Bacille Calmette-Guérin vaccine-related disease in HIV-infected children: a systematic review.

OBJECTIVE: To describe the characteristics and risk of bacille Calmette-Guérin (BCG) vaccine related disease in human immunodeficiency virus (HIV) infected infants. METHODS: Systematic literature review of articles published from 1950 to April 2009 in the English language. We identified all microbiologically confirmed cases of disseminated BCG disease in vertically HIV-infected children reported in the literature. RESULTS: Sixteen observational studies and 11 case reports/series were included. Observational studies suffered from high rates of loss to follow-up and death. Loco-regional BCG disease was reported in both HIV-infected and non-infected children. Disseminated BCG disease was reported only in children with immunodeficiency and only in studies employing sophisticated laboratory techniques. Sixty-nine cases of disseminated BCG were identified in the literature: 47 cases were reported in six observational studies, the majority (41/47) from the Western Cape of South Africa. A Brazilian cohort study reported no cases of disseminated BCG amongst 66 HIV-infected children observed over a 7-year period. A recent South African surveillance study reported 32 cases of disseminated BCG over a 3-year period, estimating the risk of disseminated BCG to be 992 per 100,000 vaccinations in HIV-infected children. Few cases of severe disseminated TB were reported in the cohort studies among HIV-infected children vaccinated with BCG. CONCLUSION: Data on the risk of BCG vaccination in HIV-infected children are limited. Targeted surveillance for BCG complications employing sophisticated diagnostic techniques is required to inform vaccination policy.

Pattern electroretinograms after cerebral hemispherectomy.

Cortically blind patients with brain damage restricted to the optic radiations or primary visual cortex may be able to detect and discriminate visual stimuli presented in their field defects, even though they deny seeing them. In contrast, patients who are hemianopic as a result of cerebral hemispherectomy cannot explicitly discriminate visual stimuli in their field defects, even when forced choice procedures are used. A possible explanation for this difference is that retrograde, transneuronal degeneration of the retina, which affects approximately 85% of wavelength-sensitive ganglion cells (approximately 70% of the total) after damage restricted to striate cortex, could be far more extensive after hemispherectomy, rendering the retina incapable of processing and conveying visual information to the brain. To test this, we assessed retinal ganglion cell function by means of electroretinography in three patients with cerebral hemispherectomy who were functionally blind. Steady-state pattern electroretinograms elicited by achromatic and isoluminant-chromatic (red-green) sinusoidal gratings, whose contrast was temporally modulated, were recorded from both blind and sighted hemiretinae. The electroretinograms were qualitatively indistinguishable from those of a control patient with a unilateral striate cortical lesion with documented visual capacity in his field defect. Within-subject analysis of variance revealed significant differences in the amplitude of the second harmonic (2f(0)) component of the averaged signal (diagnostic of retinal ganglion cell function) with respect to stimulus, but no significant differences between blind and sighted hemiretinae. This indicates that many retinal ganglion cells must have survived in the hemispherectomized patients. Isoluminant chromatic stimuli tended to elicit stronger signals than achromatic stimuli, which was unexpected given that wavelength-opponent Pbeta ganglion cells are far more susceptible than broad-band Palpha ganglion cells to transneuronal degeneration after cortical damage. It suggests that the 2f(0) component of the response to isoluminant chromatic stimuli might not reflect the activity of chromatic processes. Overall, the results show that the absence of residual vision in the blind fields of patients with cerebral hemispherectomy cannot be due to complete degeneration of retinal ganglion cells and, by extension, complete degeneration of their subcortical targets. This supports an alternative explanation, which is that intact extrastriate cortex is required for mediating voluntary responses to visual stimuli presented in the scotoma.

Motion discrimination in cortically blind patients.

