Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia.

Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.

Addressing the needs of adolescent children when a parent becomes aphasic: one family's experiences.

There are several reports of the psychosocial effects of aphasia on family members and of factors that may influence a family's emotional adjustment. Most of these, however, have included only spouses or the adult children of individuals with aphasia. Therefore, to address how children of adolescent age or younger react to and cope with parental aphasia, this article provides an account of one family's experiences with stroke and aphasia. Specifically, the impact of a father's aphasia on his adolescent daughter as well as how the parents attempted to help their daughter adjust during acute and chronic recovery phases are described.

Pupil responses to stimulus color, structure and light flux increments in the rhesus monkey.

Visual stimuli that isolate pupil color and pupil grating responses in human vision have been used to investigate the properties, of stimulus-specific pupil responses in the rhesus monkey. We measured and compared pupil responses to light flux increments, isoluminant chromatic stimuli, and gratings of equal and lower space-averaged luminance. The parameters investigated were luminance contrast and chromatic saturation. The results demonstrate clearly the existence of pupil color, pupil grating and pupil light reflex responses in the rhesus monkey. Comparison of pupil color and pupil grating responses of equivalent amplitude reveals similar onset response latencies. However, both are approximately 40 ms longer than the corresponding pupil light reflex latency. In general these pupil responses are qualitatively similar to those observed in humans. However, when compared to equivalent human data, pupil onset response latencies are some 80-100 ms shorter and the pupil shows more rapid recovery from constriction.

Insights into the different exploits of colour in the visual cortex.

A new method that allows controlled masking of luminance contrast has been developed to study the use of chromatic signals in human vision. The method also makes it possible to examine the different uses of chromatic signals (e.g. the generation of perceived colour, or the construction and representation of object structure and form). By using this technique, we studied the threshold detection of chromatic signals in normal trichromats. The results show that chromatic signals are virtually unaffected by ongoing, randomly varying, luminance contrast changes. These findings suggest that chromatic signals are either processed independently or can be separated completely from any confounding luminance contrast components in the stimulus. Thresholds for detection of colour changes only, and for extraction of stimulus structure from chromatic signals in normal trichromats, in subjects with single cone receptor deficiency (i.e. dichromats) and in three subjects with abnormal colour vision caused by bilateral damage to ventromedial, extra-striate visual cortex (i.e. subjects with cerebral achromatopsia) have also been measured. No significant difference in thresholds for the two conditions was observed either in normal trichromats or in dichromats. Subjects with cerebral achromatopsia, however, reveal markedly different thresholds. The results suggest that chromatic signals are processed independently to generate perceived object colour or to construct spatially structured objects, and that these functions involve different neural substrates. The results help to explain, at least in part, why cerebral achromatopsia is a heterogeneous disorder, and why there can be significant differences in the effective use of chromatic signals in subjects described as cerebral achromatopsics.

Spatial and temporal response properties of residual vision in a case of hemianopia.

Residual vision in subjects with damage of the primary visual cortex (striate cortex) has been demonstrated in many previous studies and is taken to reflect the properties of known subcortical and extrastriate visual pathways. In this report we describe psychophysical experiments carried out on a subject clinically blind in half of his visual field (i.e. homonymous hemianopia) caused by striate cortex damage. They reveal the existence of two distinct channels mediating such vision. One channel responds to spatial structure and the other to light flux changes. The spatially tuned channel has a peak response at about 1.2 cycles per degree and shows rapid loss of sensitivity at both high and low spatial frequencies. This channel does not respond to diffuse illumination. The light flux channel, however, responds only to sudden increments in light flux levels on the retina and shows extensive spatial summation. Both channels require transient inputs, with a peak sensitivity at about 10 cycles per second and show virtually complete attenuation at temporal frequencies below 2 cycles per second. The spatiotemporal characteristics of these two channels account for much of the reported limits of visual performance attributed to subcortical or extrastriate pathways in some patients, and especially for their relatively good sensitivity for the detection of abrupt, transient stimuli or fast-moving targets. A new method is also applied to the measurement of the amount of light scatter in the eye. The measurements show that light scatter into the sighted hemifield could not account for the results obtained with the stimuli used to characterized the residual vision of this subject.

New method based on random luminance masking for measuring isochromatic zones using high resolution colour displays.

A new method of measuring normal hue discrimination ellipses and dichromatic zones using a high resolution colour monitor is described. The test involves the detection of chromatic bars on a grey background (x = 0.305, y = 0.323) having a luminance of 34 cd m-2. Elements of the background matrix of square checks are varied randomly in luminance in space and time to provide random luminance masking (RLM) which compensates for differences in the relative luminous efficiency of different observers. The measurement technique provides a rapid and comprehensive colour vision test. Typical results are presented for normal trichromats, protanopes and deuteranopes without RLM and with the RLM set of 25%. The size of the discrimination ellipse in normal observers is the same in both viewing conditions, but the use of the RLM technique reveals the extent of the isochromatic zones in colour deficient observers.

Pupillary responses to stimulus structure, colour and movement.

