. The stronger inhibitory effect of TMS on visual perception and the failure of IPS to shorten the CSP in PPR-positive participants may possibly reflect adaptive changes that prevent the provocation of seizures during the PPR.

Links between global and local shape perception, coloured backgrounds, colour discrimination, and non-verbal IQ.

This study explored associations between local and global shape perception on coloured backgrounds, colour discrimination, and non-verbal IQ (NVIQ). Five background colours were chosen for the local and global shape tasks that were tailored for the cone-opponent pathways early in the visual system (cardinal colour directions: L-M, loosely, reddish-greenish; and S-(L + M), or tritan colours, loosely, blueish-yellowish; where L, M and S refer to the long, middle and short wavelength sensitive cones). Participants also completed the Farnsworth-Munsell 100-hue test (FM100) to determine whether performance on the local and global shape tasks correlated with colour discrimination overall, or with performance on the L-M and tritan subsets of the FM100 test. Overall performance on the local and global shape tasks did correlate with scores on the FM100 tests, despite the colour of the background being irrelevant to the shape tasks. There were also significantly larger associations between scores for the L-M subset of the FM100 test, compared to the tritan subset, and accuracy on some of the shape tasks on the reddish, greenish and neutral backgrounds. Participants also completed the non-verbal components of the WAIS and the SPM+ version of Raven's progressive matrices, to determine whether performance on the FM100 test, and on the local and global shape tasks, correlated with NVIQ. FM100 scores correlated significantly with both WAIS and SPM+ scores. These results extend previous work that has indicated FM100 performance is not purely a measure of colour discrimination, but also involves aspects of each participant's NVIQ, such as the ability to attend to local and global aspects of the test, part-whole relationships, perceptual organisation and good visuomotor skills. Overall performance on the local and global shape tasks correlated only with the WAIS scores, not the SPM+. These results indicate that those aspects of NVIQ that engage spatial comprehension of local-global relationships and manual manipulation (WAIS), rather than more abstract reasoning (SPM+), are related to performance on the local and global shape tasks. Links are presented between various measures of NVIQ and performance on visual tasks, but they are currently seldom addressed in studies of either shape or colour perception. Further studies to explore these issues are recommended.

Transient tritanopia in migraine: evidence for a large-field retinal abnormality in blue-yellow opponent pathways.

PURPOSE: To determine whether the magnitude of transient tritanopia (TT) differs between migraine and control groups. TT is a retinal phenomenon characterized by a paradoxical reduction in sensitivity to short-wavelength (purple) stimuli after extinction of long-wavelength (yellow) adapting displays. A group difference in the magnitude of TT would provide evidence for a retinal contribution to the S-cone-specific color-processing abnormalities that have been reported in migraine. METHODS: Thirty-two migraineurs and 32 age- and sex-matched control participants were tested with a four-alternative, forced-choice procedure to determine S-cone increment and decrement detection thresholds before and after adaptation to a long-wavelength (yellow) display and a neutral (white) display. Migraine history, migraine triggers, and pattern sensitivity were also assessed. RESULTS: Both groups' detection thresholds for increment (purple) S-cone stimuli were increased after extinction of the long-wavelength adapting display compared with the neutral display, demonstrating TT. This loss of sensitivity was significantly greater in the migraine group. In contrast, loss of sensitivity to decrement (yellow) S-cone stimuli was less marked and did not differ between the groups. The magnitude of TT correlated positively with indices of pattern sensitivity and susceptibility to visually triggered migraines but not with migraine history. CONCLUSIONS: These results demonstrate that abnormalities in a specific retinal circuit contribute to decreased short-wavelength sensitivity after adaptation in migraine. As thresholds did not correlate with indices of migraine history, it is unlikely that this finding reflects cumulative damage induced by repeated migraine episodes.

Orientation discrimination and contrast detection thresholds in migraine for cardinal and oblique angles.

PURPOSE: To determine whether orientation discrimination deficits in migraine, which have been found to depend on the spatial frequency of the stimulus, are due to precortical dysfunction or to abnormal patterns of orientation tuning at cortical loci. Further, to assess whether any cortical involvement is restricted to the striate cortex or whether higher cortical areas are also involved. Orientation-specific abnormalities would provide evidence of cortical dysfunction. METHODS: Orientation-discrimination and contrast-detection thresholds were assessed at cardinal (0 degrees) and oblique (45 degrees) orientations using explicit lines defined by Gabor patches. To test for extrastriate dysfunction, participants made orientation judgments using virtual lines defined by two widely spaced circles. Migraine history, migraine triggers, and pattern sensitivity were also assessed. Twenty migraineurs (10 with visual aura, 10 without) and 20 control participants were tested. RESULTS: Orientation-discrimination thresholds were lower for discriminations made about the cardinal axis than for discriminations made about the oblique axis, a well-documented phenomenon known as the oblique effect. Relative to the control group, the migraine group exhibited orientation-specific sensitivity losses on explicit and virtual judgments. Orientation-discrimination thresholds about the oblique axis were significantly elevated in the migraine group. In contrast, the migraine and control groups' detection thresholds did not differ. CONCLUSIONS: These findings reflect abnormal function of striate and extrastriate cortex in migraine. In addition, the discrimination data are consistent with wider orientation-tuning curves for orientation-sensitive cells in migraine, whereas the detection data suggest peak sensitivity does not differ between the groups.

