Medicine (RMH) - Research Publications

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    EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract
    Dottori, M ; Hartley, L ; Galea, M ; Paxinos, G ; Polizzotto, M ; Kilpatrick, T ; Bartlett, PF ; Murphy, M ; Köntgen, F ; Boyd, AW (NATL ACAD SCIENCES, 1998-10-27)
    Members of the Eph family of tyrosine kinase receptors have been implicated in the regulation of developmental processes and, in particular, axon guidance in the developing nervous system. The function of the EphA4 (Sek1) receptor was explored through creation of a null mutant mouse. Mice with a null mutation in the EphA4 gene are viable and fertile but have a gross motor dysfunction, which is evidenced by a loss of coordination of limb movement and a resultant hopping, kangaroo-like gait. Consistent with the observed phenotype, anatomical studies and anterograde tracing experiments reveal major disruptions of the corticospinal tract within the medulla and spinal cord in the null mutant animals. These results demonstrate a critical role for EphA4 in establishing the corticospinal projection.
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    Manual dexterity and corticospinal connectivity following unilateral section of the cervical spinal cord in the macaque monkey
    Galea, MP ; DarianSmith, I (WILEY-BLACKWELL, 1997-05-12)
    The macaque recovers quite rapidly from the immediate severe flaccid hemiparesis that results from unilateral section of the cervical spinal cord (between C3 and C6) and starts to use the impaired hand to pick up objects within about 30 days following the surgery. Within another 60 days, the monkey is quite dexterous; nonetheless, there is a persisting deficit. We used video recording to study the long-term recovery of manual dexterity following unilateral section of the cervical cord in newborn and juvenile monkeys. A reach-and-retrieve manual task was examined. By using a preset oppositional force, opposition of the pads of the index finger and thumb in the vertical plane was needed to retrieve the desired target object. The corticospinal connectivity of each monkey was also examined by using retrograde or anterograde tracers at the end of the experimental period (Galea and Darian-Smith [1997] J. Comp. Neurol., this issue) and was correlated with the manual performance. Manually retrieving an object depends on the coordination of several control processes acting in parallel, including 1) visually guided components, such as directing the arm toward the object, aligning the digits with the target object by pronating the forearm, and preshaping the index/thumb separation to match with the size and shape of the target, and 2) manipulative components that depend on tactual input and that also include independent movements of the digits and the application of the appropriate oppositional forces. The impairment of manual dexterity that persisted after a cervical section, although it was small, involved these processes and was evident in 1) the less direct trajectory used in reaching, 2) the loss of preshaping of the separated index finger and thumb prior to grasping the target object, and 3) a weakening of the oppositional forces that could be developed between the pads of the index finger and thumb. Although, in the accompanying paper, we did not preclude some regeneration of severed corticospinal connections, we did show that, if any such reconstruction occurred, then it was limited. The remarkable but incomplete recovery of dexterity over a period of 6-12 months, therefore, must be achieved by 1) optimizing the transmission of information from the cortex to the spinal cord by the substantially reduced populations of corticospinal neurons and corticobulbospinal projections and/or 2) the effective use of spinal circuitry in regulating the more stereotyped elements of the manual task.
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    Corticospinal projection patterns following unilateral section of the cervical spinal cord in the newborn and juvenile macaque monkey
    Galea, MP ; DarianSmith, I (WILEY, 1997-05-12)
    Immediately following a unilateral section of the midcervical spinal cord that interrupts the dorsolateral, lateral, and ventral columns, the macaque monkey has a severe flaccid paralysis on the side of the lesion. Recovery of hand function is rapid, and, although it is incomplete, within a few months, the monkey uses the initially disabled hand and fingers with considerable skill. We examined the accompanying changes in the pattern of projection of corticospinal neurons to the cervical spinal cord that occurred following such a lesion. Spinal section was done both in newborn and juvenile macaques, and the postlesion period was followed for up to 150 weeks. Corticospinal neuron populations were visualized by using both anterogradely and retrogradely transported labels, and their origins, spinal pathways, and terminations were examined at intervals during the period of recovery of hand function. Immediately following unilateral section of the spinal cord at C3, sampled counts of soma profiles of retrogradely labeled neurons indicated that there was a profound reduction in the corticospinal projection to the hemicord caudal to the lesion. The few labeled corticospinal axons spared by the lesion bypassed the spinal lesion by descending in the contralateral cord and then crossing the midline caudal to the lesion. A few corticospinal axons may also have bypassed the lesion in the ipsilateral ventromedial column when this was not fully interrupted by the lesion. In every monkey, we observed a similar, profound reduction in the corticospinal (and rubrospinal) projections to the hemicord caudal to the lesion: This pattern did not alter significantly over an extended recovery period. An unchanging corticospinal projection to the cervical spinal cord contralateral to the lesion was also visualized in each monkey and resembled that seen in the normal macaque. Although the resolution of the labeling and counting procedures used precluded the identification of small increases in the numbers of corticospinal neurons projecting to the hemicord caudal to the lesion, we concluded that there was no substantial reconstruction of this projection over a recovery period of more than 2 years.
