Medicine (RMH) - Research Publications

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    Postnatal maturation of the direct corticospinal projections in the macaque monkey
    GALEA, MP ; DARIANSMITH, I (Oxford University Press, 1995-11-01)
    Postnatal changes in the topography of the multiple corticospinal projections in the macaque monkey were followed using retrogradely transported fluorescent tracers, and related to the monkey's acquisition of manual dexterity; both behavioral and anatomical maturation were completed by about 8 postnatal months. Cortical origins of the corticospinal projections were examined by constructing planar projection maps of the distributions of labeled corticospinal neuron somas; these somas were found only in lamina V. At birth elaborate somatotopically organized corticospinal projections from primary motor cortex (area 4), the mesial supplementary motor area and cingulate areas 23 and 24, area 12, dorsolateral area 6a beta, the dorsolateral and ventral area 6a alpha (area F4), parietal areas 2/5, 7b and the peri-insular cortex (including area SII), were clearly defined, with axons extending to all spinal cord segments. While this pattern of regional projections broadly resembled that of the mature macaque, there were, however, substantial maturational changes during the 8 months after birth. These included (1) a halving of the area of cerebral cortex from which the contralateral corticospinal projection originated and (2) a threefold reduction in the number of labeled corticospinal neurons projecting to all segments of the cord. Collateral elimination rather than neuronal cell death was the likely mechanism for this reduction in the population and areal extent of corticospinal neurons in the maturing macaque. The surviving corticospinal axon terminals also developed substantially during the postnatal period. At birth some terminals had invaded the intermediate zone in each spinal segment, but few had penetrated the dorsal and ventral horns. By 6 postnatal months, however, many corticospinal neurons were retrogradely labeled following the injection of fluorescent labels into each of these spinal zones in cervical and lumbar spinal segments. These data demonstrate a considerable postnatal reduction in corticospinal neurons projecting to the contralateral spinal cord, and imply that many of the axons that are eliminated never synapse on spinal neurons. It is suggested that during the middle fetal period the axons of many of the cortical neurons in lamina V that in the mature monkey will terminate on particular neuron populations in the thalamus, brainstem, or spinal cord, traverse a common pathway down through the internal capsule into the spinal cord, passing close to these successive targets, and possibly forming collaterals at these levels. In the postnatal period each such neuron establishes a stable, effective synaptic input to only one or a few of these subcortical target populations, and the remaining collateral branches regress. The postnatal maturation of corticospinal neurons, examined in this study, is compatible with such a model.
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    Multiple corticospinal neuron populations in the macaque monkey are specified by their unique cortical origins, spinal terminations, and connections
    GALEA, MP ; DARIANSMITH, I (Oxford University Press, 1994-03-01)
    In primates, multiple corticospinal projections from the sensorimotor cortex operate in concert to regulate voluntary action. We examined the soma distributions of all those corticospinal neuron populations projecting to different zones in the cervical and more caudal spinal segments in the macaque that are labeled with retrogradely transported fluorescent tracers; 2-4 differentiable dyes were injected into different sites in the cervical spinal cord of each of 11 monkeys. Lamina V of the cerebral cortex, in which all corticospinal neuron somas were located, was unfolded with computer assistance to form a flat surface, and local soma densities were displayed on this plane as contour and 3-D maps. At least nine discrete, somatotopically organized corticospinal projections were identified. Three separate corticospinal projections originated in frontal cortex. The first projected mostly from area 4 (approximately 35% of the total contralateral neuron population), but also from the adjacent dorsolateral area 6a alpha (approximately 6% of total). The second large corticospinal projection (approximately 15% of total) originated in the supplementary motor area and a third small projection (approximately 2.6% of total) projected from the "postarcuate" cortex. Two separate corticospinal neuron populations were identified in areas 24 (approximately 6% of total) and 23 (approximately 4% of total) of the cingulate cortex. Thus, nearly 70% of the contralateral corticospinal projection originated in frontal and cingulate cortex. At the boundary between the primary motor and somatosensory cortex there was a sharp change in the pattern of projections. Only approximately 2.2% of the contralateral corticospinal projection originated in area 3a, rising to approximately 9% in areas 3b/1, and approximately 13% in areas 2/5. The projections from SII and insula totaled 3.4%. Ipsilateral and contralateral corticospinal projection patterns were similar, but the ipsilateral projection was only approximately 8.1% of that from the contralateral cortex. Each corticospinal neuron population had terminals in the intermediate zone of all spinal segments; additionally, there were ventral horn projections from the primary motor and cingulate cortex, and dorsal horn projections from the somatosensory cortex. Recognizing a number of separate populations of corticospinal neurons in the frontal, parietal, and insular cortex, each with unique thalamic and cortical inputs, and each of which has continuous access to all spinal motoneuron populations, underlines the importance of cortical and spinal connections linking them and coordinating their action. No coherent model of the cortical control of limb movements that incorporates this functional anatomy yet exists.