Pupillary responses to stimuli which favour the preferential stimulation of neural mechanisms involved in the detection of visual attributes such as colour, spatial structure, movement and light flux changes on the retina have been measured and compared. Pupil responses to a decrement in stimulus luminance (i.e., a flash of darkness), suggest that at least three components are involved in this response, their relative contribution being determined largely by stimulus size, contrast and presentation time. A comparison of pupil responses to gratings of equal and lower space-averaged luminance shows that the amplitude of pupillary constriction at grating onset for the equal luminance condition is about twice that measured with similar gratings in the lower luminance condition. Pupillary responses to chromatic isoluminant gratings are in general of longer latency when compared to responses of similar amplitude elicited by achromatic gratings. Small pupillary constrictions elicited by the onset of coherent movement in dynamic, random dot patterns are also demonstrated under stimulus conditions which eliminate pupillary responses to sudden light flux changes on the retina. The results support an earlier hypothesis which suggests that the onset of sudden changes in neural activity in the visual cortex when a visual stimulus is presented to the eye causes an overall perturbation which weakens transiently the regulatory inhibitory input to the pupillomotor nucleus. This, in turn, results in a transient increase in the efferent parasympathetic innervation of the iris sphincter muscle and hence the observed constriction of the pupil. The characteristics of the pupillary response reflect the properties of the mechanisms and the number of neurones which participate in the detection of each stimulus attribute.

Factors affecting visual sensitivity in a hemianopic subject.

A well-studied subject with visual cortex damage (G.Y.) was tested in his hemianopic field with temporally modulated sinusoidal and square-wave gratings. The purpose was to use an extended range of parameters to obtain a detailed spatiotemporal specification of his residual vision and to try to resolve the discrepancy between negative findings of Hess and Pointer (1989) and previous positive claims. Both the spatial and temporal parameters could be Gaussian-weighted. Detection as a function of spatial frequency, contrast, temporal modulation frequency, stimulus size, and slope of the temporal and spatial Gaussian functions was investigated using a two-alternative forced-choice procedure. The most important parameters for this subject were found to be the slope of the temporal Gaussian function and the size and contrast of gratings. With optimum parameters he could reliably achieve a score of 95-100% correct in his 'blind' field. The results are consistent with earlier studies of this subject, especially his ability to respond to moving stimuli, and also may account for why negative results had been reported for him when particular fixed parameters were used.

In vitro palmitate and glucose metabolism in the postmature fetus.

Fetuses from term and postmature rabbits were obtained and their livers incubated with palmitate-1-14C in room air. The net incorporation of the fatty acids into ketone bodies, lipids, and Co2 was measured at fixed and variable concentrations of cold glucose. Data from postmature liver show that lipid synthesis is decreased, 14CO2 production is increased, and ketone body formation is unchanged when compared with data from the term liver. The addition of cold glucose to a constant concentration of palmitate-1-14C causes a slight increase in lipid synthesis in thepostmature liver, in contrast to a decrease in the term liver. The experimental results indicate that liver lipid synthesis and glucose utilization are diminished in the postmature preparation. This suggests that the postmature fetal liver responds to the decreased availability of free fatty acid from the placenta and to the increasing hypoxia by metabolic adaptations resembling those observed during fasting and tissue hypoxia. These changes are somewhat similar to those observed in the neonate before the onset of breast-feeding. Fetal metabolism is, therefore, responsive to changes in placental transfer of fatty acids and to postmaturity.

Plasma glucose, cholesterol, triglyceride, and glycerol concentrations in the postmature rabbit.

Plasma cholesterol, triglycerides, glycerol, and glucose concentrations were measured in term and postmature rabbits. The data show that the term and postmature mothers have significantly higher glycemia than their fetuses. However, triglyceride and cholesterol concentrations are lower in the postmature mother than in her fetus. Postmature fetuses are characterized by very high plasma triglyceride and cholesterol concentrations. The results demonstrate that postmaturity is accompanied by maternal and fetal lipid metabolic changes related to a decrease in the transfer of maternal fatty acids through the placenta and to a diminution in fetal liver glucose utilization. The postmature fetus is then in a relative state of fasting and must rely on its own supply of fuel (glycogen and lipids) to provide cells for growth and survival. The maternal metabolic changes can possibly be explained by a decreased utilization of maternal substrates by the fetus, the placenta becoming insufficient. The close interrelationship of fetal and maternal lipid metabolism with the activity of the placenta suggests that an accurate knowledge of the metabolic changes taking place in the fetus during alteration of the maternal environment is indispensable to the understanding of the short- and long-term effects of maternal disease on the fetus.

Placental uptake and transfer of lipid in the postterm rabbit.

Gonadotropin-injected pregnant rabbits were delivered by cesarean section near term (30 days after conception (term, 31 days) and 3 1/2 and 4 days post term. Lipid metabolism of the postterm and near-term fetus was compared. Fetal and placental uptake of radioactivity and rate of lipid entry into the fetus, as well as fetal and maternal plasma free fatty acid (FFA) specific activities (at equilibrium) were determined following a single maternal injection of [1-14C]palmitate (50 muCi) administered at cesarean section. Evidence of placental malfunction in the postterm period includes decreased placental uptake and transport of labeled FFA occurring while maternal and fetal FFA dynamics (half times) remain unchanged and a loss in "organization": The strong positive correlation (p less than 0.001) between placental uptake and transfer to the fetus at 30 days' gestation is lost 5 days later. A comparison of maternal and fetal plasma FFA specific activities indicates a substantial (62%) near-term fetal contribution to its own circulating FFA pool. Total plasma FFA is elevated in the postterm fetus concomitant with a decreasing maternal supply. A postterm fetus must therefore contribute lipid from its own reserves (probably liver) in excess of amounts attributed to a near-term fetus, i.e., greater than 62%.