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    Maximum voluntary weight-bearing by the affected and unaffected legs in standing following stroke
    Goldie, PA ; Matyas, TA ; Evans, OM ; Galea, M ; Bach, TM (Elsevier, 1996-09-01)
    Objective. To compare stroke patients to control subjects for ability to transfer body weight onto the affected and unaffected leg in standing; to investigate intra-session reliability. Design. Comparative clinical study conducted within a single session. Background. There is a paucity of quantitative data about maximum voluntary weight-bearing in patients during rehabilitation following stroke. Methods. A Kistler force platform was used to quantify maximum amount of body weight transferred to a single limb in the lateral and forward directions during weight-shifting. Twelve control subjects matched by gender and age (median 64 years) were compared to 12 inpatient stroke patients after a median of 37 days post-onset. Results. The median score for control subjects was approximately 95% of body weight to each leg in both directions. In contrast, stroke patients transferred less body weight (P < 0.01) to the affected leg (65.5% lateral; 54.9% forward) and also to the unaffected leg (85.0% lateral; 80.1% forward). For the stroke patients, transfer of body weight was more challenging in the forward direction than the lateral direction on the affected leg (P < 0.05). Relative to individual differences in the stroke group, error due to the repeated measurement process was low. Conclusion. The testing procedure was found to discriminate between stroke patients and control patients and had high retest reliability within a single session.
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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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    Facilitation of the maximum voluntary contraction in hemiplegia by concomitant cutaneous stimulation
    MATYAS, TA ; GALEA, MP ; SPICER, SD (Lippincott Williams & Wilkins Ltd., 1986-06-01)
    The effects of rapid brushing on the maximum voluntary contraction (MVC) and tonic vibratory reflex (TVR) of various muscles requiring facilitation (quadriceps, biceps femoris and tibialis anterior) were studied in two samples of hemiplegics. Brushing was studied under experimental and placebo conditions. In the first experiment, brushing produced significant facilitation of MVC and TVR in the quadriceps, replicating the findings of Spicer and Matyas (1980) and Matyas and Spicer (1980). However, the effect of the TVR failed to predict the gain in MVC that resulted from brushing. In the second sample of hemiplegics, brushing produced significant facilitation of the MVC and TVR in the biceps femoris but not in the tibialis anterior. The results for biceps femoris confirmed the results obtained with quadriceps. The failure to replicate this effect with tibialis anterior may have resulted from problems with the application of the stimulus to the relevant dermatome. Further exploration of the effect of cutaneous stimulation relating to this muscle is required to resolve this issue. The results of this experiment, with its replication of the facilitatory effect of brushing on TVR and MVC in two muscle groups, suggest that investigations of the effect of cutaneous stimulation on the acquisition and retention of voluntary movement should now take place.
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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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    Macrophage stimulation and the inflammatory response to asbestos.
    Hamilton, JA (Environmental Health Perspectives, 1980-02)
    Chrysotile fibers injected into the peritoneal cavity of mice elicit a cellular exudate. Macrophages appearing in this exudate produce high levels of the neutral protease, plasminogen activator, when compared with the resident peritoneal macrophage population. In contrast, the levels of lysozyme and two lysosomal enzymes are the same for the two macrophage types. The asbestos-induced macrophages producing the plasminogen activator appear to have descended from recently divided precursors. Low concentrations of anti-inflammatory glucocorticoids inhibit macrophage plasminogen activator synthesis. Preliminary experiments indicate that different asbestos types induce hyperemia in skin, and also shorten the partial thromboplastin time of plasma and generate the release of kinins. These observations could be interrelated and are suggested as representing some aspects of the inflammatory response of the host to asbestos exposure.