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    PRIOR CHEMOTHERAPY DOES NOT PREVENT EFFECTIVE MOBILIZATION BY G-CSF OF PERIPHERAL-BLOOD PROGENITOR CELLS
    DELUCA, E ; SHERIDAN, WP ; WATSON, D ; SZER, J ; BEGLEY, CG (CHURCHILL LIVINGSTONE, 1992-11)
    In this study we demonstrate that the hemopoietic growth factor, G-CSF successfully mobilised progenitor cell populations into the peripheral blood in a population of patients despite intensive pretreatment with chemotherapy. Administration of G-CSF increased the numbers of peripheral blood progenitor cells (PBPC) by a median of 76-fold above basal levels. Maximal levels of PBPC were observed on days 5 and 6 after G-CSF treatment. In two patients a second cycle of G-CSF mobilised PBPC to levels comparable with those seen after the first cycle of G-CSF treatment. An earlier hemopoietic cell population (pre-CFC's) was also mobilised with levels increased up to 50-fold above basal levels. Using a standard mononuclear cell leukapheresis technique the PBPC were collected extremely efficiently (essentially 100%) and could be further successfully enriched by separation using a Ficoll gradient. For patients who underwent the optimal collection protocol (i.e. leukapheresis on days 5, 6 and 7) a total of 32 +/- 6 x 10(4) GM-CFC kg-1 were collected. The ability to mobilise PBPC using G-CSF alone and to successfully and efficiently harvest these cells has important implications for the future of transplantation and high dose chemotherapy procedures.
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    A VOLTAGE-DEPENDENT PERSISTENT SODIUM CURRENT IN MAMMALIAN HIPPOCAMPAL-NEURONS
    FRENCH, CR ; SAH, P ; BUCKETT, KJ ; GAGE, PW (ROCKEFELLER UNIV PRESS, 1990-06)
    Currents generated by depolarizing voltage pulses were recorded in neurons from the pyramidal cell layer of the CA1 region of rat or guinea pig hippocampus with single electrode voltage-clamp or tight-seal whole-cell voltage-clamp techniques. In neurons in situ in slices, and in dissociated neurons, subtraction of currents generated by identical depolarizing voltage pulses before and after exposure to tetrodotoxin revealed a small, persistent current after the transient current. These currents could also be recorded directly in dissociated neurons in which other ionic currents were effectively suppressed. It was concluded that the persistent current was carried by sodium ions because it was blocked by TTX, decreased in amplitude when extracellular sodium concentration was reduced, and was not blocked by cadmium. The amplitude of the persistent sodium current varied with clamp potential, being detectable at potentials as negative as -70 mV and reaching a maximum at approximately -40 mV. The maximum amplitude at -40 mV in 21 cells in slices was -0.34 +/- 0.05 nA (mean +/- 1 SEM) and -0.21 +/- 0.05 nA in 10 dissociated neurons. Persistent sodium conductance increased sigmoidally with a potential between -70 and -30 mV and could be fitted with the Boltzmann equation, g = gmax/(1 + exp[(V' - V)/k)]). The average gmax was 7.8 +/- 1.1 nS in the 21 neurons in slices and 4.4 +/- 1.6 nS in the 10 dissociated cells that had lost their processes indicating that the channels responsible are probably most densely aggregated on or close to the soma. The half-maximum conductance occurred close to -50 mV, both in neurons in slices and in dissociated neurons, and the slope factor (k) was 5-9 mV. The persistent sodium current was much more resistant to inactivation by depolarization than the transient current and could be recorded at greater than 50% of its normal amplitude when the transient current was completely inactivated. Because the persistent sodium current activates at potentials close to the resting membrane potential and is very resistant to inactivation, it probably plays an important role in the repetitive firing of action potentials caused by prolonged depolarizations such as those that occur during barrages of synaptic inputs into these cells.
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    CHONDROITIN SULFATE A IS A CELL-SURFACE RECEPTOR FOR PLASMODIUM-FALCIPARUM-INFECTED ERYTHROCYTES
    ROGERSON, SJ ; CHAIYAROJ, SC ; NG, K ; REEDER, JC ; BROWN, GV (ROCKEFELLER UNIV PRESS, 1995-07-01)
    Adherence of Plasmodium falciparum-infected erythrocytes to cerebral postcapillary venular endothelium is believed to be a critical step in the development of cerebral malaria. Some of the possible receptors mediating adherence have been identified, but the process of adherence in vivo is poorly understood. We investigated the role of carbohydrate ligands in adherence, and we identified chondroitin sulfate (CS) as a specific receptor for P. falciparum-infected erythrocytes. Parasitized cells bound to Chinese hamster ovary (CHO) cells and C32 melanoma cells in a chondroitin sulfate-dependent manner, whereas glycosylation mutants lacking chondroitin sulfate A (CSA) supported little or no binding. Chondroitinase treatment of wild-type CHO cells reduced binding by up to 90%. Soluble CSA inhibited binding to CHO cells by 99.2 +/- 0.2% at 10 mg/ml and by 72.5 +/- 3.8% at 1 mg/ml, whereas a range of other glycosaminoglycans such as heparan sulfate had no effect. Parasite lines selected for increased binding to CHO cells and most patient isolates bound specifically to immobilized CSA. We conclude that P. falciparum can express or expose proteins at the surface of the infected erythrocyte that mediate specific binding to CSA. This mechanism of adherence may contribute to the pathogenesis of P. falciparum malaria, but has wider implications as an example of an infectious agent with the capacity to bind specifically to cell-associated or immobilized CS.
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    KNOB-INDEPENDENT CYTOADHERENCE OF PLASMODIUM-FALCIPARUM TO THE LEUKOCYTE DIFFERENTIATION ANTIGEN CD36
    BIGGS, BA ; GOOZE, L ; WYCHERLEY, K ; WILKINSON, D ; BOYD, AW ; FORSYTH, KP ; EDELMAN, L ; BROWN, GV ; LEECH, JH (ROCKEFELLER UNIV PRESS, 1990-06-01)
    The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.