Development of visual cortical axons: layer-specific effects of extrinsic influences and activity blockade.

During normal cortical development, individual pyramidal neurons form intracortical axonal arbors that are specific for particular cortical layers. Pyramidal neurons within layer 6 are able to develop layer-specific projections in cultured slices of ferret visual cortex, indicating that extrinsic influences, including patterned visual activity, are not required (Dantzker and Callaway [1998] J Neurosci 18:4145-4154). However, when spontaneous activity is blocked in cultures with tetrodotoxin, layer 6 pyramidal neurons fail to preferentially target their axons to layer 4. To determine whether mechanisms that regulate the development of layer 6 pyramidal neuron arbors can be generalized to pyramidal neurons in other layers, we examined the development of layer 5 and layer 2/3 pyramidal neurons in cultured slices of ferret visual cortex prepared on postnatal day 14 or 15. Layer 5 pyramidal neurons developed layer-specific axonal arbors during 5-7 days in vitro. However, unlike layer 6 pyramidal neurons, layer 5 pyramidal neurons formed layer-specific axonal arbors in the presence of tetrodotoxin. In contrast to layer 5 and layer 6 pyramidal neurons, layer 2/3 pyramidal neurons did not form appropriate layer-specific projections during 5-7 days in vitro. Taken together, these data suggest that the development of layer-specific axons is regulated by different mechanisms for neurons in different layers and cannot be categorically classified as either activity-dependent or independent. Instead, the type of pyramidal neuron, the layers targeted, and the type of activity must be considered.

Laminar specificity of local circuits in barrel cortex of ephrin-A5 knockout mice.

Cortical circuits are characterized by layer-specific axonal arbors. Molecular laminar cues are believed to direct the development of this specificity. We have tested the hypothesis that ephrin-A5 is responsible for preventing layer 2/3 pyramidal cell axons from branching within layer 4 (Castellani et al., 1998) by assessing the laminar specificity of axonal arbors in ephrin-A5 knockout mice. We find that in barrel cortex of knockout mice, layer 2/3 pyramidal neurons form axonal arbors specifically in layers 2/3 and 5, avoiding layer 4. This pattern of arborization is indistinguishable from that of wild-type littermates. Furthermore, we find that in wild-type mice, laminar patterns of ephrin-A5 expression differ between cortical areas despite the similarity of layer-specific local cortical circuits across areas. Most notably, ephrin-A5 is not expressed preferentially in layer 4 of wild-type mouse barrel cortex. We conclude that ephrin-A5 is not responsible for preventing the development of layer 2/3 pyramidal cell axonal arbors in layer 4 of mouse barrel cortex. These observations also suggest that if ephrin-A5 plays a role in the emergence of layer-specific circuits, that role must differ between cortical areas.

The effects of age upon the perception of depth and 3-D shape from differential motion and binocular disparity.

The ability of younger and older adults to perceive the 3-D shape, depth, and curvature of smooth surfaces defined by differential motion and binocular disparity was evaluated in six experiments. The number of points defining the surfaces and their spatial and temporal correspondences were manipulated. For stereoscopic sinusoidal surfaces, the spatial frequency of the corrugations was also varied. For surfaces defined by motion, the lifetimes of the individual points in the patterns were varied, and comparisons were made between the perception of surfaces defined by points and that of more ecologically valid textured surfaces. In all experiments, the older observers were less sensitive to the depths and curvatures of the surfaces, although the deficits were much larger for motion-defined surfaces. The results demonstrate that older adults can extract depth and shape from optical patterns containing only differential motion or binocular disparity, but these abilities are often manifested at reduced levels of performance.

N-methyl-D-aspartate receptor blockade affects polysialylated neural cell adhesion molecule expression and synaptic density during striatal development.