Some patients with brain damage affecting the striate cortex, though clinically blind in their field defects, can still discriminate visual stimuli when forced choice procedures are used. Such patients seem particularly sensitive to moving stimuli in their scotomata, though there are conflicting reports as to whether they can discriminate the direction of motion. We tested three patients with areas of cortical blindness for their ability to detect and discriminate the direction of motion of a variety of first-order motion stimuli, namely bars, gratings, plaids and random dot kinematograms depicting translation and motion in depth, during forced choice tasks. The patients could detect the presence of movement in any kind of stimulus, and could discriminate the direction of single bars, but none could discriminate the direction of motion of the more complex stimuli (gratings, plaids and random dot kinematograms) or discriminate between 0 and 100% coherent random dot kinematograms at any speed tested (from 4 to 64 degrees /s). Similar results were obtained from one of the patients who was additionally tested with second-order versions of the translated bar and random dot kinematograms, eliminating light scatter as an explanation. Overall, the results suggest that motion processing in the scotoma is severely impaired, and that the puzzling discrepancies between previous studies can be accounted for by the type of stimulus used. The motion discrimination impairment caused by brain damage affecting the primary visual cortex is inconsistent with the proposed existence of a subcortical pathway to extrastriate cortical motion areas (such as areas MT and MST) which bypasses the striate cortex and is specialized for analysing 'fast' motion.

Uneven mapping of magnocellular and parvocellular projections from the lateral geniculate nucleus to the striate cortex in the macaque monkey.

Central vision is substantially over represented in the lateral geniculate nucleus (dLGN) and striate cortex. The over representation could be accompanied by a selective expansion of central vision in parvocellular dLGN, in which case the ratio of parvocellular to magnocellular inputs to striate cortex should change with retinal eccentricity. To test this, sample ratios were determined from counts of neurons in dLGN labelled retrogradely with WGA-HRP from striate cortex at the cortical representations of various eccentricities. Parvocellular to magnocellular ratios decreased from a mean of 35:1 at the fovea to 5:1 at 15 degrees eccentricity. Furthermore, they exceeded the ratio of P beta to P alpha ganglion cells in central retina, but not in peripheral retina, showing that the uneven P to M ratio in the LGN does not merely mirror the distribution of ganglion cells in the retina. This provides direct evidence for selective over representation of central vision in parvocellular dLGN.

Blindsight and visual awareness.

Some patients with damaged striate cortex have blindsight-the ability to discriminate unseen stimuli in their clinically blind visual field defects when forced-choice procedures are used. Blindsight implies a sharp dissociation between visual performance and visual awareness, but signal detection theory indicates that it might be indistinguishable from the behavior of normal subjects near the lower limit of conscious vision, where the dissociations could arise trivially from using different response criteria during clinical and forced-choice tests. We tested the latter possibility with a hemianopic subject during yes-no and forced-choice detection of static and moving targets. His response criterion differed significantly between yes-no and forced-choice responding, and the difference was sufficient to produce a blindsight-like dissociation with bias-sensitive measures of performance. When measured independently of bias, his sensitivity to static targets was greater in the forced-choice than in the yes-no task (unlike normal control subjects), but his sensitivity to moving targets did not differ. Differences in response criterion could therefore account for dissociations between yes-no and forced-choice detection of motion, but not of static pattern. The results explain why patients with blindsight are apparently more often "aware" of moving stimuli than of static stimuli. However, they also imply that blindsight is unlike normal vision near threshold, and that pattern- and motion-detection in blindsight may depend on different sets of neural mechanisms during yes-no and forced-choice tests.

Is blindsight like normal, near-threshold vision?

Blindsight is the rare and paradoxical ability of some human subjects with occipital lobe brain damage to discriminate unseen stimuli in their clinically blind field defects when forced-choice procedures are used, implying that lesions of striate cortex produce a sharp dissociation between visual performance and visual awareness. Skeptics have argued that this is no different from the behavior of normal subjects at the lower limits of conscious vision, at which such dissociations could arise trivially by using different response criteria during clinical and forced-choice tests. We tested this claim explicitly by measuring the sensitivity of a hemianopic patient independently of his response criterion in yes-no and forced-choice detection tasks with the same stimulus and found that, unlike normal controls, his sensitivity was significantly higher during the forced-choice task. Thus, the dissociation by which blindsight is defined is not simply due to a difference in the patients' response bias between the two paradigms. This result implies that blindsight is unlike normal, near-threshold vision and that information about the stimulus is processed in blindsighted patients in an unusual way.