Enhanced Motion Aftereffects in Migraine Are Related to Contrast Sensitivity: Implications for Models of Differences in Precortical/Cortical Function.

PURPOSE: Visual tests can be used as noninvasive tools to test models of the pathophysiology underlying neurological conditions, such as migraine. For example, there are reports that the motion aftereffect, which involves neural processing in several cortical areas, is prolonged in migraine. There also are reports of impaired contrast sensitivity in migraine, however, attributed to a precortical dysfunction. This study explored associations between these two tests of visual function. Specifically, it aimed to clarify whether the magnitude of the motion aftereffect is affected by contrast and contrast sensitivity. METHODS: The motion aftereffect was elicited after observers viewed a coherently moving pattern for 45 seconds. The duration of the subsequent aftereffect was measured with three different test display contrasts (high, medium, low). Contrast sensitivity also was assessed. RESULTS: For each test display contrast, the motion aftereffect was prolonged in migraine compared to the control group. Contrast sensitivity was poorer in the migraine group and was a significant predictor of motion aftereffect duration. CONCLUSIONS: These results suggest an anomaly in early motion processing pathways in migraine that likely is linked with those pathways underlying contrast sensitivity. They provide further evidence for differences in visual processing that begin early, potentially starting at the retina, which have consequences for performance on tasks that putatively examine cortical processing. Differences in precortical and cortical visual pathways are implicated in the pathophysiology underlying migraine.

Age- and sex-specific differences in blood-borne microvesicles from apparently healthy humans.

BACKGROUND: Sex differences in incidence of cardiovascular disease may reflect age-associated intravascular cellular activation resulting in shedding of cell membrane-derived bioactive microvesicles (MV or microparticles) into the blood. Concentrations of cell-specific MV in blood have the potential to be a diagnostic/prognostic marker of pathology, but ranges of MV must first be established in healthy individuals. This study identified cellular origin of blood-borne MV >0.2 µm in blood of apparently healthy women and men aged from 20-70 years. METHODS: Venous blood from apparently healthy participants in the Mayo Clinic Biobank was collected into tubes containing protease inhibitors as the anticoagulant. MV were isolated by standardized differential centrifugation and characterized by digital flow cytometer. Each cellular origin of MV was verified by two different antibodies with strong correlation between the two distinct antibodies (e.g., for platelet-derived MV, r (2) = 0.97). RESULTS: MV derived from platelets were the most abundant type of MV in blood from women and men in all age groups. Total numbers of phosphatidylserine, P-selectin, and platelet- and endothelium-derived MV were significantly (P < 0.05) greater in women than men. Numbers of MV from erythrocytes and stem/progenitor cells were significantly lower in premenopausal women than age-matched men. Number of tissue factor pathway inhibitor positive MV were significantly (P < 0.05) lower whereas erythrocyte-derived MV were significantly higher in postmenopausal women compared to premenopausal women. In women, there was a positive relationship between age and erythrocyte-derived MV (ρ = 0.28; P = 0.009), while in men adipocyte-derived MV increased with age (ρ = 0.33; P = 0.01). CONCLUSIONS: This study provides ranges for cellular origin of blood-borne MV in age-matched, apparently healthy women and men from which to compare diagnostic and prognostic uses of blood-borne MV in larger studies and patient population. In addition, sex- and age-specific differences in phosphatidylserine, platelet-, endothelium-, erythrocyte-, and adipocyte-derived blood-borne MV may contribute to differential progression of cardiovascular disease in women compared to men.

Generality and specificity in the effects of musical expertise on perception and cognition.

Performing musicians invest thousands of hours becoming experts in a range of perceptual, attentional, and cognitive skills. The duration and intensity of musicians' training - far greater than that of most educational or rehabilitation programs - provides a useful model to test the extent to which skills acquired in one particular context (music) generalize to different domains. Here, we asked whether the instrument-specific and more instrument-general skills acquired during professional violinists' and pianists' training would generalize to superior performance on a wide range of analogous (largely non-musical) skills, when compared to closely matched non-musicians. Violinists and pianists outperformed non-musicians on fine-grained auditory psychophysical measures, but surprisingly did not differ from each other, despite the different demands of their instruments. Musician groups did differ on a tuning system perception task: violinists showed clearest biases towards the tuning system specific to their instrument, suggesting that long-term experience leads to selective perceptual benefits given a training-relevant context. However, we found only weak evidence of group differences in non-musical skills, with musicians differing marginally in one measure of sustained auditory attention, but not significantly on auditory scene analysis or multi-modal sequencing measures. Further, regression analyses showed that this sustained auditory attention metric predicted more variance in one auditory psychophysical measure than did musical expertise. Our findings suggest that specific musical expertise may yield distinct perceptual outcomes within contexts close to the area of training. Generalization of expertise to relevant cognitive domains may be less clear, particularly where the task context is non-musical.