Glutamatergic neurons innervate the striatum and form asymmetric synapses with the dendritic spines of striatal efferent neurons. The role of glutamate in striatal development, however, remains largely unknown. Previous studies have shown a dramatic increase in the density of asymmetric synapses in the rat striatum during the third postnatal week, followed by a decrease to adult levels by postnatal day 25. At the same time, the highly polysialylated form of the neural cell adhesion molecule becomes progressively restricted to synaptic regions and then disappears. We have now examined the effects of antagonists of the N-methyl-D-aspartate subtype of glutamatergic receptors on the expression of the polysialylated form of the neural cell adhesion molecule and on synaptic density during this late period of striatal development. Peripheral administration of the N-methyl-D-aspartate receptor antagonist dizocilpine maleate markedly decreased immunoreactivity for the highly polysialylated form of the neural cell adhesion molecule in the dorsolateral striatum and cerebral cortex when drug treatment included postnatal day 20, but not earlier in development. This effect was regionally specific and loss of the polysialylated neural cell adhesion molecule in the striatum was reproduced by the local administration of dizocilpine maleate, DL-2-amino-5-phosphonovalerate or ketamine on postnatal day 20. Quantitative ultrastructural studies of synaptic density with the physical disector method performed after one of the regimens inducing loss of the polysialylated neural cell adhesion molecule (postnatal days 18-20) revealed a 30% decrease in asymmetric synapses in the dorsolateral striatum of treated rats. Symmetric synapses, which presumably do not use glutamate, were not affected. The data indicate that N-methyl-D-aspartate receptors play a role in the late stages of synaptogenesis in the striatum and suggest that a subset of synapses expressing immunoreactivity for the highly polysialylated form of the neural cell adhesion molecule may be dependent on N-methyl-D-aspartate receptor stimulation during a critical period of striatal development.

Synaptogenesis and ultrastructural localization of the polysialylated neural cell adhesion molecule in the developing striatum.

The polysialylated neural cell adhesion molecule (PSA-NCAM) plays a role in axonal development and synaptic plasticity. Its pattern of expression is regulated temporally and topographically in the brain during development. However, it is unclear whether or not its subcellular location also changes. We have examined PSA-NCAM expression in relation to synapse formation in the developing rat striatum with immunohistochemistry and electron microscopy. Early in development, PSA-NCAM was present along the cytoplasmic membranes of neurons and in growth cones. PSA-NCAM expression became progressively confined to pre- and postsynaptic elements as neurons matured morphologically. Confirming previous results, a marked increase in the density of asymmetric synapses determined by using the physical dissector method was observed in the dorsolateral striatum between postnatal day 14 (P14) and P18. It was followed by a reduction between P18 and P25, when asymmetric synapse density reached adult levels. In contrast, the density of symmetric synapses had surpassed adult levels by P14. In the dorsomedial striatum, the density of asymmetric and symmetric synapses was similar at P18, at P25, and in adults. PSA-NCAM was associated with most asymmetric and symmetric synapses at P14 and P18 and was expressed in both pre- and postsynaptic elements of a majority (P14) or approximately half (P18) of the synapses. Most synapses lost PSA-NCAM expression between P18 and P25 in the dorsolateral striatum and between P25 and adult in the dorsomedial striatum. The data indicate that PSA-NCAM expression becomes restricted topographically during neuronal maturation but remains strategically associated with developing synapses during late postnatal development in the striatum.

A role for N-methyl-D-aspartate receptors in the regulation of synaptogenesis and expression of the polysialylated form of the neural cell adhesion molecule in the developing striatum.

Striatal development proceeds during a protracted postnatal period in rats. In the dorsolateral striatum, the number of asymmetric synapses, formed mostly by glutamatergic afferents innervating the dendritic spines of medium-sized striatal neurons, increases during the 3rd postnatal week and then rapidly declines before reaching adult levels. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is widely expressed along neuronal membranes early in development, becomes progressively localized to synapses, and is no longer detectable in remaining synapses after synaptic pruning has occurred. Administration of MK-801, an antagonist of N-methyl-D-aspartate receptors, on day 20, either peripherally or locally into the striatum, decreases asymmetric synapse number by 30% and totally abolishes immunolabelling for PSA-NCAM in the dorsolateral striatum.