Models of ganglion cell topography in the retina of macaque monkeys and their application to sensory cortical scaling.

We devised mathematical models of the topography of ganglion cells in the retina of macaque monkeys. The models consisted of a sum-of-three exponentials function fitted to measurements of ganglion cell density made on the nasal horizontal meridian, combined with known anisotropies across the horizontal and vertical meridians by means of elliptic interpolation to provide a full description of their density across the whole of the retinal surface. Integration using standard numerical techniques allowed the number of ganglion cells in arbitrary regions of the retina to be estimated. The topography of actual and effective total ganglion cell populations, and of primate alpha and gamma retinal ganglion cells, was modelled on previously published data. The models were used to test the hypothesis that the retinal projection to the striate cortex in macaque monkeys is peripherally scaled (i.e. merely reflects the eccentricity-dependent variation in density of ganglion cells in the retina) by comparing the cumulative proportion of ganglion cells with the cumulative proportion of cortical area as a function of eccentricity in the visual field. Discrepancies between the two curves indicated that the fovea and immediately surrounding retina are overrepresented in the striate cortex (i.e. there is more cortex per ganglion cell in and near the fovea than in the periphery), and the fact that the discrepancies persisted out to 25-50 degrees of eccentricity showed that the overrepresentation cannot be explained by the lateral displacement of foveal ganglion cells.

The overrepresentation of the fovea and adjacent retina in the striate cortex and dorsal lateral geniculate nucleus of the macaque monkey.

The central part of the retina, which includes the fovea, is substantially overrepresented in the topographic map of the retina in the striate cortex. We tested whether this simply reflects the uneven distribution of ganglion cells in the retina in accordance with the "principle" of peripheral scaling, or whether there is additional expansion of the fovea and adjacent retina in the retinocortical projection. Wheatgerm agglutinated horseradish peroxidase was injected into the striate cortex of three rhesus macaque monkeys so as to surround the representation of the fovea at a mean eccentricity of 8.6 degrees, and the retinae were processed histochemically to stain the retrogradely and transneuronally labelled ganglion cells which projected topographically to the injection sites. This enabled regions of the striate cortex to be related precisely to corresponding regions of the dorsal lateral geniculate nucleus and retina. Mathematical models of the distribution of ganglion cells in the retina, clipped, three-dimensional computer reconstructions of the striate cortex and lateral geniculate nucleus, and counts of neurons in the latter, were used to calculate the proportion of neurons allocated to the marked perifoveal region at each stage of projection. This was used to calculate the relative allocation of neurons to the representation of the fovea and surrounding retina among the different stages of the visual pathway. The values obtained showed that the cortical representation of the perifovea was expanded two to three times more than could be accounted for on the basis of ganglion cell topography in the retina, and that the expansion occurred both between the retina and the thalamus, and between the thalamus and the cortex. These results are inconsistent with the idea that peripheral scaling is a general principle of sensory representation in the cortex. They could also explain why many visual thresholds, including hyperacuities, cannot be accounted for by peripheral factors such as ganglion cell density.

Perception of motion-in-depth in patients with partial or complete cerebral hemispherectomy.

Four patients with functional hemispherectomy, one patient with a complete anatomical hemispherectomy, and one patient with unilateral removal of the temporal, parietal and occipital lobes took part in two sets of experiments designed to investigate their residual sensitivity to motion-in-depth in the hemianopic visual field. Two types of computer-generated visual displays were used; in the first set of experiments, a dot pattern and in the second, a circular checkerboard. These simulated either convergent, divergent or reversed rotational motion. Each set of experiments consisted of two parts; in the first part, electrodermal responses were monitored during stimulus presentation while the subjects performed a simple distracting task. In the second part, subjects were asked to state verbally the direction of stimulus motion. Contrary to expectations, no reliable changes in skin conductance were elicited from any of the subjects by changes in the direction of motion of the component parts of either the dot pattern display or the circular checkerboard display. Furthermore, none of the subjects were able to discriminate the direction of motion of the target patterns when presented in the hemianopic field. The most parsimonious explanation is that the subcortical visual pathways which survive hemispherectomy are unable to process visual information relating to motion in depth.