Regulation of the polysialylated form of the neural cell adhesion molecule in the developing striatum: effects of cortical lesions.

Early in development, the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed by growth cones, neuronal processes, and neuronal cell bodies. In rat striatum, PSA-NCAM expression becomes progressively restricted to pre- and postsynaptic membranes and is undetectable by postnatal day 25 (P25), i.e., after corticostriatal synaptogenesis. This study examined the effects of cortical lesions performed on P14, when the corticostriatal projection is already primarily unilateral and cortical inputs have not yet formed asymmetric synapses on striatal neurons. Rats were killed on P25, and PSA-NCAM expression was examined by immunoblotting and immunohistochemistry with light and electron microscopy. In contrast to the case in controls, PSA-NCAM expression was maintained in the striatum of lesioned pups. Ultrastructural studies showed that PSA-NCAM was present 1) in growth cone-like structures and neuronal processes and 2) in striatal neurons. Together with the presence of growth cones, the observation that the number of asymmetric synapses was unchanged in the denervated striatum suggests that axonal sprouting occurred in response to the lesion. This was confirmed by axonal labeling in the denervated striatum after injection of Fluoro-Ruby in the contralateral cortex. The data indicate that P14 cortical lesions affect PSA-NCAM expression in the developing striatum 1) by inducing a robust axonal plasticity resulting in the presence of immature presynaptic elements that contain PSA-NCAM and 2) by delaying the loss of PSA-NCAM expression in striatal neurons, suggesting that the lesion affects the time course of striatal maturation.

Anatomical and functional evidence for lesion-specific sprouting of corticostriatal input in the adult rat.

Previous studies in our laboratory have shown that cortical lesions induced by thermocoagulation of pial blood vessels, but not by acute aspiration, result in 1) the preservation of control levels of the growth-associated protein (GAP)-43 and 2) a prolonged increase in neurotransmitter gene expression in the denervated dorsolateral striatum. We have examined whether corticostriatal projections from the spared homotypic contralateral cortex contribute to these effects. Adult rats received either a thermocoagulatory or aspiration lesion of the cerebral cortex and, after 30 days, received an injection of the anterograde tracer, Fluoro-Ruby, in the contralateral homotypic cortex. Rats were killed 7 days later, and labeled fibers were examined with fluorescence microscopy in the ipsilateral and contralateral striata. Ipsilateral corticostriatal projections were detected in lesioned and unlesioned rats. Numerous labeled fibers were detected in the contralateral striatum of thermocoagulatory-lesioned but not aspiration-lesioned or control animals, suggesting that contralateral cortical neurons may undergo axonal sprouting in the denervated striatum following a thermocoagulatory lesion of the cortex. To determine whether contralateral corticostriatal fibers play a role in the changes in striatal gene expression induced by the thermocoagulatory lesions, the effects of aspiration lesions, as well as unilateral and bilateral thermocoagulatory lesions of the cortex were compared. Confirming previous results, striatal enkephalin mRNA levels were increased after a unilateral thermocoagulatory lesion. However, they were unchanged after aspiration or bilateral thermocoagulatory lesions, suggesting that sprouting or overactivity of contralateral corticostriatal input contributes to the increase seen after unilateral thermocoagulatory lesions.

Trauma outcome improves following the advanced trauma life support program in a developing country.

Trauma outcome variables before and after the institution of the Advanced Trauma Life Support (ATLS) program were compared for the largest hospital in Trinidad and Tobago from July 1981 through December 1985 (pre-ATLS) and from January 1986 to June 1990 (post-ATLS). A total of 199 physicians were ATLS trained by June 1990. Outcome data were analyzed for all dead or severely injured patients (ISS > or = 16; n = 413 pre-ATLS and n = 400 post-ATLS). Trauma mortality decreased post-ATLS (134 of 400 vs. 279 of 413) throughout the hospital, including the ICU (13.6% post-ATLS ICU mortality vs. 55.2% pre-ATLS). The odds of dying from trauma increased with age (1.02 for each year), ISS score (1.24 for each ISS increment), and blunt injury, both pre-ATLS and post-ATLS. Post-ATLS mortality was associated with a higher ISS (31.6 vs. 28.8). Although there was a higher percentage of blunt injury pre-ATLS (84.0%) versus post-ATLS (68.3%), the mortality rates for both blunt and penetrating injuries were higher in the pre-ATLS group (19.7% pre-ATLS vs. 6.3% post-ATLS for penetrating and 76.6% pre-ATLS versus 46.2% post-ATLS for blunt). For each ISS category, mortality was greater in the pre-ATLS group (ISS > or = 24 pre-ATLS mortality 47.9% vs. 16.7% post-ATLS; ISS 25-40 pre-ATLS mortality 91.0% vs. 71.0% post-ATLS). The overall ratio of observed to expected mortality based on the MTOS data base was lower for the post-ATLS period (pre-ATLS ratio 3.16; post-ATLS ratio 1.94).(ABSTRACT TRUNCATED AT 250 WORDS)

Trauma outcome improves following the advanced trauma life support program in a developing country

Trauma outcome variables before and after the institution of the Advanced Trauma Life Support (ATLS) program were compared for the largest hospital in Trinidad and Tobago from July 1981 through December 1985 (pre-ATLS) and from January 1986 to June 1990 (post-ATLS). A total of 199 physicians were ATLS trained by June 19990. Outcome data were analysed for all dead or severely injured patients (ISS greater than and equal to 16; n=413 pre-ATLAS and n=400 post ATLS). Trauma mortality decreased post ATLS (134 ICU mortality vs. 279 of 413) throughout the hospital, including the ICU (13.6 percent post-ATLS ICU mortality vs. 55.2 percent pre-ATLS). The odds of dying from trauma increased with age (1.02 for each year), ISS score (1.24 for each ISS increment), and blunt injury, both pre-ATLS and post-ATLS. Post-ATLS mortality was associated with a higher ISS (31.6 vs 28.8). Although there was a higher percentage of blunt injury pre-ATLS (84.0 percent) versus post-ATLS (68.3 percent), the mortality rates for both blunt and penetrating injuries were higher in the pre-ATLS group (19.7 percent pre-ATLS vs 6.3 percent post ATLS for penetrating and 76.6 percent pre-ATLS versus 46.2 percent post-ATLS for blunt). For each ISS category, mortalilty was greater in the pre-ATLS group (ISS greater than and equal to 24 pre-ATLS mortality 47;9 percent vs. 16.7 percent post-Atls; ISS 25-40 pre-ATLS mortality 91.0 percent vs. 71.0 percent post-ATLS). The overall ration of observed to expected mortality based on the MTOS data base was lower for the post-ATLS period (pre-ATLS ratio 3.16; post-ATLS ratio 1.94). Multiple logistic regression analysis indicated that although post-ATLS mortality was affected by the lower incidence of blunt injury and a lower overall ISS score, the ATLS program was a significant factor in determing the observed decrease in mortality. Postinjury functional status among survivors was improved post-ATLS (minor disabiltiy 88.3 percent post-ATLS vs. 22.4 percent pre-ATLS and major disability 1.9 percent post-ATLS vs. 6.7 percent pre-ATLS). Our data demonstrate that the ATLS program significantly improved trauma patient outcome in a developing country, thus supporting the concept of international promulgation of this program for physicians(AU)

Pseudo-obstruction and a sprue-like syndrome from stronglyloidiasis.

Symptomatic disease from Strongyloides stercoralis has been recognized for the first time in Trinidad. Five cases are reported, all showing clinical features suggestive of a sprue-like syndrome. Subtotal jejunal villous atrophy was seen in one case and partial villous atrophy in two. Three patients had laparotomies because of suspected partial intestinal obstruction. A sprue-like syndrome in certain Caribbean immigrants should arouse a suspicion of S. stercoralis.