The role of light scatter in the residual visual sensitivity of patients with complete cerebral hemispherectomy.

Various residual visual capacities have been reported for the phenomenally blind field of hemispherectomized patients, providing evidence for the relative roles of cortical and subcortical pathways in vision. We attempted to characterize these functions by examining the ability of five patients to detect, localize, and discriminate high-contrast flashed, flickering and moving targets. Dependent measures were verbal, manual, and oculomotor responses. As a control for light scatter, intensity thresholds for monocular detection of targets in the hemianopic field were compared with thresholds obtained when using an additional half eyepatch to occlude the blind hemiretina of the tested eye. One unilaterally destriate patient was tested on the same tasks. In photopic conditions, none of the hemispherectomized patients could respond to visual cues in their impaired fields, whereas the destriate patient could detect, discriminate, and point to targets, and appreciate the apparent motion of stimuli across his midline. Under reduced lighting, the threshold luminance required by hemispherectomized patients to detect stimuli presented monocularly was similar to that required for their detection when all visual information was occluded in the blind field, and only available to the visual system indirectly via light scatter. In contrast, the destriate patient's monocular threshold in his blind field was substantially lower than that for stimuli directly occluded in the blind field. As we found no range of stimuli which the hemispherectomized patients could detect or discriminate that was not also associated with discriminable scattered light, we conclude that the subcortical pathways which survive hemispherectomy cannot mediate voluntary behavioural responses to visual information in the hemianopic field.

Nasal and temporal retinal ganglion cells projecting to the midbrain: implications for "blindsight".

We placed pellets of horseradish peroxidase in the superior colliculus of four macaque monkeys and retrogradely labelled the retinal ganglion cells of both eyes. The ratio of labelled cells in the contralateral nasal retina and the ipsilateral temporal retina was no different from the ratio found after implants in the optic nerve, which label the entire afferent pathway. Our finding therefore invalidates the proposal that prominent differences in the properties of "blindsight" in monocular nasal and temporal visual fields arise from differences in the projection from the nasal and temporal retina to the midbrain. We also measured the size of the soma and dendritic field of the labelled ganglion cells (mostly gamma cells) and compared them with those of alpha and beta cells that project to the dorsal lateral geniculate nucleus. Soma size was very close to that of beta cells at all eccentricities but was much smaller than that of alpha cells. Dendritic field size was significantly larger than that of beta cells but was smaller than that of alpha cells. The number of primary dendrites was counted for cells labelled from the midbrain and in samples of alpha and beta cells labelled from the optic nerve. At eccentricities of 3-7 mm there was a consistent and prominent difference between beta and gamma cells. The results show that at intermediate eccentricities even ganglion cells whose distal dendrites are too poorly labelled to reveal their morphological class can never the less be categorized as alpha, beta or gamma by using a combination of soma size and number of primary dendrites. This is particularly useful when attempting to classify retinal ganglion cells following microinjections into selected target nuclei of optic axons.

Translation invariance in the responses to faces of single neurons in the temporal visual cortical areas of the alert macaque.

1. The responses of single neurons in the inferior temporal cortex and the cortex in the banks of the anterior part of the superior temporal sulcus of three awake, behaving macaques were recorded during a visual fixation task. Stimulus images subtending 17 or 8.5 degrees were presented in the center of the display area, and fixation was either at the center of the display area, or at one of four positions that were on the stimulus, or several degrees off the edge of the test stimulus. The experiments were performed with face-selective cells, and the responses were compared for fixation at each position for both effective and noneffective face stimuli for each cell. 2. The firing rates of most neurons to an effective image did not significantly alter when visual fixation was as far eccentric as the edge of the face, and they showed only a small reduction when the fixation point was up to 4 degrees from the edge of the face. Moreover, stimulus selectivity across faces was maintained throughout this region of the visual field. 3. The centers of the receptive fields of the cells, as shown by the calculated "centers of gravity," were close to the fovea, with almost all being within 3 degrees of the fovea. 4. The receptive fields of the cells typically crossed the vertical midline for at least 5 degrees. 5. Information theory procedures were used to analyze the spike trains of the visual neurons. Nearly six times more information was carried by these neurons' firing rate about the identity of an image than about its position in the visual field. Thus the information theory analysis showed that the responses of these neurons reflected information about which stimulus had been seen in a relatively translation invariant way. 6. Principal component analysis showed that principal component 1 (PC1) is related primarily to firing rate and reflected information primarily about stimulus identity. (For identity PC2 added only 14% more information to that contained in PC1.) Principal component 2 (PC2) was more closely related to neuronal response latencies, which increased with increasing eccentricity of the image in the visual field. PC2 reflected information about the position of the stimulus in the visual field, in that PC2 added 109% more information to that contained in PC1 about the position of the stimulus in the visual field.(ABSTRACT TRUNCATED AT 400 WORDS)

The responses of neurons in the temporal cortex of primates, and face identification and detection.

The ability of a human observer to detect the presence of a briefly flashed picture of a face can depend on the picture's spatial configuration, that is on whether its features are rearranged (jumbled) or are in their normal configuration. The face-detection effect (FDE) is found under conditions of backward masking, when the presence of a face can be detected with shorter masking intervals when it is in the normal than when in the rear-ranged configuration. A similar effect is found when the subject is asked to classify the face as rearranged or not - the face-classification effect (FCE). Part of the interest of the FDE and the FCE is that they show how the configuration of a stimulus can be an important factor in the perceptual processing which leads to detection and classification of the stimulus. To analyse these effects we recorded from single neurons in the cortex in the superior temporal sulcus of macaques when they were shown (in a visual fixation task) normal and rearranged faces under backward masking conditions shown in experiments 2 and 3 to produce, with the same apparatus, the FCE, and also to produce comparable effects on the identification of which face was present (called hereafter the face-identification effect), and also of the clarity of the face. We found in experiment 1 that there are some face-selective neurons which respond to faces only, or better, when the features in the faces are in their normal configuration rather than rearranged. We also showed in this experiment that the difference in the response to the normal as compared to the rearranged faces became greater when the masking stimulus was delayed more. Thus, at intermediate delays, there are more neurons active for the normal than for the rearranged face. We therefore propose that the FDE, the FCE, and the face-identification effect arise because the total number of neurons activated by faces in their normal configuration is greater than that activated by rearranged faces, because of the sensitivity of some face-selective neurons to the spatial arrangement of the features. The experiments also show that backward visual masking does produce abrupt termination of the firing of neurons in the temporal cortical visual system, so that the duration of a neuronal response is very short when visual stimuli can just be perceived.

Preferential representation of the fovea in the primary visual cortex.

The retinal fovea, which corresponds to the central degree or so of vision, is spatially over-represented in the visual cortex. It is about 0.01% of retina area, but at least 8% of the striate cortex. Does this simply reflect an equivalently uneven distribution of ganglion cells in the retina, or is the cortical representation of the fovea preferentially expanded? The answer hinges on the resolution of long-standing discrepancies between the retinal and cortical magnification factors. We approached the problem in a different way, using a retrograde transneuronal tracer from cortex to retina to relate directly the number of ganglion cells projecting to marked areas of striate cortex. We report here that ganglion cells near the fovea were allocated 3.3 to 5.9 times more cortical tissue than more peripheral ones, and conclude that the cortical representation of the most central retina is much greater than expected from the density of its ganglion cells.